| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 1996;93:2212-2245.)
© 1996 American Heart Association, Inc.
Articles |
Management of Deep Vein Thrombosis and Pulmonary Embolism
A Statement for Healthcare Professionals From the Council on Thrombosis (in Consultation With the Council on Cardiovascular Radiology), American Heart Association
Key Words: thrombosis • embolism • AHA Medical/Scientific Statements
 |
Introduction |
|---|
Top
Introduction
PurposeDeep vein thrombosis (DVT) is a common but elusive illness that can result in suffering and death if not recognized and treated effectively. DVT occurs in
2 million
Americans each year. Death can occur when the venous thrombi break off
and form pulmonary emboli, which pass to and obstruct the
arteries of the lungs. DVT and pulmonary embolism (PE) most
often complicate the course of sick, hospitalized patients but may also
affect ambulatory and otherwise healthy persons.1 2 3 4 It is
estimated that each year 600 000 patients develop PE and that 60 000
die of this complication.5 6 7 This number exceeds the
number of American women who die each year from breast cancer. PE is
now the most frequent cause of death associated with
childbirth.8 Women are a prime target for PE, being
affected more often than men. Deep vein thrombosis is a major complication in orthopedic surgical patients and patients with cancer and other chronic illnesses. DVT can be a chronic disease. Patients who survive the initial episode of DVT are prone to chronic swelling of the leg and pain because the valves in the veins can be damaged by the thrombotic process, leading to venous hypertension. In some instances skin ulceration and impaired mobility prevent patients from leading normal, active lives. In addition, patients with DVT are prone to recurrent episodes. In those instances in which DVT and PE develop as complications of a surgical or medical illness, in addition to the mortality risk, hospitalization is prolonged and healthcare costs are increased.
|
Purpose |
|---|
Over the past 20 years results of clinical trials have provided information that has revolutionized the approach to management of venous thromboembolic disease. New diagnostic modalities and therapeutic agents have been developed that are more effective, less expensive, and more convenient. Patients with venous thromboembolic disease (VTE) are seen by a variety of medical specialists, including general physicians, surgeons, obstetricians, hematologists, radiologists, and chest physicians. Because thromboembolic disease forms only a small part of the practice of most of these clinicians, it is difficult for them to keep abreast of advances that are important for optimal patient care.
The purpose of this report is to provide medical trainees and clinicians with the information required to manage venous thromboembolic problems that they are likely to encounter in daily practice.
|
Pathogenesis of Venous Thromboembolism |
|---|
Venous thrombi are intravascular deposits composed of fibrin and red cells with a variable platelet and leukocyte component.9 They usually form in regions of slow or disturbed flow in large venous sinuses and in valve cusp pockets in the deep veins of the calf (Fig 1
) or in venous segments that
have been exposed to direct trauma.10 11 12 Venous thrombi
often break off to form PE. The formation, growth, and dissolution of
venous thrombi and PE reflect a balance between the effects of
thrombogenic stimuli and a variety of protective
mechanisms.13 14 15
|
The factors traditionally implicated in the pathogenesis of venous thrombosis are activation of blood coagulation, venous stasis, and vascular injury.13 14 15 Vascular damage contributes to the genesis of venous thrombosis through either direct trauma9 12 13 15 or activation of endothelial cells by cytokines (interleukin-1 and tumor necrosis factor) released as a result of tissue injury and inflammation. Blood coagulation can be activated by intravascular stimuli released at a remote site (eg, products of injured or infarcted tissue) or it can be activated locally by vessel wall damage (eg, damage to the femoral vein during hip surgery) or by cytokine-induced nondenuding endothelial stimulation.12 15 16 17 18 These cytokines stimulate endothelial cells to synthesize tissue factor and plasminogen activator inhibitor-1 and lead to a reduction in thrombomodulin, thereby reversing the protective properties of normal endothelium.
The thrombogenic effects of activation of blood coagulation are amplified by stasis and counteracted by rapid flow. Venous stasis predisposes the patient to local thrombosis by impairing the clearance of activated coagulation factors and limiting the accessibility of thrombin formed in veins to endothelial protein thrombomodulin, which is present in greatest density in the capillaries.
The mechanisms that protect against thrombosis are inactivation of activated coagulation factors by circulating inhibitors, dilution and clearance of activated coagulation factors by flowing blood, inhibition of the coagulant activity of thrombin by thrombomodulin, enhancement of the anticoagulant activity of thrombin by thrombomodulin through activation of protein C, and dissolution of fibrin by the fibrinolytic system.19 20 21 22 23 24 25
|
Natural History |
|---|
Venous thrombosis in the lower limb can involve the superficial leg veins, the deep veins of the calf (calf vein thrombosis), the more proximal veins, including popliteal veins, the superficial femoral, common femoral, and iliac veins. Less commonly, thrombosis involves other veins in the body. Thrombosis of the superficial veins of the legs usually occurs in varicosities and is benign and self-limiting. Occasionally, however, the thrombi in superficial veins extend into the deep veins and give rise to major PE. Deep calf vein thrombosis is a less serious disorder than proximal vein thrombosis because thrombi in calf veins are generally small and are therefore not usually associated with clinical disability or major complications.
Most calf vein thrombi are asymptomatic,10 but these thrombi can extend proximally and become dangerous. Venous thrombi produce symptoms because they obstruct venous outflow, cause inflammation of the vein wall or perivascular tissue, or embolize into the pulmonary circulation. Extension of thrombosis is more likely if the original thrombogenic stimulus persists.
Complete spontaneous lysis of large venous thrombi is uncommon, and even when patients with venous thrombosis are treated with heparin, complete lysis occurs in fewer than 10% of cases.26 In contrast, complete dissolution of small, asymptomatic calf vein thrombi occurs quite frequently.10
There is a strong association between DVT and PE. Pulmonary
emboli are detected by perfusion lung scanning in 50% of patients
with documented DVT,3 27 28 29 30 and
asymptomatic venous thrombosis is found in 70% of
patients with confirmed clinically symptomatic PE. If the
thrombus that embolizes is small (which is frequently the case
when it is located in the calf), the embolus is usually
asymptomatic and clinically insignificant, although the
cumulative effect, if there are repeated showers of small emboli, can
cause cor pulmonale. If the thrombus is large and involves the proximal
veins, it often produces clinical manifestations; if it is very large
or if the patient has a compromised cardiorespiratory system, it can be
fatal. Most clinically significant and virtually all fatal emboli arise
from thrombi in the proximal veins.1
Venous thrombi usually organize slowly and can be complicated by the postthrombotic syndrome.31 The residual abnormality can also act as a nidus for recurrent thrombosis,32 which occurs in approximately one third of patients over an 8-year follow-up period.33
|
Prognosis |
|---|
Studies done before the introduction of anticoagulant therapy reported that the mortality rate for PE was
20% in hospitalized
patients with clinically obvious venous thrombosis.34 In a
small study, Kakkar and colleagues10 reported that without
treatment, 20% of silent calf vein thrombi extended into the
popliteal vein and that extension was associated with a 40% to 50%
risk of clinically detectable PE.
In a study of patients with clinically suspected DVT, Huisman and
associates35 reported that 6.5% (20 of 307) who had
negative impedance plethysmography at presentation
developed evidence of extension over the next 10 days. Others have
reported a lower frequency of impedance plethysmography (IPG)
conversion during serial testing. The estimated frequency of extension
rate of untreated symptomatic calf vein thrombosis is
30%, based on the results of these serial IPG studies.
In contrast to untreated thrombosis, the short-term prognosis of
patients with proximal DVT treated with adequate doses of
anticoagulants for 3 months is good.36 37 38 Clinically
significant recurrent events take place in 5% of patients with
proximal vein thrombosis treated with an initial course of heparin
followed by oral anticoagulants or intermediate doses of subcutaneous
heparin for 3 months.37 38 39 40 41 42 Thereafter, DVT recurs in 5%
to 10% of patients the year after anticoagulant therapy is
discontinued36 37 38 and in 30% of patients after 8
years.33
|
Clinical Course in Symptomatic Patients |
|---|
A comprehensive prospective follow-up study examining long-term prognosis in consecutive patients with a first episode of documented symptomatic DVT of the leg was recently completed by Prandoni and associates.33 The study assessed the long-term incidence of recurrent venous thromboembolism and postthrombotic syndrome.
Patients were treated with an initial course of high dose–adjusted intravenous standard heparin or low-molecular-weight heparin (LMWH) followed by oral anticoagulants, which were started during the first week of treatment and continued for at least 3 months.42 The dose of oral anticoagulant therapy was adjusted daily to maintain the International Normalized Ratio (INR) between 2.0 and 3.0. All patients were instructed to wear graduated compression stockings (40 mm Hg at the ankle) for at least 2 years. They were seen at 3 and 6 months after presentation and every 6 months thereafter for follow-up assessments. Patients were asked to return immediately if they developed symptoms suggestive of recurrent venous thromboembolism. Follow-up continued for up to 8 years.
A total of 355 consecutive patients with a first episode of DVT
confirmed by venography were included in the study. Seventy-eight
patients experienced one or more episodes of objectively confirmed
recurrent venous thromboembolic events. Of the first
recurrences, 35 (44.9%) occurred in a leg that was initially
involved, 28 (35.9%) in the contralateral leg, and 15 (19.2%) were
PE, which was fatal in 9 patients (11.5%). The cumulative incidence of
recurrent VTE after 3 months was 4.9%; after 6 months it was 8.6%.
The incidence of recurrent events gradually increased to 17.5% after 2
years, 24.6% after 5 years, and 30.3% after 8 years of follow-up
(Fig 2).
|
The risk of recurrent VTE was increased by the presence of malignancy and coagulation abnormalities and reduced in patients who had a reversible risk factor (eg, surgery and trauma or fracture).
Of the 355 patients, 83 developed postthrombotic syndrome and 24 developed severe postthrombotic manifestations. The cumulative incidence of postthrombotic syndrome was 17.3% after 1 year and 22.8% after 2 years. Thereafter, the incidence of postthrombotic syndrome rose very gradually to 28.0% after 5 years and 29.1% at 8 years. Thus, in more than 80% of patients manifestations of postthrombotic syndrome became apparent in the first 2 years after acute thrombosis. The cumulative incidence of severe postthrombotic manifestations increased gradually from 2.6% after 1 year to 9.3% after 5 years. Thereafter, the cumulative incidence of severe postthrombotic manifestations did not increase further. It is likely that the use of compression stockings contributed to this low incidence of postthrombotic syndrome, as indicated by a recent controlled study.43 Ipsilateral recurrent DVT was associated with a strong increase in risk for postthrombotic syndrome (risk ratio 6:4).
Surprisingly, there were no significant associations between occurrence of postthrombotic syndrome and size or location of the thrombus. Twenty-six of the 297 patients without a malignancy at baseline developed cancer. This occurred mainly in patients with idiopathic DVT at presentation.44
Of the 355 patients, 90 died during follow-up. The causes of death included malignancy (n=52), ischemic stroke (n=8), acute myocardial infarction (n=4), PE (n=9), heart failure (n=3), anticoagulant-related hemorrhage (n=2), and miscellaneous (n=6). In 6 patients who died suddenly, a definite cause of death was not established.
Other studies have also reported that most recurrences take
place in patients who have idiopathic venous thrombosis or who are
exposed to a continuing risk factor (such as cancer). In these groups,
the rate of recurrence is 15% in the 12 months after
treatment is stopped. In contrast, the long-term prognosis in
patients who develop venous thrombosis following exposure to a
predisposing cause such as surgery or trauma is very
good.45 Thus, provided they are treated with
anticoagulants for 3 months,36 37 38 fewer than 4% of these
patients develop recurrences in the following
year.45 46 47
|
Acute Recurrent Venous Thrombosis |
|---|
The label of recurrent venous thrombosis carries important prognostic implications. Patients are usually treated with anticoagulants for life and may suffer considerable mental anguish. Therefore, it is important to ensure that the diagnosis of recurrent DVT is correct. In many patients with clinically suspected recurrence, the diagnosis of recurrence is not confirmed by objective tests. For example, in a prospective study of patients with clinically suspected acute DVT, almost two thirds did not have this diagnosis confirmed by objective tests, and these patients did very well without anticoagulant therapy.48
The diagnosis of recurrent venous thrombosis can be difficult because venography, the diagnostic standard for acute venous thrombosis, is less reliable for diagnosis of recurrent venous thrombosis.48 However, the accuracy of diagnosis of acute recurrence has been improved by the introduction of noninvasive techniques (see below).
|
Postthrombotic Syndrome |
|---|
In early descriptive studies, postthrombotic syndrome was reported to occur in
50% of patients with symptomatic
venous thrombosis. More recently and possibly as a consequence of
better initial anticoagulation and the use of graduated compression
stockings, the incidence of postthrombotic syndrome after 8 years of
follow-up was reported to be no more than 25%.33
The postthrombotic syndrome is caused by venous hypertension, which
occurs as a consequence of recanalization of major
venous thrombi leading to patent but scarred and incompetent valves or,
less frequently, persistent outflow obstruction produced by large
proximal vein thrombi.31 49 50 51
Recanalization and valve destruction result in a
malfunction of the muscular pump mechanism, which leads to increased
pressure in the deep veins of the calf. This high pressure results in
progressive incompetence of the valves of the perforating veins of the
calf, and when this occurs, flow is directed from the deep vein into
the superficial system during muscle contraction, leading to edema and
impaired viability of subcutaneous tissues and, in its most severe
form, ulceration of venous origin. Follow-up studies of patients
with proximal vein thrombosis have demonstrated that outflow
obstruction (measured by IPG) is relieved either by
recanalization or collateral flow in 30% of
patients at 3 weeks and in 70% of patients at 3 months.52
Valvular incompetence is a more important cause of
postthrombotic syndrome than is outflow obstruction.53 In patients with extensive thrombosis in the iliofemoral veins, swelling may never disappear, while in patients with less severe proximal vein thrombosis, swelling may subside after the initial event but return in the next few years. Other manifestations of postthrombotic syndrome are pain in the calf relieved by rest and elevation of the leg, pigmentation and induration around the ankle and the lower third of the leg, and, less commonly, ulceration and venous claudication, a bursting calf pain that occurs during exercise.
Patients with extensive thrombosis involving the iliofemoral vein have a higher frequency of venous claudication and frequently have greater disability than patients with more distal vein thrombosis.50 However, incompetence of perforating veins may follow thrombosis confined to calf veins and may lead to stasis changes. In a follow-up study of calf vein thrombosis in Sweden, the frequency of postthrombotic syndrome was reported to be 13 of 79 or 16% in 2 years' follow-up.54 There is evidence from recent studies that recurrent venous thrombosis is an important risk factor for development of postthrombotic syndrome33 and that risk of developing postthrombotic syndrome is reduced by the use of graduated compression stockings.43 The role of thrombolytic therapy in prevention of postthrombotic syndrome is uncertain. Clinical trials in acute DVT evaluating the effect of thrombolytic therapy on subsequent development of postthrombotic syndrome have produced equivocal results,55 although on balance, it is probable that the incidence of clinical symptoms is reduced in patients who receive thrombolysis.55
The prevalence of postthrombotic syndrome in the general population has been estimated in several countries. In Sweden it has been reported to occur in 2% of the population, and in a study of more than 4000 chemical-industry workers in Switzerland, the frequency of severe venous insufficiency with venous ulceration was reported to be between 1% and 1.5%.54 56 In an investigation in Michigan involving more than 9000 adults older than 20 years, the prevalence of active or healed venous ulcers was 5 per 1000.2 Extrapolation of this figure to the general population in the United States suggests that about 500 000 Americans have or have had venous ulceration.
The diagnosis of postthrombotic syndrome is sometimes obvious on clinical grounds if the symptoms are gradual in onset. However, patients can have subacute symptoms of leg pain and swelling, which may mimic acute recurrence of DVT. Although these symptoms are usually superimposed on a background of chronic pain and swelling, it may be difficult to exclude acute recurrence on clinical grounds alone, and a diagnosis of postthrombotic syndrome as the cause of the patient's symptoms can be made only after acute recurrent venous thrombosis has been excluded.
The diagnosis of postthrombotic syndrome should include demonstration of deep venous incompetence using Doppler ultrasound or plethysmography57 58 59 and more recently by techniques such as volume plethysmography and duplex ultrasound.
In some patients with recurrent leg pain not due to acute recurrent venous thrombosis or postthrombotic syndrome, an alternative cause is not found, and symptoms may be due to thromboneurosis. This clinical syndrome tends to occur in patients who have a morbid fear of the complications of DVT/PE. These patients may have had a previous episode of DVT and some have evidence of postthrombotic syndrome, but some have never had objectively documented episodes of venous thrombosis. These patients usually present with pain and tenderness that may be disproportionate to physical signs of swelling. In its most severe form, patients may be incapacitated by fear of recurrence, loss of the leg, or death. Patients frequently have a history of multiple hospital admissions for treatment of alleged recurrent venous thrombosis. Many are on long-term anticoagulant therapy or antiplatelet drugs, and some have undergone caval interruption procedures. Unfortunately, thromboneurosis is often iatrogenic, and fear of recurrence is reinforced each time the attending physician admits the patient to the hospital and orders treatment based on clinical suspicion alone. Thromboneurosis is best prevented by ensuring that a clinical suspicion of acute venous thrombosis (either first episode or recurrence) is always confirmed by appropriate objective tests.
|
Prophylaxis |
|---|
The most effective way of reducing death from PE and morbidity from postthrombotic syndrome is to institute a comprehensive institutional policy of primary prophylaxis in patients at risk for VTE. Patients can be classified as being at low, moderate, or high risk for developing VTE on the basis of well-defined clinical criteria60 (Tables 1 and 2), and the choice of prophylaxis should be tailored to the patient's risk. In the absence of prophylaxis, the frequency of postoperative fatal PE ranges from 0.1% to 0.8% in patients undergoing elective general surgery, 0.3% to 1.7% in patients undergoing elective hip surgery, and 4% to 7% in patients undergoing emergency hip surgery.60 Safe and effective forms of prophylaxis are available for patients at high risk, and primary prophylaxis is cost-effective.61
Prophylaxis is achieved by either modulating activation of blood
coagulation or preventing venous stasis. The following
prophylactic approaches are of proven value: low-dose
subcutaneous heparin,61 62 intermittent pneumatic
compression of the legs,60 61 oral
anticoagulants,60 61 adjusted doses of subcutaneous
heparin,63 graduated compression stockings,64
and LMWHs65 (Table 3). Antiplatelet
agents such as aspirin are less effective for preventing
VTE.60
|
Low-dose heparin is given subcutaneously at a dose of 5000 U 2 hours before surgery and is then given postoperatively at a dose of 5000 U every 8 or 12 hours. Low-dose heparin prophylaxis is the method of choice for moderate-risk general surgical and medical patients.60 Low-dose heparin reduces the risk of VTE by 50% to 70%62 ; it does not require laboratory monitoring and is simple, inexpensive, convenient, and safe. However, because of the potential for minor bleeding, it should not be used in patients undergoing cerebral, ocular, or spinal surgery. Low-dose heparin is less effective than warfarin,60 adjusted-dose heparin,63 and LMWH in patients undergoing major orthopedic surgical procedures.65 66 Intermittent pneumatic compression of the legs enhances blood flow in the deep veins and increases blood fibrinolytic activity.60 This method of prophylaxis is free of clinically important side effects and is particularly useful in patients with a high risk of serious bleeding. Therefore, it is the method of choice for preventing venous thrombosis in patients undergoing neurosurgery,64 is effective in patients undergoing major knee surgery,67 and is as effective as low-dose heparin in patients undergoing abdominal surgery.60
Graduated compression stockings reduce venous stasis and are effective for preventing postoperative venous thrombosis in general surgical patients60 and in medical or surgical patients with neurological disorders, including paralysis of the lower limbs.64 In surgical patients the combination of graduated compression stockings and low-dose heparin is significantly more effective than low-dose heparin alone.68 69 Graduated compression stockings are relatively inexpensive and should be considered for all high-risk surgical patients, even if other forms of prophylaxis are used.
Moderate-dose warfarin (INR, 2.0) is effective for preventing postoperative VTE in all risk categories.60 Warfarin can be started preoperatively, at the time of operation, or in the early postoperative period. Although the full, measurable anticoagulant effect is not achieved until the third or fourth postoperative day, when treatment is started at the time of surgery or in the early postoperative period, warfarin is still effective in very high–risk patient groups, including patients with hip fractures.70 Prophylaxis with warfarin is less convenient than low-dose heparin or LMWHs because of the need for careful laboratory monitoring.
Adjusted-dose heparin is given subcutaneously in a dose of 3500 U three times daily, starting 2 days before surgery. The dose is then adjusted to maintain the activated partial thromboplastin time (aPTT) at the upper limit of the normal range. Adjusted-dose heparin is more effective than fixed low-dose heparin in patients undergoing elective hip surgery63 but is less effective in preventing proximal vein thrombosis than LMWH following elective hip surgery.71 Adjusted-dose heparin is inconvenient because it requires careful laboratory monitoring.
LMWHs have recently been approved for use as prophylactic agents in North America. LMWHs are safe and effective for prophylaxis in the following high-risk areas65 : elective hip surgery, hip fracture, major general surgery, major knee surgery, spinal injury, and stroke. LMWH has been reported to be more effective than standard low-dose heparin in general surgical patients,65 patients undergoing elective hip surgery,65 66 and patients with stroke65 or spinal injury.65 In addition, LMWHs have also been more effective than warfarin in patients undergoing hip66 or major knee surgery,65 66 67 68 69 70 71 72 and better than adjusted-dose heparin at preventing proximal vein thrombosis after elective hip surgery.71
Choice of Prophylaxis
General Surgery and Illness
Patients at moderate risk should be given prophylaxis (Table 3) with low-dose heparin. If anticoagulants are contraindicated
because of an unusually high risk of bleeding, intermittent pneumatic
compression should be used.
|
Hip Surgery
LMWH, oral anticoagulants, or adjusted-dose heparin is
effective following hip surgery. Of these three approaches, LMWH is the
most convenient because laboratory monitoring is not required.
Major Knee Surgery
Both LMWHs and intermittent pneumatic compression are effective in
preventing venous thrombosis in patients undergoing major knee surgery.
LMWH is more convenient and is the prophylactic method of
choice.
Genitourinary Surgery, Neurosurgery, and Ocular
Surgery
Intermittent pneumatic compression, with or without static
graduated compression stockings, is effective and does not increase the
risk of bleeding.
|
Diagnosis of Venous Thrombosis |
|---|
A clinical suspicion of venous thrombosis should always be confirmed by objective tests because patients with minimal leg symptoms may have extensive venous thrombosis, whereas the classic symptoms and signs of pain, tenderness, and swelling of the leg can be caused by nonthrombotic disorders.11 72 73 74 75 76 In most contemporary studies of ambulatory patients with symptoms compatible with venous thrombosis, the diagnosis of venous thrombosis is confirmed in only approximately one third when reliable objective tests are performed.76 77 78 Alternative diagnoses include superficial thrombophlebitis, cellulitis, ruptured muscle or tendon, muscle strain, internal derangement of the knee, ruptured popliteal cyst, cutaneous vasculitis, and lymphedema.79
Despite the nonspecificity of clinical features, history and physical
examination are important components of the diagnostic
process because they may uncover an alternative cause of the patient's
symptoms and because they allow patients to be classified as having a
high, intermediate, or low probability for venous
thrombosis.80 With a simple clinical scoring system that
included three main components (symptoms and signs at
presentation, presence or absence of risk factors, and
presence or absence of a possible alternative diagnosis), Wells and
associates80 showed that 80% of patients with high
clinical probability have venous thrombosis, while only 5% of patients
with low clinical probability have venous thrombosis. When combined
with the results of noninvasive tests, these pretest probabilities can
be used to both simplify and reduce costs of the diagnostic
process (Table 4).
|
Methods of Testing
Although a number of tests have been evaluated over the
years, only three have been shown to be accurate for diagnosing venous
thrombosis in symptomatic patients:
venography,81 82 83 IPG,3 4 35 77 84 85 86 87 88 89 90 and
venous ultrasonography.77 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105
If used properly, any one of these methods is acceptable, although venous ultrasonography (also known as B-mode imaging) is the diagnostic method of choice in most patients with clinically suspected venous thrombosis.77 99 In addition, the Simpli-red D-dimer test, which is performed on blood obtained by finger prick at the patient's side and which has high sensitivity and moderate specificity, shows considerable promise as a test to rule out venous thrombosis.106 The D-dimer test is often false-positive after surgery or trauma, thereby limiting its value in these clinical situations.
Performance of Testing
Venography is performed by injecting
radiographic material into a superficial vein on the dorsum
of the foot. The contrast material mixes with the blood and flows
proximally. An x-ray image of the leg and pelvis will show the calf
and thigh veins, which drain into the external iliac vein. With good
technique, the entire deep venous system of the leg, including the
external iliac and common iliac veins, may be imaged. A thrombus is
diagnosed by the presence of an intraluminal filling
defect.81 82 83
Impedance plethysmography is performed by placing two sets of electrodes around the patient's calf and an oversized blood pressure cuff around the thigh. The electrodes sense a change in blood volume (increased blood volume decreases electrical impedance) in the calf veins, which is recorded on a strip chart. Changes in venous filling are produced by inflating the thigh cuff to obstruct venous return and then reestablishing blood flow by deflating the cuff and assessing the time taken for venous volume in the calf to return to baseline. If an occlusive thrombus is present in the popliteal or more proximal veins, venous emptying is delayed. The test may also detect extensive calf vein thrombosis if venous outflow is obstructed, but it fails to detect the majority of calf vein thrombi.84 86 87
Venous ultrasound imaging of the venous system is obtained with high-resolution equipment to produce two-dimensional images by real-time computation of reflected signals from an array of ultrasound sources.77 94 95 99 102 The ultrasound probe is first placed over the common femoral vein in the groin. The transducer is then moved distally to visualize the superficial femoral vein over its course. The entire popliteal vein is then visualized in the popliteal fossa and traced distally to its trifurcation with the deep veins of the calf. Gentle pressure is applied with the probe to determine whether the vein under examination is compressible. The most accurate ultrasonic criterion for diagnosing venous thrombosis is noncompressibility of the venous lumen under gentle probe pressure.77 99 Vein compressibility is best evaluated in the transverse plane. Visualization of the proximal portion of calf veins can often be achieved by experienced operators,95 but resolution can be suboptimal, and the sensitivity and specificity of venous ultrasonography is much lower for calf vein thrombosis than for proximal vein thrombosis. Duplex ultrasound, which combines real-time imaging with pulsed gated Doppler and color-coded Doppler technology, facilitates identification of veins, and as technology improves, diagnostic accuracy for calf vein thrombosis may increase.91 92 93 103 104 105 106 107 Although it has been claimed that color-coded Doppler is accurate for calf vein thrombosis, this contention has not been demonstrated by an appropriately designed clinical study.
