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Circulation. 1996;93:2212-2245

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Medline Plus Health Information
*Pulmonary Embolism
*Thrombophlebitis

(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

Jack Hirsh, MD; John Hoak, MD


Key Words: thrombosis • embolism • AHA Medical/Scientific Statements


*    Introduction
up arrowTop
*Introduction
down arrowPurpose
down arrowPathogenesis of Venous...
down arrowNatural History
down arrowPrognosis
down arrowClinical Course in Symptomatic...
down arrowAcute Recurrent Venous...
down arrowPostthrombotic Syndrome
down arrowProphylaxis
down arrowDiagnosis of Venous Thrombosis
down arrowDiagnosis of Recurrent Venous...
down arrowDiagnosis of Pulmonary Embolism
down arrowApproach to Treatment
down arrowUse of Anticoagulant Therapy
down arrowUpper-Extremity DVT
down arrowDiagnosis of Venous...
down arrowManagement of Venous...
down arrowManagement of Venous...
down arrowComplications of Anticoagulation
down arrowManagement When Anticoagulants...
down arrowLong-term Warfarin Therapy and...
down arrowApproach to Thrombophilia
down arrowReferences
 
Deep 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 {approx}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
up arrowTop
up arrowIntroduction
*Purpose
down arrowPathogenesis of Venous...
down arrowNatural History
down arrowPrognosis
down arrowClinical Course in Symptomatic...
down arrowAcute Recurrent Venous...
down arrowPostthrombotic Syndrome
down arrowProphylaxis
down arrowDiagnosis of Venous Thrombosis
down arrowDiagnosis of Recurrent Venous...
down arrowDiagnosis of Pulmonary Embolism
down arrowApproach to Treatment
down arrowUse of Anticoagulant Therapy
down arrowUpper-Extremity DVT
down arrowDiagnosis of Venous...
down arrowManagement of Venous...
down arrowManagement of Venous...
down arrowComplications of Anticoagulation
down arrowManagement When Anticoagulants...
down arrowLong-term Warfarin Therapy and...
down arrowApproach to Thrombophilia
down arrowReferences
 
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
up arrowTop
up arrowIntroduction
up arrowPurpose
*Pathogenesis of Venous...
down arrowNatural History
down arrowPrognosis
down arrowClinical Course in Symptomatic...
down arrowAcute Recurrent Venous...
down arrowPostthrombotic Syndrome
down arrowProphylaxis
down arrowDiagnosis of Venous Thrombosis
down arrowDiagnosis of Recurrent Venous...
down arrowDiagnosis of Pulmonary Embolism
down arrowApproach to Treatment
down arrowUse of Anticoagulant Therapy
down arrowUpper-Extremity DVT
down arrowDiagnosis of Venous...
down arrowManagement of Venous...
down arrowManagement of Venous...
down arrowComplications of Anticoagulation
down arrowManagement When Anticoagulants...
down arrowLong-term Warfarin Therapy and...
down arrowApproach to Thrombophilia
down arrowReferences
 
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 1Down) 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



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Figure 1. Valve cusp thrombus (autopsy specimen).

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
up arrowTop
up arrowIntroduction
up arrowPurpose
up arrowPathogenesis of Venous...
*Natural History
down arrowPrognosis
down arrowClinical Course in Symptomatic...
down arrowAcute Recurrent Venous...
down arrowPostthrombotic Syndrome
down arrowProphylaxis
down arrowDiagnosis of Venous Thrombosis
down arrowDiagnosis of Recurrent Venous...
down arrowDiagnosis of Pulmonary Embolism
down arrowApproach to Treatment
down arrowUse of Anticoagulant Therapy
down arrowUpper-Extremity DVT
down arrowDiagnosis of Venous...
down arrowManagement of Venous...
down arrowManagement of Venous...
down arrowComplications of Anticoagulation
down arrowManagement When Anticoagulants...
down arrowLong-term Warfarin Therapy and...
down arrowApproach to Thrombophilia
down arrowReferences
 
