The risk of recurrent venous thromboembolism

Venous thromboembolism (VTE) is a chronic rather than acute disease. After withdrawal of secondary thromboprophylaxis, many patients will experience a subsequent episode of thrombosis. Of these patients, approximately 5% will die from pulmonary embolism. The risk of recurrent VTE depends on the number of risk factors and their severity. High-risk patients, i.e. those with a natural coagulation inhibitor deficiency, recurrent thrombosis, active cancer, the lupus anticoagulant or compound clotting defects most probably benefit from indefinite oral anticoagulation. In these patients the risk of bleeding due to anticoagulant treatment seems to be outweighed by the risk of VTE. Patients with hyperhomocysteinemia or high factor (F) VIII plasma levels are also at an increased risk of recurrence. The optimal duration of secondary thromboprophylaxis in these patients is currently under investigation. Patients with the heterozygous F V Leiden mutation or the G20210A mutation in the F II gene do not require extended anticoagulation since their risk of recurrence is similar as in patients without the aforementioned mutations. Patients with VTE secondary to surgery or trauma have a relatively low risk of recurrence. In these patients short-term secondary thromboprophylaxis (6 to 12 weeks) is justified whereas patients with a first episode of spontaneous VTE should be treated with oral anticoagulants for a longer period of time (3 to 6 months).     

Increased plasma levels of lipoprotein(a) and the risk of idiopathic and recurrent venous thromboembolism

PURPOSE: Elevated lipoprotein(a) [Lp(a)] levels are a recognized risk factor for cardiovascular disease; however, little is known about their effects on venous thromboembolism. METHODS: We conducted a case-control study of 603 adult patients with a history of venous thromboembolism (at least 6 months after the acute event) and 430 healthy subjects. We measured Lp(a), homocysteine, and antithrombin levels, factor V Leiden and factor II (prothrombin) polymorphisms, and anticardiolipin antibodies. RESULTS: Lp(a) levels >300 mg/L were found in 24% (n = 146) of the patients and in 13% (n = 58) of the controls (P = 0.005). In a multivariate analysis adjusted for acquired and hemostasis-related risk factors, there was an independent association between elevated (>300 mg/L) Lp(a) levels and venous thromboembolism (odds ratio = 2.1; 95% confidence interval: 1.4 to 3.2; P = 0.002). These results were confirmed in the 341 patients with idiopathic venous thromboembolism, as well as in those with recurrent thromboembolism. CONCLUSION: These results show that Lp(a) is an independent risk factor for venous thromboembolism in adults, suggesting that it may be involved in the pathogenesis of idiopathic and recurrent disease.     

Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism

BACKGROUND: In patients with a first symptomatic pulmonary embolism (PE), the risk of recurrence is unknown. We therefore investigated the risk of recurrence among patients with spontaneous symptomatic PE and among those with deep vein thrombosis (DVT) without symptoms of PE. METHODS: After discontinuation of secondary thromboprophylaxis for a first venous thromboembolism (VTE), we prospectively observed 436 patients for an average of 30 months. Patients with secondary VTE, natural inhibitor deficiencies, lupus anticoagulant, cancer, long-term antithrombotic therapy, vena cava filters, or pregnancy were excluded. The study outcome was objectively documented recurrent symptomatic VTE. RESULTS: Recurrent VTE was seen among 28 (17.3%) of 162 patients with symptomatic PE and among 26 (9.5%) of 274 patients with DVT without symptoms of PE. Compared with patients with DVT, the relative risk of recurrent VTE among patients with symptomatic PE was 2.2 (95% confidence interval, 1.3-3.7; P =.005). The relative risk was not affected by age, sex, presence of factor V Leiden or prothrombin G20210A, hyperhomocysteinemia, or high factor VIII levels. Compared with patients with DVT without symptoms of PE, patients with symptomatic PE had an adjusted relative risk of PE at recurrence of 4.0 (95% confidence interval, 1.3-12.3; P =.03). CONCLUSION: Patients with a first symptomatic PE not only have a higher risk of recurrent VTE than those with DVT without symptoms of PE, but are also at high risk of symptomatic PE at recurrence.     

