(Circulation. 1997;96:2938-2943.)
© 1997 American Heart Association, Inc.
Articles |
High Concentration of Thrombomodulin in Plasma Is Associated With Hemorrhage
A Prospective Study in Patients Receiving Long-term Anticoagulant Treatment
From the Department of Medicine, Skellefteå Hospital (J.-H.J., K.B., M.B.) and Department of Clinical Chemistry, Umeå University Hospital (T.K.N.), Umeå, Sweden.
Correspondence to Jan-Håkan Jansson, Department of Medicine, Skellefteå Hospital, S-93186 Skellefteå, Sweden.
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Abstract |
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Background The aim of this study was to prospectively test whether the risk of bleeding complications in 212 consecutive outpatients treated with oral anticoagulants could be predicted by levels of endothelium-derived hemostatic variables.
Methods and Results All bleeding complications were recorded during 5 years of follow-up; serious bleeding was defined as intracranial bleeding or hemorrhage causing death or necessitating hospitalization. The relationships of bleeding complications and plasma concentrations of tissue plasminogen activator, von Willebrand factor, and thrombomodulin, plasminogen activator inhibitor activity, and other possible risk factors were studied.
Twenty-two patients suffered from bleeding complications during anticoagulant treatment; in 14 patients, these were serious. We found that the numbers both of serious hemorrhages and of total hemorrhages were significantly associated with increased levels of thrombomodulin. The number of bleeding episodes increased exponentially through quartiles one to four of the thrombomodulin distribution.
Conclusions Thrombomodulin concentrations in plasma are related to the risk of hemorrhage in patients treated with oral anticoagulants.
Key Words: thrombomodulin • plasminogen activator inhibitor • tissue plasminogen activator • von Willebrand factor • hemorrhage • anticoagulants
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Introduction |
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Anticoagulant treatment with coumarin derivates and warfarin is widely used in the prevention of thromboembolic events of both the venous and the arterial sides of the vascular system. Hemorrhage is the dominating adverse effect of this treatment.1,2 No clinically useful coagulation factor measurement has been shown to predict bleeding in groups of patients with warfarin dosage properly controlled by PT levels. However, it is conceivable that measurements of other components of the hemostatic system, notably those synthesized by the endothelial cells, could give an indication of the risk of bleeding. Decreased functional activity of PAI-1 has been associated with bleeding diathesis in some subjects3; serum fibrin degradation products were shown to be an independent powerful predictor of outcome in patients with upper gastrointestinal tract bleeding4; and it is known that bleeding in prostatic surgery and during tooth extraction and upper gastrointestinal bleeding can be reduced by antifibrinolytic drugs.5 The low vWF levels (or dysfunctional vWF molecule) characteristic of von Willebrand's disease are another well-known cause of hemorrhage. Another endothelium-derived antithrombotic substance is TM, a cell-surface glycoprotein that is mainly present on the luminal surface of endothelial cells. The anticoagulant properties of TM are due to its binding to thrombin and subsequent activation of protein C, which in turn acts as an anticoagulant by inactivating the coagulation factors Va and VIIIa in the presence of protein S. Fibrin formation, platelet activation, and protein S inactivation by thrombin are also inhibited when the TM-thrombin complex is formed.
TM has been suggested as a marker of endothelial cell dysfunction, for instance, in disseminated intravascular coagulation.6 High levels of plasma TM have also been found in some patients with thrombotic thrombocytopenic purpura,7,8 diabetic microangiopathy,9 and atheromatous arterial disease.10 TM has also been suggested as a marker of vascular injuries in collagen vascular disease.11
In the present study, we therefore evaluated t-PA, PAI-1, vWF, and TM mass concentrations in plasma as predictors of hemorrhage in patients receiving oral anticoagulant treatment.
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Methods |
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Patients
On March 1, 1987, a total of 258 patients were registered at the outpatient clinic of the Department of Medicine, Umeå University Hospital for monitoring of anticoagulant treatment. Recruitment for this study took place during the month of March 1987, when 212 of the eventual study patients attended the clinic for their regular PT sampling. These 212 consecutive subjects formed the basis of the present study. Clinical characteristics at baseline are shown in Table 1
. The indications for
anticoagulant treatment were as follows: (1) valvular heart
disease, which comprised both patients who did and did not have
surgery; (2) arterial thromboembolism, including patients
with ischemic stroke, transient ischemic attack, and
peripheral arterial thromboembolism; (3) atrial
fibrillation; (4) deep vein thrombosis or pulmonary embolism;
and (5) miscellaneous indications. In 48 subjects (23%), the
indication for anticoagulant treatment was a combination of two of the
above factors, and 11 subjects (5%) had three underlying disorders;
each is recorded herein as a separate indication. Thus, there were
more indications than patients. The distribution of the indications is
shown in Table 1. The five most recent PT values before inclusion in
the study were recorded (with exclusion of values taken during the
first month of anticoagulant treatment). Of these 993 PT values, 17
(1.6%) were above the therapeutic interval (INR=2.0 to 4.0), 819
(82%) fell within the interval, and 157 (16%) were below it. Two
hundred patients were treated with warfarin and 12 with dicoumarol.
