***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: In a recent r and omized , double-blind , placebo-controlled trial of women with a history of venous thromboembolism ( VTE ) , we found that hormone replacement therapy ( HRT ) was associated with an early excess risk of recurrent thrombosis . The aims of the present study were to characterize the effects of HRT on coagulation in these women to eluci date the mechanism(s ) by which HRT increases the risk of thrombosis . The study comprised 140 women who were r and omized to receive continuous treatment for 24 months with once daily 2 mg 17-beta-estradiol plus 1 mg norethisterone acetate  ( n = 71 ) or placebo ( n = 69 ) . HRT caused significant increases in prothrombin fragments 1 + 2 , thrombin-antithrombin complex , and D-Dimer after 3 months , but these changes were less pronounced on prolonged treatment . The increases in markers of activated coagulation was higher in those women who subsequently developed recurrent thrombosis , but was similar in carriers and non-carriers of the factor V Leiden mutation . HRT had no effects on fibrinogen and factor VIII . Activated factor VII , but not factor VII antigen , decreased significantly on HRT as compared with placebo . The coagulation inhibitors antithrombin , protein C , and TFPI , but not protein S , all showed significant sustained decreases in the HRT group as compared with placebo . Antithrombin and protein C decreased by 8 - 12 % on HRT , whereas TFPI activity decreased by 12 - 17 % and TFPI free antigen by 29 - 30 % . In multivariate analysis , only TFPI activity was a significant predictor for the increased activation of coagulation . We conclude that HRT was associated with early activation of coagulation , which corroborates the finding of an early risk of recurrent VTE . This activation may in part be explained by reduction in circulating anticoagulants BACKGROUND Elevated plasma D-dimer and factor VIII coagulant activity ( FVIIIc ) may be associated with the risk of recurrent venous thromboembolism ( VTE ) . OBJECTIVES To evaluate D-dimer and FVIIIc as risk factors for recurrent VTE and assess the efficacy of extended low-intensity warfarin ( target International Normalized Ratio 1.5 - 2.0 ) in preventing recurrence by biomarker level . PATIENTS AND METHODS In the Prevention of Recurrent Venous Thromboembolism trial , 508 idiopathic VTE patients treated for > or = 3 months with full-intensity warfarin , and who had stopped warfarin for 7 weeks on average , were r and omized to low-intensity warfarin or placebo  and followed for 2.1 years for recurrent VTE . Prer and omization blood sample s were analysed for D-dimer and FVIIIc . RESULTS One-third of participants had elevated baseline D-dimer ( > or = 500 ng mL(-1 ) ) and one-fourth , elevated FVIIIc ( > or = 150 IU dL(-1 ) ) . Adjusting for other risk factors , the hazard ratios ( HRs ) for recurrent VTE with elevated D-dimer or FVIIIc were 2.0 [ 95 % confidence interval ( CI ) 1.2 - 3.4 ] and 1.5 ( 95 % CI 0.8 - 2.8 ) , respectively . The association of elevated D-dimer with recurrence was larger among patients with one prior VTE ( HR 3.2 , 95 % CI 1.3 - 8.0 ) than in patients with more than one event ( HR 1.4 , 95 % CI 0.7 - 2.2 ) . For patients with one prior VTE on placebo , the annual recurrence incidence was 10.9 % with elevated D-dimer and 2.9 % with normal values . Low-intensity warfarin was equally effective in recurrence risk reduction in those with normal or elevated biomarkers . CONCLUSIONS Among patients with idiopathic VTE , measurement of D-dimer , but not FVIIIc , might be useful for risk stratification . The efficacy of extended low-intensity warfarin therapy did not vary by biomarker level OBJECTIVE Plasma markers of coagulation and fibrinolysis have proved sensitive in the initial diagnosis of acute deep venous thrombosis ( DVT ) . The purpose of this study was to examine the evolution and utility of measuring  D-dimer and prothrombin fragment 1 + 2 ( F 1 + 2 ) levels after an acute DVT . METHODS Subjects with DVT confirmed by ultrasonography had quantitative plasma D-dimer and F 1 + 2 levels determined before anticoagulation . Ultrasound scan and coagulation studies were repeated at 3 , 7 , and 14 days ; 1 month ; and every 3 months for 1 year . RESULTS Sixty-one