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 {approx}50% of patients with documented DVT,3 27 28 29 30 and asymptomatic venous thrombosis is found in {approx}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
up arrowTop
up arrowIntroduction
up arrowPurpose
up arrowPathogenesis of Venous...
up arrowNatural History
*Prognosis
down arrowClinical Course in Symptomatic...
down arrowAcute Recurrent Venous...
down arrowPostthrombotic Syndrome
down arrowProphylaxis
down arrowDiagnosis of Venous Thrombosis
down arrowDiagnosis of Recurrent Venous...
down arrowDiagnosis of Pulmonary Embolism
down arrowApproach to Treatment
down arrowUse of Anticoagulant Therapy
down arrowUpper-Extremity DVT
down arrowDiagnosis of Venous...
down arrowManagement of Venous...
down arrowManagement of Venous...
down arrowComplications of Anticoagulation
down arrowManagement When Anticoagulants...
down arrowLong-term Warfarin Therapy and...
down arrowApproach to Thrombophilia
down arrowReferences
 
Studies done before the introduction of anticoagulant therapy reported that the mortality rate for PE was {approx}20% in hospitalized patients with clinically obvious venous thrombosis.34 In a small study, Kakkar and colleagues10 reported that without treatment, {approx}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 {approx}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 {approx}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 {approx}30% of patients after 8 years.33


*    Clinical Course in Symptomatic Patients
up arrowTop
up arrowIntroduction
up arrowPurpose
up arrowPathogenesis of Venous...
up arrowNatural History
up arrowPrognosis
*Clinical Course in Symptomatic...
down arrowAcute Recurrent Venous...
down arrowPostthrombotic Syndrome
down arrowProphylaxis
down arrowDiagnosis of Venous Thrombosis
down arrowDiagnosis of Recurrent Venous...
down arrowDiagnosis of Pulmonary Embolism
down arrowApproach to Treatment
down arrowUse of Anticoagulant Therapy
down arrowUpper-Extremity DVT
down arrowDiagnosis of Venous...
down arrowManagement of Venous...
down arrowManagement of Venous...
down arrowComplications of Anticoagulation
down arrowManagement When Anticoagulants...
down arrowLong-term Warfarin Therapy and...
down arrowApproach to Thrombophilia
down arrowReferences
 
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 2Down).



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Figure 2. Cumulative incidence of recurrent venous thromboembolism after the first episode of symptomatic deep vein thrombosis.

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 {approx}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
up arrowTop
up arrowIntroduction
up arrowPurpose
up arrowPathogenesis of Venous...
up arrowNatural History
up arrowPrognosis
up arrowClinical Course in Symptomatic...
*Acute Recurrent Venous...
down arrowPostthrombotic Syndrome
down arrowProphylaxis
down arrowDiagnosis of Venous Thrombosis
down arrowDiagnosis of Recurrent Venous...
down arrowDiagnosis of Pulmonary Embolism
down arrowApproach to Treatment
down arrowUse of Anticoagulant Therapy
down arrowUpper-Extremity DVT
down arrowDiagnosis of Venous...
down arrowManagement of Venous...
down arrowManagement of Venous...
down arrowComplications of Anticoagulation
down arrowManagement When Anticoagulants...
down arrowLong-term Warfarin Therapy and...
down arrowApproach to Thrombophilia
down arrowReferences
 
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
up arrowTop
up arrowIntroduction
up arrowPurpose
up arrowPathogenesis of Venous...
up arrowNatural History
up arrowPrognosis
up arrowClinical Course in Symptomatic...
up arrowAcute Recurrent Venous...
*Postthrombotic Syndrome
down arrowProphylaxis
down arrowDiagnosis of Venous Thrombosis
down arrowDiagnosis of Recurrent Venous...
down arrowDiagnosis of Pulmonary Embolism
down arrowApproach to Treatment
down arrowUse of Anticoagulant Therapy
down arrowUpper-Extremity DVT
down arrowDiagnosis of Venous...
down arrowManagement of Venous...
down arrowManagement of Venous...
down arrowComplications of Anticoagulation
down arrowManagement When Anticoagulants...
down arrowLong-term Warfarin Therapy and...
down arrowApproach to Thrombophilia
down arrowReferences
 