Venography is the reference standard, but it is invasive; the other two
tests are noninvasive. All three tests are sensitive and specific for
proximal vein thrombosis (thrombi in the popliteal and more proximal
veins) in symptomatic patients, although IPG is less
sensitive and less specific than venous ultrasound.108 109 110
Venography detects calf vein thrombosis. Venous ultrasonography detects
50% of symptomatic calf vein thrombosis; sensitivity is
said to be higher in the hands of some experts, but this impression
awaits confirmation in large clinical trials. Impedance plethysmography
is insensitive to calf vein thrombosis, detecting <20%. Venous
ultrasonography is now the diagnostic method of choice in
patients with symptoms suggestive of DVT.
Venography can be painful, it is relatively expensive and inconvenient to perform, and, on rare occasions, can be complicated by phlebitis. In addition, when performed by nonexpert radiologists, up to 30% of venograms are technically inadequate and therefore impossible to interpret. In contrast, venous ultrasonography is readily available, painless, and can be performed at bedside. However, like venography, this test is operator dependent.
There is evidence from diagnostic studies using serial
noninvasive testing in patients with symptoms of DVT that calf vein
thrombi are not dangerous, provided that they remain confined to calf
veins.3 35 85 111 However, calf vein thrombi can extend
and do so in 30% of cases.74 Because only 5% of
patients with symptoms of DVT have calf vein thrombosis
(Fig 3),78 it is safe to exclude clinically
important venous thrombosis if the venous ultrasonography is negative
at presentation in patients who have low pretest clinical
probability, because the negative predictive value of a negative venous
ultrasound is more than 99%.80 In patients at moderate or
high clinical probability, however, it would be prudent to repeat the
test once after 5 to 7 days to detect the small percentage of patients
with calf vein thrombosis that extends (Fig 4).
|
|
The safety of withholding treatment when either the IPG or venous
ultrasound test result is negative at presentation and
subsequently on repeated testing over the next week has been
demonstrated in a number of well-designed
studies.3 35 85 111 Between 1% and 2% of patients with
negative IPG at presentation and <1% of patients with
negative venous ultrasonography develop clinically important events
during the first 7 days of serial testing. When these patients with
negative venous ultrasonography (or IPG) are followed up after 6
months, 99% have had no recurrences (Fig 5).111 112
|
|
Diagnosis of Recurrent Venous Thrombosis |
|---|
The diagnosis of clinically suspected recurrent venous thrombosis is often more difficult to establish than diagnosis of the first episode of venous thrombosis.48 113 As with patients with suspected acute venous thrombosis, most patients referred with a diagnosis of recurrence do not have recurrent venous thrombosis. The clinical diagnosis of recurrent venous thrombosis is less specific than the diagnosis of the first episode of venous thrombosis48 because patients fear recurrence and physicians are sensitized to the possibility of this diagnosis. As a consequence, there is a tendency to overdiagnose recurrent venous thrombosis by attributing any new episodes of leg pain or swelling to a recurrent episode. Any other cause of leg pain or swelling can be confused with recurrence, but the most important mimic is postthrombotic syndrome, particularly because this disorder occurs in
30% of patients who have experienced proximal vein
thrombosis.43 114 115 116 The most common manifestations of
postthrombotic syndrome, chronic aching and swelling of the calf, are
unlikely to be confused with recurrent venous thrombosis. However,
subacute exacerbations of pain and swelling can occur after
episodes of increased activity or sometimes without an obvious
precipitating cause and can be difficult to differentiate from
recurrence. Because of their fear of recurrent venous
thrombosis, patients often become concerned if they develop even
minimal exacerbations of symptoms or signs. Finally, some patients
develop recurrent episodes of superficial phlebitis or local
cellulitis, which can be confused with recurrent DVT. For these
reasons, and because overdiagnosis of recurrent venous thrombosis often
results in unnecessary prolongation of anticoagulant treatment, every
effort should be made to confirm a diagnosis of suspected
recurrence.
The diagnosis of recurrent venous thrombosis is made or excluded by a
combination of either IPG and venography113 or venous
ultrasonography and venography (Fig 6). A correct diagnosis
of recurrent venous thrombosis is made by repeating the test used to
make the initial diagnosis when the patient presents with suspected
recurrence. The diagnostic process is facilitated
by obtaining a baseline noninvasive test (either IPG or venous
ultrasonography) when anticoagulants are discontinued and repeating the
test if it is still abnormal at this time.48 113 The
negative test result can then be used as a baseline against which
future tests can be compared.113
|
The rate of conversion is different for IPG and venous ultrasonography.
The IPG result is negative in 60% of patients with proximal vein
thrombosis by 3 months and in 90% by 12 months.51 113 The
rates of conversion for venous ultrasonography are lower than those for
IPG.112 117 118 When the results of IPG or venous
ultrasound are negative before presentation with a
suspected recurrence, a positive result can be used to make a
diagnosis of recurrent venous thrombosis. If the IPG performed at the
previous visit was abnormal and remains abnormal at
presentation with suspected recurrence, further
testing with venography is required; if there is a new intraluminal
filling defect, a diagnosis of recurrence can be made. If the
results of venous ultrasound were abnormal at the previous visit, it is
often possible to diagnose recurrence by demonstrating
extension into a previously normal venous segment or by an increase in
diameter of the venous lumen in a previously affected
segment.112 Recurrence can be excluded if
venography shows either no change or improvement compared with the
previous examination or if a negative IPG or venous ultrasound remains
negative on serial testing over the next 7 days (Fig 6
).
|
Diagnosis of Pulmonary Embolism |
|---|
The clinical diagnosis of PE is also highly nonspecific because the clinical features may be simulated by other cardiorespiratory or musculoskeletal disorders.3 119 120 121 122 123 124 125 126 Accordingly, the diagnosis should always be confirmed by objective tests.
Patients may present with clinical features of minor or major PE. Patients with minor PE can have one or a combination of the following symptoms: transient shortness of breath, sharp localized chest pain aggravated by inspiration (pleuritic-type pain), and hemoptysis. The clinical features of minor PE are nonspecific and can also occur in patients with viral or bacterial pulmonary infections, postoperative atelectasis and pneumonia, acute bronchitis, and musculoskeletal chest wall pain. Esophageal spasm can cause severe chest pain that is not usually aggravated by breathing but may be confused with PE. Pleuritic-type chest pain may accompany pericarditis or immune pleuritis. In addition, patients with a past history of VTE may suffer anxiety attacks that are manifested as shortness of breath and occasionally as chest pain. These patients often have fleeting attacks of sharp chest pain that last for seconds or a feeling that they cannot take a deep breath.
Patients with chronic obstructive lung disease who become acutely short of breath or develop pleuritic-type chest pain or hemoptysis present a difficult problem, because all of these complications can be produced by chest infection as well as by PE. Likewise, it can be difficult to differentiate between postoperative PE and postoperative atelectasis and infection, because both of these disorders can cause shortness of breath and pleuritic-type chest pain.
Patients with major PE usually have severe shortness of breath with or without associated right-heart failure. Patients who sustain a massive embolism or have impaired cardiorespiratory reserve and sustain a moderate-sized embolus may present with hypotension, syncope, and peripheral circulatory failure. Sometimes there is associated dull central chest pain.
Some of these features also occur in patients with acute myocardial infarction, a fulminating pneumonia, dissecting aortic aneurysm, pericardial tamponade, a massive hidden bleed, or septic shock.
PE may also present with nonspecific manifestations such as arrhythmia, fever, unexplained heart failure, mental confusion, or, rarely, as bronchospasm.
Approach to Diagnosis of Pulmonary Embolism
The most reliable test for diagnosis of PE is
pulmonary angiography, because a normal well-performed
pulmonary angiogram excludes the diagnosis of PE, whereas
demonstration of a constant intraluminal filling defect in a
pulmonary artery establishes diagnosis.127 128 129 130 131 132
However, pulmonary angiography is expensive, invasive, and not
readily available in most hospitals and unavailable in many. Therefore,
other less direct approaches are usually taken. The most useful test is
the perfusion lung scan, because if the test result is normal,
diagnosis of PE is excluded.133 134 However, before the
scan is performed, the patient should have a thorough clinical
evaluation, because the combination of clinical probability and
pulmonary scanning is important in clinical decision making.
Using clinical features, presence or absence of risk factors, and
presence or absence of features that suggest an alternative diagnosis,
it is possible to classify patients into three groups: high, low, and
intermediate probability. In addition, the patient should undergo chest
radiography and
electrocardiography. Although the latter tests
are often not helpful,135 136 they can be useful in ruling
out other disorders that simulate PE. In addition, a chest radiograph
is required for proper interpretation of the perfusion lung
scan.137 138
A second approach, which is complementary to the first, is to look for
a source of PE in the deep veins of the leg with either venous
ultrasound or venography. This approach can be very helpful, because
although <20% of patients with proven PE have clinical symptoms or
signs suggestive of leg vein thrombosis,3 70% have
venographic evidence of venous thrombosis.3
The perfusion scan remains the pivotal test. If the perfusion scan is
normal, the diagnosis of PE is excluded. If the perfusion scan is
abnormal, then the diagnostic approach depends on the
clinical probabilities and the size and V/Q pattern of the defect. A
diagnosis of PE can be made if the lung scan shows a segmental or
greater perfusion defect and normal ventilation and the clinical
probability is high or intermediate. A decision can be made to exclude
a diagnosis of PE if clinical probability is low and the perfusion
defect is small, particularly if it is matched (low-probability
defect) (Table 5).
|
All other combinations of clinical and lung scan probabilities require
further investigation before a diagnosis of PE can be ruled in or out.
In such patients, venous ultrasonography or venography is useful
because a positive result allows a diagnosis of VTE to be made.
Unfortunately, a negative test result for venous thrombosis cannot be
used to rule out a diagnosis of PE because tests for venous thrombosis
are negative in 30% of patients with established PE. The venogram
or venous ultrasound may be negative for venous thrombosis in these
patients because the source thrombus has embolized completely
or because it originated in the deep femoral, internal iliac, or renal
veins or the inferior vena cava, which are not usually
visualized by venography. Alternatively, the embolism could have
originated in upper limb veins, the right side of the heart, or the
pulmonary arteries.
Electrocardiography and Chest
Radiography
With PE, the ECG is often normal or shows nonspecific
changes.135 136 In patients with pericarditis or acute
myocardial infarction, ECG changes may be diagnostic. In
the appropriate setting, ECG changes of acute right-heart strain
strongly suggest PE.
The chest radiograph is rarely, if ever, diagnostic.119 135 It may show a pneumothorax, pulmonary edema, or findings suggestive of primary or secondary malignancy. The finding of a Hampton hump (a semicircular opacity with the base abutting the pleural surface) is strongly suggestive of pulmonary infarction, but in the vast majority of patients chest radiography findings are nonspecific or normal. Other radiographic features compatible with PE include pleural effusion, subsegmental atelectasis, pulmonary infiltrate, raised hemidiaphragm, regions of apparent oligemia, or a prominent pulmonary vascular shadow at the hilum. However, none of these features are diagnostic of PE because they can be produced by other conditions, including obstructive lung disease, pulmonary infection, or atelectasis.
Arterial Blood Gases
Measurement of arterial blood gases in patients
with PE is rarely useful because arterial blood gas
measurements lack specificity and are only moderately sensitive for
PE.121 125 135 Hypoxemia and hypocarbia occur in
conditions that simulate PE, and arterial oxygen tensions
can be normal in patients with minor PE.
Significant hypoxemia excludes hyperventilation as the cause of the patient's symptoms, although this condition is rare.
Lung Scans
Perfusion scanning is performed by injecting isotopically
labeled human macroaggregates of albumin
intravenously. The macroaggregates are trapped in the
pulmonary capillary bed and their distribution, which reflects
the distribution of lung blood flow, is recorded with an external
photoscanner. The perfusion lung scan is an important test because it
is safe, readily available, essentially noninvasive, and, if entirely
normal, rules out a diagnosis of PE.126 133 134
Ventilation scanning is performed with the use of radioactive aerosols
that are inhaled and exhaled by the patient while a gamma camera
records the distribution of the radioactivity in the alveolar
spaces.
An abnormal perfusion lung scan by itself is nonspecific and seen in a variety of cardiorespiratory disorders.3 120 122 125 137 138 By combining perfusion and ventilation scanning, certain patterns occur that can be used to assign probabilities of PE.3 122 123 137 138 139 140 In general, the probability of PE is reflected in the size and pattern of perfusion defects. Thus, large defects are more likely to be caused by PE than small defects, and mismatched defects (abnormal perfusion and normal ventilation) are more likely to be caused by PE than are matched defects.3 122 123 137 138 139 140 However, these distinctions are not absolute. Thus, between 30% and 40% of patients with large perfusion defects with a matching ventilation defect have PE, and a small mismatched defect may not be diagnostic of PE.3 122 123
Patients with subsegmental perfusion mismatches have a probability of
PE of 40%, and those with subsegmental matches have a probability
of 25%.3 122 123 The probability is lower in patients
in whom clinical suspicion of PE is low.3 122 123
A high clinical probability of PE combined with a high-probability
lung scan pattern is associated with PE in 96% of
patients.123 A moderate clinical probability combined with
a high-probability lung scan pattern is positively associated with
PE in 80% to 88% of cases.3 123 In most circumstances,
the presence of these combinations of clinical probabilities and lung
scan findings can be used to make a clinical decision to diagnose PE
and treat the patient accordingly. Unfortunately, these two
combinations of clinical/lung scan patterns (ie, a high-probability
lung scan with a high or moderate clinical probability) occur in only
12% to 32% of patients with abnormal perfusion
scans.3 123 In addition, only 50% of patients with a
high-probability lung scan but a low clinical probability have
PE.123 Although this combination is uncommon, it is
important, because it would be inappropriate to make a diagnosis of PE
without further investigation in this group.
If both clinical probability and lung scan probability are low, then PE
is very unlikely (occurring in <6% of patients), and for practical
purposes a diagnosis of PE can be excluded.123 This
combination of clinical/lung scan pattern occurs in 15% of patients
with an abnormal lung scan. Thus, a management decision to either treat
or not treat without further investigation can be made in <50% of
patients with clinically suspected PE with an abnormal lung
scan.3 123 In the remaining patients with suspected PE and
an abnormal perfusion scan, further investigations for venous
thrombosis or PE are required to either rule in or rule out a diagnosis
of PE.3 123 An approach to diagnosis of venous thrombosis
is shown in Fig 7.
|
Other combinations include low clinical probability and
intermediate or indeterminant lung scans and intermediate clinical
probability and low-probability lung scans. |
Approach to Treatment |
|---|
The objectives of treating venous thrombosis and PE are to prevent local extension of the thrombus, prevent the thrombus from embolizing, and, in certain clinical circumstances, accelerate fibrinolysis. Anticoagulants are effective in most patients for preventing clinically important local extension of thrombosis, but they must be continued for weeks to months after the acute event and they may not prevent long-term complications of thrombosis.
Of the two anticoagulants in current use, heparin acts immediately by catalyzing the inhibition of activated coagulation factors (principally thrombin and factor Xa) by antithrombin III (AT-III), while coumarins act much more slowly by inhibiting synthesis of fully gamma-carboxylated vitamin K–dependent coagulation proteins. Both classes of anticoagulants inhibit the generation of factor Xa and thrombin when administered in relatively low doses. Oral anticoagulants do not inhibit thrombin activity directly but modulate further thrombin generation by lowering functional coagulation factors that participate in positive feedback loops. Heparin can inhibit thrombin activity as well as further thrombin generation by modulating positive feedback loops.
Low concentrations of heparin can inhibit the early stages of blood coagulation, but higher concentrations are needed to inhibit the much higher concentrations of thrombin that are generated if the coagulation process resists modulation. If fibrin is formed, even higher concentrations of heparin are required to modulate the procoagulant effects of clot-bound thrombin, which is site-protected from inhibition by heparin/AT-III and can provide an ongoing procoagulant stimulus in the vicinity of the clot.141 Some of the new anticoagulants, including hirudin and its fragments, are effective inhibitors of clot-bound thrombin and may therefore be more effective than heparin in neutralizing the procoagulant effects of the fibrin-bound thrombin.141
The fibrinolytic enzymes streptokinase, urokinase, and TPA accelerate the rate of dissolution of thrombi and emboli. Thrombolysis is more expensive than anticoagulant therapy and is associated with a higher risk of bleeding, so its use should be restricted to patients who are likely to benefit from it. Two types of patient groups have the potential to benefit from thrombolytic therapy: those with major PE and selected patients with major venous thrombosis. Surgical removal of the thrombus (venous thrombectomy) or the embolus (pulmonary embolectomy) is rarely indicated. In patients with venous thrombosis, PE can be prevented very effectively with anticoagulant therapy. Pulmonary emboli can also be prevented by inserting a filter into the vena cava, but this approach is used only if anticoagulant therapy is contraindicated because of bleeding or if PE has recurred despite adequate treatment with anticoagulants (see below for definition of adequate anticoagulant therapy).
There is good evidence that patients with PE have a high mortality and a high rate of recurrence if untreated.142 There is also good evidence that patients with symptomatic proximal143 144 or calf vein thrombosis145 have a high recurrence rate without treatment. Anticoagulation reduces mortality and recurrence in patients with acute PE and reduces recurrence in patients with DVT.143 144 145
|
Use of Anticoagulant Therapy |
|---|
A working approach to the use of anticoagulants is described below. A more comprehensive guide, "Guidelines to Anticoagulant Therapy," (Circulation 1994;89:1449-1489) is available in reprints from the Office of Scientific Affairs, American Heart Association, 7272 Greenville Ave, Dallas, TX 75231-4596. (Telephone 800-242-8721.)
Heparin
Heparin should be initiated with an intravenous
bolus of 5000 U followed either by an intravenous infusion
of 1400 U/h or a subcutaneous injection of 17 500 U twice
daily.146 147 148 A weight-adjusted dose regimen can also
be used.149 This regimen consists of a continuous
intravenous infusion in a bolus dose of 80 U/kg followed by
an infusion at 18 U/kg per hour. The aPTT should be performed 6
hours after the bolus and initiation of the continuous infusion and at
least daily thereafter to maintain the aPTT in the therapeutic range
equivalent to an anti–factor Xa heparin level of 0.3 to 0.7 U/mL.
Warfarin can be started within the first 24 hours. Heparin is continued
for 5 days150 151 or longer until prothombin time (PT) has
been in the therapeutic range for a minimum of 2 consecutive days. It
is essential that the initial dose of heparin be adequate to achieve a
therapeutic aPTT and that the period of overlap of heparin and warfarin
is sufficient to allow the full antithrombotic effects of warfarin to
be expressed (Table 6). The distinction between
expression of the anticoagulant and antithrombotic effects of warfarin
is discussed in a subsequent section of this report.
|
Therapeutic Range
The concept of a therapeutic range is based on experimental
studies in animals152 and subgroup analysis of the
results of two prospective studies in humans.41 153 The
animal studies demonstrated that prevention of growth of experimental
venous thrombi required doses of heparin that prolonged the aPTT to
approximately twice that of control subjects. These doses were
equivalent to a heparin level of 0.2 U/mL by protamine titration of the
thrombin time. In the clinical studies, comparisons of the rates of
recurrence between patient subgroups demonstrated that risk of
recurrence was increased if the aPTT ratio was less than 1.5
times the mean of the normal range.
The results of these studies have led to the recommendation that the
therapeutic range of heparin should be an aPTT ex vivo (ie, measured on
plasma of patients treated with heparin), which is equivalent to a
heparin level by protamine titration of the thrombin time of 0.2 to 0.4
U/mL or an anti–factor Xa heparin level of 0.3 to 0.7 U/mL. For many
commercial aPTT reagents, the therapeutic range is 1.8 to
3.0,98 although for less sensitive reagents it is 1.5 to
2.0154 (Table 7).
|
A large between-patient variation in dosage is required to achieve a therapeutic aPTT response in patients with VTE.146 155
With a continuous infusion of heparin started at a dose of 32 000 U
per 24 hours after a bolus of 5000 U, approximately one third of
patients are below the therapeutic range at 6 hours, one third are in
the therapeutic range, and one third are above the therapeutic
range.146 By adjusting the dose according to a specially
developed dose-adjustment nomogram146
(Table 8) in which the aPTT response is obtained every 6
hours until the therapeutic range has been achieved, more than 80% of
patients are within the therapeutic range at 24 hours and more than
90% are within this range at 48 hours.146
|
The anticoagulant effect of heparin is influenced by its nonspecific binding to plasma proteins that compete with AT-III for heparin binding and by the rate of heparin clearance.156 157 Many of the heparin-binding proteins are acute-phase reactants that are elevated to a variable degree in sick patients. The elevated levels of these plasma proteins contribute to heparin resistance seen in sick patients, and the variable concentrations of these binding proteins contribute to the differences in anticoagulant response among patients.156 157 One of these acute-phase reactant proteins, factor VIII, also reduces the effect of heparin on the aPTT; thus, in many sick patients the observed resistance to heparin and variability in dose response is greater when monitored with an aPTT than with an anti–factor Xa heparin assay or a thrombin clotting time.158 Differences in the rates of heparin clearance between patients also contribute to interindividual variability in patients' responses.
Treatment of patients who fail to achieve an adequate aPTT response despite high doses of heparin has been clarified by the results of a randomized trial.158 Patients with venous thrombosis whose aPTT response to high doses of heparin (more than 35 000 U per 24 hours) was subtherapeutic were randomly allocated to monitoring with either aPTT or a heparin level of 0.3 to 0.7 anti–factor Xa units. These therapeutic ranges (for both methods of monitoring) correspond to a heparin level by thrombin time protamine titration of 0.2 to 0.4 U/mL.159 Many patients who had subtherapeutic aPTT values had heparin levels >0.3 U/mL. In patients randomly assigned to monitoring by aPTT, the dose of heparin was increased until the test result was in the therapeutic range. Despite receiving a lower dose of heparin, patients randomly assigned to monitoring by heparin level had a low rate of recurrence that was no different than the group randomly assigned to monitoring with aPTT. Heparin assays based on an anti–factor Xa assay or a thrombin time should be used to monitor heparin therapy in patients who have a long aPTT due to a "lupus anticoagulant." The targeted therapeutic range should be 0.3 to 0.7 anti–factor Xa units or 0.2 to 0.4 U/mL by protamine titration of the thrombin time.159
Heparin Assays
Heparin assays using a chromogenic substrate are easy
to perform in any clinical laboratory, although they are not often
available clinically. Heparin assays are more expensive than aPTT
assays; therefore, it is recommended that their use be limited to the
10% to 20% of patients whose aPTT response is below the lower limit
of the therapeutic range with heparin doses of 40 000 U per 24
hours.
In patients with an inadequate response to heparin therapy by both the aPTT and heparin assay, the dosage of heparin is increased, and an assay for AT-III is obtained. If the AT-III level is <50% of normal, the patient is treated with infusions of plasma or AT-III concentrate to elevate the AT-III level. However, if the AT-III level is above 60%, the dose of heparin is increased with the use of a heparin dose-adjustment nomogram.146
Duration of Heparin Therapy
The practice of a 7- to 10-day course of heparin therapy has been
changed because of the findings of two randomized studies performed in
patients with DVT. The studies reported that a 4- to 5-day course of
heparin was as effective as a 9- to 10-day course of
heparin.150 151 The results of these two studies have
important practical implications because the shorter course of heparin
facilitates early discharge of patients from the hospital.
Although the findings of these studies can likely be generalized to most patients, they may not be applicable to patients with large iliofemoral vein thrombosis or major PE, because these two classes of patients were excluded from one study150 and formed only a small proportion of patients in the second.151 It is our practice to treat patients with large iliofemoral vein thrombi and those with major PE with a 7- to 10-day course of heparin and to delay starting warfarin therapy until the aPTT has been in the therapeutic range for 3 days. The delay in starting warfarin is used to ensure that patients receive an adequate dose of heparin for at least 5 days.
Subcutaneous Heparin
The relative efficacy and safety of heparin administered by
subcutaneous and continuous intravenous infusion have been
compared in randomized trials. These studies demonstrate that the two
methods are equally safe and effective, provided that heparin is given
in an adequate starting dose and that the dose is adjusted according to
the aPTT (Table 9).148 160 161 162 163
|
However, there is a clinically important reduction in the bioavailability of heparin when administered subcutaneously in doses up to 15 000 U twice daily that results in subtherapeutic anticoagulant and antithrombotic effects in a large percentage of patients.153 On the other hand, there is good evidence from one large study that heparin administered subcutaneously is both safe and effective when started at a dose of 17 500 U twice daily after an intravenous bolus of 5000 U. The dose is then adjusted according to the aPTT.148 The aPTT is performed 6 hours after the morning injection and the dose is then adjusted to maintain the midinterval aPTT at 1.5 to 3.0 times the control value.148 Dose estimation is a little more difficult than with continuous infusion, but the feasibility of this approach has been demonstrated in a number of clinical trials.148 160 Subcutaneous administration is difficult in patients in shock or heart failure because of poor and variable subcutaneous tissue blood flow.
Low-Molecular-Weight Heparins
Administration of LMWHs in a fixed dose by subcutaneous injection
has been compared with administration of dose-adjusted heparin by
continuous infusion for treatment of venous thrombosis. The results,
which have been summarized in a
meta-analysis,164 indicate that LMWHs are at
least as effective and safe as standard heparin. These findings raise
the possibility that selected patients with venous thrombosis might be
suitable candidates for treatment at home, an advance that would reduce
cost and improve patient convenience.
Like heparin,165 LMWHs do not cross the placental barrier,166 167 168 and descriptive studies suggest they might be safe and effective171 in pregnancy. In a randomized trial LMWHs were associated with a much lower incidence of heparin-induced thrombocytopenia than heparin170 and a lower incidence of osteoporosis.164
Oral Anticoagulants
The need for oral anticoagulants after an initial course of
heparin is based on the results of two randomized studies that
demonstrated that the incidence of out-of-hospital
recurrences could be markedly reduced if heparin therapy was
followed by a 3-month course of warfarin.143 145 In one
study in which the dose of warfarin was adjusted to obtain an INR of
3.0 to 4.5, the incidence of bleeding was very high. Another study was
then conducted in which patients with proximal vein thrombosis were
randomly assigned to treatment with either high- (INR, 3.0 to 4.5) or
moderate-intensity (INR, 2.0 to 3.0) warfarin after an initial
course of heparin therapy.37 The incidence of
recurrence was equally low in both groups, but bleeding was
approximately four times higher in the high-intensity group. Based
on the results of this study, and subsequent experience with other
prospective clinical studies, the recommended therapeutic range is an
INR of 2.0 to 3.0.