Thrombin-activatable fibrinolysis inhibitor and the risk for recurrent venous thromboembolism

The impact of fibrinolysis for predicting the risk for recurrent venous thromboembolism (VTE) is low. We prospectively followed up 600 patients with a first VTE and evaluated the thrombin-activatable fibrinolysis inhibitor (TAFI) as a risk factor for recurrence. A high TAFI level (75th or higher percentile in thrombosis patients) was associated with a 2-fold higher risk for recurrence compared with lower levels. The probability of recurrence 2 years after anticoagulation was 14.5% (95% confidence interval [CI], 8.6-20.4) among patients with high TAFI levels and 6.8% (95% CI, 4.3-9.3) among patients with lower levels (P =.006). Our data also support the concept of a linkage between fibrinolysis and the coagulation system. Patients with high TAFI levels had significantly higher levels of factors XI, VIII, and IX, and a high risk of recurrence was seen among patients with high TAFI levels and high levels of one of these factors. The relative risk (RR) for recurrence was highest among patients with high TAFI and high factor XI (RR, 2.9; 95% CI, 1.3-6.9), high factor VIII (RR, 6.5; 95% CI, 2.9-14.8), or high factor IX (RR, 2.0; 95% CI, 1.0-3.9) levels compared with patients with low levels of TAFI and one of these factors.     

High-density lipoprotein cholesterol and venous thromboembolism in the Longitudinal Investigation of Thromboembolism Etiology (LITE)

We determined prospectively the risk of venous thromboembolism (VTE) in relation to baseline high-density lipoprotein cholesterol (HDL-c) in 19 049 participants of the Longitudinal Investigation of Thromboembolism Etiology (LITE), which was composed of 14 490 participants of the Atherosclerosis Risk in Communities (ARIC) study and 4559 participants of the Cardiovascular Health Study (CHS). In addition, we determined the risk of VTE in relation to baseline subfractions of HDL (HDL(2) and HDL(3)) and apolipoprotein A-I (apoA-I) in 14 488 participants of the ARIC study. Age-adjusted incidence rates of VTE by HDL-c quartile ranged from 1.64 to 1.91 per 1000 person-years in men and 1.40 to 1.94 per 1000 person-years in women; however, there was no apparent trend of VTE incidence across HDL-c quartiles for either sex. The multivariate adjusted hazard ratios of VTE by HDL-c quartiles (with quartile 4 as the reference) were nonsignificant for both sexes and ranged between 0.91 and 0.99 for men and 0.78 and 1.22 for women. Results did not differ in separate evaluations of idiopathic and secondary VTE. In the ARIC study, there was no trend of VTE hazard ratios across quartiles of HDL(2), HDL(3), or apoA-I. Low HDL-c does not appear to be an important VTE risk factor.     

Circumstances of provoked recurrent venous thromboembolism: the Austrian study on recurrent venous thromboembolism

Journal of Thrombosis and Thrombolysis - Patients with unprovoked deep-vein thrombosis (DVT) of the leg or pulmonary embolism (PE) have a high recurrence risk. How often these recurrences are...     

Low vitamin B6 levels and the risk of recurrent venous thromboembolism

Low plasma vitamin B6, measured as pyridoxal-5'-phosphate (PLP), is associated with an increased risk of first venous thromboembolism (VTE). In a prospective cohort of 757 patients with first VTE we investigated the association of PLP levels with risk of recurrent VTE. After 4 years, the likelihood of VTE recurrence among patients with PLP < or =23.3 nmol/L and 14.4% (11.5%-17.4%) among those with PLP >23.3 nmol/L was 22.5% (95% CI 13.6%-31.5%) (p=0.01). Patients with PLP '23.3 nmol/L had 1.8-fold higher recurrence risk (1.01-3.14) than patients with PLP >23.3 nmol/L (adjusted for confounders including homocysteine). Therefore, low vitamin B6 is a risk factor of recurrent VTE.     