Twenty-five variables possibly associated with increased risk of
bleeding were registered from the patients' records: age; sex;
smoking habit; body mass index; systolic or
diastolic blood pressure; ECG (normal/not normal);
relative heart volume at roentgenography; type of anticoagulant drug
(warfarin/dicumarol); prescribed dose of warfarin at baseline;
indication for treatment; history of hypertension; heart disease;
diabetes; connective tissue disorders; history of malignancy; prior
peptic ulcer; prior recorded trauma; prior recorded bleeding
episode during anticoagulant treatment; concomitant use of nonsteroid
anti-inflammatory drugs, dipyridamole, or oral
antidiabetic drugs; white blood cell count; platelet count; and
number of PT values below or above the therapeutic interval before
inclusion.
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Sampling
Blood samples were drawn in March 1987, and a preparation of
citrated plasma was made, which was assayed for mass concentrations of
t-PA and for PAI-1 with ELISAs.12 The reagents
for these assays (Imulyse t-PA and Imulyse PAI-1, respectively) were
purchased from Biopool. vWF was also measured with an
ELISA,13 using reagents purchased from DAKO. TM
was measured by use of a commercially available
ELISA.14 The TM ELISA takes 
5 hours from
sampling until delivery of the test result, which is adequate for a
nonemergency task such as an oral anticoagulant office situation, and
the cost is presently $12 to $15. TM kits are
currently sold exclusively as a research tool; its establishment in the
clinical routine would lead to a more reasonable price level over time.
PT was measured in a prothrombin and proconvertin assay using Nycotest
(Nycomed). Cholesterol and triglyceride levels
were determined with the use of enzymatic method kits
(Boehringer Mannheim GmbH Diagnostica).
Follow-up Study Protocol
The patients were prospectively followed up until first serious
bleeding, death, or March 1992 (mean follow-up of 3.7±1.2 years), and
all bleeding complications were registered. Serious bleeding was
defined as intracranial bleeding or hemorrhage causing death or
necessitating hospitalization. Death certificates were obtained for all
patients who had died. No patient was lost to follow-up. The
investigators of the clinical outcomes were unaware of the results of
t-PA, PAI-1, vWF, and TM measurements.
Statistical Analysis
Statistical analyses were performed with the use of the
SAS system.15 To illustrate the relation between
a possible prognostic factor and the incidence of bleeding, baseline
variables were divided into quartiles, and the incidence of
vascular events in each quartile (Q1 through Q4) was calculated per
1000 patient-months. These quartiles were not used to test
relationships; for this, a Cox regression analysis was
performed.15 Two-tailed tests were performed and
a value of P
.05 was regarded as statistically significant.
RR was calculated as incidence Q4/incidence Q1.
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Results |
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The follow-up period comprised 9478 patient-months (mean, 3.7±1.2 years), which included 7839 months with anticoagulant treatment and 1639 without anticoagulant treatment. During anticoagulant treatment, 22 patients (11%) had at least one bleeding complication, and 14 (7%) suffered a serious bleed (Fig 1
). After
cessation of anticoagulant treatment, 1 patient had a subdural hematoma
and another had an episode of hematuria. The annual risks for any
hemorrhage during anticoagulation or not during
anticoagulation, respectively, were 3.4% and 1.5%, and for serious
hemorrhage, the annual risks were 2.1% and 0.6%. In one case,
serious bleeding occurred within the first year of anticoagulant
treatment (2.5 months after initiation of treatment). Two patients each
had three episodes with gastrointestinal bleedings. All others had one
bleeding episode. The sites of the hemorrhages are shown in
Table 2. Three hemorrhages were
fatal: one subdural hemorrhage, one subarachnoidal
hemorrhage, and one aortic rupture. Two of these patients had
TM values in the highest quartile (89 and 98 µg/L) and one had
values in the next highest quartile (57 µg/L). The last
recorded PT preceding a serious hemorrhage was above the
therapeutic interval (INR of 2.0 to 4.0) in 2 cases, within the
interval in 10 cases, and below it in 2 cases. The relations between
all hemorrhages and serious hemorrhage and the TM level
and PT value are demonstrated in Fig 2.