An INR of 3.0 to 4.0 has been recommended for patients with antiphospholipid antibodies,171 172 173 although there is some disagreement on this issue.174
Antithrombotic Effect of Warfarin
Warfarin therapy is usually monitored by prothrombin time
(PT), a test that is responsive to reduction of 3 of the 4 vitamin
K–dependent procoagulant clotting factors (factors II, VII, and X).
The conventional view is that the antithrombotic effect of warfarin is
reflected by its anticoagulant effect as measured by PT. However, this
view may not be correct during the induction phase of warfarin therapy.
During the first few days of warfarin therapy, PT primarily reflects
the reduction of factor VII activity, which has a half-life of only
6 hours, which is similar to the half-life of the natural
anticoagulant protein C. Subsequently PT is prolonged by depression of
factors X and II (prothrombin). Therefore, for the first 24 hours of
warfarin therapy there is potential for a transient hypercoagulable
state, resulting from a reduction of levels of protein C before the
effects of warfarin on the activities of factors X and II are fully
expressed. There is evidence that reductions of factor II and,
possibly, factor X are more important than reduction of factors VII and
IX for the antithrombotic effect of warfarin. The evidence supporting
this view comes from the following observations. First, the experiments
of Wessler and Gitel,175 performed more than 40 years ago
with a stasis model of thrombosis in rabbits, showed that the
antithrombotic effects of warfarin require 6 days of treatment, whereas
the anticoagulant effect of warfarin as reflected by prolongation of PT
is seen within 2 days. These findings are consistent with an
explanation that the antithrombotic effect of warfarin requires a
reduction in activity of factor II, which has a half-life of 60
hours. Second, in more recent experiments in a rabbit model of tissue
factor–induced intravascular coagulation, Zivelin et
al176 demonstrated that the protective effect of warfarin
primarily reflects its ability to lower factor II levels. Thus,
selective infusion of factor II, and to a lesser extent factor X,
abolished the protective effects of warfarin in this model. In
contrast, infusion of factor VII or IX had no effect.
The concept that the antithrombotic effect of warfarin reflects its
ability to lower factor II levels provides a rationale for overlapping
heparin with warfarin in treatment of patients with thrombotic disease
until the factor II level is lowered into the therapeutic range. Given
that factor II has a half-life of 60 hours, an overlap of at
least 4 days is necessary.
Optimal Duration
Patients with VTE are usually treated with oral
anticoagulants for 3 to 6 months. Shorter courses of oral anticoagulant
therapy have been investigated in randomized trials, but the results
have been inconclusive.177 178 179 It is now clear that risk
of recurrence varies in different subgroups. The risk of PE in
patients with isolated calf DVT is very low.85 There also
is evidence46 180 that risk of recurrence is less
in patients with a temporary or reversible risk factor (eg, thrombosis
secondary to surgery or trauma) than it is in those with a continuing
risk factor (such as associated malignancy) or with idiopathic DVT
(thrombosis in the absence of a recognized risk factor). Prandoni and
associates180 reported that in patients with proximal vein
thrombosis treated with oral anticoagulants for 3 months, the rate of
recurrent VTE was 24% over 80 weeks in patients with idiopathic venous
thrombosis compared with 4.8% in those with a reversible risk factor.
A similar observation was made by Levine and associates.46
In 301 patients with proximal DVT given 3 months of warfarin and then
followed for an additional 9 months, there were 26 recurrent
thromboembolic events in 212 patients (12.3%) with either continuing
risk factors or idiopathic DVT, compared with 0 in 89 patients with a
transient reversible risk factor (P=.0007). None of the
recurrences were fatal. Thus, patients with an identifiable
reversible risk factor (such as surgery) appear to respond well to a
6-week to 3-month course of therapy, whereas patients without a
reversible risk factor have a high incidence of recurrence
despite 3 months of oral anticoagulation.
Similar findings have been reported in two randomized studies. In the first report, 712 patients with DVT and PE were randomly assigned to either 4 or 12 weeks of anticoagulant therapy.47 The rate of recurrent VTE was 7.8% in patients treated for 4 weeks and 4.0% in those treated for 12 weeks. Only 1 of 116 patients (0.86%) with postoperative VTE had a recurrent event; whereas among the 506 "medical" patients, 4.0% of patients treated for 12 weeks and 9.1% of patients treated for 4 weeks experienced a recurrence. Only 1% of all patients had fatal PE. These results suggest that a short course of anticoagulation might be adequate for patients with postoperative thrombosis, but a longer course of treatment is necessary for patients without a reversible risk factor. In a more recent study,181 897 patients with a first episode of DVT or PE were treated with at least 5 days of heparin or LMWH and randomly allocated to receive 6 weeks or 6 months of warfarin, with the goal of reaching an INR of 2.0 to 2.85. The incidence of recurrence over 2 years of follow-up was 18.1% in the 443 patients who received 6 weeks of oral anticoagulation compared with 9.5% in the 454 patients who received 6 months of therapy (P<.001). However, as in the other studies, the incidence of recurrent thromboembolism was much lower in both groups in patients with reversible risk factors.
The observed difference in recurrence rates between patients with and without reversible risk factors is relevant to the issue of optimal duration of oral anticoagulant therapy. Thus, the low absolute incidence of thrombosis in patients with temporary risk factors suggests that a short course of treatment might be appropriate for the subgroup of patients with reversible risk factors, whereas long-term anticoagulant therapy should be considered for patients without a reversible predisposing factor. At present, however, there is insufficient evidence to support lifelong treatment for all patients with idiopathic thrombosis. Instead, it would be reasonable to use anticoagulant therapy for 6 weeks in patients with a reversible risk factor and to continue anticoagulation for up to 6 months in patients with idiopathic venous thrombosis. An indefinite duration of anticoagulation should be considered in patients with venous thrombosis associated with active malignant disease who are often bedridden and receiving chemotherapy, which contributes to their hypercoagulable state.182 Long-term anticoagulant therapy should also be considered for patients who have multiple recurrent episodes of idiopathic VTE and those with inherited thrombophilia who have suffered one or more unprovoked episodes of major VTE.45
Recommendations for Duration of Warfarin Therapy
Patients with a first episode of VTE should be treated
for 6 weeks to 3 months if they have a reversible risk factor and for 3
to 6 months if they have idiopathic venous thrombosis. Warfarin therapy
should be continued for longer periods, possibly for life, in patients
with documented idiopathic thrombosis who have 1 of the 4 inherited
molecular abnormalities (deficiencies of AT-III, protein C, protein S,
or activated protein C resistance) and in those who have a
lupus anticoagulant or anticardiolipin antibody, because these
laboratory abnormalities predispose them to recurrent venous
thrombosis. Treatment of patients with these blood abnormalities who
develop venous thrombosis after a well-recognized provocation (eg,
surgery) is uncertain. Indefinite anticoagulation might not be
warranted, although some authorities believe so. The AHA also
recommends that patients who have more than two documented episodes of
recurrent venous thrombosis and patients with at least one episode of
thrombosis and active cancer should be treated with anticoagulants
indefinitely. Finally, patients with ongoing risk factors (eg,
immobilization in a plaster cast) should be treated until the period of
risk is over.
Most patients requiring long-term anticoagulant therapy respond well to warfarin targeted to an INR of 2.0 to 3.0. However, some patients with cancer have a resistance to warfarin and require long-term treatment with heparin, administered in full doses by subcutaneous injection. The optimal intensity of anticoagulation therapy is uncertain for patients with a lupus anticoagulant or cardiolipin antibody who require long-term anticoagulation. There are reports, based on retrospective analyses of observational studies, that patients with the antiphospholipid antibody syndrome and thrombosis are inadequately protected from recurrent episodes of VTE if treated at a targeted INR of 2.0 to 3.0.171 172 173 In contrast, a recent smaller prospective study in lupus anticoagulant–positive patients with venous thrombosis174 but without other manifestations of the antiphospholipid antibody syndrome reported that these patients with fewer complications respond well to warfarin at an INR intensity of 2.0 to 3.0. It is uncertain whether the discrepant findings reported in these studies result from differences in patient populations or differences in the responsiveness of PT reagents to the lupus anticoagulant in patients who receive anticoagulation with warfarin. Thus, it is possible that with some PT reagents the INR result is artifactually prolonged by the lupus anticoagulant and therefore does not reflect the true anticoagulant effects of warfarin.
Thrombolytic Therapy
Thrombolytic therapy is more effective than
heparin in producing rapid lysis of thromboemboli. However, it is more
expensive than heparin, it is associated with a higher risk of
bleeding,55 183 and it is not indicated in most patients
with PE because they do well clinically with anticoagulant therapy. It
is contraindicated in the postoperative period and in other situations
in which there is a high risk of bleeding. Thrombolytic
therapy has lifesaving potential for patients with massive
PE184 185 and should be considered in patients with major
PE who have syncope, hypotension, severe hypoxemia, or heart
failure.184 185 186 Thrombolytic therapy should
also be considered for patients with a submassive embolism and
underlying cardiac or respiratory disease. Limited evidence suggests
that thrombolytic therapy prevents postthrombotic
syndrome in some patients with acute venous thrombosis of recent
onset.183 187 Thrombolytic therapy may also be
indicated in selected patients (both young and old without risk factors
for bleeding) with extensive proximal vein
thrombosis.187 188
Caval Interruption
Although anticoagulation is the standard treatment for acute
venous thrombosis and PE, venous interruption procedures may be
indicated for VTE when anticoagulation is ineffective or unsafe. The
most common indication for venous interruption in patients with DVT or
PE is anticoagulant-induced bleeding or anticipation of hemorrhagic
complications in a patient with a predisposing lesion, such as a
bleeding peptic ulcer, gastrointestinal malignancy, recent intracranial
operation, or an underlying hemorrhagic state (eg, liver failure or
thrombocytopenia). The second indication for venous interruption is
failure of anticoagulation, provided that the anticoagulant effect has
been within the prescribed therapeutic range (an aPTT corresponding to
an anti–factor Xa heparin level >0.3 U/mL or an INR >2.0).
Development of new PE or substantial extension of venous thrombosis
should be documented by objective tests before recurrent
thromboembolism is accepted as a diagnosis, because new symptoms in a
patient with an established venous thrombosis of PE are often
misinterpreted as evidence for recurrence in a patient
receiving anticoagulation.
Other indications for venous interruption are more controversial. These include
Major PE with severe cardiovascular
instability
As an adjunctive procedure in patients who undergo
pulmonary embolectomy
Prophylactic interruption of the inferior
vena cava in patients at exceptionally high risk of VTE, particularly
if there is a relative contraindication to anticoagulation
Intracaval Devices
The first intracaval device to be widely used was the
inferior vena caval umbrella devised by Mobin-Uddin et
al.189 The umbrella filter is inserted through a cutdown
in the internal jugular vein and passed under fluoroscopic control
through the superior vena cava and right atrium into the
inferior vena cava, where its position below the renal
veins is confirmed by phlebography. When it is expelled from its
capsule applicator, the pointed struts engage the wall of the cava and
hold the filter in place. The device contains fenestrations to maintain
venous blood flow.
The results following implantation of 4699 filters during the first 6 years after the umbrella filter became available were summarized by Mobin-Uddin.190 The initial design had a diameter of 23 mm and was associated with proximal migration in 27 of 2848 applications (0.9%). The frequency of proximal migration was reduced to 0.4% by increasing the diameter to 28 mm. Complete occlusion of the filter occurred in 30% to 45% of patients due to thrombosis around the device or trapping of an embolus.190 191 The reported rate of recurrent PE was 12%.192 Less common complications included perforation of adjacent organs (eg, duodenum or ureter) and breakage.
The Greenfield filter has essentially replaced the Mobin-Uddin umbrella. The filter, which resembles an umbrella consisting only of struts, is placed with its apex directed proximally. With this design, emboli are retained in the center of the cone, where the spokes are closer together and the trapping efficiency greater.193 The central positioning of entrapped emboli facilitates blood flow past the trapped embolus and may encourage fibrinolysis, thereby accounting for the high rate of patency with this device (95%).191 Magnant and coworkers194 reviewed the experience with placement of the Greenfield filter. They concluded that percutaneous placement of inferior vena caval filters had supplanted operative placement and that no major morbidity had been associated with use of the Greenfield filter. The bird's nest filter was invented by Roehm and described in 1984.195 When compared directly with the Greenfield device, the bird's nest filter appeared to be more readily dislodged and more easily subjected to local thrombosis.195
Occlusion of the cava by a balloon has been proposed by Hunter et al196 and Moser et al.197 The balloon is inserted as a percutaneous procedure. A potential advantage of balloon occlusion is that caval obstruction can be temporary; once the threat of embolization has subsided, the balloon can be deflated and removed. However, thrombosis can occur around the balloon. In a report of up to 18 years of experience involving 191 cases, Hunter and associates198 reported no malfunction of the inflation mechanism and no migration from the site of inflation. No patients had recurrent PE after balloon inflation. In 39% of patients, the legs appeared normal and free of edema.
Surgical Removal
Thrombectomy for acute venous thrombosis and
pulmonary embolectomy for acute PE to relieve acute obstruction
are rarely used. Thrombectomy is of limited benefit because it is
usually complicated by acute recurrence despite postoperative
anticoagulant therapy; it leaves a
de-endothelialized venous surface that is highly
thrombogenic.199 However, it is indicated to rapidly
reduce venous obstruction in patients with phlegmasia cerulea dolens
with impending venous gangrene. Although pulmonary embolectomy
can be a lifesaving procedure in a patient with massive
embolism,200 most hospitals do not have the resources,
personnel, or facilities for this type of surgery. Furthermore, most
patients who are likely to benefit from pulmonary embolectomy
die before they can be diagnosed and treated,201 and some
candidates for emergency pulmonary embolectomy survive and do
well with medical therapy. On the other hand, elective
pulmonary thromboendarterectomy can be
very effective and lifesaving in selected patients with chronic
large-vessel thromboembolic pulmonary
hypertension.202 203 This operation, which has been
available for years but abandoned by many centers because of a high
postoperative mortality, has been revived by the work of the San Diego
group.202 203 The success of the procedure is highly
dependent on the availability of a skilled and experienced team of
surgeons and internists.
|
Upper-Extremity DVT |
|---|
The frequency of upper-extremity venous thrombosis involving the axillary and/or subclavian veins has increased in the last decade with the increasing use of long-term indwelling catheters. Upper-extremity venous thrombosis is classified as primary and secondary. Primary upper extremity thrombosis can be caused by local venous compression produced by unusual movements or positions of the arm ("effort thrombosis"), whereas secondary thrombosis is usually caused by indwelling intravenous devices.204 205 Effort thrombosis has been described following weight-lifting, pole-vaulting, racquet sports, or direct and prolonged pressure to the axilla. Axillary vein thrombosis can also be a manifestation of the thoracic inlet syndrome or can be caused by direct trauma or compression by tumor.206 Axillary or subclavian vein thrombosis has been described in AT-III deficiency, protein S deficiency, hypoplasminogenemia, and antiphospholipid syndrome.207 208 209 210 Thrombosis secondary to the use of long-term indwelling catheters, often used in administration of chemotherapy, is now a much more common cause of upper-extremity thrombosis than effort thrombosis.
Upper-extremity venous thrombosis can be complicated by PE211 and rarely by massive PE.212 213 The most important complications are long-term disability caused by venous hypertension and loss of venous access in patients requiring long-term chemotherapy. Venous hypertension can produce swelling, fatigability, aching, and weakness of the affected arm, particularly following activity. The symptoms can be disabling in athletes or manual laborers during and after activity involving the affected arm. The reported frequency of disabling upper-extremity venous hypertension after spontaneous axillary/subclavian vein thrombosis varies from 25% to 47%.214 215 216 Lower rates (12%) have been reported in a series of patients treated with thrombolysis,217 but no randomized trials have been reported comparing anticoagulants with thrombolysis.
The diagnosis of upper-extremity vein thrombosis is usually suspected on clinical grounds and confirmed by venography. Optimal visualization of the thrombosed axillary/subclavian veins is best achieved by injecting the radiographic contrast into the median basilic vein. Injection of contrast material into a distal vein in the hand or wrist will demonstrate an obstruction and the presence of collateral vessels but does not usually outline the thrombus. Imaging studies in which color flow duplex ultrasound was used lack the sensitivity of venography for upper-extremity thrombosis.218
Various treatments have been advocated for primary upper-extremity thrombosis. Resolution of acute symptoms can usually be obtained with either anticoagulant or lytic agents.145 146 147 Anticoagulant therapy is not usually associated with anatomic resolution of the thrombus and clinical improvement because collaterals develop and bypass the obstruction. Thrombolytic therapy appears to be more effective than anticoagulants in producing early resolution.219 220 Local therapy administered through a small catheter introduced through the basilic vein and advanced into the clot has been advocated. A loading dose of 250 000 IU urokinase infused into the clot over 1 hour and then continued at a lower dose of 1000 IU/min for up to 24 hours has been used successfully.221 The patient is then treated with heparin for 5 days, followed by warfarin for 3 months. Surgical removal of the first rib has been advocated by some if symptoms of venous obstruction persist after a course of conservative treatment. However, the effectiveness of this invasive approach has never been evaluated in an appropriately designed clinical trial.
Long-term venous access through a central venous catheter is required for treatment of long-term disorders requiring chemotherapy, antibiotics, or hyperalimentation. Thrombosis of the subclavian/axillary vein is a common complication of central venous catheterization. These thrombi may be asymptomatic,222 223 although spontaneous resolution is uncommon when long-term venographic follow-up studies are performed.224
The standard treatment of secondary axillary/subclavian vein thrombosis has been removal of the catheter, limb elevation, and anticoagulation. This approach usually results in rapid improvement of symptoms, but on follow-up 70% of patients have been reported to have some pain and/or swelling in the affected arm.225 Of greater importance, the venous lumen is obliterated and cannot be used again for venous access. Thrombolytic therapy has been used successfully to treat secondary upper-extremity thrombosis.226 227 228 Initial reports used high-dose systemic therapy. More recently local catheter-directed thrombolytic therapy has been used with apparent success.229
A dosage regimen of urokinase has been established, empirically
consisting of 250 000 IU/h for 2 hours followed by 60 000 IU/h until
clot lysis has been achieved. Heparin can be given in full doses either
during or after completion of thrombolytic therapy and
anticoagulation with heparin, followed by warfarin for 3 months.
With this approach, a 78% lysis rate has been reported in a small
study of 31 patients.229 Successful lysis is more common
with fresh thrombi.230
|
Diagnosis of Venous Thromboembolism in the Pregnant Patient |
|---|
The diagnosis of VTE during pregnancy is difficult because leg pain and swelling are frequent and usually not due to DVT,231 and performance of radiological procedures is a problem because of the fear of exposing the fetus to radiation.
Deep Vein Thrombosis
As in the nonpregnant patient, venous ultrasonography is used
as the initial diagnostic test. If venographic confirmation
of an equivocal test result is required, a limited venogram can be
performed without risk to the fetus by covering the patient's abdomen
with a lead-lined apron. A limited venogram allows visualization of
the calf veins, popliteal vein, and most of the superficial femoral
vein but not the iliac vein. Therefore, a normal limited venogram does
not exclude iliac vein thrombosis.
Pulmonary Embolism
The diagnosis of PE in pregnancy is essentially the same as
in the nonpregnant patient, with three exceptions designed to avoid
exposure of the fetus to ionizing radiation: (1) Ventilation and
perfusion scanning are performed at 50% of the usual dose; (2)
pulmonary angiography, if indicated, should be performed via
the brachial route rather than the femoral route; and (3) venography,
if indicated, should be limited, with shielding of the abdomen.
Chest radiography, perfusion, and ventilation lung scanning are performed with a reduced dose of radioisotope for the perfusion scan (1 to 2 MCi). If the perfusion scan is normal, PE is excluded; if the lung scan indicates a high probability of PE, the diagnosis is made and the patient is treated with anticoagulants. If the scan is nondiagnostic, the patient is investigated for DVT by IPG or duplex ultrasound; if the test results are abnormal, the patient should be treated with anticoagulants. If the results are normal, a pulmonary angiogram should be considered.
|
Management of Venous Thromboembolism During Pregnancy |
|---|
An excellent review of this subject has been published,232 and the recommendations outlined below follow this report, which should be read for additional details.
Heparin
A recent critical review of the literature of heparin therapy
during pregnancy233 reported that, contrary to a previous
report,234 heparin therapy during pregnancy is safe for
the fetus. The conclusion is corroborated by a cohort study in which
the rates of premature birth, spontaneous abortion, stillbirth,
neonatal death, and congenital malformation were not significantly
higher in 100 pregnant women treated with heparin than in the normal
population.235 Because heparin does not cross the
placenta, there is no increased risk of bleeding for the fetus.
Warfarin
In the review cited previously, the pooled rate of adverse
effects associated with warfarin therapy was high
(26.1%).233 Warfarin exposure between 6 and 12 weeks of
gestation can be associated with warfarin embryopathy, which is
characterized by stippled epiphyses and nasal hypoplasia. In a study by
Iturbe-Alessio et al,236 10 of 35 term pregnancies in
which warfarin was administered between 6 and 12 weeks were associated
with warfarin embryopathy. This is likely to be an overestimate, and
the true incidence of warfarin embryopathy is likely to be 5% of
infants if maternal exposure occurs between 6 and 12 weeks of
gestation. Warfarin embryopathy has not been reported with warfarin
exposure outside this time period. Central nervous system
abnormalities, both hemorrhage and malformations, have been
reported after warfarin exposure at any time during pregnancy, but the
incidence is very low.233 236 Therefore, heparin is the
anticoagulant of choice for treatment of VTE during pregnancy. If
warfarin is used, it should be restricted to the second and early third
trimesters and avoided between 6 and 12 weeks of gestation and near
term to avoid delivery of an anticoagulated fetus.
Treatment of Acute Deep Venous Thrombosis and
Pulmonary Embolism
Heparin is usually initiated with an intravenous
bolus of 5000 U followed by a maintenance dose administered as
a continuous intravenous infusion of 32 000 U per 24 hours
to prolong the aPTT into the therapeutic range (1.8 to 2.5 times
control for most reagents) for 5 to 7 days. After the initial
intravenous dose of heparin, subcutaneous heparin should be
administered every 12 hours in doses adjusted to prolong a 6-hour
postinjection aPTT into the therapeutic range. The aPTT should be
checked regularly, because heparin requirements may vary as pregnancy
progresses. The patient should be monitored three times in the first
week and then at least weekly thereafter. Anticoagulant therapy should
be continued throughout pregnancy and for 4 to 6 weeks after delivery.
If the episode of VTE occurs late in pregnancy, anticoagulation should
be continued for a total of 3 months after the episode.
Long-term Anticoagulant Therapy Before
Pregnancy
Patients who receive long-term warfarin therapy before
pregnancy for DVT/PE or prevention of systemic embolism should be
treated with subcutaneous heparin every 12 hours throughout pregnancy
in doses adjusted to prolong the 6-hour postinjection aPTT to 1.5 to
2.5 times control. Two options are available when patients receiving
long-term anticoagulant therapy decide to conceive. The first is to
switch the patient to heparin before conception. This has the advantage
of avoiding any exposure of the fetus to warfarin but increases the
duration of heparin exposure if conception is delayed. The second
option is to continue warfarin and perform regular pregnancy tests when
conception is attempted. As soon as the pregnancy test result is
positive, warfarin should be stopped and heparin started. This is
probably safe for the fetus, provided warfarin is discontinued before 6
weeks of gestation. As mentioned above, no cases of fetal embryopathy
have been described with warfarin exposure before 6 weeks of gestation.
Warfarin therapy can be resumed after delivery.
Previous Deep Venous Thrombosis and Pulmonary
Embolism
The optimal treatment of pregnant patients with previous
DVT/PE is unknown because there are no large prospective trials to
provide reliable estimates of the incidence of recurrence
during pregnancy. Prophylaxis with standard heparin, 5000 U every 12
hours, is a reasonable approach and is associated with a very low
recurrence rate.235 Surveillance with weekly IPG
or duplex ultrasonography may be a reasonable alternative to heparin
during pregnancy.
Delivery and Postpartum
If the patient is receiving 5000 U of heparin every 12 hours at
term, heparin can be discontinued at onset of labor. No increase in
bleeding is anticipated with this approach. If adjusted-dose
heparin is being administered at term, some pregnant patients can have
a prolonged aPTT for as long as 20 hours after their last dose of
subcutaneous heparin.237 To overcome the potential risk of
a long aPTT at delivery, elective induction can be planned and heparin
therapy discontinued 24 hours before induction. In patients considered
to be at high risk for thrombotic complications, an
intravenous heparin infusion can be started after
discontinuation of subcutaneous heparin. Because the half-life of
intravenous heparin is short,238 heparin can
be discontinued 4 to 6 hours before delivery with the expectation that
the aPTT will be normal at time of delivery.
After delivery, heparin and warfarin should be restarted as soon as hemostasis is obtained, and heparin can be discontinued after an appropriate period of overlap. When administered to the nursing mother, warfarin is safe for the breastfed infant.239 240
Other Therapeutic Modalities
There are very few reports on the use of
thrombolysis during pregnancy. As a general rule,
pregnancy is a relative contraindication to
thrombolytic therapy, and its use should be restricted
to patients with massive PE.241 242 LMWHs do not cross the
placenta and have been used successfully during
pregnancy.169 243 244 Their advantage over standard
heparin is a more predictable dose response and a longer half-life
after subcutaneous injection, which allows administration once daily
without frequent monitoring.244
|
Management of Venous Thromboembolism in Children |
|---|
Venous thromboembolism in children is much less common than in adults. In general, recommendations for antithrombotic therapy have been extrapolated from those used for adults. However, optimal dosing for antithrombotic therapy in children is likely to differ from adults because the anticoagulant response to antithrombotic agents is different.
Incidence
Incidence of DVT/PE in the adult population is 2.5%
to 5.0%.2 54 245 In comparison, incidence of DVT/PE in
the general pediatric population is reported to be 0.07 per 10 000 and
5.3 per 10 000 hospital admissions.246 247 248 Other
comparisons illustrating the lower risk of DVT/PE during childhood are
the <1% incidence of clinically apparent DVT/PE after lower limb or
scoliosis surgery249 and the relative absence of DVT/PE in
children with congenital thrombophilias.250 251
Clinical Features
Ninety-five percent of DVT/PE in pediatric patients
occurs as a complication of serious diseases such as prematurity,
cancer, trauma/surgery, and congenital heart
disease.250 251 252 253 Congenital prethrombotic disorders account
for <10% of DVT/PE in children.250 251 Children at
greatest risk for DVT/PE are younger than 1 year or
teenaged.250 251 252 253 DVT in the lower extremities is the most
frequent noncentral venous line thrombotic complication in
children.251 The clinical presentations of DVT
and PE are similar to those in adults.248 250 251 253
Central Venous Lines
Forty percent of DVT in children and more than 80% in
newborns occurs in the upper venous system secondary to use of central
venous lines,250 251 252 which are employed for short-term
intensive care or long-term supportive care in children requiring
total parenteral nutrition or therapy for cancer. Central venous
line–related DVT requires repeat anesthesia for
replacement and can be complicated by PE254 255 256 257 ; it can
cause superior vena cava syndrome257 258 259 260 261 and
chylothorax257 258 262 263 and can obliterate the upper
venous system264 265 and so lead to postthrombotic
syndrome in the upper extremities.