patients with a median initial thrombus score of 3 ( interquartile range , 2 - 7 ) were followed up for 266 days ( interquartile range , 91.5 - 364 days ) . Initial D-dimer levels were elevated in 92.7 % of patients and were associated with thrombus extent ( P = .003 ) , whereas F 1 + 2 levels were increased in 94.5 % of patients and were lower in patients with isolated calf vein thrombosis ( P = .001 ) . Initial D-dimer ( P = .002 ) and F 1 + 2 levels ( P = .009 ) were significantly higher in the 26 ( 43 % ) patients with recurrent thrombosis during follow-up . Initial D-dimer levels of 2000 ng/mL or greater were predictive of recurrent events after both proximal and isolated calf vein thrombosis . Although interval increases in these markers had little value in detecting recurrent thrombotic events , D-dimer levels of 1000 ng/mL or greater and 500 ng/mL or greater had respective sensitivities of 89.3 % and 100 % in detecting early and late recurrences . Corresponding specificities were 35.6 % and 53.9 % . CONCLUSIONS Initial D-dimer levels are determined by total thrombus load and remain elevated long after an acute DVT . F 1 + 2 levels are less sensitive to thrombus score and return to baseline more quickly . Initial levels of these markers may have some utility in predicting the risk of ultrasound scan-documented recurrences , whereas increased D-dimer levels are a sensitive but nonspecific marker of these events PURPOSE To evaluate the accuracy and clinical utility of the Outpatient Bleeding Risk Index for estimating the probability of  major bleeding in out patients treated with warfarin .  The index was previously derived in a retrospective cohort of 556 patients from a different hospital ( derivation cohort ) . SUBJECTS AND METHODS We enrolled 264 out patients starting warfarin ( validation cohort ) to vali date the index prospect ively . All patients were identified upon hospital discharge , and physician estimates of the probability of major bleeding were obtained before discharge in the validation cohort . RESULTS Major bleeding occurred in 87 of 820 out patients ( 6.5%/yr ) . The index included four independent risk factors for major bleeding : age 65 years or greater ; history of gastrointestinal bleeding ; history of stroke ; and one or more of four specific comorbid conditions . In the validation cohort , the index predicted major bleeding : the cumulative incidence at 48 months was 3 % in 80 low-risk patients , 12 % in 166 intermediate-risk patients , and 53 % in 18 high-risk patients ( c index , 0.78 ) . The index performed better than physicians , who estimated the probability of major bleeding no better than expected by chance . Of the 18 episodes of major bleeding that occurred in high-risk patients , 17 were potentially preventable . CONCLUSIONS The Outpatient Bleeding Risk Index prospect ively classified patients according to risk of major bleeding and performed better than physicians . Major bleeding may be preventable in many high-risk patients by avoidance of over-anticoagulation and nonsteroidal anti-inflammatory agents Background We have shown that normal D‐dimer levels obtained after the discontinuation of oral anticoagulant treatment ( OAT ) has a high negative predictive value for recurrent venous thromboembolism ( VTE ) . The aim of the present study was to assess the predictive value of D‐dimer for recurrent VTE in subjects with a previous unprovoked event who are either carriers of inherited thrombophilia or not . Methods and Results We prospect ively evaluated 599 patients ( 301 males ) with a previous VTE episode . They were repeatedly examined for D‐dimer levels after OAT withdrawal and were screened for inherited thrombophilic alterations . Alterations were detected in 130 patients ( 21.7 % ) , factor V Leiden ( 70 patients ; 2 of whom were homozygotes ) and prothrombin mutation ( 38 patients ) were the most prevalent ones . Recurrent events were recorded in 58 subjects ( 9.7 % ) during a follow‐up of 870.7 patient‐years . Altered D‐dimer levels at 1 month after OAT withdrawal were associated with a higher rate of subsequent recurrence in all subjects investigated , especially in those with an unprovoked qualifying VTE event ( hazard ratio , 2.43 ; 95 % confidence interval , 1.18 to 4.61 ) and in those with thrombophilia ( hazard ratio , 8.34 ; 95 % confidence interval , 2.72 to 17.43 ) . The higher relative risk for recurrence of altered D‐dimer was confirmed by multivariate analysis after adjustment for other risk factors . The negative predictive value of D‐dimer was 92.9 % and 95.8 % in subjects with an unprovoked qualifying event or with thrombophilia , respectively . Conclusions D‐dimer levels measured 1 month after OAT withdrawal have a high negative predictive value for recurrence in subjects with unprovoked VTE who are either carriers or not carriers of congenital thrombophilia . ( Circulation . 