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In univariate Cox regression analyses, the following variables were included: age; sex; smoking habit; body mass index; systolic or diastolic blood pressure; ECG (normal/not normal); relative heart volume at roentgenography; type of anticoagulant drug (warfarin/dicumarol); prescribed dose of warfarin at baseline; indication for treatment; history of hypertension; heart disease; diabetes; connective tissue disorders; history of malignancy; prior peptic ulcer; prior recorded trauma; prior recorded bleeding episode during anticoagulant treatment; concomitant use of nonsteroid anti-inflammatory drugs, dipyridamole, or oral antidiabetic drugs; white blood cell count; platelet count; number of PT values below or above the therapeutic interval before inclusion; TM; vWF; and mass concentration of t-PA or its inhibitor, PAI-1.
With total hemorrhages as the response variable, mass concentrations of TM (P=.001, RR=1.024), and t-PA (P=.0268, RR=1.107) were related to events. With serious hemorrhage as the response variable, TM (P=.0001, RR=1.034), connective tissue disorder (P=.0056, RR=6.3), and treatment with oral antidiabetic drugs (P=.0078, risk ratio=7.9) were related to the event rate. In multivariate Cox regression analyses including variables significant in the univariate analyses, with serious bleeds as the response variable, mass concentrations of TM (P=.0001, RR=1.03) and connective tissue disorder (P=.0023, RR=5.9) were related to the event rate.
To illustrate the strength of the relationship, the absolute
numbers of patients with serious bleeding through quartiles 1 through 4
of the TM distribution are shown in Fig 3
(these quartiles were not used to test relationships). Serious
hemorrhages per 100 patient-years seemed to increase
exponentially with increasing TM concentration. Eleven of the 14 major
bleeds (79% of all major bleedings) occurred among the 75 patients
with TM >56 µg/L (36% of all patients), including all 3
fatal bleeds. In the group with a TM value <57 µg/L at
baseline sampling, the risk of serious bleeding was 0.53 per 1000
patient-months compared with 3.59 per 1000 patient-months if the value
was >56 µg/L. Thus, the RR of serious hemorrhage in
patients with a TM value >56 µg/L was calculated to be 6.77,
with a 95% CI of 1.89 to 24.26.
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A TM value >39 µg/L (upper limit of first quartile) had a
sensitivity of 93% and a specificity of 26% for detection of serious
bleeding, a TM value >50 µg/L (upper limit of second
quartile) had a sensitivity of 78% and a specificity of 52%, and a TM
value >61 µg/L (upper limit of third quartile) had a
sensitivity and a specificity of 50% and 77%, respectively. When a TM
value of 56 µg/L was used as the cutoff point, sensitivity was
79% and specificity was 68% (Fig 4).
With this cutoff point, the negative predictive value was 98% and the
positive predictive value was 15%.
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Five patients were treated with oral antidiabetic drugs, 2 of whom had serious bleeds. Four of the 10 patients with connective tissue disorders had serious bleeds.
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Discussion |
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The main finding of the present study is that plasma TM predicts the risk of bleeding in patients treated with oral anticoagulants. Several other variables that have previously been associated with bleeding were unrelated in this study, possibly due to size limitations, which demonstrates how powerful TM is as a predictor in this type of patient (cf Fig 3
). Among the other possible risk
factors, we did find positive associations with serious bleeding for
concomitant connective tissue diseases and treatment with oral
antidiabetics using the Cox regression analysis model. However,
the numbers of patients taking oral antidiabetics and patients with
connective tissue disease were few and could only explain a small
number of the bleeding events; furthermore, there were 29 variables
tested, and the probability values for these two variables were
>.0017 (.05/29); thus, we cannot rule out the possibility that these
associations are spurious and may be due to mass test significance. We have previously shown that increased levels of TM, like t-PA and PAI-1, are associated with vascular mortality in patients taking oral anticoagulants.16,17 However, the most likely consequence of a high level of TM would be an increased risk of bleeding due to its anticoagulant property by binding to thrombin and activating protein C, thereby inhibiting the coagulation cascade. The finding of a dose-response relationship between the TM level and the risk of bleeding strengthens the hypothesis that TM is a predictor of subsequent bleeding. The reason TM is elevated is still a matter of speculation, but high levels have been found in atheromatous disease10 and as a marker of vascular injuries in collagen vascular disease11 and in endothelial dysfunction.6 All this links TM to vascular endothelial dysfunction in general. Further studies are needed to clarify why and by which specific mechanism TM is increased in various cardiovascular disorders.