Treatment of Children
Children older than 2 months who have DVT or PE should be
treated with intravenous heparin (bolus 75 U/kg; initial
maintenance of 20 U/kg per hour) sufficient to prolong the aPTT
to a range that corresponds to an anti–factor Xa level of 0.3 to 0.7
U/mL.
Treatment with heparin should be continued for 5 to 10 days and oral anticoagulation overlapped with heparin for 4 to 5 days. For many patients heparin and warfarin can be started together and heparin discontinued on day 6 if the INR is therapeutic. Heparin therapy should be used for a longer period for massive PE or iliofemoral thrombosis.
Long-term anticoagulant therapy should be continued for at least 3 months, with oral agents (initial dose 0.2 mg/kg per day) to prolong PT to an INR of 2.0 to 3.0.
Either indefinite warfarin therapy with an INR of 2.0 to 3.0, low-dose anticoagulant therapy (INR, <2.0), or close monitoring should be considered for children with a second recurrence of venous thrombosis or a continuing risk factor such as central venous line, antithrombin deficiency, or protein C or S deficiency.
Newborns with a central venous line in place should be treated with intravenous heparin in doses of 1 to 5 U/h through the catheter.266 267 268 269 270
Treatment of Newborns
The optimal regimen for anticoagulation therapy in treatment
of newborns with DVT, PE, or arterial thrombosis is
uncertain. If anticoagulation is indicated, a short course (10 to 14
days) of intravenous heparin (75 U/kg bolus;
maintenance 28 U/kg per hour), sufficient to prolong the aPTT
to an anti–factor Xa level of 0.3 U/mL, should be used.
The role of thrombolytic agents in treatment of VTE is uncertain. Further clinical investigation is needed before more definitive recommendations can be made. If thrombolytic therapy is used, either urokinase or TPA is preferable to streptokinase, and supplementation with plasminogen may be helpful.
|
Complications of Anticoagulation |
|---|
Treatment of patients who develop complications during anticoagulant therapy involves management of the actual complication and subsequent management of the thromboembolic event for which the patient is being treated.
Bleeding is by far the most important complication of anticoagulant therapy. The approach to bleeding depends on the severity of bleeding, the anticoagulant and dose used, results of laboratory tests at the time of bleeding, the length of time the patient has been treated with anticoagulants, and the seriousness of the thromboembolic event for which the patient is being treated.
Heparin
The frequency of clinically important bleeding during a 5- to
10-day course of heparin therapy varies between 3% and 10%, depending
on whether the patient is at high or low
risk.148 151 153 160 162 271 272 In many cases bleeding is
not life-threatening and does not require discontinuation of heparin.
Because heparin has a relatively short circulating half-life (60
minutes),273 274 275 276 the anticoagulant effect is reversed
fairly rapidly after treatment is discontinued. In most cases bleeding
is treated by discontinuing heparin, applying local pressure as
appropriate, and replacing blood if necessary.
If bleeding is potentially life-threatening (eg,
intracerebral, intraspinal, retroperitoneal, or severe
gastrointestinal), heparin should be stopped and the anticoagulant
effect reversed with protamine sulfate. Protamine sulfate is a strong
basic substance that rapidly neutralizes the effect of heparin. The
appropriate neutralizing dose depends on the dose of heparin and route
and time of administration. If protamine sulfate is used within minutes
of intravenous heparin injection, then a full neutralizing
dose, 1 mg protamine per 100 U heparin, should be given. Since the
half-life of heparin is 60 minutes, only 50% of a full
neutralizing dose is required 1 hour after the last heparin injection,
and only 25% of the full neutralizing dose is required after 2
hours.147
Protamine sulfate can produce a hypotensive response if given rapidly, so the dose should be injected slowly over a 20-minute period.277 278 279 Some patients may also develop a hypersensitivity reaction to protamine sulfate.
Heparin rebound may occur if very large doses of heparin are given.280 281 282 283 Therefore, it may be necessary to repeat administration of protamine if laboratory tests demonstrate a residual heparin effect.169 A direct assay of heparin activity, thrombin time, or aPTT should be performed both before and immediately after protamine is infused, and the test should be repeated 2 hours later to determine whether the neutralizing effect of protamine on heparin is permanent or transient.
If bleeding occurs when the aPTT response is in the therapeutic range or just beyond the therapeutic range, or if the anticoagulant-associated bleeding is potentially life-threatening, treatment with anticoagulant therapy should be stopped, and an alternative form of treatment should be used to manage the thromboembolic event. If the patient has proximal vein thrombosis or major PE, a caval interruption procedure should be considered.284 If the patient has calf vein thrombosis, the course of the thrombus can be monitored with serial venous ultrasound imaging99 111 and a caval interruption procedure used if thrombosis is extended.
The risk of bleeding is influenced by five variables: the patient's clinical condition,151 the dose of heparin,285 286 the anticoagulant response,286 287 method of administration,151 288 and concomitant use of aspirin or thrombolytic agents.289 290 291 292
The most important risk factor for bleeding is recent surgery or trauma. Other risk factors are renal failure, old age, and peptic ulcer disease. There is a relation between bleeding and both heparin dose and anticoagulant effect.285 286 287 293 294 Bleeding is greater when heparin is administered by intermittent intravenous injection.162 288
Other Complications of Heparin Therapy
Other complications of heparin are
thrombocytopenia,295 296 with or without
thrombosis296 ; osteoporosis,297 298 299 300 301 302
which occurs only with long-term treatment; and local skin
hypersensitivity and skin necrosis confined to subcutaneous injection
sites.303 Other complications are very rare and include
anaphylaxis, hypoaldosteronism,304 305 306 and alopecia. In
addition, patients treated with heparin can develop
hyperkalemia307 and often develop an
asymptomatic increase in plasma levels of hepatic
transaminases.308
If a patient develops local skin reactions at the site of injection, the source of heparin should be changed because local reactions may not occur with a different preparation of heparin, including LMWHs.
Thrombocytopenia
Thrombocytopenia is a well-recognized complication of
heparin therapy. Two forms of thrombocytopenia are described: an early
benign, reversible nonimmune thrombocytopenia and a late, more serious
IgG-mediated immune thrombocytopenia. The mechanism of the early form,
which is not associated with adverse clinical sequelae, is uncertain
but could be the result of direct weak activation of platelets by
heparin.309 310 311 312 The immune form of heparin-induced
thrombocytopenia is characterized by strong IgG-mediated platelet
activation170 296 313 and is associated with a substantial
risk of thrombotic complications.
The incidence of serologically confirmed heparin-induced
thrombocytopenia was investigated in a large clinical trial that
compared unfractionated heparin (7500 U twice daily) with LMWH (30 mg
enoxaparin twice daily) for prophylaxis after elective hip
surgery.170 The incidence of heparin-induced
thrombocytopenia was 1% at 7 days and 3% at 14 days in patients
receiving unfractionated heparin and 0% in those receiving LMWH. Other
prospective studies with higher (therapeutic) doses of heparin have
reported a similar incidence of
thrombocytopenia.314 315 316 317 318 319 320 321 322 323 324
Heparin-induced thrombocytopenia usually begins between 5 and 15 days after the start of heparin therapy (median, 10 days),170 295 325 but it has been reported within hours of starting heparin in patients who have received heparin within the previous 3 months.295 303 326 Thrombosis associated with heparin-induced thrombocytopenia can be heralded by a fall in platelet count without overt thrombocytopenia (eg, from 350 000 to 150 000). For this reason, patients who receive heparin should undergo a platelet count daily, and if the platelet count falls by 50% or more, heparin should be stopped and an alternative management strategy instituted.
Thrombocytopenia and Paradoxical Thrombosis
Heparin-induced thrombocytopenia is a highly
prothrombotic disorder. In a large prospective study of heparin therapy
after elective hip surgery, risk for thrombosis was dramatically
increased (odds ratio, 37) in patients with heparin-induced
thrombocytopenia, compared with those who did not develop
it.173 Although many case series have emphasized the
association of heparin-induced thrombocytopenia with
arterial thrombosis ("white clot syndrome"), it is
now clear that venous thrombosis is much more common with
heparin-induced thrombocytopenia than arterial
thrombosis.170 327 Overall, prospective studies suggest
that thrombosis associated with heparin-induced thrombocytopenia
occurs in 1% of patients who receive unfractionated heparin for
more than 5 days.170 324
Bleeding complications have been described in patients with heparin-induced thrombocytopenia, but they are less frequent and much less important than thrombotic complications.325
Laboratory Manifestations and Pathogenesis
Typically, the platelet count nadir in
heparin-induced thrombocytopenia is between 20 and 150 000 per
milliliter (median nadir, 50 000).325 Approximately 5%
of patients have concomitant hypofibrinogenemia associated with
disseminated intravascular coagulation.325 The
platelet count usually returns to baseline levels within 1 week of
discontinuing heparin.
Heparin-induced thrombocytopenia is caused by an IgG that
activates platelets via their Fc
II
receptors.328 329 The major target antigen is a heparin
sulphate/platelet factor IV complex that localizes the IgG on the
platelet surface.330 331 332 333 The thrombogenic diathesis
results from in vivo platelet activation334 as well as
generation of procoagulant platelet-derived
microparticles.335 In addition, heparin-induced
thrombocytopenia IgG has been shown to activate
endothelium in vitro via recognition of a heparin
sulfate/platelet factor IV complex.332 333 336
Laboratory Testing
Platelet activation assays that use washed target
platelets337 338 have a sensitivity and specificity
for heparin-induced thrombocytopenia of at least
95%.170 Typically, heparin-induced thrombocytopenia
IgG activates platelets at low (0.5 to 1.0 U/mL) but not
high (10 to 100 U/mL) concentrations of
heparin.337 339 340 Aggregation studies in which citrated
plasma is used are much less sensitive to heparin-induced
thrombocytopenia IgG than assays in which washed platelets are
used.340 341 342 An ELISA assay with the platelet factor
IV/heparin target antigen has been developed330 that shows
good concordance with the platelet activation
assay.342
Although heparin-induced thrombocytopenia is much less common with
LMWH preparations than standard heparin, in vitro studies indicate that
LMWHs show immune cross-reactivity in 70% of
instances.170 343 In contrast, in vitro
cross-reactivity is much less common (10%) with the
heparinoid Orgaran,344 which has been used
successfully as a substitute for heparin in patients with
heparin-induced thrombocytopenia.345
Treatment
Two different antithrombotic agents have been evaluated in
descriptive studies. These are Orgaran344 345 and the
defibrinogenating snake venom ancrod (Arvin).346 347
Intravenous administration of Orgaran produces immediate
onset of anticoagulation after bolus administration. Ancrod has the
advantage of exhibiting no cross-reactivity with heparin, but there
is a delay of 12 hours before effective defibrinogenation can be
achieved. In addition, neither thrombin generation nor platelet
activation are inhibited by ancrod348 and the magnitude of
the anticoagulant effect is less predictable than with Orgaran. Ancrod
is also contraindicated in patients with disseminated intravascular
coagulation or septicemia.349 Long-term (ie, >3
weeks) anticoagulation with ancrod is limited by development of
antibodies that render patients resistant to its
effects.346 350 Unfortunately, neither of these agents is
approved for use in the United States, but they can be obtained for
compassionate use. Initial experience with hirudin from Europe is very
promising, but it is not approved for use in North America.
Complications of Oral Anticoagulants
Bleeding is by far the most common complication of oral
anticoagulant therapy.351 Randomized studies have shown
that the risk of bleeding is influenced by the intensity of
anticoagulation,37 352 353 354 and several studies have shown
that the risk of clinically important bleeding is reduced by lowering
the therapeutic range for the INR from 3.0 to 4.5 to 2.0 to 3.0.
Although this difference in anticoagulant intensity is produced by a
mean reduction in the dose of warfarin of only 1 mg, the effect on
bleeding is profound. Randomized studies have also shown that the rate
of oral anticoagulant–induced bleeding is increased by concomitant
use of high doses of aspirin that both impair platelet function and
produce gastric erosions.351 355 356
Multivariate analysis of cohort studies also
suggests that risk of bleeding is influenced by the underlying clinical
disorder.354 357 These studies reported that the risk of
major bleeding is increased by age >65 years, a history of stroke or
gastrointestinal bleeding, and the presence of serious comorbid
conditions such as renal insufficiency or anemia.358 359 360
Bleeding that occurs when the INR is <3.0 is frequently associated
with an obvious underlying cause37 or an occult
gastrointestinal or renal lesion.353
Drugs that are known to interact with coumarins should be avoided if possible.361 However, if concomitant use of drugs that interact with warfarin is necessary, PT should be monitored more frequently in the first few days to weeks of combined use to anticipate a change in dosage. Furthermore, all new drugs should be viewed as having the potential to interact with coumarins, and the frequency of PT monitoring should be increased in the initial period after introduction. Drugs known to inhibit platelet function should be avoided unless prescribed to augment the antithrombotic effects of warfarin. For example, low-dose aspirin (100 mg/d) augments the antithrombotic effects of coumarins in patients with prosthetic heart valves but at an increased risk of minor bleeding.362
The frequency of bleeding depends very much on intensity of the anticoagulant effect and patient-related risk factors.352 358 363 If moderate-dose anticoagulant therapy is used to prolong the INR to between 2.0 and 3.0, bleeding is relatively uncommon.352 358 363 364 365 366 367 Most episodes occur in patients with a potential bleeding source such as a peptic ulcer, gastritis, renal calculus, or malignancy. Bleeding complications in patients on long-term anticoagulant therapy tend to occur early and may unmask an underlying local source. In randomized trials of moderate-intensity warfarin (INR, 2.0 to 3.0) in patients with nonvalvular atrial fibrillation versus untreated control subjects, the typical annual incidence of major bleeding was between 1.0% and 1.5% in the warfarin groups and 0.5% to 1.0% in the control groups. However, patients selected for these trials were at low risk for bleeding, so in practice, bleeding on warfarin is higher than reported by these studies.
Management of Bleeding
If bleeding occurs during oral anticoagulant treatment in a
patient with VTE, management depends on severity of bleeding, INR at
the time of bleeding, and whether or not the patient has completed most
of the prescribed course of anticoagulant therapy.
If the INR is above the therapeutic range, treatment can be discontinued until bleeding has stopped and then reintroduced cautiously at a lower intensity. If the INR is within the therapeutic range, a local source of bleeding should be sought, particularly if bleeding is gastrointestinal or from the urinary tract. However, if the INR is markedly prolonged, it is not usually necessary to look for a source of bleeding.
If bleeding is life-threatening and the INR prolonged, the coagulation defect should be reversed immediately by infusion of plasma, and vitamin K1 should be administered in a dose of 10 mg to 25 mg either intravenously by slow infusion or by subcutaneous injection.
If bleeding is not life-threatening and the INR is markedly prolonged, then the anticoagulant effect can be reversed by administering 5 mg vitamin K1 by subcutaneous injection.
Vitamin K1 can interfere with subsequent warfarin therapy when doses of 10 mg or more are used, and it can cause refractoriness to further warfarin therapy for up to 2 weeks.
Skin Necrosis
The most important nonhemorrhagic side effect of warfarin is skin
necrosis. This uncommon complication is usually observed on the third
to eighth day of therapy353 354 357 360 365 366 368 369 370 371 372 373
and is caused by extensive thrombosis of the venules and capillaries
within the subcutaneous fat. An association has been reported between
warfarin-induced skin necrosis and protein C
deficiency,368 372 373 and less commonly, protein S
deficiency,374 but this complication can also occur in
persons without a deficiency. A role for protein C deficiency seems
probable and is supported by the similarity of the lesions to those
seen in neonatal purpura fulminans, which complicates homozygous
protein C deficiency. The reason for the unusual localization of the
lesions to subcutaneous fat deposits remains a mystery. The optimal
technique for initiating anticoagulant therapy in patients with known
protein C or protein S deficiency is uncertain. A reasonable empirical
approach is to start with an initial course of heparin, begin warfarin
at a maintenance dose of 5 mg, and give both anticoagulants in
combination for 7 days.
In patients who develop warfarin-induced skin necrosis, warfarin should be discontinued, vitamin K1 should be given to increase levels of protein C, and full doses of heparin should be administered to achieve a rapid anticoagulant effect. Treatment of patients with warfarin-induced skin necrosis who require anticoagulant therapy for an indefinite period is difficult. These patients can be treated with subcutaneous heparin long term, but this is inconvenient and carries a risk of osteoporosis. It might be safe to reintroduce warfarin in low doses initially in combination with heparin and to use combined treatment for 10 to 14 days, during which time the warfarin dose is gradually increased.373 It should be noted, however, that heparin may not terminate coumarin necrosis,375 376 and some have reported that heparin failed to prevent continuing skin necrosis in homozygous protein C deficiency with very low protein C levels.377 378 379 380
|
Management When Anticoagulants Are Stopped |
|---|
Management of thromboembolism is influenced by the nature of the thromboembolic event, the time during the course of anticoagulant therapy that bleeding occurred, and the INR level during bleeding.
If bleeding occurs in a patient with calf vein thrombosis who has received an adequate course of heparin therapy, then oral anticoagulant therapy can be stopped and replaced with low-dose heparin 5000 U twice daily SC. If bleeding occurs toward the end of a course of anticoagulant therapy (eg, >2 months after starting treatment) in a patient with proximal vein thrombosis, a decision can be made to terminate the course of anticoagulants.
|
Long-term Warfarin Therapy and Elective Surgery |
|---|
Long-term anticoagulation is indicated in patients with a sustained high risk of arterial or venous thromboembolism. Elective surgery in such patients can be difficult. A number of approaches are available, but none have been evaluated in appropriately designed clinical studies. In general, the management choice should take into account the risk of thromboembolism if the patient is left untreated and the risk of bleeding if aggressive perioperative-operative anticoagulation is used.
The least complicated approach is to stop oral anticoagulants and
perform elective surgery when the INR has returned to the normal range.
Oral anticoagulants can then be started postoperatively in combination
with low-dose or full-dose heparin, the choice of heparin
regimens depending on the anticipated risk of postoperative bleeding.
White and associates381 have reported that it takes 4
to 5 days for an INR between 2.0 and 3.0 to return to the normal range
after warfarin is discontinued. Stopping anticoagulants 4 to 5 days
preoperatively is appropriate in patients with atrial fibrillation or
mechanical prosthetic valves because the risk of thrombosis in
untreated patients is <10% per year.382 383 This annual
incidence translates to a risk of thromboembolism of <0.1% over
the 2 or 3 days that patients are without protection. A modification of
this approach, which would further decrease risk, is to delay stopping
warfarin until 2 days before surgery and reverse the anticoagulant
effect with a 1- or 2-mg dose of vitamin K by subcutaneous injection,
repeated if the INR is still prolonged 24 hours after injection. Low
doses of vitamin K1 (1 to 2 mg) have been reported to lower
the INR within 24 hours without producing warfarin resistance when
anticoagulant treatment is reintroduced
postoperatively.384
A more aggressive approach should be considered for patients who are at
high risk of developing postoperative venous thrombosis. These include
patients with a past history of venous thrombosis or recurrent venous
thrombosis, particularly if they have a persistent risk factor for
venous thrombosis. Two treatment options are available for these
high-risk patients. The first is to lower the dose of warfarin and
perform the operation at an INR of 1.5; this approach has been shown
to be safe and effective in preventing postoperative venous thrombosis
in high-risk orthopedic surgical patients.385 The
second option is to stop warfarin and replace the oral anticoagulant
with full-dose heparin by continuous intravenous
infusion preoperatively, stop heparin 6 hours before surgery, and
restart anticoagulant therapy with heparin and warfarin
postoperatively. Postoperative heparin should be delayed for at least
12 hours or longer if there is evidence of excessive bleeding or risk
of serious postoperative bleeding.
|
Approach to Thrombophilia |
|---|
Thrombophilia is defined as an increased tendency to thrombosis. It can be inherited or acquired.386 The term implies that there is an ongoing stimulus to thrombogenesis or a defect of the natural anticoagulant or fibrinolytic mechanism that predisposes the patient to thrombosis or recurrent thrombosis. Thrombophilia is often suspected on clinical grounds because a patient presents with clinical features listed in Table 10
. The most important of
these clinical features are idiopathic thrombosis, a family history of
thrombosis, recurrent thrombosis, thrombosis at a young age, thrombosis
after trivial provocation, and thrombosis in an unusual site. The
spectrum of thrombophilia can range from an increased tendency to
thrombosis, which is easily controlled by anticoagulant therapy, to
progressive and intractable thrombosis, which is resistant to
all forms of therapy. The former manifestations of thrombophilia are
much more common than the latter, which is sometimes seen in malignant
disease.
|
Patients are considered thrombophilic if they have laboratory or
clinical disorders that are known to be associated with an increased
risk of thrombosis. Thrombophilic conditions can be inherited or
acquired (Table 11). The inherited molecular abnormalities
associated with an increased risk of venous thromboembolism are AT-III
deficiency, protein C and protein S deficiencies, dysfibrinogenemia,
and activated protein C resistance.387 388 389 390 391 392 393 394 395 396 Of
these, AT-III deficiency and protein C and protein S deficiency are
seen in 10% of patients with idiopathic venous thrombosis and
dysfibrinogenemia in <0.5%. Thus, until recently only 10% of
patients with clinically suspected thrombophilia had an associated
observable genetic defect. This state of affairs changed dramatically
with the discovery of activated protein C (APC) resistance by
Dahlback and colleagues in 1993.397 These investigators
found that adding APC to plasma obtained from a patient with recurrent
thrombosis failed to prolong aPTT, and the term "APC resistance"
was introduced to describe the abnormality. This laboratory finding was
confirmed by other investigators, who reported that between 20% and
60% of patients with recurrent thrombosis had APC
resistance.398 399 400
|
APC resistance is transmitted in an autosomal dominant
manner.399 The genetic defect underlying many cases of APC
resistance was described in 1994. Most patients with APC resistance
have a mutant factor V molecule (factor V Leiden), which resists
proteolysis by APC when activated to factor Va.401
The genetic defect causing APC resistance is common; it occurs in
5% of normal populations.398 399 Sixty percent of
women in whom thrombosis occurred while they were taking oral
contraceptives have been reported to have APC
resistance.402
Thus, 1 of the 4 inherited disorders (APC resistance, protein C deficiency, protein S deficiency, and AT-III deficiency) is found in at least half of all patients with idiopathic venous thrombosis.
The main acquired factors that predispose a patient to thrombosis are the presence of an anticardiolipin antibody (lupus anticoagulant), malignancy,182 403 and chemotherapy for cancer.182 Less common are paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders, nephrotic syndrome, and hormonal treatment for infertility.404 405 Other inherited laboratory abnormalities for which an association has not been proved are plasminogen deficiency, heparin cofactor II deficiency, increase in histidine-rich acid glycoprotein, and reduced plasminogen activator activity due to either increased levels of plasminogen activator inhibitor or reduced levels of TPA.
In addition, preoperative and postoperative reductions in fibrinolytic activity associated with increased plasminogen activator inhibitor and reduced activity of plasminogen activator have been shown to be associated with an increased risk of postoperative thrombosis.406
Investigation of Thrombophilia
Laboratory testing for inherited AT-III, protein C or protein
S deficiency, and resistance to activated protein C should be
performed when the patient is not being treated with anticoagulants, at
a time remote from the acute thrombotic event, and after excluding the
various acquired disorders known to perturb the levels of some of these
naturally occurring anticoagulants. Whenever possible, the diagnosis of
inherited deficiency should be confirmed by family studies. If
anticoagulant therapy is indicated because of the underlying thrombotic
process, then testing for AT-III deficiency can be done while the
patient is being treated with oral anticoagulants (a low result would
be diagnostic, although an AT-III level in the normal range
would not exclude AT-III deficiency). Assays for protein C and protein
S can be performed while the patient is on high-dose subcutaneous
heparin. Testing for APC resistance with coagulation-based assays
during anticoagulant therapy has been difficult in the past. The
problem can be overcome by using genetic testing for factor V Leiden or
a tissue factor–dependent factor V assay that permits reliable
diagnosis of APC-resistant factor Va in patients receiving
anticoagulant therapy.407
Before labeling the patient as having a deficiency, it is important to repeat the test on several occasions, exclude an underlying acquired abnormality that could produce a falsely low test result, and, if possible, perform studies in family members to confirm the inherited nature of the deficiency. If a laboratory marker of thrombophilia is found, comprehensive family studies should be performed to determine whether other family members have the defect, since asymptomatic carriers should be counseled about the need for prophylaxis when they are exposed to high-risk situations. In addition, female patients with thrombophilia or asymptomatic carriers of AT-III, protein C or protein S deficiency, and those with factor V Leiden require counseling with regard to future pregnancies, oral contraceptives, and postmenopausal estrogen replacement therapy.
Many investigations for an acquired thrombophilic state can be performed at the same time as assays for inherited thrombophilia. The antiphospholipid antibody syndrome should be investigated by both an antiphospholipid antibody test and tests for circulating anticoagulants. Malignancy should be suspected in patients without other detectable causes for venous thrombosis who present with idiopathic venous thrombosis, recurrent venous thrombosis, including recurrent superficial venous thrombosis, and thrombosis in an unusual site such as the portal vein, mesenteric vein, or vena cava. Malignancy should also be suspected in patients who develop recurrent thrombosis despite adequate oral anticoagulant or heparin therapy and in patients with the syndrome of thrombophlebitis migrans. Malignancy is usually suspected on the basis of compatible clinical manifestations, although patients with occult malignancy can present with thrombosis. However, in patients with first-episode typical DVT, without special features of a thrombophilic state, expensive or uncomfortable investigations for malignant disease should not be performed if simple investigations (complete blood count, chest radiograph, and fecal occult blood testing) are negative. If malignancy is suspected, a computed tomography scan of the abdomen and/or an ultrasound of the abdomen and pelvis should be performed. If there is evidence of an iron deficiency anemia or if testing for fecal occult blood is positive, then endoscopy and/or barium studies should be performed to investigate the lower and upper gastrointestinal tract.
Screening for a myeloproliferative disorder is performed by a complete blood count, including a platelet count. Paroxysmal nocturnal hemoglobinuria is suspected from the results of a complete blood count that usually show anemia with evidence of either hemolysis or bone marrow hypoplasia and the diagnosis is confirmed by demonstrating hemoglobinemia, hemoglobinuria, and hemosiderinuria and by performing Ham's test or Hartman's sugar/water test. The nephrotic syndrome is suspected if there is generalized edema, hypoalbuminemia, and proteinuria.