The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first spontaneous venous thromboembolism

BACKGROUND: Factor V (FV) Leiden is a risk factor for venous thrombosis (VT). Data on its influence on the risk of recurrent venous thromboembolism (VTE) are controversial owing to different study designs and patient cohorts. METHODS: We reevaluated the risk of recurrence among heterozygous carriers and noncarriers of FV Leiden with a first spontaneous proximal VT of the leg and/or pulmonary embolism. Patients with secondary VTE, homozygous FV Leiden, natural inhibitor deficiencies, lupus anticoagulant, cancer, or long-term anticoagulation were excluded. The study end point was objectively documented, symptomatic, recurrent VTE. RESULTS: After discontinuation of oral anticoagulant therapy for a first VTE, we prospectively observed 287 patients, 83 (29%) of whom were heterozygous for FV Leiden. Recurrent VTE was seen in 17 (20%) of 83 patients with and 44 (21.6%) of 204 without FV Leiden. The probability of recurrence among heterozygotes was 12% (95% confidence interval [CI], 8%-16%), 27% (95% CI, 21%-33%), and 27% (95% CI, 21%-33%) after 2, 4, and 6 years, respectively, and was not higher than that among patients without the mutation (16%, 23%, and 34%, respectively). The relative risk of recurrence in heterozygotes was 0.9 (95% CI, 0.5-1.6; P =.60) after adjustment for confounding variables. The risk of recurrence among patients with and without FV Leiden was not different when sex distribution or duration of anticoagulation therapy was taken into account. CONCLUSIONS: The risk of recurrence is similar among carriers and noncarriers of FV Leiden. Heterozygous patients should receive secondary thromboprophylaxis for a similar length of time as patients without FV Leiden.     

FV Leiden mutation and risk of recurrent venous thromboembolism in Serbian population

The absolute rate of recurrence of venous thromboembolism (VTE) is approximately 5% per year. There is a lower rate of recurrence in provoked VTE, and higher in idiopathic one. So far, there is no consensus whether hereditary thrombophilia should be considered as a persistent risk factor, and whether it requires long-term anticoagulant therapy. The aim of our study was to estimate the risk of recurrent VTE in patients carrying FV Leiden mutation in Serbian population.In retrospective study (1994-2006), we have evaluated the risk of recurrent VTE in 56 patients who are carriers of FV Leiden mutation, in comparison to group consisting of 56 patients non-carriers of FV Leiden mutation. Patients with FII G20210A and MTHFR C677T mutations, antiphospholipid antibodies, antithrombin III, protein C or protein S deficiency, malignancies and diabetes were excluded from the study.Recurrent VTE occurred in 44.6% of the patients, carriers of the FV Leiden mutations, vs. 26.7% in non-carriers group (P<0.05). The incidence rate was 3.7 and 2.2% per year, respectively. The estimated relative risk of recurrence for FV Leiden carriers was 1.67 (95% CI 0.99-2.81, P=0.049). The 60% of patients with mutation and only 13% without mutation develop rethrombosis during first year after discontinuance of therapy (P<0.01).In our study patients with symptomatic VTE who are carriers of the FV Leiden gene mutations have a higher risk of recurrent VTE than non-carriers. Our data suggest the importance of the FV Leiden mutation detection and the estimation of the clinical condition for successful secondary prophylaxis of VTE.     

Posttreatment ultrasound-detected residual venous thrombosis: a risk factor for recurrent venous thromboembolism and mortality

PURPOSE OF REVIEW: The cumulative risk of recurrent venous thrombosis may rise to 30% over 8 years. Extended oral anticoagulation is effective but major bleeding is increased. To balance these risks attention has focused on identifying patients with the highest likelihood of recurrence for whom continued therapy is most beneficial. Another issue of interest has been the increased probability of death after venous thrombosis, due primarily to malignancy but also to vascular disease. RECENT FINDINGS: Unprovoked events and cancer are known to be associated with recurrent thrombosis. Residual posttreatment thrombosis confirmed by compression ultrasound is regarded as another risk for recurrence. Confounders in the published studies are the patient mix and the ultrasound technique employed. Other variables such as gender and D-dimer may also predict risk. Although arterial disease is increased in patients with venous thromboses, the association between idiopathic venous thromboembolism and atherosclerosis remains circumstantial. SUMMARY: There are no validated approaches for predicting recurrent venous events. Ultrasound interrogation for residual thrombosis after primary therapy may improve treatment stratification by defining patients suitable for extended anticoagulation.     