In a retrospective study of the present patients18 representing 696 patient-years, there were 6 major bleeds (0.9 per 100 patient-years). In patients with mechanical heart valve prostheses treated with coumarin derivatives, the incidence of major bleeding was 1.4 and the incidence of cerebral bleeding was 0.5 per 100 patient-years.20 In a Danish study of patients treated with vitamin K antagonists, the incidence of bleeding necessitating hospital admission was 2.7 per 100 patient-years.20 Independent risk factors for bleeding were older age (>75 years), hypertension, treatment with thiazide diuretics, and INR values >4.0. The risk of bleeding complications during anticoagulant treatment has also been reported to be related to an indication for treatment and was most marked in patients with ischemic cerebrovascular disease (29%), venous thromboembolism (23%), and ischemic heart disease (19%).21 Major bleeding was frequently associated with underlying risk factors (cancer, recent surgery) in venous thromboembolism, and major bleeding in cerebrovascular disease was almost always intracerebral. Hemorrhagic episodes frequently occurred when PT was within the targeted therapeutic range.21 In atrial fibrillation, the rate of annual serious hemorrhage has been reported to be 2.1%, and such hemorrhages are most likely to occur in those individuals with previous thromboembolism and among those with unstable PT control.22 Thus, the complication rate of 2.1% for serious hemorrhage and 0.3% for intracranial bleeding in the present study is representative of most similar studies. Lower rates have been reported from trials with patients with atrial fibrillation for whom the annual bleeding rates were 1.3% for major and 0.3% for intracranial hemorrhage.23 The longer the duration of warfarin therapy, the higher the risk of bleeding, and the probability of major hemorrhage increased almost linearly from 1 week through 5 years in patients with venous thromboembolism.24
There are, however, a number of limitations of the present study including, for instance, that the blood was sampled during anticoagulant treatment. Whether sampling before anticoagulant treatment is initiated or during antiplatelet therapy has the same predictive value must be evaluated in future studies. Because the observation time has been limited to <4 years, it is not possible to draw conclusions about lifelong therapy. The studied group is too small to allow subgroup analyses according to treatment indication, sex, age, and concomitant diseases or drug treatment. Whether prediction of the risk of hemorrhage by just one measurement of TM, as shown here, can be further improved by repetitive sampling is an important issue to be resolved. Forthcoming studies should also focus on the TM concentration in relation to the type of underlying cardiovascular disorder as well as the pathophysiological mechanisms involved.
Treatment with anticoagulants has doubled during the last decade and is likely to increase further due to findings in the atrial fibrillation and postmyocardial infarction trials25-28 and official recommendations.29 In Sweden, bleeding complications during anticoagulant treatment are the most common cause of drug-related mortality.30 It is quite obvious that there is a need for more efficient and safer strategies for oral anticoagulant therapy. In the European Atrial Fibrillation Trial,31 it was found that half of the hemorrhagic events occurred even when INR was within the therapeutic range. In our study, all fatal cases had PT values within the desired therapeutic limit. This implies a strong need for markers, of which TM may be one, to identify those patients with the highest risk of serious bleeding complications. This strategy will thus be of great importance in the clinical setting in initiating anticoagulant therapy and determining the duration and intensity of treatment.
Recently, disturbances in the fibrinolytic system and increased concentrations of vWF have been associated with increased risk of thrombotic cardiovascular events.32-39 It is suggested that basic research on the role of hemostasis in atherosclerosis and its thrombotic complications be given high priority because it is likely to become an important approach to prevention.40 This will improve the evaluation of risk and benefit so that treatment with a potent antithrombotic effect can be done safely. The present results add a new dimension to the concept by introducing a novel modality to assess the risk of the other side of the disease panorama facing these patient groups, namely, bleeding.
In conclusion, we describe the first measurement of a plasma factor that can predict an increased risk of developing hemorrhagic complications during oral anticoagulant treatment. Further prospective studies are needed to evaluate whether individualizing the prophylactic antithrombotic treatment on the basis of the patient's risk factor profile will actually affect outcome. Considering the large and growing patient group presently involved in oral anticoagulant treatment, the possible clinical implications of this finding may be important in improving the risk/benefit ratio of anticoagulant therapy.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by grants from the Swedish Medical Research Council (No. 08267), The National Association for Heart and Lung Patients, the Anny and Ragnar Wikstens foundation, and the Regional Councils of Northern Sweden. We are indebted to Kjell Pennert, Gothenburg for statistical advice.
Received October 24, 1996; revision received July 24, 1997; accepted August 5, 1997.
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