Antiphospholipid Syndrome
Antiphospholipid syndrome can present in a number of
ways.403 Acquired circulating anticoagulants were first
identified in patients with systemic lupus
erythematosus in 1948,408 and an
association with thrombosis was noted 15 years later.409
The phenomenon was called the lupus anticoagulant, but
this anticoagulant is not restricted to patients with systemic
lupus erythematosus.
Antiphospholipid syndrome is diagnosed when patients with a positive assay for antibody against phospholipids have one or more of the following manifestations: venous or arterial thrombosis, thrombocytopenia, or recurrent fetal wastage.403 410 411 412 413 The laboratory tests developed to detect lupus anticoagulants include aPTT,414 kaolin clotting time, dilute phospholipid test, platelet neutralization tests, and tissue thromboplastin inhibition tests415 ; the coexistence of antibodies to cardiolipin has been noted.416 IgG and IgM antibodies to phosphatidylserine, phosphatidylinositol, phosphatidic acid, and cardiolipin were found in subjects with the lupus anticoagulant.417
Both arterial and venous thromboses occur in patients with antiphospholipid syndrome. Thrombosis in unusual sites has been described, including the Budd-Chiari syndrome, portal vein thrombosis, and inferior vena caval thrombosis. Antiphospholipid syndrome has been reported in patients with transient ischemic attacks, multi-infarct dementia, and myocardial infarction410 ; thrombosis of the cerebral, splenic, portal, hepatic, renal, subclavian, and retinal veins and of the inferior vena cava; and coumarin skin necrosis, adrenal gland hemorrhage, and infarction.210 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 Antiphospholipid syndrome may be the cause of cerebral ischemic events in patients.433
Myeloproliferative Syndromes
Myeloproliferative syndromes have been associated with
cerebral or mesenteric venous thrombosis; thrombosis of the splenic
vein, portal vein, and hepatic vein; and a variety of
arterial events, including strokes, myocardial infarction,
vague neurological symptoms, and ischemia of the fingers and
toes.434 435 436 437 438 439 440 441 442 In polycythemia vera, hypercoagulability is
caused by increased viscosity of blood resulting from the increased
hematocrit.443 Treatment with phlebotomy should be aimed
at maintaining the hematocrit in the low-normal range (40% to
45%).443 However, other agents may be needed to lower the
platelet count.
Anagrelide, a quinazolin compound, is a new drug available for the management of thrombocythemia. Silverstein et al444 have accumulated data on more than 500 patients with essential thrombocythemia treated with anagrelide, with a 93% success rate in reducing platelet count to less than 650x109/L. This reduction is associated with parallel relief of symptoms (transient ishemic attacks, venous thrombosis, erythromelalgia) without a significant number of side effects. Fluid retention may be a side effect of its use in some patients, including those with congestive heart failure. Anagrelide may become front-line therapy for thrombocythemic states not only because of its selective efficacy in inhibiting megakaryocyte maturation but because no documented leukemogenic effect has been found after 8 years of use.
Anagrelide will not likely displace two other agents, hydroxyurea and
-interferon, that are effective in treatment of thrombocythemia.
Even though rare cases of leukemia have followed the use of hydroxyurea
in myeloproliferative disorders, the ease and effectiveness of its
low-cost administration continue to make it a valuable agent for
these patients. The cytokine -interferon requires frequent
subcutaneous injection of an expensive agent whose use may be
accompanied by significant side effects. Because the side effects of
interferon are usually manageable and transitory, and because
injections may be decreased from three times weekly to once weekly,
this cytokine should be considered for some patients.
No absolute relation between platelet number and frequency of thrombotic complications has been established in thrombocythemia, but it has been demonstrated that the longer the platelet count is less than 600x109/L, the lower the incidence of thrombotic complications.445 High vascular complication rates in patients >60 years and in patients with a history of a thrombotic event make both of these patient groups candidates for therapeutic intervention. A randomized trial of hydroxyurea has demonstrated a significant reduction in thrombotic events (3.6% versus 24%) in favor of those treated with drug therapy.446 In younger patients with asymptomatic thrombocythemia, therapeutic recommendations should remain conservative.447 Low-dose aspirin appears adequate for most patients.
Trousseau's Syndrome
Most patients with malignancy and thrombosis do not have
Trousseau's syndrome, which refers to a thrombus that is
characteristically migratory and recurrent. Thrombosis occurs in leg
veins, neck veins, superficial veins of the thorax and abdomen, the
dorsal vein of the penis, subclavian and axillary veins, cerebral
veins, and visceral veins.444 445 446 Arterial
thromboses can also occur.447 Thrombosis tends to be
associated with mucinogenic adenocarcinoma.
Treatment of Trousseau's syndrome can be difficult. Coumarin is usually not effective.448 449 Heparin often controls the thromboembolic manifestations and can be given long term on an outpatient basis in full therapeutic doses.448
Management of Thrombophilia
All thrombophilic patients should receive prophylaxis in
high-risk situations, and some require long-term anticoagulant
therapy. Lifelong anticoagulant treatment should be considered for
thrombophilic patients with a documented episode of thrombosis, with or
without a laboratory abnormality, while thrombophilic patients without
documented evidence of thrombosis should receive prophylaxis when
exposed to high-risk situations (eg, surgery, prolonged
immobilization, pregnancy). In patients with polycythemia vera, the
hematocrit and platelet count should be controlled with appropriate
therapy. In addition, female patients with thrombophilia and
asymptomatic carriers of AT-III, protein C or protein S
deficiency, and the factor V gene mutation require counseling about
future pregnancy, use of oral contraceptives, and postmenopausal
estrogen replacement therapy.
Descriptive studies in AT-III deficiency suggest that risk of thrombosis in the unprotected pregnant patient is very high.450 451 While the risk of thrombosis for protein C and protein S deficiencies during pregnancy is lower than for AT-III deficiency, risk of postpartum thrombosis is high in all three groups.451
Three approaches can be used to treat a thrombophilic patient during pregnancy:
- Full-dose heparin by subcutaneous injection every 12 hours for the duration of pregnancy. The dose should be adjusted to maintain the aPTT in a range equivalent to a heparin level of 0.2 to 0.4 U/mL by protamine titration.
- Low-dose heparin 5000 U SC every 12 hours for the duration of pregnancy.
- Frequent surveillance with IPG or duplex ultrasound imaging for the duration of pregnancy.
The first option should be considered for patients who must take oral anticoagulants as long as they live, including those at risk of cardiac embolism; patients with previous venous thrombosis associated with deficiencies of AT-III, protein C, and protein S or with lupus anticoagulant; and any patient with two or more previous episodes of venous thrombosis. The second option should be considered in asymptomatic carriers of AT-III deficiency and patients with previous idiopathic venous thrombosis or thrombosis during an uncomplicated pregnancy. It would be reasonable to consider either the second or third option in asymptomatic carriers of protein C or protein S deficiency and the third option in patients with only one episode of previous venous thrombosis after provocation.
|
|
Footnotes |
|---|
"Management of Deep Vein Thrombosis and Pulmonary Embolism" was approved by the American Heart Association Science Advisory and Coordinating Committee on February 15, 1996.
Requests for reprints should be sent to the Office of Science and Medicine, American Heart Association, 7272 Greenville Ave, Dallas, TX 75231-4596.
|
References |
|---|
1. Hume M, Sevitt S, Thomas DP. Mechanisms of venous thromboembolism. In: Hume M, Sevitt S, Thomas DP, eds. Venous Thrombosis and Pulmonary Embolism. Cambridge, Mass: Harvard University Press; 1970:85-114.
2.
Coon WW, Willis PW III, Keller JB. Venous
thromboembolism and other venous disease in the Tecumseh community
health study. Circulation. 1973;48:839-846.
3. Hull RD, Hirsh J, Carter CJ, Jay RM, Dodd PE, Ockelford PA, Coates G, Gill GJ, Turpie AGG, Doyle DJ, Buller HR, Raskob GE. Pulmonary angiography, ventilation lung scanning, and venography for clinically suspected pulmonary embolism with abnormal perfusion lung scan. Ann Intern Med. 1983;98:891-899.
4. Hull RD, Hirsh J, Carter CJ, Jay RM, Ockelford PA, Buller HR, Turpie AGG, Powers P, Kinch D, Dodd PE, Gill GJ, Leclerc JR, Gent M. Diagnostic efficacy of impedance plethysmography for clinically suspected deep-vein thrombosis: a randomized trial. Ann Intern Med. 1985;102:21-28.
5.
Rubinstein I, Murray D, Hoffstein V. Fatal
pulmonary emboli in hospitalized patients: an autopsy study.
Arch Intern Med. 1988;148:1425-1426.
6. Dalen JE, Alpert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis.. 1975;17:259-270. [Medline] [Order article via Infotrieve]
7. Bell WR, Simon TL. Current status of pulmonary thromboembolic disease: pathophysiology, diagnosis, prevention, and treatment. Am Heart J. 1982;103:239-262. [Medline] [Order article via Infotrieve]
8. Kaunitz AM, Hughes JM, Grimes DA, Smith JC, Rochat RW, Kafrissen ME. Causes of maternal mortality in the United States. Obstet Gynecol. 1985;65:605-612.[Medline] [Order article via Infotrieve]
9. Freiman DG. The structure of thrombi. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Thrombosis and Hemostasis: Basic Principles and Clinical Practice. Philadelphia, Pa: JB Lippincott; 1987:1123-1135.
10. Kakkar VV, Howe CT, Flanc C, Clarke MB. Natural history of postoperative deep vein thrombosis. Lancet. 1969;2:230-232. [Medline] [Order article via Infotrieve]
11.
Nicolaides AN, Kakkar VV, Field ES, Renney JT.
The origin of deep vein thrombosis: a venographic study.
Br J Radiol. 1971;44:653-663.
12. Stamatakis JD, Kakkar VV, Sagar S, Lawrence D, Nairn D, Bentley PG. Femoral vein thrombosis and total hip replacement. Br Med J. 1977;2:223-225.
13. Hirsh J, Genton E. Thrombogenesis. In: Root WS, Hofman FG, eds. Physiological Pharmacology: A Comprehensive Treatise. New York, NY: Academic Press Inc; 1974:99-133.
14. Wessler S, Yin ET. On the mechanism of thrombosis. Prog Hematol. 1969;6:201-232. [Medline] [Order article via Infotrieve]
15. Davies GS, Salzman EW. The pathogenesis of deep vein thrombosis. In: Joist HJ, Sherman LA, eds. Venous and Arterial Thrombosis: Pathogenesis, Diagnosis, Prevention, and Therapy. New York, NY: Grune & Stratton; 1979:1-22.
16. Borgstrom S, Gelin LE, Zenderfeld B. The formation of vein thrombi following tissue injury. Acta Chir Scand Suppl. 1959;247:1-36.
17. Moschos CB, Khan MI, Regan TJ. Thrombogenic properties of blood during early ischemic and nonischemic injury. Am J Physiol. 1971;220:1882-1884.
18. Bjorklid E, Giercksky KE, Prydz H. An immunoradiometric assay for factor III (tissue thromboplastin). Br J Haematol.. 1978;39:445-458. [Medline] [Order article via Infotrieve]
19. Kisiel W, Canfield WM, Ericsson LH, Davie EW. Anticoagulant properties of bovine plasma protein C following activation by thrombin. Biochemistry. 1977;16:5824-5831. [Medline] [Order article via Infotrieve]
20. Harpel PC, Rosenberg RD. Alpha 2-macroglobulin and antithrombin-heparin cofactor: modulators of hemostatic and inflammatory reactions. Prog Hemost Thromb. 1976;3:145-189. [Medline] [Order article via Infotrieve]
21. Rosenberg RD. Hypercoagulability and methods for monitoring anticoagulant therapy. In: Fratantoni J, Wessler S, eds. Prophylactic Therapy of Deep Vein Thrombosis and Pulmonary Embolism Proceedings of a Conference. Bethesda, Md: National Institutes of Health; 1975. US Dept of Health, Education, and Welfare Publication NIH 76-866.
22. Marlar RA, Kleiss AJ, Griffin JH. Human protein C: inactivation of factors V and VIII in plasma by the activated molecule. Ann N Y Acad Sci. 1981;370:303-310. [Medline] [Order article via Infotrieve]
23. Deykin D, Cochios F, DeCamp G, Lopez A. Hepatic removal of activated factor X by the perfused rabbit liver. Am J Physiol. 1968;214:414-419.
24. Lee L. Reticuloendothelial clearance of circulating fibrin in the pathogenesis of the generalized Shwartzman reaction. J Exp Med. 1962;115:1065-1082. [Abstract]
25. Collen D. On the regulation and control of fibrinolysis: Edward Kowalski Memorial Lecture. Thromb Haemost. 1980;43:77-89. [Medline] [Order article via Infotrieve]
26. Gallus AS, Hirsh J. Treatment of venous thromboembolic disease. Semin Thromb Hemost. 1976;2:291-331. [Medline] [Order article via Infotrieve]
27. Browse NL, Thomas ML. Source of non-lethal pulmonary emboli. Lancet. 1974;1:258-259. [Medline] [Order article via Infotrieve]
28. Browse NL, Clemenson G, Croft DN. Fibrinogen-detectable thrombosis in the legs and pulmonary embolism. Br Med J. 1974;1:603-604.
29. Plate G, Ohlin P, Eklof B. Pulmonary embolism in acute iliofemoral venous thrombosis. Br J Surg. 1985;72:912-915. [Medline] [Order article via Infotrieve]
30. Corrigan TP, Fossard DP, Spindler J, Armstrong P, Strachan CJ, Johnston KW, Kakkar VV. Phlebography in the management of pulmonary embolism. Br J Surg. 1974;61:484-488. [Medline] [Order article via Infotrieve]
31.
Shull KC, Nicolaides AN, Fernandes e Fernandes J,
Miles C, Horner J, Needham T, Cooke ED, Eastcott FH.
Significance of popliteal reflux in relation to ambulatory venous
pressure and ulceration. Arch Surg. 1979;114:1304-1306.
32. Kakkar VV, Howe CT, Nicolaides AN, Renney JT, Clarke MB. Deep vein thrombosis of the leg: is there a high risk group? Am J Surg. 1970;120:527-530.[Medline] [Order article via Infotrieve]
33. Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH. The long-term clinical course of acute deep-vein thrombosis. Ann Intern Med. In press.
34. Zilliacus H. On the specific treatment of thrombosis and pulmonary embolism with anticoagulants, with a particular reference to the post thrombotic sequelae. Acta Med Scand. 1946;170:1-221.
35. Huisman MV, Buller HR, ten Cate JW, Vreeken J. Serial impedance plethysmography for suspected deep vein thrombosis in outpatients: the Amsterdam General Practitioner Study. N Engl J Med. 1986;314:823-828. [Abstract]
36. Hull R, Delmore T, Carter C, Hirsh J, Genton E, Gent M, Turpie AGG, McLoughlin D. Adjusted subcutaneous heparin vs warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med. 1982;306:189-194. [Abstract]
37. Hull R, Hirsh J, Jay RM, Carter C, England C, Gent M, Turpie AGG, McLoughlin D, Dodd P, Thomas M, Raskob G, Ockelford P. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med. 1982;307:1676-1681. [Abstract]
38. Hull R, Delmore T, Genton E, Hirsh J, Gent M, Sackett D, McLoughlin D, Armstrong P. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med. 1979;301:855-858. [Abstract]
39. Salzman EW, Deykin D, Shapiro RM, Rosenberg R. Management of heparin therapy: controlled prospective trial. N Engl J Med. 1975;292:1046-1050.[Abstract]
40.
Glazier RL, Crowell EB. Randomized prospective
trial of continuous vs intermittent heparin therapy.
JAMA. 1976;236:1365-1367.
41. Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med. 1972;287:324-327.
42. Prandoni P, Lensing AWA, Buller HR, Carta M, Cogo A, Vigo AM, Casara D, Ruol A, ten Cate JW. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet. 1992;339:441-445. [Medline] [Order article via Infotrieve]
43. Brandjes DPM, Heijboer H, de Rijk M, Jagt J, Buller HR, ten Cate JW, Huisman MV. The effect of graded compression stockings on the development of the post-thrombotic syndrome in patients with proximal deep-vein thrombosis. Thromb Haemost. 1991;65(suppl):1131. Abstract.
44. Prandoni P, Lensing AWA, Buller HR, Cogo A, Prins MH, Cattelan AM, Cuppini S, Noventa F, ten Cate JW. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med. 1992;327:1128-1133.[Abstract]
45.
Hirsh J. The optimal duration of anticoagulant
therapy for venous thrombosis. N Engl J
Med. 1995;332:1710-1711.
46. Levine MN, Hirsh J, Gent M, Turpie AGG, Weitz J, Ginsberg J, Geerts W, Leclerc J, Neemeh J, Powers P, Piovella F. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost. 1995;74:606-611. [Medline] [Order article via Infotrieve]
47. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet. 1992;340:873-876. [Medline] [Order article via Infotrieve]
48.
Hull RD, Carter CJ, Jay RM, Ockelford PA, Hirsh J,
Turpie AGG, Zielinsky A, Gent M, Powers PJ. The diagnosis of
acute, recurrent, deep-vein thrombosis: a diagnostic
challenge. Circulation. 1983;67:901-906.
49. O'Donnell TF, Browse NL, Burnand KG, et al. The socioeconomic effects of iliofemoral venous thrombosis. J Surg Res. 1977;22:483-488. [Medline] [Order article via Infotrieve]
50. Cockett FB, Thomas ML, Negus D. Iliac vein compression: its relation to iliofemoral thrombosis and the post-thrombotic syndrome. Br Med J. 1967;2:14-19.
51. Negus D. The post-thrombotic syndrome. Ann R Coll Surg Engl.. 1970;47:92-105. [Medline] [Order article via Infotrieve]
52. Jay R, Hull R, Carter C, Ockelford P, Buller H, Turpie AGG, Hirsh J. Outcome of abnormal impedance plethysmography results in patients with proximal-vein thrombosis: frequency of return to normal. Thromb Res. 1984;36:259-263. [Medline] [Order article via Infotrieve]
53.
Strandness DE Jr, Langlois T, Cramer M, Randlett A,
Thiele BL. Long-term sequelae of acute venous
thrombosis. JAMA. 1983;250:1289-1292.
54. Gjores JE. The incidence of venous thrombosis and its sequelae in certain districts in Sweden. Acta Chir Scand. 1956;206:11-88.
55. Lensing AWA, Hirsh J. Rationale and results of thrombolytic therapy for deep vein thrombosis. In: Bernstein EF, ed. Vascular Diagnosis. St Louis, Mo: Mosby-Year Book, Inc; 1993:875-879.
56. da Silva A, Widmer LK, Martin H, Mall T, Glaus L, Schneider M. Varicose veins and chronic venous insufficiency. Vasa. 1974;3:118-125. [Medline] [Order article via Infotrieve]
57.
Ginsberg JS, Shin A, Turpie AGG, Hirsh J.
Detection of previous proximal venous thrombosis with Doppler
ultrasonography and photoplethysmography. Arch Intern
Med.. 1989;149:2255-2257.
58. Fernandes JF, Horner J, Needham T, Nicolaides A. Ambulatory calf volume plethysmography in the assessment of venous insufficiency. Br J Surg. 1979;66:327-330. [Medline] [Order article via Infotrieve]
59. Li J-M, Anderson FA, Wheeler HB. Noninvasive testing for venous reflux using photoplethysmography: standardization of technique and evaluation of interpretation criteria. Bruit. 1983;7:25.
60. Gallus AS, Salzman EW, Hirsh J. Prevention of venous thromboembolism. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Haemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd ed. Philadelphia, Pa: JB Lippincott; 1994:1331-1345.
61. Salzman EW, Davies GC. Prophylaxis of venous thromboembolism: analysis of cost effectiveness. Ann Surg. 1980;191:207-218. [Medline] [Order article via Infotrieve]
62. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin: overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med. 1988;318:1162-1173. [Medline] [Order article via Infotrieve]
63. Leyvraz PF, Richard J, Bachmann F, Van Melle G, Treyvaud JM, Livio JJ, Candardjis G. Adjusted versus fixed-dose subcutaneous heparin in the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med. 1983;309:954-958. [Abstract]
64.
Turpie AGG, Hirsh J, Gent M, Julian D, Johnson
J. Prevention of deep vein thrombosis in potential neurosurgical
patients: a randomized trial comparing graduated compression stockings
alone or graduated compression stockings plus intermittent pneumatic
compression with control. Arch Intern Med. 1989;149:679-681.
65.
Hirsh J, Levine MN. Low molecular weight
heparin. Blood. 1992;79:1-77.
66.
Anderson DR, O'Brien BJ, Levine MN, Roberts R, Wells
PS, Hirsh J. Efficacy and cost of low-molecular-weight
heparin compared with standard heparin for the prevention of deep vein
thrombosis after total hip arthroplasty. Ann Intern
Med. 1993;119:1105-1112.
67. Hull R, Delmore TJ, Hirsh J, Gent M, Armstrong P, Lofthouse R, MacMillan A, Blackstone I, Reed-Davis R, Detwiler RC. Effectiveness of intermittent pulsatile elastic stockings for the prevention of calf and thigh vein thrombosis in patients undergoing elective knee surgery. Thromb Res. 1979;16:37-45. [Medline] [Order article via Infotrieve]
68. Wille-Jorgensen P, Thorup J, Fischer A, Holst-Christensen J, Flamsholt R. Heparin with and without graded compression stockings in the prevention of thromboembolic complications of major abdominal surgery: a randomized trial. Br J Surg. 1985;72:579-581. [Medline] [Order article via Infotrieve]
69. Wille-Jorgensen P, Christense BW, Bjerg-Nielsen A, Stadeager C, Kjaer L. Prevention of thromboembolism following elective hip surgery: the value of regional anesthesia and graded compression stockings. Clin Orthop. 1989;247:163-167.
70.
Powers PJ, Gent M, Jay RM, Julian DH, Turpie AGG,
Levine M, Hirsh J. A randomized trial of less intense
postoperative warfarin or aspirin therapy in the prevention of venous
thromboembolism after surgery for fractured hip. Arch
Intern Med. 1989;149:771-774.
71. Leyvraz PF, Bachmann F, Hoek J, Buller HR, Postel M, Samama M. Prevention of deep vein thrombosis after hip replacement: randomised comparison between unfractionated heparin and low molecular weight heparin. BMJ. 1991;303:543-548.
72.
Hull RD, Raskob GE, Pineo G, Rosenbloom D, Evans W,
Mallory T, Anquist K, Smith F, Hughes G, Green D, Elliott G, Panju A,
Brant R. A comparison of subcutaneous
low-molecular-weight heparin with warfarin sodium for
prophylaxis against deep-vein thrombosis after hip or knee
implantation. N Engl J Med. 1993;329:1370-1376.
73. McLachlin J, Richards T, Paterson JC. An evaluation of clinical signs in the diagnosis of venous thrombosis. Arch Surg. 1962;85:738-744.
74. Haeger K. Problems of acute deep venous thrombosis, I: the interpretation of signs and symptoms. Angiology. 1969;20:219-223.
75. Johnston KW, Kakkar VV. Plethysmographic diagnosis of deep vein thrombosis. Surg Gynecol Obstet. 1974;139:41-44. [Medline] [Order article via Infotrieve]
76. Hull RD, Raskob GE, LeClerc JR, Jay RM, Hirsh J. The diagnosis of clinically suspected venous thrombosis. Clin Chest Med. 1984;5:439-456. [Medline] [Order article via Infotrieve]
77. Büller HR, Lensing AWA, Hirsh J, ten Cate JW. Deep venous thrombosis: new noninvasive tests. Thromb Haemost. 1991;66:133-137. [Medline] [Order article via Infotrieve]
78.
Cogo A, Lensing AWA, Prandoni P, Hirsh J.
Distribution of thrombosis in patients with deep-vein thrombosis:
implications for simplifying the diagnostic process with compression
ultrasound. Arch Intern Med. 1993;153:2777-2780.
79.
Hull RD, Hirsh J, Sackett DL, Taylor DW, Carter C,
Turpie AGG, Powers P, Gent M. Clinical validity of a negative
venogram in patients with clinically suspected venous
thrombosis. Circulation. 1981;64:622-625.
80. Wells PS, Hirsh J, Anderson DR, Lensing AWA, Foster G, Kearon C, Weitz J, D'Ovidio R, Cogo A, Prandoni P, Girolami A, Ginsberg JS. Accuracy of clnical assessment of deep-vein thrombosis. Lancet. 1995;345:1326-1330. [Medline] [Order article via Infotrieve]
81.
Thomas ML. Phlebography. Arch
Surg. 1972;104:145-151.
82.
Rabinov K, Paulin S. Roentgen diagnosis of
venous thrombosis in the leg. Arch Surg. 1972;104:134-144.
83. Lensing AWA, Buller HR, Prandoni P, Batchelor D, Molenaar AH, Cogo A, Vigo M, Huisman PM, ten Cate JW. Contrast venography, the gold standard for the diagnosis of deep-vein thrombosis: improvement in observer agreement. Thromb Haemost. 1992;67:8-12. [Medline] [Order article via Infotrieve]
84.
Hull R, van Aken WG, Hirsh J, Gallus AS, Hoicka G,
Turpie AGG, Walker I, Gent M. Impedance plethysmography using
the occlusive cuff technique in the diagnosis of venous
thrombosis. Circulation. 1976;53:696-700.
85.
Huisman MV, Buller HR, ten Cate JW, Heijermans HSF,
van der Laan J, van Maanen DJ. Management of clinically
suspected acute venous thrombosis in outpatients with serial impedance
plethysmography in a community hospital setting. Arch
Intern Med. 1989;149:511-513.
86. Wheeler HB, O'Donnell JA, Anderson FA Jr, Penney BC, Peura RA, Benedict C Jr. Bedside screening for venous thrombosis using occlusive impedance phlebography. Angiology. 1975;26:199-210.
87.
Wheeler HB, Pearson D, O'Connell D, Mullick
SC. Impedance phlebography: technique, interpretation, and
results. Arch Surg. 1972;104:164-169.
88. Peters SHA, Jonker JJC, de Boer AC, den Ottolander GJ. Home-diagnosis of deep venous thrombosis with impedance plethysmography. Thromb Haemost. 1982;48:297-300. [Medline] [Order article via Infotrieve]
89.
Wheeler HB, Anderson FA Jr, Cardullo PA, Patwardhan
NA, Jian-Ming L, Cutler BS. Suspected deep-vein thrombosis:
management by impedance plethysmography. Arch Surg. 1982;117:1206-1209.