2003;108:313‐318 . BACKGROUND The aim of the study was to determine the predictive value of D-dimer measurement for unprovoked recurrent venous thrombosis and the influence of sex , age and type of first event ( unprovoked or provoked ) . METHODS Prospect i ve cohort study of 272 patients with a first episode of venous thrombosis that was unprovoked or provoked by a non-surgical trigger . FINDINGS The cumulative rate of unprovoked recurrence in patients with a positive D-dimer was 20 % at 5 years [ 5.5/100 patient-years , 95 % confidence interval ( CI ) 3.7 - 7.8 ] and in patients with a negative D-dimer 17 % ( 4.1/100 patient-years , 95 % CI 2.3 - 6.9 ) . The rates are not different ( hazard ratio 1.3 , 95 % CI 0.7 - 2.5 ) . After adjustment for clinical risk factors a positive D-dimer result was significantly associated with an increased risk of unprovoked recurrent thrombosis ( hazard ratio 2.0 , 95 % CI 1.01 - 3.9 ) . The strongest indicator of risk of recurrence was male sex ( hazard ratio 3.3 unadjusted and 2.9 after adjustment ) . The only determinant of D-dimer in a linear regression model was age ( P < 0.001 ) . CONCLUSIONS The analysis indicates that clinical risk factors confound the association between D-dimer and risk of recurrence and when adjusted for these confounders a positive D-dimer result is significantly associated with unprovoked recurrence . The clinical utility of D-dimer measurement in individual patients should be interpreted in conjunction with clinical risk factors CONTEXT Data on the recurrence rate of venous thrombotic events and the effect of several risk factors , including thrombophilia , remain controversial . The potential benefit of screening for thrombophilia with respect to prophylactic strategies and duration of anticoagulant treatment is not yet known . OBJECTIVES To estimate the recurrence rate of thrombotic  events in patients after a first thrombotic event and its determinants , including thrombophilic abnormalities . DESIGN , SETTING , AND PATIENTS Prospect i ve follow-up study of 474 consecutive patients aged 18 to 70 years without a known malignancy treated for a first objective ly confirmed thrombotic event at anticoagulation clinics in the Netherl and s. The Leiden Thrombophilia Study ( LETS ) was conducted from 1988 through 1992 and patients were followed up through 2000 . MAIN OUTCOME MEASURES Recurrent thrombotic event based on thrombophilic risk factors , sex , type of initial thrombotic event ( idiopathic or provoked ) , oral contraceptive use , elevated levels of factors VIII , IX , XI , fibrinogen , homocysteine , and anticoagulant deficiencies . RESULTS A total of 474 patients were followed up for mean ( SD ) of 7.3 ( 2.7 ) years and complete follow-up was achieved in 447 ( 94 % ) . Recurrence of thrombotic events occurred in 90 patients during a total of 3477 patient-years . The rate of thrombotic event recurrence was 25.9 per 1000 patient-years ( 95 % confidence interval [ CI ] , 20.8 - 31.8 per 1000 patient-years ) 
    Output:
    
Implication d-dimer tests are a promising method for discriminating between patients with higher and lower risks for recurrent VTE .
However , recent r and omized trials indicate that the duration of anticoagulation seems to have little effect on the rate of disease recurrence in patients with unprovoked VTE ; longer treatment only delays recurrence until after anticoagulation is stopped ( 5 , 6 ) .
This decision is important because stopping anticoagulant therapy may place some patients at risk for morbidity and mortality due to recurrent VTE , whereas continuing anticoagulation exposes patients to the increased bleeding risk , inconvenience , and costs of such treatment .