In early descriptive studies, postthrombotic syndrome was reported to occur in {approx}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 {approx}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
up arrowTop
up arrowIntroduction
up arrowPurpose
up arrowPathogenesis of Venous...
up arrowNatural History
up arrowPrognosis
up arrowClinical Course in Symptomatic...
up arrowAcute Recurrent Venous...
up arrowPostthrombotic Syndrome
*Prophylaxis
down arrowDiagnosis of Venous Thrombosis
down arrowDiagnosis of Recurrent Venous...
down arrowDiagnosis of Pulmonary Embolism
down arrowApproach to Treatment
down arrowUse of Anticoagulant Therapy
down arrowUpper-Extremity DVT
down arrowDiagnosis of Venous...
down arrowManagement of Venous...
down arrowManagement of Venous...
down arrowComplications of Anticoagulation
down arrowManagement When Anticoagulants...
down arrowLong-term Warfarin Therapy and...
down arrowApproach to Thrombophilia
down arrowReferences
 
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 (TableDown 3). Antiplatelet agents such as aspirin are less effective for preventing VTE.60


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Table 1. Risk Factors for Venous Thromboembolism

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 3Down) with low-dose heparin. If anticoagulants are contraindicated because of an unusually high risk of bleeding, intermittent pneumatic compression should be used.


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Table 3. Recommended Prophylaxis

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
up arrowTop
up arrowIntroduction
up arrowPurpose
up arrowPathogenesis of Venous...
up arrowNatural History
up arrowPrognosis
up arrowClinical Course in Symptomatic...
up arrowAcute Recurrent Venous...
up arrowPostthrombotic Syndrome
up arrowProphylaxis
*Diagnosis of Venous Thrombosis
down arrowDiagnosis of Recurrent Venous...
down arrowDiagnosis of Pulmonary Embolism
down arrowApproach to Treatment
down arrowUse of Anticoagulant Therapy
down arrowUpper-Extremity DVT
down arrowDiagnosis of Venous...
down arrowManagement of Venous...
down arrowManagement of Venous...
down arrowComplications of Anticoagulation
down arrowManagement When Anticoagulants...
down arrowLong-term Warfarin Therapy and...
down arrowApproach to Thrombophilia
down arrowReferences
 
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 {approx}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 4Down).


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Table 4. Criteria for Clinical Pretest Probabilities

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 {approx}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 {approx}30% of cases.74 Because only {approx}5% of patients with symptoms of DVT have calf vein thrombosis (Fig 3Down),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 4Down).



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Figure 3. Location of venous thrombi in symptomatic outpatients. Reprinted from Cogo et al78 with permission.



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Figure 4. Diagnostic approach to deep vein thrombosis.

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 5Down).111 112



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Figure 5. Management of clinically suspected deep vein thrombosis with venous ultrasonography at presentation and on day 7. Reprinted from Prandoni et al.112


*    Diagnosis of Recurrent Venous Thrombosis
up arrowTop
up arrowIntroduction
up arrowPurpose
up arrowPathogenesis of Venous...
up arrowNatural History
up arrowPrognosis
up arrowClinical Course in Symptomatic...
up arrowAcute Recurrent Venous...
up arrowPostthrombotic Syndrome
up arrowProphylaxis
up arrowDiagnosis of Venous Thrombosis
*Diagnosis of Recurrent Venous...
down arrowDiagnosis of Pulmonary Embolism
down arrowApproach to Treatment
down arrowUse of Anticoagulant Therapy
down arrowUpper-Extremity DVT
down arrowDiagnosis of Venous...
down arrowManagement of Venous...
down arrowManagement of Venous...
down arrowComplications of Anticoagulation
down arrowManagement When Anticoagulants...
down arrowLong-term Warfarin Therapy and...
down arrowApproach to Thrombophilia
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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 {approx}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 6Down). 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



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Figure 6. Diagnosis of recurrent venous thrombosis. *On venous ultrasonography; if positive in a venous segment that had been compressible on previous assessment.

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 6Up).


*    Diagnosis of Pulmonary Embolism
up arrowTop
up arrowIntroduction
up arrowPurpose
up arrowPathogenesis of Venous...
up arrowNatural History
up arrowPrognosis
up arrowClinical Course in Symptomatic...
up arrowAcute Recurrent Venous...
up arrowPostthrombotic Syndrome
up arrowProphylaxis
up arrowDiagnosis of Venous Thrombosis
up arrowDiagnosis of Recurrent Venous...
*Diagnosis of Pulmonary Embolism
down arrowApproach to Treatment
down arrowUse of Anticoagulant Therapy
down arrowUpper-Extremity DVT
down arrowDiagnosis of Venous...
down arrowManagement of Venous...
down arrowManagement of Venous...