90. Hull RD, Raskob GE, Carter CJ. Serial impedance plethysmography in pregnant patients with clinically suspected deep-vein thrombosis: clinical validity of negative findings. Ann Intern Med. 1990;112:663-667.
91.
Foley WD, Middleton WD, Lawson TL, Erickson S, Quiroz
FA, Macrander S. Color Doppler ultrasound imaging of
lower-extremity venous disease. AJR Am J
Roentgenol.. 1989;152:371-376.
92.
Rose SC, Zwiebel WJ, Nelson BD, Priest DL, Knighton
RA, Brown JW, Lawrence PF, Stults BM, Reading JC, Miller FJ.
Symptomatic lower extremity deep venous thrombosis: accuracy,
limitations, and role of color duplex flow imaging in
diagnosis. Radiology. 1990;175:639-644.
93. Baxter GM, McKechnie S, Duffy P. Colour Doppler ultrasound in deep venous thrombosis: a comparison with venography. Clin Radiol.. 1990;42:32-36. [Medline] [Order article via Infotrieve]
94.
Raghavendra BN, Rosen RJ, Lam S, Riles T, Horii
SC. Deep venous thrombosis: detection by high-resolution
real-time ultrasonography. Radiology. 1984;152:789-793.
95. Elias A, Le Corff G, Bouvier JL, Benichou M, Serradimgni A. Value of real time B mode ultrasound imaging in the diagnosis of deep vein thrombosis of the lower limbs. Int Angiol. 1987;6:175-182. [Medline] [Order article via Infotrieve]
96.
Vogel P, Laing FC, Jeffrey RB Jr, Wing VW.
Deep venous thrombosis of the lower extremity: US evaluation.
Radiology. 1987;163:747-751.
97.
Cronan JJ, Dorfman GS, Scola FH, Schepps B, Alexander
J. Deep venous thrombosis: US assessment using vein
compression. Radiology. 1987;162:191-194.
98. Monreal M, Montserrat E, Salvador R, Bechini J, Donoso L, MaCallejas J, Foz M. Real-time ultrasound for diagnosis of symptomatic venous thrombosis and for screening of patients at risk: correlation with ascending conventional venography. Angiology. 1989;40:527-533.
99. Lensing AWA, Prandoni P, Brandjes D, Huisman PM, Vigo M, Tomasella G, Krekt J, ten Cate JW, Huisman MV, Buller HR. Detection of deep-vein thrombosis by real-time B-mode ultrasonography. N Engl J Med. 1989;320:342-345. [Abstract]
100. Comerota AJ, Katz ML, Greenwald LL, Leefmans E, Czeredarczuk M, White JV. Venous duplex imaging: should it replace hemodynamic tests for deep venous thrombosis. J Vasc Surg. 1990;11:53-61. [Medline] [Order article via Infotrieve]
101. Habscheid W, Hohmann M, Wilhelm T, Epping J. Real-time ultrasound in the diagnosis of acute deep venous thrombosis of the lower extremity. Angiology. 1990;41:599-608.
102. Dauzat MM, Laroche JP, Charras C, Blin B, Domingo-Faye MM, Sainte-Luce P, Domergue A, Lopez FM, Janbon C. Real-time B-mode ultrasonography for better specificity in the noninvasive diagnosis of deep venous thrombosis. J Ultrasound Med. 1986;5:625-631. [Abstract]
103. Schindler JM, Kaiser M, Gerber A, Vuilliomenet A, Popovic A, Bertel O. Colour coded duplex sonography in suspected deep vein thrombosis of the leg. BMJ. 1990;301:1369-1370.
104.
Persson AV, Jones C, Zide R, Jewell ER. Use of
the triplex scanner in diagnosis of deep venous thrombosis.
Arch Surg. 1989;124:593-596.
105. Sumner DS, Londrey GL, Spadone DP, Hodgson KJ, Leutz DW, Stauffer ES. Study of deep venous thrombosis in high-risk patients using color flow Doppler. In: Bergan JJ, Yao JST, eds. Venous Disorders. Philadelphia, Pa: WB Saunders; 1991:63-76.
106.
Wells PS, Brill-Edwards P, Stevens P, Panju A, Patel
A, Douketis J, Massicotte MP, Hirsh J, Weitz JI, Kearon C, et al. A
novel and rapid whole-blood assay for D-dimer in patients with
clinically suspected deep vein thrombosis.
Circulation. 1995;91:2184-2187.
107. Mattos MA, Londrey GL, Leutz DW, Hodgson KJ, Ramsey DE, Barkmeier LD, Stauffer ES, Spadone DP, Sumner DS. Color-flow duplex scanning for the surveillance and diagnosis of acute deep venous thrombosis. J Vasc Surg. 1992;15:366-375. [Medline] [Order article via Infotrieve]
108. Prandoni P, Lensing AWA, Buller HR, Carta M, Vigo M, Cogo A, Cuppini S, ten Cate JW. Failure of computerized impedance plethsmography in the diagnostic management of patients with clinically suspected deep vein thrombosis. Thromb Haemost. 1991;65:233-236. [Medline] [Order article via Infotrieve]
109. Hirsh J. Reliability of non-invasive tests for the diagnosis of deep vein thrombosis. Thromb Haemost. 1991;65:221-222. [Medline] [Order article via Infotrieve]
110.
Anderson DR, Lensing AWA, Wells PS, Levine MN, Weitz
JI, Hirsh J. Limitations of impedance plethysmography in the
diagnosis of clinically suspected deep-vein thrombosis.
Ann Intern Med. 1993;118:25-30.
111. Heijboer H, Brandjes D, Lensing AWA, Buller HR, ten Cate JW. Efficacy of real-time B-mode ultrasonography versus impedance plethysmography in the diagnosis of deep vein thrombosis in symptomatic outpatients. Thromb Haemost. 1991;65:804. Abstract.
112. Prandoni P, Cogo A, Bernardi E, Villalta S, Polistena P, Simioni P, Noventa F, Benedetti L, Girolami A. A simple ultrasound approach for detection of recurrent proximal-vein thrombosis. Circulation. 1993;88(pt 1):1730-1735.
113.
Huisman MV, Büller HR, ten Cate JW.
Utility of impedance plethysmography in the diagnosis of recurrent
deep-vein thrombosis. Arch Intern Med. 1988;148:681-683.
114. Prandoni P, Lensing AWA, Carta M, Cogo A, Villalta S, Ruol A. Elastic compression stockings and the postphlebitic syndrome: an interim analysis of a prospective cohort study in patients with proximal vein thrombosis. Thromb Haemost. 1991;65:1579. Abstract.
115. Common HH, Seaman AJ, Rosch J, Porter CT, Dotter CT. Deep vein thrombosis treated with streptokinase or heparin: follow-up of a randomized study. Angiology. 1976;27:645-654.
116. Strandness DE Jr, Langlois Y, Cramer M, Randlett A, Thiele BL. Long-term sequelae of acute venous thrombosis. JAMA. 1983;250:1289-1292.
117. Cronan JJ, Leen V. Recurrent deep venous thrombosis: limitations of US. Radiology. 1989;170(pt 1):739-742.
118. Heijboer H, Jongbloets LMM, Buller HR, Lensing AW, ten Cate JW. Clinical utility of real-time compression ultrasonography for diagnostic management of patients with recurrent venous thrombosis. Acta Radiol Scand. 1992;33:297-300.
119.
Hull RD, Raskob GE, Carter CJ, Coates G, Gill GJ,
Sackett DL, Hirsh J, Thompson M. Pulmonary embolism in
outpatients with pleuritic chest pain. Arch Intern
Med. 1988;148:838-844.
120. The urokinase pulmonary embolism trial: a national cooperative study. Circulation. 1973;47(suppl 2):1-108.
121. Bell WR, Simon TL, DeMets DL. The clinical features of submassive and massive pulmonary emboli. Am J Med. 1977;62:355-360. [Medline] [Order article via Infotrieve]
122.
Hull RD, Hirsh J, Carter CJ, Raskob GE, Gill GJ, Jay
RM, Leclerc JR, David M, Coates G. Diagnostic value of
ventilation-perfusion lung scanning in patients with suspected
pulmonary embolism. Chest. 1985;88:819-828.
123. Stein PD, Willis PW III, DeMets DL. History and physical examination in acute pulmonary embolism in patients without preexisting cardiac or pulmonary disease. Am J Cardiol. 1981;47:218-223. [Medline] [Order article via Infotrieve]
124. Dalen JE, Grossman W. Profiles in pulmonary embolism. In: Grossman W, ed. Cardiac Catheterization and Angiography. Philadelphia, Pa: Lea & Febiger; 1980:336-345.
125. Bell WR, Simon TL. A comparative analysis of pulmonary perfusion scans with pulmonary angiograms. Am Heart J. 1976;92:700-706. [Medline] [Order article via Infotrieve]
126.
The PIOPED Investigators. Value of the
ventilation/perfusion scan in acute pulmonary embolism: results of the
prospective investigation of pulmonary embolism diagnosis (PIOPED).
JAMA. 1990;263:2753-2759.
127. Bookstein JJ, Silver TM. The angiographic differential diagnosis of acute pulmonary embolism. Radiology. 1974;110:25-33. [Medline] [Order article via Infotrieve]
128. Novelline RA, Baltarowich OH, Athanasoulis CA, Waltman AC, Greenfield AJ, McKusick KA. The clinical course of patients with suspected pulmonary embolism and a negative pulmonary arteriogram. Radiology. 1978;126:561-567. [Abstract]
129. Bookstein JJ. Segmental arteriography by pulmonary embolism. Radiology. 1969;93:1007-1012. [Medline] [Order article via Infotrieve]
130. Grollman JH Jr, Gyepes MT, Helmer E. Transfemoral selective bilateral pulmonary arteriography with a pulmonary-artery-seeking catheter. Radiology. 1970;96:202-204. [Medline] [Order article via Infotrieve]
131. Meyerovitz MF, Levin DC, Harrington DP, Boxt LM, Bettmann MA, Garnic JD, Barry WH, Geller SC. Evaluation of optimized biplane pulmonary cineangiography. Invest Radiol. 1985;20:945-949. [Medline] [Order article via Infotrieve]
132.
Stein PD, Athanasoulis C, Alavi A, Greenspan RH, Hales
CA, Salzman HA, Vreim CE, Terrin ML, Weg JG. Complications and
validity of pulmonary angiography in acute pulmonary embolism.
Circulation. 1982;85:462-468.
133.
Hull RD, Raskob GE, Coates G, Panju AA.
Clinical validity of a normal perfusion lung scan in patients with
suspected pulmonary embolism. Chest. 1990;97:23-26.
134.
Kipper MS, Moser KM, Kortman KE, Ashburn WL.
Longterm follow-up of patients with suspected pulmonary embolism
and a normal lung scan: perfusion scans in embolic suspects.
Chest. 1982;82:411-415.
135. Szucs MM Jr, Brooks HL, Grossman W, Banas JS Jr, Meister G, Dexter L, Dalen JE. Diagnostic sensitivity of laboratory findings in acute pulmonary embolism. Ann Intern Med. 1971;74:161-166.
136. Weber DM, Phillips JH Jr. A re-evaluation of electrocardiographic changes accompanying acute pulmonary embolism. Am J Med Sci. 1966;251:381-398. [Medline] [Order article via Infotrieve]
137.
McNeil BJ. Ventilation-perfusion studies
and the diagnosis of pulmonary embolism: concise communication.
J Nucl Med. 1980;21:319-323.
138. Biello DR, Mattar AG, McKnight RC, Siegel BA. Ventilation-perfusion studies in suspected pulmonary embolism. AJR Am J Roentgenol. 1979;133:1033-1037. [Abstract]
139. Alderson PO, Rujanavech N, Sicker-Walker RH, McKnight RC. The role of 133Xe ventilation studies in the scintigraphic detection of pulmonary embolism. Radiology. 1976;120:633-640. [Abstract]
140. Cheely R, McCartney WH, Perry JR, Delany DJ, Bustad L, Wynia VH, Griggs TR. The role of noninvasive tests versus pulmonary angiography in the diagnosis of pulmonary embolism. Am J Med. 1981;70:17-22. [Medline] [Order article via Infotrieve]
141. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest. 1990;86:385-391.
142. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet. 1960;1:1309-1312. [Medline] [Order article via Infotrieve]
143. Hull R, Delmore T, Genton E, Hirsh J, Gent M, Sackett D, McLoughlin D, Armstrong P. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med. 1979;301:855-858.
144. Brandjes DPM, Heijboer H, Buller HR, de Rijk M, Jagt H, ten Cate JW. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1992;327:1485-1489. [Abstract]
145. Lagerstedt CI, Olsson CG, Fagher BO, Oqvist BW, Albrechtsson U. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet. 1985;2:515-518. [Medline] [Order article via Infotrieve]
146.
Cruickshank MK, Levine MN, Hirsh J, Roberts R,
Siquenza M. A standard heparin nomogram for the management of
heparin therapy. Arch Intern Med. 1991;151:333-337.
147. Hirsh J. Heparin. N Engl J Med. 1991;324:1565-1574. [Medline] [Order article via Infotrieve]
148. Pini M, Pattachini C, Quintavalla R, Poli T, Megha A, Tagliaferri A, Manotti C, Dettori AG. Subcutaneous vs intravenous heparin in the treatment of deep venous thrombosis: a randomized clinical trial. Thromb Haemost. 1990;64:222-226. [Medline] [Order article via Infotrieve]
149.
Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas
S. The weight-based heparin dosing nomogram compared with a
standard care nomogram: a randomized controlled trial.
Ann Intern Med. 1993;119:874-881.
150. Gallus A, Jackaman J, Tillett J, Mills W, Wycherley A. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet. 1986;2:1293-1296. [Medline] [Order article via Infotrieve]
151. Hull RD, Raskob GE, Rosenbloom D, Panju AA, Brill-Edwads P, Ginsberg JS, Hirsh J, Martin GJ, Green D. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med. 1990;322:1260-1264. [Abstract]
152.
Chiu HM, Hirsh J, Yung WL, Regoeczi E, Gent M.
Relationship between the anticoagulant and antithrombotic effects of
heparin in experimental venous thrombosis. Blood. 1977;49:171-184.
153. Hull RD, Raskob GE, Hirsh J, Jay RM, Leclerc JR, Geerts WH, Rosenbloom D, Sackett DL, Anderson C, Harrison L, Gent M. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1986;315:1109-1114. [Abstract]
154. Bjornsson JD, Nash PV. Variability in heparin sensitivity of aPTT reagents. Am J Clin Pathol. 1986;86:199-204. [Medline] [Order article via Infotrieve]
155.
Hirsh J, van Aken WG, Gallus AS, Dollery CT, Cade JF,
Yung WL. Heparin kinetics in venous thrombosis and pulmonary
embolism. Circulation. 1976;53:691-695.
156. Young E, Prins M, Levine MN, Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparin resistance. Thromb Haemost. 1992;67:639-643. [Medline] [Order article via Infotrieve]
157. Young E, Cosmi B, Weitz J, Hirsh J. Comparison of the non-specific binding of unfractionated heparin and low molecular weight heparin to plasma proteins. Thromb Haemost. 1993;70:625-630. [Medline] [Order article via Infotrieve]
158.
Levine MN, Hirsh J, Gent M, Turpie AGG, Cruickshank M,
Weitz J, Anderson D, Johnston M. A randomized trial comparing
the activated thromboplastin time with heparin assay in patients with
acute venous thromboembolism requiring large daily doses of
heparin. Arch Intern Med. 1994;154:49-56.
159.
Brill-Edwards P, Ginsberg JS, Johnston M, Hirsh
J. Establishing a therapeutic range for heparin therapy.
Ann Intern Med. 1993;119:104-109.
160. Doyle DJ, Turpie AGG, Hirsh J, Best C, Kinch D, Levine MN, Gent M. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial. Ann Intern Med. 1987;107:441-445.
161. Bentley PG, Kakkar VV, Scully MF, MacGregor IR, Webb P, Chan P, Jones N. An objective study of alternative methods of heparin administration. Thromb Res. 1980;18:177-187. [Medline] [Order article via Infotrieve]
162. Andersson G, Fagrell B, Holmgren K, Johnsson H, Ljungberg B, Nilsson E, Wilhelmsson S, Zetterquist S. Subcutaneous administration of heparin: a randomised comparison with intravenous administration of heparin to patients with deep-vein thrombosis. Thromb Res. 1982;27:631-639.[Medline] [Order article via Infotrieve]
163. Walker MG, Shaw JW, Thomson GJL, Cumming JGR, Thomas ML. Subcutaneous calcium heparin versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective randomised trial. Br J Med (Clin Res Ed). 1987;294:1189-1192.
164. Monreal M, Lafoz E, Olive A, del Rio L, Vedia C. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin. Thromb Haemost. 1994;71:7-11. [Medline] [Order article via Infotrieve]
165. Ginsberg JS, Hirsh J, Turner DC, Levine MN, Burrows R. Risk to the fetus of anticoagulant therapy during pregnancy. Thromb Haemost. 1989;61:197-203. [Medline] [Order article via Infotrieve]
166. Forestier F, Daffos F, Capella-Pavolvsky M. Low molecular weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy: study by direct fetal blood sampling under ultrasound. Thromb Res. 1984;34:557-560. [Medline] [Order article via Infotrieve]
167. Forestier F, Daffos F, Rainaut M, Toulemonde F. Low molecular weight heparin (CY 216) does not cross the placenta during the third trimester of pregnancy. Thromb Haemost. 1987;57:234. Letter. [Medline] [Order article via Infotrieve]
168. Omri A, Delaloye JF, Andersen H, Bachmann F. Low molecular weight heparin Novo (LHN-1) does not cross the placenta during the second trimester of pregnancy. Thromb Haemost. 1989;61:55-56. [Medline] [Order article via Infotrieve]
169. Melissari E, Das S, Kanthou C, Pemberton KD, Kakkar VV. The use of LMW heparin in treating thromboembolism during pregnancy and prevention of osteoporosis. Thromb Haemost. 1991;65:926. Abstract.
170.
Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts
RS, Gent M, Kelton JG. Heparin-induced thrombocytopenia in
patients treated with low-molecular-weight heparin or
unfractionated heparin. N Engl J Med. 1995;332:1330-1335.
171.
Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ,
Hughes GRV. The management of thrombosis in the
antiphospholipid-antibody syndrome. N Engl
J Med. 1995;332:993-997.
172.
Violi F, Ferro D, Valesini G. Thrombosis in the
antiphospholipid antibody syndrome. N Engl
J Med. 1995;333:665. Letter.
173.
Derksen RHWM, de Groot PG, Kater L, Nieuwenhuis
HK. Patients with antiphospholipid antibodies and venous
thrombosis should receive long term anticoagulant treatment.
Ann Rheum Dis. 1993;52:689-692.
174.
Ginsberg JS, Wells PS, Brill-Edwards P, Donovan D,
Moffatt K, Johnston M, Stevens P, Hirsh J. Antiphospholipid
antibodies and venous thromboembolism. Blood. 1995;86:3685-3691.
175. Wessler S, Gitel SN. Warfarin: from bedside to bench. N Engl J Med. 1984;311:645-652. [Medline] [Order article via Infotrieve]
176. Zivelin A, Rao LV, Rapaport SI. Mechanism of the anticoagulant effect of warfarin as evaluated in rabbits by selective depression of individual procoagulant vitamin K-dependent clotting factors. J Clin Invest. 1993;92:2131-2140.
177. O'Sullivan EF. Duration of anticoagulant therapy in venous thromboembolism. Med J Aust. 1972;2:1104-1107. [Medline] [Order article via Infotrieve]
178. Schulman S, Lockner D, Juhlin-Dannfelt A. The duration of oral anticoagulation after deep vein thrombosis: a randomized study. Acta Med Scand.. 1985;217:547-552. [Medline] [Order article via Infotrieve]
179. Holmgren K, Andersson G, Fagrell B, Johnsson H, Ljungberg B, Nilsson E, Wilhelmsson S, Zetterquist S. One-month versus six-month therapy with oral anticoagulants after symptomatic deep vein thrombosis. Acta Med Scand. 1985;218:279-284. [Medline] [Order article via Infotrieve]
180. Prandoni P, Lensing AWA, Buller HR, Cogo A, Prins MH, Cattelan AM, Cuppini S, Noventa F, ten Cate JW. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med. 1992;327:1128-1133.
181.
Schulman S, Rhedin AS, Lindmarker P, Carlsson A,
Lators G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H, et al.
A comparison of six weeks with six months of oral anticoagulation after
a first episode of venous thromboembolism: Duration of Anticoagulation
Trial Study Group. N Engl J Med. 1995;332:1661-1665.
182. Levine MN, Gent M, Hirsh J, Arnold A, Goodyear MD, Hryniuk W, De Pauw S. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med. 1988;318:404-407. [Abstract]
183. Goldhaber SZ, Buring JE, Lipnick RJ, Hennekens CH. Pooled analyses of randomized trials of streptokinase and heparin in phlebographically documented acute deep venous thrombosis. Am J Med. 1984;76:393-397. [Medline] [Order article via Infotrieve]
184. Tibbutt DA, Davies JA, Anderson JA, Fletcher EWL, Hamill J, Holt JM, Thomas ML, Lee GDJ, Miller GAH, Sharp AA, Sutton GC. Comparison by controlled clinical trial of streptokinase and heparin in treatment of life-threatening pulmonary embolism. Br Med J. 1974;1:343-347.
185. Miller GAH, Sutton GC, Kerr IH, Gibson RV, Honey M. Comparison of streptokinase and heparin in the treatment of isolated acute massive pulmonary embolism. Br Med J. 1971;2:681-684.
186. Anderson DR, Levine MN. Thrombolytic therapy for the treatment of acute pulmonary embolism. Can Med Assoc J. 1992;146:1317-1324. [Abstract]
187. Elliot MS, Immelman EJ, Jeffery P, Benatar SR, Funston MR, Smith JA, Shepstone BJ, Ferguson AD, Jacobs P, Walker W, Louw JH. A comparative randomized trial of heparin versus streptokinase in the treatment of acute proximal vein thrombosis: an interim report of a prospective trial. Br J Surg. 1979;66:838-843. [Medline] [Order article via Infotrieve]
188. Coon WW. Operative therapy of venous thromboembolism. Mod Concepts Cardiovasc Dis. 1974;43:71-75. [Medline] [Order article via Infotrieve]
189. Mobin-Uddin K, Callard GM, Bolooki H, Rubinson R, Michie D, Jude JR. Transvenous caval interruption with an umbrella filter. N Engl J Med. 1972;286:55-58.
190. Mobin-Uddin K. The intracaval umbrella in prevention of pulmonary embolism. In: Bergan JJ, Yao JST, eds. Venous Problems. Chicago, Ill: Year Book Medical Publishers Inc; 1978:333-346.
191.
Wingerd M, Bernhard VM, Maddison F, Towne JB.
Comparison of caval filters in the management of venous
thromboembolism. Arch Surg. 1978;113:1264-1271.
192. Adelson J, Steer ML, Glotzer DJ, Skillman JJ, Simon M, Salzman EW. Thromboembolism after insertion of the Mobin-Uddin caval filter. Surgery. 1980;87:184-189. [Medline] [Order article via Infotrieve]
193. Schroeder TM, Elkins RC, Greenfield LJ. Entrapment of sized emboli by the KMA-Greenfield intracaval filter. Surgery. 1978;83:435-439. [Medline] [Order article via Infotrieve]
194. Magnant JG, Walsh DB, Juravsky LI, Cronenwett JL. Current use of inferior vena cava filters. J Vasc Surg. 1992;16:701-706. [Medline] [Order article via Infotrieve]
195. Roehm JO Jr. The bird's nest filter: a new percutaneous transcatheter inferior vena cava filter. J Vasc Surg. 1984;1:498-501. [Medline] [Order article via Infotrieve]
196.
Hunter JA, Sessions R, Petasnick J. Therapeutic
balloon occlusion of the inferior vena cava. JAMA. 1975;234:1034-1037.
197. Moser KM, Harsany PG, Harvey-Smith W, Durante PL, Guisan M. Reversible interruption of inferior vena cava by means of a balloon catheter: preliminary report. J Thorac Cardiovasc Surg. 1971;62:205-212. [Medline] [Order article via Infotrieve]
198. Hunter JA, DeLaria GA, Goldin MD, Serry C, Monson DO, DaValle MJ, Najafi H. Inferior vena cava interruption with the Hunter-Sessions balloon: eighteen years' experience in 191 cases. J Vasc Surg. 1989;10:450-456. [Medline] [Order article via Infotrieve]
199. Lansing AM, Davis WM. Five-year follow-up study of iliofemoral venous thrombectomy. Ann Surg. 1968;168:620-628. [Medline] [Order article via Infotrieve]
200. Miller GAH, Hall RJC, Paneth M. Pulmonary embolectomy, heparin, and streptokinase: their place in the treatment of acute massive pulmonary embolism. Am Heart J. 1977;93:568-574. [Medline] [Order article via Infotrieve]
201. Donaldson GA, Williams C, Scannell JG, Shaw RG. A reappraisal of the application of the Trendelenburg operation for massive fatal embolism. N Engl J Med. 1963;268:171-174.
202. Moser KM, Daily PO, Peterson K, Dembitsky W, Vapnek JM, Shure D, Utley J, Archibald C. Thromboendarterectomy for chronic, major-vessel thromboembolic pulmonary hypertension: immediate and long-term results in 42 patients. Ann Intern Med. 1987;107:560-565.
203.
Moser KM, Auger WR, Fedullo PF. Chronic
major-vessel thromboembolic pulmonary hypertension.
Circulation. 1990;81:1735-1743.
204. Painter TD, Karpf M. Deep venous thrombosis of the upper extremity: five years' experience at a university hospital. Angiology. 1984;35:743-749.
205.
Becker DM, Philbrick JT, Walker FB IV. Axillary
and subclavian venous thrombosis: prognosis and treatment.
Arch Intern Med. 1991;151:1934-1943.
206. Lindblad B, Tengborn L, Bergqvist D. Deep vein thrombosis of the axillary-subclavian veins: epidemiologic data, effects of different types of treatment and late sequelae. Eur J Vasc Surg. 1988;2:161-165. [Medline] [Order article via Infotrieve]
207. Thaler E, Lechner K. Antithrombin III deficiency and thromboembolism. Clin Haematol. 1981;10:369-390. [Medline] [Order article via Infotrieve]
208. Engesser L, Broekmans AW, Briet E, Brommer EJ, Bertina RM. Hereditary protein S deficiency: clinical manifestations. Ann Intern Med. 1987;106:677-682.
209. Girolami A, Marafioti F, Rubertelli M, Cappellato MG. Congenital heterozygous plasminogen deficiency associated with a severe thrombotic tendency. Acta Haematol. 1986;75:54-57. [Medline] [Order article via Infotrieve]
210.
Mackworth-Young CG, Loizou S, Walport MJ.
Primary antiphospholipid syndrome: features of patients with raised
anticardiolipin antibodies and no other disorder. Ann
Rheum Dis. 1989;48:362-367.
211.
Monreal M, Lafoz E, Ruiz J, Valls R, Alastrue
A. Upper-extremity deep venous thrombosis and pulmonary
embolism: a prospective study. Chest. 1991;99:280-283.
212. Horattas MC, Wright DJ, Fenton AH, Evans DM, Oddi MA, Kamienski RW, Shields EF. Changing concepts of deep venous thrombosis of the upper extremity: report of a series and review of the literature. Surgery. 1988;104:561-567. [Medline] [Order article via Infotrieve]
213. Martin EC, Koser M, Gordon DH. Venography in axillary-subclavian vein thrombosis. Cardiovasc Radiol. 1979;2:261-266. [Medline] [Order article via Infotrieve]
214. Lindblad B, Bornmyr S, Kullendorff B, Bergqvist D. Venous haemodynamics of the upper extremity after subclavian vein thrombosis. Vasa. 1990;19:218-222. [Medline] [Order article via Infotrieve]
215. Donayre CE, White GH, Mehringer SM, Wilson SE. Pathogenesis determines late morbidity of axillosubclavian vein thrombosis. Am J Surg. 1986;152:179-184. [Medline] [Order article via Infotrieve]
216.
Tilney ML, Griffiths HJ, Edwards EA. Natural
history of major venous thrombosis of the upper extremity.
Arch Surg. 1970;101:792-796.
217. Machleder HI. Evaluation of a new treatment strategy for Paget-Schroetter syndrome: spontaneous thrombosis of the axillary-subclavian vein. J Vasc Surg. 1993;17:305-315. [Medline] [Order article via Infotrieve]
218. Haire WD, Lynch TG, Lieberman RP, Lund GB, Edney JA. Utility of duplex ultrasound in the diagnosis of asymptomatic catheter-induced subclavian vein thrombosis. J Ultrasound Med. 1991;10:493-496. [Abstract]
219. Machleder HI. The role of thrombolytic agents for acute subclavian vein thrombosis. Semin Vasc Surg. 1992;5:82.
220.
Becker GJ, Holden RW, Rabe FE, Castaneda-Zuniga WR,
Sears N, Dilley RS, Glover JL. Local thrombolytic therapy
for subclavian and axillary vein thrombosis: treatment of the thoracic
inlet syndrome. Radiology. 1983;149:419-423.
221.
McNamara TO, Fischer JR. Thrombolysis of
peripheral arterial and graft occlusions: improved results using
high-dose urokinase. AJR Am J Roentgenol.. 1985;144:769-775.
222.
Kleinsasser LJ. `Effort' thrombosis of the
axillary and subclavian veins. Arch Surg. 1949;59:258.
223. Smith VC, Hallett JW Jr. Subclavian vein thrombosis during prolonged catheterization for parenteral nutrition: early management and long-term follow-up. South Med J. 1983;76:603-606. [Medline] [Order article via Infotrieve]
224. Axelsson CK, Efsen F. Phlebography in long-term catheterization of the subclavian vein: a retrospective study in patients with severe gastrointestinal disorders. Scand J Gastroenterol. 1978;13:933-938. [Medline] [Order article via Infotrieve]
225. Campbell CB, Chandler JG, Tegtmeyer CJ, Bernstein EF. Axillary, subclavian, and brachiocephalic vein obstruction. Surgery. 1977;82:816-826. [Medline] [Order article via Infotrieve]
226. Wilson JJ, Lesk D, Newman H. Subclavian-axillary vein thrombosis: successful treatment with streptokinase. Can Med Assoc J. 1984;130:891-893. [Abstract]
227. Appleby DH, Heller MS. Low-dose streptokinase therapy for subclavian vein thrombosis. South Med J. 1984;77:536-537. [Medline] [Order article via Infotrieve]
228.
Rubenstein M, Creger WP. Successful
streptokinase therapy for catheter-induced subclavian vein
thrombosis. Arch Intern Med. 1980;140:1370-1371.
229.
Fraschini G, Jadeja J, Lawson M, Holmes FA, Carrasco
HC, Wallace S. Local infusion of urokinase for the lysis of
thrombosis associated with permanent central venous catheters in cancer
patients. J Clin Oncol. 1987;5:672-678.
230. Druy EM, Trout HH III, Giordano JM, Hix WR. Lytic therapy in the treatment of axillary and subclavian vein thrombosis. J Vasc Surg. 1985;2:821-827. [Medline] [Order article via Infotrieve]
231. Ginsberg JS, Brill-Edwards P, Burrows RF, Bona R, Prandoni P, Buller HR, Lensing A. Venous thrombosis during pregnancy: leg and trimester of presentation. Thromb Haemost. 1992;67:519-520. [Medline] [Order article via Infotrieve]
232. Demers C, Ginsberg JS. Deep venous thrombosis and pulmonary embolism in pregnancy. Clin Chest Med. 1992;13:645-656. [Medline] [Order article via Infotrieve]
233. Ginsberg JS, Hirsh J, Turner DC, Levine MN, Burrows R. Risks to the fetus of anticoagulant therapy during pregnancy. Thromb Haemost. 1989;61:197-203.
234. Hall JAG, Pauli RM, Wilson KM. Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med. 1980;68:122-140. [Medline] [Order article via Infotrieve]
235.
Ginsberg JS, Kowalchuk G, Hirsh J, Brill-Edwards P,
Burrows R. Heparin therapy during pregnancy: risks to the fetus
and mother. Arch Intern Med. 1989;149:2233-2236.
236. Iturbe-Alessio I, Fonseca MC, Mutchinik O, Santos MA, Zajarias A, Salazar E. Risks of anticoagulant therapy in pregnancy women with artificial heart valves. N Engl J Med. 1986;315:1390-1393. [Abstract]
237. Anderson DR, Ginsberg JS, Burrows R, Brill-Edwards P. Subcutaneous heparin therapy during pregnancy: a need for concern at the time of delivery. Thromb Haemost. 1991;65:248-250. [Medline] [Order article via Infotrieve]
238. Hirsh J, van Aken WG, Gallus AS, Dollery CT, Cade JF, Yung WL. Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation. 1976;53:691-695.
239. McKenna R, Cole ER, Vasan U. Is warfarin sodium contraindicated in the lactating mother? J Pediatr. 1983;103:325-327. [Medline] [Order article via Infotrieve]
240. Orme ML, Lewis PJ, de Swiet M, Serlin MJ, Sibeon R, Baty JD, Breckenridge AM. May mothers given warfarin breast-feed their infants? Br Med J. 1977;1:1564-1565.
241. Delclos GL, Davila F. Thrombolytic therapy for pulmonary embolism in pregnancy: a case report. Am J Obstet Gynecol. 1986;155:375-376. [Medline] [Order article via Infotrieve]
242. Hall RJ, Young C, Sutton GC, Cambell S. Treatment of acute massive pulmonary embolism by streptokinase during labour and delivery. Br Med J. 1972;4:647-649.
243. Henny CP, ten Cate H, ten Cate JW, Prummel MF, Peters M, Buller HR. Thrombosis prophylaxis in an AT III deficient pregnant woman: application of a low molecular weight heparinoid. Thromb Haemost. 1986;55:301. Letter. [Medline] [Order article via Infotrieve]
244. Priollet P, Roncato M, Aiach M, Housset E, Poissonnier MH, Chavinie J. Low-molecular-weight heparin in venous thrombosis during pregnancy. Br J Haematol. 1986;63:605-606. [Medline] [Order article via Infotrieve]
245. Carter C, Gent M. The epidemiology of venous thrombosis. In: Colman R, Hirsh J, Marder V, Salzman E, eds. Haemostasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia, Pa: JB Lippincott Co; 1982:805-819.
246. Castaman G, Rodeghiero F, Dini E. Thrombotic complications during L-asparaginase treatment for acute lymphocytic leukemia. Haematologica. 1990;75:567-569. [Medline] [Order article via Infotrieve]
247.
Wise RC, Todd JK. Spontaneous,
lower-extremity venous thrombosis in children. Am J
Dis Child. 1973;126:766-769.
248.
Bernstein D, Coupey S, Schonberg SK. Pulmonary
embolism in adolescents. Am J Dis Child. 1986;140:667-671.
249. Uden A. Thromboembolic complications following scoliosis surgery in Scandinavia. Acta Orthop Scand. 1979;50:175-178. [Medline] [Order article via Infotrieve]
250.
Andrew M, David M, Adams M, Ali K, Anderson R, Barnard
D, Bernstein M, Brisson L, Cairney B, DeSai D, Grant R, Israels S,
Jardine L, Luke B, Massicotte P, Silva M. Venous thromboembolic
complications (VTE) in children: first analyses of the Canadian
Registry of VTE. Blood. 1994;83:1251-1257.
251. David M, Andrew M. Venous thromboembolic complications in children. J Pediatr. 1993;123:337-346. [Medline] [Order article via Infotrieve]
252. Schmidt B, Andrew A. A prospective international registry of neonatal thrombotic diseases. Pediatr Res. 1994;35(pt 2):170a. Abstract.
253.
Green RM, Meyer TJ, Dunn M, Glassroth J.
Pulmonary embolism in younger adults. Chest. 1992;101:1507-1511.
254. Lindblad B, Bergqvist D. Aggressive or conservative treatment in subclavian vein thrombosis. In: Eklof B, Gjores J, Thulesius O, Bergqvist D, eds. Controversies in the Management of Venous Disorders: Scandinavian Contributions on Venous Problems With Comments by International Authorities. London, UK: Butterworths; 1989:141-158.
255. Rockoff MA, Gang DL, Vacanti JP. Fatal pulmonary embolism following removal of a central venous catheter. J Pediatr Surg. 1984;19:307-309. [Medline] [Order article via Infotrieve]
256. Mulvihill SJ, Fonkalsrud EW. Complications of superior versus inferior vena cava occlusion in infants receiving central total parenteral nutrition. J Pediatr Surg. 1984;19:752-757. [Medline] [Order article via Infotrieve]
257. Mollitt DL, Golladay ES. Complications of TPN catheter-induced vena caval thrombosis in children less than one year of age. J Pediatr Surg. 1983;18:462-467. [Medline] [Order article via Infotrieve]
258. Le Coultre C, Oberhansli I, Mossaz A, Bugmann P, Faidutti B, Belli DC. Postoperative chylothorax in children: differences between vascular and traumatic origin. J Pediatr Surg.. 1991;26:519-523. [Medline] [Order article via Infotrieve]
259. Tanaka K, Takao M, Yada I, Yuasa H, Kusagawa M, Deguchi K. Alterations in coagulation and fibrinolysis associated with cardiopulmonary bypass during open heart surgery. J Cardiothorac Anesth. 1989;3:181-188. [Medline] [Order article via Infotrieve]
260.
Graham L Jr, Gumbiner CH. Right atrial thrombus
and superior vena cava syndrome in a child.
Pediatrics. 1984;73:225-229.
261. Bertrand M, Presant CA, Klein L, Scott E. Iatrogenic superior vena cava syndrome: a new entity. Cancer. 1984;54:376-378. [Medline] [Order article via Infotrieve]
262.
Kramer SS, Taylor GA, Garfinkel DJ, Simmons MA.
Lethal chylothoraces due to superior vena caval thrombosis in
infants. AJR Am J Roentgenol. 1981;137:559-563.
263.
Dhande V, Kattwinkel J, Alford B. Recurrent
bilateral pleural effusions secondary to superior vena cava obstruction
as a complication of central venous catheterization.
Pediatrics. 1983;72:109-113.
264.
Duke W. The relation of blood platelets to
hemorrhagic disease: description of a method for determining the
bleeding time and coagulation time and report of three cases of
hemorrhagic disease relieved by transfusion. JAMA. 1910;55:1185-1192.
265. Andrew M, Marzinotto V, Pencharz P, Zlotkin S, Burrows P, Ingram J, Adams M, Filler R. A cross-sectional study of catheter-related thrombosis in children receiving total parenteral nutrition at home. J Pediatr. 1995;126:358-363. [Medline] [Order article via Infotrieve]
266.
Rajani K, Goetzman BW, Wennberg RP, Turner E,
Abildgaard C. Effect of heparinization of fluids infused through
an umbilical artery catheter on catheter patency and frequency of
complications. Pediatrics. 1979;63:552-556.
267. David R, Merten D, Anderson JC, Gross S. Prevention of umbilical artery catheter clots with heparinized infusates. Dev Pharmacol Ther. 1981;2:117-126. [Medline] [Order article via Infotrieve]
268. Bosque E, Weaver L. Continuous versus intermittent heparin infusion of umbilical artery catheters in the newborn infant. J Pediatr. 1986;108:141-143. [Medline] [Order article via Infotrieve]
269. Horgan MJ, Bartoletti A, Polansky S, Peters JC, Manning TJ, Lamont BM. Effect of heparin infusates in umbilical arterial catheters on frequency of thrombotic complications. J Pediatr. 1987;111:774-778. [Medline] [Order article via Infotrieve]
270. Ankola PA, Atakent YS. Effect of adding heparin in very low concentration to the infusate to prolong the patency of umbilical artery catheters. Am J Perinatol. 1993;10:229-232. [Medline] [Order article via Infotrieve]
271. Salzman EW, Deykin D, Shapiro RM, Rosenberg R. Management of heparin therapy: controlled prospective trial. N Engl J Med. 1975;292:1046-1050.
272. Hommes DW, Bura A, Mazzolai L, Buller HR, ten Cate JW. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis: a meta-analysis. Ann Intern Med. 1992;116:279-284.
273. Hirsh J, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest. 1992;102(suppl 4):337S-351S.
274.
de Swart CAM, Nijmeyer B, Roelofs JMM, Sixma
JJ. Kinetics of intravenously administered heparin in normal
humans. Blood. 1982;60:1251-1258.
275. Olsson P, Lagergren H, Ek S. The elimination from plasma of intravenous heparin: an experimental study on dogs and humans. Acta Med Scand. 1963;173:619-630. [Medline] [Order article via Infotrieve]
276. Bjornsson TD, Wolfram KM, Kitchell BB. Heparin kinetics determined by three assay methods. Clin Pharmacol Ther. 1982;31:104-113. [Medline] [Order article via Infotrieve]
277. Racanelli A, Fareed J, Walenga JM, Coyne E. Biochemical and pharmacologic studies on the protamine interactions with heparin, its fractions and fragments. Semin Thromb Hemost. 1985;11:176-189. [Medline] [Order article via Infotrieve]
278. Sharath MD, Metzger WJ, Richerson HB, Scupham RK, Meng RL, Ginsberg BH, Weiler JM. Protamine-induced fatal anaphylaxis: prevalence of antiprotamine immunoglobulin E antibody. J Thorac Cardiovasc Surg. 1985;90:86-90. [Abstract]
279. Shapira N, Schaff HV, Piehler JM, White RD, Still JC, Pluth JR. Cardiovascular effects of protamine sulfate in man. J Thorac Cardiovasc Surg. 1982;84:505-514. [Abstract]
280. Ellison N, Beatty CP, Blake DR, Wurzel HA, MacVaugh H III. Heparin-rebound: studies in patients and volunteers. J Thorac Cardiovasc Surg. 1974;67:723-729. [Medline] [Order article via Infotrieve]
281. Gollub S. Heparin rebound in open heart surgery. Surg Gynecol Obstet. 1967;124:337-346. [Medline] [Order article via Infotrieve]
282. Pifarre R, Sullivan HJ, Montoya A, Bakhos M, Grieco J, Foy BKB, Blakeman B. Management of blood loss and heparin rebound following cardiopulmonary bypass. Semin Thromb Hemost. 1989;15:173-177. [Medline] [Order article via Infotrieve]
283. Teoh KHT, Young E, Bradley CA, Hirsh J. Heparin binding proteins: contribution to heparin rebound after cardiopulmonary bypass. Circulation. 1993;88(pt 2):II-420- II-425.
284. Jones TK, Barnes RW, Greenfield LJ. Greenfield vena caval filter: rationale and current indications. Ann Thorac Surg. 1986;42(suppl):S48-S55.
285. Levine MN, Hirsh J, Kelton JG. Heparin-induced bleeding. In: Lane DA, Lindahl U, eds. Heparin: Chemical and Biological Properties, Clinical Applications. London, UK: Edward Arnold; 1989:517-532.
286.
Green D, Lee MY, Ito VY, Cohn T, Press J, Filbrandt
PR, VandenBerg WC, Yarkony GM, Meyer PR Jr. Fixed- vs adjusted-dose
heparin in the prophylaxis of thromboembolism in spinal cord injury.
JAMA. 1988;260:1255-1258.
287. Wilson JR, Lampman J. Heparin therapy: a randomized prospective study. Am Heart J. 1979;97:155-158. [Medline] [Order article via Infotrieve]
288. Levine MN, Hirsh J, Landefeld S, Raskob G. Hemorrhagic complications of anticoagulant treatment. Chest. 1992;102(suppl):352S-363S.
289. Yett HS, Skillman JJ, Salzman EW. The hazards of aspirin plus heparin. N Engl J Med. 1978;298:1092. Letter. [Medline] [Order article via Infotrieve]
290. Sethi GK, Copeland JG, Goldman S, Moritz T, Zadina K, Henderson WG. Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting: Department of Veterans Affairs Cooperative Study on Antiplatelet Therapy. J Am Coll Cardiol. 1990;15:15-20. [Abstract]
291. GISSI-2. A factorial randomised trial alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction: Gruppo Italiano per lo Studio della Sopravvivenza Nell'infarto Miocardico. Lancet. 1990;336:65-71. [Medline] [Order article via Infotrieve]
292. ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. Lancet. 1992;339:753-770.[Medline] [Order article via Infotrieve]
293. Urokinase-Pulmonary Embolism Trial: morbidity and mortality. Circulation. 1973;58:II-66-II-72.
294. Norman CS, Provan JL. Control and complications of intermittent heparin therapy. Surg Gynecol Obstet. 1977;145:338-342. [Medline] [Order article via Infotrieve]
295. King DJ, Kelton JG. Heparin-associated thrombocytopenia. Ann Intern Med. 1984;100:535-540.
296. Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Annu Rev Med. 1989;40:31-44. [Medline] [Order article via Infotrieve]
297. Ginsberg JS, Kowalchuk G, Hirsh J, Brill-Edwards P, Burrows R, Coates G, Webber C. Heparin effect on bone density. Thromb Haemost. 1990;64:286-289. [Medline] [Order article via Infotrieve]
298. Avioli LV. Heparin-induced osteopenia: an appraisal. Adv Exp Med Biol. 1975;52:375-387. [Medline] [Order article via Infotrieve]
299. Dahlman T, Lindvall N, Hellgren M. Osteopenia in pregnancy during long-term heparin treatment: a radiological study post partum. Br J Obstet Gynaecol. 1990;97:221-228. [Medline] [Order article via Infotrieve]
300. Wise PH, Hall AJ. Heparin-induced osteopenia in pregnancy. Br Med J. 1980;281:110-111.
301.
Squires JW, Pinch LWC. Heparin-induced
spinal fractures. JAMA. 1979;241:2417-2418.
302.
Griffiths HT, Liu DTY. Severe heparin
osteoporosis in pregnancy. Postgrad Med J. 1984;60:424-425.
303. White PW, Sadd JR, Nensel RE. Thrombotic complications of heparin therapy: including six cases of heparin-induced skin necrosis. Ann Surg. 1979;190:595-608. [Medline] [Order article via Infotrieve]
304. Abbott EC, Gornall AG, Sutherland DJA, Laidlaw JC, Stiefel M. The influence of a heparin-like compound on hypertension electrolytes and aldosterone in man. Can Med Assoc J. 1966;94:1155-1164. [Medline] [Order article via Infotrieve]
305.
Conn JW, Rovner DR, Cohen EL, Anderson JE Jr.
Inhibition by heparinoid of aldosterone biosynthesis in man.
J Clin Endocrinol Metab.. 1966;26:527-532.
306.
Leehey D, Gantt C, Lim V. Heparin-induced
hypoaldosteronism: report of a case. JAMA. 1981;246:2189-2190.
307. Phelps KR, Oh MS, Carroll HJ. Heparin-induced hyperkalemia: report of a case. Nephron. 1980;25:254-258. [Medline] [Order article via Infotrieve]
308. Dukes GE Jr, Sanders SW, Russo J Jr, Swenson E, Burnakis TG, Saffle JR, Warden GD. Transaminase elevations in patients receiving bovine or porcine heparin. Ann Intern Med. 1984;100:646-650.
309.
Nelson JC, Lerner RG, Goldstein R, Cagin NA.
Heparin-induced thrombocytopenia. Arch Intern
Med. 1978;138:548-552.
310. Salzman EW, Rosenberg RD, Smith MN, Lindon JN, Favreau L. Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest. 1980;65:64-73.
311. Barradas MA, Mikhailidis DP, Epemolu O, Jeremy JY, Fonseca V, Dandona P. Comparison of the platelet pro-aggregatory effect of conventional unfractionated heparins and a low molecular weight heparin fraction (CY 222). Br J Haematol. 1987;67:451-457. [Medline] [Order article via Infotrieve]
312. Chong BH, Ismail F. The mechanism of heparin-induced platelet aggregation. Eur J Haematol. 1989;43:245-251. [Medline] [Order article via Infotrieve]
313. Chong BH, Pitney WR, Castaldi PA. Heparin-induced thrombocytopenia: association of thrombotic complications with heparin-dependent IgG antibody that induces thromboxane synthesis and platelet aggregation. Lancet. 1982;2:1246-1249. [Medline] [Order article via Infotrieve]
314. Ansell J, Slepchuk N Jr, Kumar R, Lopez A, Southard L, Deykin D. Heparin- induced thrombocytopenia: a prospective study. Thromb Haemost. 1980;43:61-65. [Medline] [Order article via Infotrieve]
315.
Ansell JE, Price JM, Shah S, Beckner RR.
Heparin-induced thrombocytopenia: what is its real
frequency? Chest. 1985;88:878-882.
316. Bailey RT Jr, Ursick JA, Heim KL, Hilleman DE, Reich JW. Heparin-associated thrombocytopenia: a prospective comparison of bovine lung heparin, manufactured by a new process, and porcine intestinal heparin. Drug Intell Clin Pharm. 1986;20:374-378. [Abstract]
317.
Ramirez-Lassepas M, Cipolle RJ, Rodvold KA, Seifert
RD, Strand L, Taddeini L, Cusulos M. Heparin-induced
thrombocytopenia in patients with cerebrovascular ischemic
disease. Neurology. 1984;34:736-740.
318. Cipolle RJ, Rodvold KA, Seifert R, Clarens R, Ramirez-Lassepas M. Heparin-associated thrombocytopenia: a prospective evaluation of 211 patients. Ther Drug Monit. 1983;5:205-211. [Medline] [Order article via Infotrieve]
319. Gallus AS, Goodall KT, Beswick W, Chesterman CN. Heparin-associated thrombocytopenia: case report and prospective study. Aust N Z J Med. 1980;10:25-31. [Medline] [Order article via Infotrieve]
320. Green D, Martin GJ, Shoichet SH, DeBacker N, Bomalaski JS, Lind RN. Thrombocytopenia in a prospective, randomized, double-blind trial of bovine and porcine heparin. Am J Med Sci. 1984;288:60-64. [Medline] [Order article via Infotrieve]
321. Green D. Heparin-immune thrombocytopenia. Med J Aust. 1986;144:37-39. [Medline] [Order article via Infotrieve]
322.
Powers PJ, Cuthbert D, Hirsh J.
Thrombocytopenia found uncommonly during heparin therapy.
JAMA. 1979;241:2396-2397.
323. Powers PJ, Kelton JG, Carter CJ. Studies on the frequency of heparin-associated thrombocytopenia. Thromb Res. 1984;33:439-443. [Medline] [Order article via Infotrieve]
324.
Rao AK, White GC, Sherman L, Colman R, Lan G, Ball
AP. Low incidence of thrombocytopenia with porcine mucosal
heparin: a prospective multicenter study. Arch Intern
Med. 1989;149:1285-1288.
325. Warkentin TE, Kelton JG. Interaction of heparin with platelets, including heparin-induced thrombocytopenia. In: Bounameaux H, ed. Low-Molecular-Weight Heparins in Prophylaxis and Therapy of Thromboembolic Diseases. New York, NY: Marcel Dekker Inc; 1994:75-127.
326. Kapsch DN, Adelstein EH, Rhodes GR, Silver D. Heparin-induced thrombocytopenia, thrombosis, and hemorrhage. Surgery. 1979;86:148-155. [Medline] [Order article via Infotrieve]
327. Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia: predominance of venous thrombotic complications, and a high risk for subsequent thrombosis in patients who are initially recognized with isolated thrombocytopenia. Blood. 1994;84(suppl 1):188A. Abstract.
328.
Kelton JG, Sheridan D, Santos A, Smith J, Steeves K,
Smith C, Brown C, Murphy WG. Heparin-induced
thrombocytopenia: laboratory studies. Blood. 1988;72:925-930.
329. Chong BH, Fawaz I, Chesterman CN, Berndt MC. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol. 1989;73:235-240. [Medline] [Order article via Infotrieve]
330. Amiral J, Bridey F, Dreyfus M, Vissoc AM, Fressinaud E, Wolf M, Meyer D. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost. 1992;68:95-96. Letter. [Medline] [Order article via Infotrieve]
331.
Kelton JG, Smith JW, Warkentin TE, Hayward CPM,
Denomme GA, Horsewood P. Immunoglobulin G from patients with
heparin-induced thrombocytopenia binds to a complex of heparin and
platelet factor 4. Blood. 1994;83:3232-3239.
332. Visentin GP, Ford SE, Scott JP, Aster RH. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest. 1994;93:81-88.
333. Greinacher A, Potzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost. 1994;71:247-251. [Medline] [Order article via Infotrieve]
334.
Chong BH, Murray B, Berndt MC, Dunlop LC, Brighton T,
Chesterman CN. Plasma P-selectin is increased in thrombotic
consumptive platelet disorders. Blood. 1994;83:1535-1541.
335.
Warkentin TE, Hayward CPM, Boshkov LK, Santos AV,
Sheppard JA, Bode AP, Kelton JG. Sera from patients with
heparin-induced thrombocytopenia generate platelet-derived
microparticles with procoagulant activity: an explanation for the
thrombotic complications of heparin-induced
thrombocytopenia. Blood. 1994;84:3691-3699.
336. Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med. 1987;316:581-589. [Abstract]
337.
Sheridan D, Carter C, Kelton JG. A diagnostic
test for heparin-induced thrombocytopenia.
Blood. 1986;67:27-30.
338. Greinacher A, Michels I, Kiefel V, Mueller-Eckhardt C. A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia. Thromb Haemost. 1991;66:734-736. [Medline] [Order article via Infotrieve]
339. Chong BH, Burgess J, Ismail F. The clinical usefulness of the platelet aggregation test for the diagnosis of heparin-induced thrombocytopenia. Thromb Haemost. 1993;69:344-350. [Medline] [Order article via Infotrieve]
340. Favaloro EJ, Bernal-Hoyos E, Exner T, Koutts J. Heparin-induced thrombocytopenia: laboratory investigation and confirmation of diagnosis. Pathology. 1992;24:177-183. [Medline] [Order article via Infotrieve]
341. Kelton JG, Sheridan D, Brain H, Powers PJ, Turpie AGG, Carter CJ. Clinical usefulness of testing for a heparin-dependent platelet-aggregating factor in patients with suspected heparin-associated thrombocytopenia. J Lab Clin Med. 1984;103:606-612. [Medline] [Order article via Infotrieve]
342. Greinacher A, Amiral J, Dummel V, Vissac A, Kiefel V, Mueller-Eckhardt C. Laboratory diagnosis of heparin-associated thrombocytopenia and comparison of platelet aggregation test, heparin-induced platelet activation test, and platelet factor 4/heparin enzyme-linked immunosorbent assay. Transfusion. 1994;34:381-385. [Medline] [Order article via Infotrieve]
343. Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the antibody is not heparin specific. Thromb Haemost. 1992;67:545-549. [Medline] [Order article via Infotrieve]
344.
Chong BH, Ismail F, Cade J, Gallus AS, Gordon S,
Chesterman CN. Heparin-induced thrombocytopenia: studies
with a new low molecular weight heparinoid, Org 10172.
Blood. 1989;73:1592-1596.
345. Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran (Org 10172). Thromb Haemost. 1993;70:554-561. [Medline] [Order article via Infotrieve]
346.
Demers C, Ginsberg JS, Brill-Edwards P, Panju A,
Warkentin TE, Anderson DR, Turner C, Kelton JG. Rapid
anticoagulation using ancrod for heparin-induced
thrombocytopenia. Blood.. 1991;78:2194-2197.
347. Cole CW, Bormanis J. Ancrod: a practical alternative to heparin. J Vasc Surg. 1988;8:59-63. [Medline] [Order article via Infotrieve]
348. Greinacher A, Liebenhoff U, Kiefel V, Presek P, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the effects of various intravenous IgG preparations on antibody mediated platelet activation: a possible new indication for high dose i.v. IgG. Thromb Haemost. 1994;71:641-645. [Medline] [Order article via Infotrieve]
349.
Krishnamurti C, Bolan CD, Reid TJ III, Alving
BM. Pharmacology and mechanism of action of ancrod: potential
for inducing thrombosis. Blood. 1992;79:2492.
Letter.
350. Pitney WR, Holt PJ, Bray C, Bolton G. Acquired resistance to treatment with arvin. Lancet. 1969;1:79-81. [Medline] [Order article via Infotrieve]
351. Turpie AGG, Gent M, Laupacis A, Latour Y, Wright D, Hoffman J, Gunstensen J, Basile F, Klimek M, Hirsh J. Reduction in mortality by adding acetylsalicylic acid (100 mg) to oral anticoagulants in patients with heart valve replacement. Can J Cardiol. 1991;7(suppl A):95A. Abstract.
352. Saour JN, Sieck JO, Mamo LAR, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med. 1990;322:428-432. [Abstract]
353. Landefeld CS, Rosenblatt MW, Goldman L. Bleeding in outpatients treated with warfarin: relation to the prothrombin time and important remediable lesions. Am J Med. 1989;87:153-159. [Medline] [Order article via Infotrieve]
354. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med. 1989;87:144-152. [Medline] [Order article via Infotrieve]
355. Dale J, Myhre E, Loew D. Bleeding during acetylsalicylic acid and anticoagulant therapy in patients with reduced platelet reactivity after aortic valve replacement. Am Heart J. 1980;99:746-752. [Medline] [Order article via Infotrieve]
356. Chesebro JH, Fuster V, Elveback LR, McGoon DC, Pluth JR, Puga FJ, Wallace RB, Danielson GK, Orszulak TA, Piehler JM, Schaff HV. Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole. Am J Cardiol. 1983;51:1537-1541. [Medline] [Order article via Infotrieve]
357. Levine MN, Raskob G, Hirsh J. Hemorrhagic complications of long-term anticoagulant therapy. Chest. 1989;95(suppl):26S-36S.
358. Altman R, Rouvier J, Gurfinkel E, D'Ortencio O, Manzanel R, de La Fuente L, Favaloro RG. Comparison of two levels of anticoagulant therapy in patients with substitute heart valves. J Thorac Cardiovasc Surg. 1991;101:427-431. [Abstract]
359. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK Study. Lancet. 1989;1:175-179. [Medline] [Order article via Infotrieve]
360. Preliminary report of the Stroke Prevention in Atrial Fibrillation Study. N Engl J Med. 1990;322:863-868. [Abstract]
361.
Wells PS, Lensing AWA, Davidson BL, Prins MH, Hirsh
J. Accuracy of ultrasound for the diagnosis of deep venous
thrombosis in asymptomatic patients after orthopedic surgery: a
meta-analysis. Ann Intern Med. 1995;122:47-53.
362.
Turpie AGG, Gent M, Laupacis A, Latour Y, Gunstensen
J, Basile F, Klimek M, Hirsh J. A comparison of aspirin with
placebo in patients treated with warfarin following heart-valve
replacement. N Engl J Med. 1993;329:524-529.
363. Turpie AGG, Gunstensen J, Hirsh J, Nelson H, Gent M. Randomised comparison of two intensities of oral anticoagulant therapy after tissue heart valve replacement. Lancet. 1988;1:1242-1245. [Medline] [Order article via Infotrieve]
364.
Stroke Prevention in Atrial Fibrillation Study: final
results. Circulation. 1991;84:527-539.
365. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med. 1990;323:1505-1511.[Abstract]
366. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol. 1991;18:349-355. [Abstract]
367. Ezekowitz MD, Bridgers SL, James KE, Carliner NH, Colling CL, Gornick CC, Krause-Steinrauf H, Kurtzke JF, Nazarian SM, Radford MJ, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation: Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med. 1992;327:1406-1412. [Abstract]
368. Broekmans AW, Bertina RM, Loeliger EA, Hofmann V, Klingemann HG. Protein C and the development of skin necrosis during anticoagulant therapy. Thromb Haemost. 1983;49:251. [Medline] [Order article via Infotrieve]
369. Sherman DG, Dyken ML, Fisher M, Harrison MJG, Hart RG. Antithrombotic therapy for cerebrovascular disorders. Chest. 1989;95(suppl):140S-155S.
370. Verhagen H. Local hemorrhage and necrosis of the skin and underlying tissues at starting therapy with dicumarol or dicumacyl. Acta Med Scand. 1954;148:453-467. [Medline] [Order article via Infotrieve]
371. Weinberg AC, Lieskovsky G, McGehee WG, Skinner DG. Warfarin necrosis of the skin and subcutaneous tissue of the male genitalia. J Urol. 1983;130:352-354. [Medline] [Order article via Infotrieve]
372. Zauber NP, Stark MW. Successful warfarin anticoagulation despite protein C deficiency and a history of warfarin necrosis. Ann Intern Med. 1986;104:659-660.
373. Samama M, Horellou MH, Soria J, Conard J, Nicolas G. Successful progressive anticoagulation in a severe protein C deficiency and previous skin necrosis at the initiation of oral anticoagulation treatment. Thromb Haemost. 1984;51:132-133. Letter. [Medline] [Order article via Infotrieve]
374. Grimaudo V, Gueissaz F, Hauert J, Sarraj A, Kruithof EKO, Bachmann F. Necrosis of skin induced by coumarin in a patient deficient in protein S. BMJ. 1989;298:233-234.
375. Pabinger-Fasching I, Deutsch E. Protein C deficiency in Austria. Semin Thromb Hemost. 1985;11:347-351. [Medline] [Order article via Infotrieve]
376. Hofmann V, Frick PG. Repeated occurrence of skin necrosis twice following coumarin intake and subsequently during decrease of vitamin K dependent coagulation factors associated with cholestasis. Thromb Haemost. 1982;48:245-246. [Medline] [Order article via Infotrieve]
377. Sills RH, Marlar RA, Montgomery RR, Deshpande GN, Humbert JR. Severe homozygous protein C deficiency. J Pediatr. 1984;105:409-413. [Medline] [Order article via Infotrieve]
378. Estelles A, Garcia-Plaza I, Dasi A, Aznar K, Duart M, Sanz G, Perez-Requejo JL, Espana F, Jimenez C, Abeledo G. Severe inherited homozygous protein C deficiency in a newborn infant. Thromb Haemost. 1984;52:53-56. [Medline] [Order article via Infotrieve]
379.
Marciniak E, Wilson HD, Marlar RA. Neonatal
purpura fulminans: a genetic disorder related to the absence of protein
C in blood. Blood. 1985;65:15-20.
380. Branson HE, Katz J, Marble R, Griffin JH. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet. 1983;2:1165-1168. [Medline] [Order article via Infotrieve]
381.
White RH, McKittrick T, Hutchinson R, Twitchell
J. Temporary discontinuation of warfarin therapy: changes in the
international normalized ratio. Ann Intern Med. 1995;122:40-42.
382.
Risk factors for stroke and efficacy of antithrombotic
therapy in atrial fibrillation: analysis of pooled data from five
randomized controlled trials. Arch Intern Med. 1994;154:1449-1457.
383.
Cannegieter SC, Rosendaal FR, Briet E.
Thromboembolic and bleeding complications in patients with mechanical
heart valve prostheses. Circulation. 1994;89:635-641.
384. Shetty HG, Blackhouse G, Bentley DP, Routledge PA. Effective reversal of warfarin-induced excessive anticoagulation with low dose vitamin K1. Thromb Haemost. 1992;67:13-15. [Medline] [Order article via Infotrieve]
385.
Francis CW, Marder VJ, Evarts CM, Yaukoolbodi
S. Two step warfarin therapy: prevention of postoperative venous
thrombosis without excessive bleeding. JAMA. 1983;249:374-378.
386. Hirsh J, Prins MH, Samama M. Approach to the thrombophilic patient for hemostasis and thrombosis: basic principles and clinical practice. In: Colman W, Hirsh J, Marder VJ, Salzman EW, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 3rd ed. Philadelphia, Pa: JB Lippincott Co; 1994:1543-1561.
387. Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh. 1965;13:516-530. [Medline] [Order article via Infotrieve]
388. Gladson CL, Scharrer I, Hach V, Beck KH, Griffin JH. The frequency of type I heterozygous protein S and protein C deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost. 1988;59:18-22. [Medline] [Order article via Infotrieve]
389. Heijboer H, Brandjes DP, Buller HR, Sturk A, ten Cate, JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med. 1990;323:1512-1516.[Abstract]
390.
Coller BS, Owen J, Jesty J, Horowitz D, Reitman MJ,
Spear J, Yeh T, Comp PC. Deficiency of plasma protein S, protein
C, or antithrombin III and arterial thrombosis.
Arteriosclerosis. 1987;7:456-462.
391. Allaart CF, Aronson DC, Ruys T, Rosendaal FR, van Bockel JH, Bertina RM, Briet E. Hereditary protein S deficiency in young adults with arterial occlusive disease. Thromb Haemost. 1990;64:206-210. [Medline] [Order article via Infotrieve]
392.
Bovill EG, Bauer KA, Dickerman JD, Callas P, West
B. The clinical spectrum of heterozygous protein C deficiency in
a large New England kindred. Blood. 1989;73:712-717.
393. Mannucci PM, Tripodi A, Bertina RM. Protein S deficiency associated with juvenile arterial and venous thromboses. Thromb Haemost. 1986;55:440. Letter. [Medline] [Order article via Infotrieve]
394. Broekmans AW, Veltkamp JJ, Bertina RM. Congenital protein C deficiency and venous thromboembolism: a study in three Dutch families. N Engl J Med. 1983;309:340-344. [Abstract]
395. Horellou MH, Conard J, Bertina RM, Samama M. Congenital protein C deficiency and thrombotic disease in nine French families. Br Med J (Clin Res Ed). 1984;289:1285-1287.
396. Rodgers GM. Activated protein C resistance and inherited thrombosis. Am J Clin Pathol. 1995;103:261-262. [Medline] [Order article via Infotrieve]
397.
Dahlback B, Carlsson M, Svensson PJ. Familial
thrombophilia due to a previously unrecognized mechanism characterized
by poor anticoagulant response to activated protein C: prediction of a
cofactor to activated protein C. Proc Natl Acad Sci
U S A. 1993;90:1004-1008.
398. Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet. 1993;342:1503-1506. [Medline] [Order article via Infotrieve]
399.
Svensson PJ, Dahlback B. Resistance to
activated protein C as a basis for venous thrombosis.
N Engl J Med. 1994;330:517-522.
400.
Griffin JHY, Evatt B, Wideman C, Fernandez JA.
Anticoagulant protein C pathway defective in majority of thrombophilic
patients. Blood. 1993;82:1989-1993.
401. Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma RH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64-67. [Medline] [Order article via Infotrieve]
402. Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344:1453-1457. [Medline] [Order article via Infotrieve]
403. Triplett DA, Brandt JT. Lupus anticoagulants: misnomer, paradox, riddle, epiphenomenon. Hematol Pathol. 1988;2:121-143. [Medline] [Order article via Infotrieve]
404. Benifla JL, Madelenat P. Hyperstimulation ofareienne et risque thrombogene. Arteres et Veines. 1990;8:748.
405. Clarke CS, Otridge BW, Carney DN. Thromboembolism: a complication of weekly chemotherapy in the treatment of non-Hodgkin's lymphoma. Cancer. 1990;66:2027-2030. [Medline] [Order article via Infotrieve]
406.
Prins MH, Hirsh J. A critical review of the
evidence supporting a relationship between impaired fibrinolytic
activity and venous thromboembolism. Arch Intern
Med. 1991;151:1721-1731.
407.
Le DT, Griffin JH, Greengard JS, Mujumdar V, Rapaport
SI. Use of a generally applicable tissue factor-dependent
factor V assay to detect activated protein C-resistant factor Va in
patients receiving warfarin and in patients with a lupus
anticoagulant. Blood. 1995;85:1704-1711.
408. Conley CL, Rathburn HK, Monse WI II, Robinson JE Jr. Circulating anticoagulant as a cause of hemorrhagic diathesis in man. Bull Johns Hopkins Hospital. 1948;83:288-296. [Medline] [Order article via Infotrieve]
409. Bowie EJW, Thompson JH, Pascuzzi CA, Owen CA Jr. Thrombosis in systemic lupus erythematosus despite circulating anticoagulants. J Lab Clin Med. 1963;62:416-430. [Medline] [Order article via Infotrieve]
410. Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RH, Machin SJB, Barquinero J, Outt HH, Harris EN, Vilardell-Torres M, Hughes GR. The primary antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore). 1989;68:366-374. [Medline] [Order article via Infotrieve]
411. Alarcon-Segovia D, Deleze M, Oria CV, Sanchez-Guerrero J, Gomez-Pacheco L, Cabiedes J, Fernandez L, Ponce de Leon S. Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus: a prospective analysis of 500 consecutive patients. Medicine (Baltimore). 1989;68:353-365. [Medline] [Order article via Infotrieve]
412. Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders: prevalence and clinical significance. Ann Intern Med. 1990;112:682-698.
413.
Lockshin MD. Antiphospholipid antibody
syndrome. JAMA. 1992;268:1451-1453.
414. Kitchens CS. Prolonged activated partial thromboplastin time of unknown etiology: a prospective study of 100 consecutive cases referred for consultation. Am J Hematol. 1988;27:38-45. [Medline] [Order article via Infotrieve]
415.
Derksen RHWM, Hasselaar P, Blokzijl L, Gmelig Meyling
FH, De Groot PG. Coagulation screen is more specific than the
anticardiolipin antibody ELISA in defining a thrombotic subset of lupus
patients. Ann Rheum Dis. 1988;47:364-371.
416. Harris EN, Gharavi AE, Boey ML, Patel BM, Mackworth-Young CG, Loizou S, Hughes GR. Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus. Lancet. 1983;2:1211-1214. [Medline] [Order article via Infotrieve]
417.
Triplett DA, Brandt JT, Musgrave KA, Orr CA.
The relationship between lupus anticoagulants and antibodies to
phosphilipid. JAMA. 1988;259:550-554.
418.
Levine SR, Kieran S, Puzio K, Feit H, Patel SC, Welch
KM. Cerebral venous thrombosis with lupus anticoagulants: report
of two cases. Stroke. 1987;18:801-804.
419. Moreb J, Kitchens CS. Acquired functional protein S deficiency, cerebral venous thrombosis, and coumarin skin necrosis in association with antiphospholipid syndrome: report of two cases. Am J Med. 1989;87:207-210. [Medline] [Order article via Infotrieve]
420. Pertuiset E, Tribout B, Wechsler B, Bellin MF, Godeau P, Jian R, Rambaud JC. Systemic lupus erythematosus presenting with portal venous thrombosis. Am J Med. 1989;86:501-502. [Medline] [Order article via Infotrieve]
421. Case records of the Massachusetts General Hospital—weekly clinicopathological exercises: case 11-1990, a 38-year-old woman with fever, skin lesions, thrombocytopenia, and venous thromboses. N Engl J Med. 1990;322:754-769. [Medline] [Order article via Infotrieve]
422.
Glueck HI, Kant KS, Weiss MA, Pollak VE, Miller MA,
Coots M. Thrombosis in systemic lupus erythematosus: relation to
the presence of circulating anticoagulants. Arch Intern
Med. 1985;145:1389-1395.
423. Mintz G, Acevedo-Vazquez E, Gutierrez-Espinosa G, Avelar-Garnica F. Renal vein thrombosis and inferior vena cava thrombosis in systemic lupus erythematosus: frequency and risk factors. Arthritis Rheum. 1984;27:539-544. [Medline] [Order article via Infotrieve]
424. Yap AS, Powell EE, Yelland CE, Mortimer RH, Perry-Keene DA. Lupus anticoagulant. Ann Intern Med. 1989;111:262-263.
425. Lechner K, Pabinger-Fasching I. Lupus anticoagulants and thrombosis: a study of 25 cases and review of the literature. Haemostasis. 1985;15:254-262. [Medline] [Order article via Infotrieve]
426. Gastineau DA, Kazmier FJ, Nichols WL, Bowie EJ. Lupus anticoagulant: an analysis of the clinical and laboratory features of 219 cases. Am J Hematol. 1985;19:265-275. [Medline] [Order article via Infotrieve]
427. Gardlund B. The lupus inhibitor in thromboembolic disease and intrauterine death in the absence of systemic lupus. Acta Med Scand. 1984;215:293-298. [Medline] [Order article via Infotrieve]
428.
Asherson RA, Merry P, Acheson JF, Harris EN, Hughes
GR. Antiphospholipid antibodies: a risk factor for occlusive
ocular vascular disease in systemic lupus erythematosus and the
`primary antiphospholipid syndrome.' Ann Rheum
Dis. 1989;48:358-361.
429. Heckerling PS, Froelich CJ, Schade SG. Retinal vein thrombosis in a patient with pernicious anemia and anticardiolipin antibodies. J Rheumatol. 1989;16:1144-1146. [Medline] [Order article via Infotrieve]
430. Rao RH, Vagnucci AH, Amico JA. Bilateral massive adrenal hemorrhage: early recognition and treatment. Ann Intern Med. 1989;110:227-235.
431.
Carette S, Jobin F. Acute adrenal insufficiency
as a manifestation of the anticardiolipin syndrome? Ann
Rheum Dis. 1989;48:430-431.
432. Alperin N, Babu S, Weinstein A. Acute adrenal insufficiency and the antiphospholipid syndrome. Ann Intern Med. 1989;111:950. Letter.
433. Pope JM, Canny CLB, Bell DA. Cerebral ischemic events associated with endocarditis, retinal vascular disease, and lupus anticoagulant. Am J Med. 1991;90:299-309. [Medline] [Order article via Infotrieve]
434. Ostermiller W Jr, Carter R. Mesenteric venous thrombosis secondary to polycythemia vera. Am Surg. 1969;35:407-409. [Medline] [Order article via Infotrieve]
435. Kneeland JB, Auh YH, Zirinsky K, Rubenstein W, Kazam E. MR, CT, and ultrasonographic demonstration of splenic vein thrombosis. J Comput Assist Tomogr. 1984;8:1199-1200. [Medline] [Order article via Infotrieve]
436. Shaldon S, Sherlock L. Portal hypertension in the myeoloproliferative syndrome and the reticuloses. Am J Med. 1962;32:758-764. [Medline] [Order article via Infotrieve]
437. Conlan MG, Haire WD. Low protein S in essential thrombocythemia with thrombosis. Am J Hematol. 1989;32:88-93. [Medline] [Order article via Infotrieve]
438. Teofili L, De Stefano V, Leone G, Micalizzi P, Iovino MS, Alfano G, Bizzi B. Hematological causes of venous thrombosis in young people: high incidence of myeloproliferative disorder as underlying disease in patients with splanchnic venous thrombosis. Thromb Haemost. 1992;67:297-301. [Medline] [Order article via Infotrieve]
439. White CL, Brewer ML, Witte MH, Pond GB. Protean manifestations of pylethrombosis: a review of thirty-four patients. Ann Surg. 1985;202:191-202. [Medline] [Order article via Infotrieve]
440. Wasserman LR, Gilbert HS. Complications of polycythemia vera. Semin Hematol. 1966;3:199-208.
441. Jabaily J, Iland HJ, Laszlo J, Massey EW, Faguet GB, Briere J, Landaw SA, Pisciotta AV. Neurologic manifestations of essential thrombocythemia. Ann Intern Med. 1983;99:513-518.
442. Singh AK, Wetherley-Mein G. Microvascular occlusive lesions in primary thrombocythaemia. Br J Haematol. 1977;36:553-564. [Medline] [Order article via Infotrieve]
443.
Conley CL. Polycythemia vera.
JAMA. 1990;263:2481-2483.
444. Anagrelide Study Group. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Am J Med.. 1992;92:69-76. [Medline] [Order article via Infotrieve]
445. Cortelazzo S, Viero P, Finazzi G, D'Emilio A, Rodeghiero F, Barbui T. Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia. J Clin Oncol.. 1990;8:556-562. [Abstract]
446.
Cortelazzo S, Finazzi G, Ruggeri M, Vestri O, Galli M,
Rodeghiero F, Barbui T. Hydroxyurea for patients with essential
thrombocythemia and a high risk of thrombosis. N
Engl J Med.. 1995;332:1132-1136.
447. McIntyre KJ, Hoagland HC, Silverstein MN, Petitt RM. Essential thrombocythemia in young adults. Mayo Clin Proc.. 1991;66:149-154. [Medline] [Order article via Infotrieve]
448. Liu PG, Jacobs JB, Reede D. Trousseau's syndrome in the head and neck. Am J Otolaryngol. 1985;6:405-408. [Medline] [Order article via Infotrieve]
449. James WD. Trousseau's syndrome. Int J Dermatol. 1984;23:205-206. [Medline] [Order article via Infotrieve]
450. Hickey WF, Garnick MB, Henderson IC, Dawson DM. Primary cerebral venous thrombosis in patients with cancer. A rarely diagnosed paraneoplastic syndrome: report of three cases and a review of the literature. Am J Med. 1982;73:740-750. [Medline] [Order article via Infotrieve]
451. Sack GH Jr, Levin J, Bell WR. Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic and therapeutic features. Medicine (Baltimore). 1977;56:1-37.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A Verdu, A Maestre, P Lopez, V Gil, A Martin-Hidalgo, and J A Castano Clinical pathways as a healthcare tool: design, implementation and assessment of a clinical pathway for lower-extremity deep venous thrombosis Qual. Saf. Health Care, August 1, 2009; 18(4): 314 - 320. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Al Sayegh, W. Almahmeed, S. Al Humood, M. Marashi, A. Bahr, H. Al Mahdi, S. Bakir, and M. Al Farhan Global Risk Profile Verification in Patients with Venous Thromboembolism (GRIP VTE) in 5 Gulf Countries Clinical and Applied Thrombosis/Hemostasis, June 1, 2009; 15(3): 289 - 296. [Abstract] [PDF]
|
|
|
|
 |
|
 K. J.M. Janssen, Y. Vergouwe, A. R. T. Donders, F. E. Harrell Jr., Q. Chen, D. E. Grobbee, and K. G.M. Moons Dealing with Missing Predictor Values When Applying Clinical Prediction Models Clin. Chem., May 1, 2009; 55(5): 994 - 1001. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Bauer, D. S. Chun, and T. A. Karpinski Pharmacist-led program to improve venous thromboembolism prophylaxis in a community hospital Am. J. Health Syst. Pharm., September 1, 2008; 65(17): 1643 - 1647. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Dewar, C Selby, K Jamieson, and S Rogers Emergency department nurse-based outpatient diagnosis of DVT using an evidence-based protocol Emerg. Med. J., July 1, 2008; 25(7): 411 - 416. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zagorski, N. Sanapareddy, M. A. Gellar, J. A. Kline, and J. A. Watts Transcriptional profile of right ventricular tissue during acute pulmonary embolism in rats Physiol Genomics, June 1, 2008; 34(1): 101 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Silverstein, K. A. Bauer, M. Cushman, C. T. Esmon, W. B. Ershler, and R. P. Tracy Venous thrombosis in the elderly: more questions than answers Blood, November 1, 2007; 110(9): 3097 - 3101. [Full Text] [PDF]
|
|
|
|
 |
|
 W. M. Stone, B. H. Tonnessen, and S. R. Money The New Anticoagulants Perspectives in Vascular Surgery and Endovascular Therapy, September 1, 2007; 19(3): 332 - 335. [Abstract] [PDF]
|
|
|
|
 |
|
 R. L. Levine, D. McCollum, and M. J. Hursting How frequently is venous thromboembolism in heparin-treated patients associated with heparin-induced thrombocytopenia? Chest, September 1, 2006; 130(3): 681 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Rubin, H. Xie, K. Kim, W. F. Weitzel, S. Y. Emelianov, S. R. Aglyamov, T. W. Wakefield, A. G. Urquhart, and M. O'Donnell Sonographic elasticity imaging of acute and chronic deep venous thrombosis in humans. J. Ultrasound Med., September 1, 2006; 25(9): 1179 - 1186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T Yamagami, T Kato, T Hirota, R Yoshimatsu, T Matsumoto, and T Nishimura Prophylactic implantation of inferior vena cava filter during interventional radiological treatment for deep venous thrombosis of the lower extremity. Br. J. Radiol., July 1, 2006; 79(943): 584 - 591. [Abstract] [Full Text] |