The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis

Whether or not pregnant women with a previous episode of venous thromboembolism (VTE) should receive antithrombotic prophylaxis is a matter of debate. In order to estimate the rate of recurrent deep venous thrombosis (DVT) or pulmonary embolism (PE) during pregnancy and puerperium we retrospectively investigated a cohort of 1104 women with previous VTE; after a single DVT or isolated PE, 88 of them became pregnant at least once without receiving antithrombotic prophylaxis. Overall, 155 pregnancies and 120 puerperium periods without prophylaxis were recorded. There were nine recurrences during pregnancy and 10 during puerperium, with a rate of 5.8% [95% confidence interval (CI) 3.0-10.6] and 8.3% (95%CI 4.5-14.6) respectively. In pregnancy, the rate of recurrence was 7.5% (95%CI 4.0-13.7) if the first VTE was unprovoked, related to pregnancy or to oral contraceptive use, whereas no recurrence occurred if the first VTE was related to other transient risk factors. In puerperium, the rate of recurrence was 15.5% (95%CI 7.7-28.7) in women with a pregnancy-related first VTE, with a risk 3.9-times higher than in the remaining women. Inherited thrombophilia was not associated with a statistically significant increase in risk of recurrence in pregnancy or in puerperium, yet the rate of recurrence in puerperium was 14.2% (95%CI 5.7-31.4) in overall carriers of factor V Leiden and 30% (95%CI 10.7-60.3) in carriers with a pregnancy-related first VTE, with a risk 6.8 times higher than in women without thrombophilia and with a non pregnancy-related first VTE.     

G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism

OBJECTIVES: The study was done to determine whether the G20210A mutation in the prothrombin gene increases the risk of recurrent venous thromboembolism (VTE), both alone and in combination with factor V Leiden. BACKGROUND: Several inherited defects of coagulation are associated with increased risk of first VTE, including a recently identified G20210A mutation in the prothrombin gene. However, whether the presence of this mutation confers an increased risk of recurrent venous thromboembolism is controversial. METHODS: A total of 218 men with incident venous thromboembolism were genotyped for the prothrombin mutation and for factor V Leiden and were followed prospectively for recurrent VTE over a follow-up period of 7.3 years. RESULTS: A total of 29 men (13.3%) suffered recurrent VTE. Five of the 14 carriers of the prothrombin mutation developed recurrent VTE (35.7%; incidence rate = 8.70 per 100 person-years), while 24 of 204 individuals who did not carry the prothrombin mutation developed recurrent VTE (11.8%; incidence rate = 1.76 per 100 person-years). Thus, presence of the G20210A mutation was associated with an approximate fivefold increased risk for recurrent VTE (crude relative risk [RR] 4.93; 95% confidence interval [CI] 1.9-12.9; p = 0.001; age-, smoking-, and body mass index-adjusted RR 5.28; 95% CI 2.0-14.0; p = 0.001). In these data, recurrence rates were similar among those with an isolated mutation in the prothrombin gene (18.2%) as compared to those with an isolated factor V Leiden mutation (19.2%). However, all three study participants who carried both mutations (100%) suffered a recurrent event during follow-up. CONCLUSIONS: In a prospective evaluation of 218 men, the presence ofprothrombin mutation was associated with a significantly increased risk of recurrent VTE, particularly among those who co-inherited factor V Leiden.     

Gender and the risk of venous thromboembolism

The role of gender in the causation of first and recurrent venous thromboembolism (VTE) is uncertain. The use of hormonal therapy and pregnancy has been associated with VTE in women. Epidemiological studies have described a higher incidence of first VTE in women of childbearing age. Nevertheless, no consistent differences in the overall incidence of VTE between males and females have been found. Recent studies have shown that women exhibit a lower risk of recurrent VTE than men, although these data were not confirmed in other studies that evaluated only women with idiopathic VTE. This article reviews the role of gender as a risk factor for first and recurrent VTE.     

Risk prediction of recurrent venous thromboembolism: a multiple genetic risk model

Journal of Thrombosis and Thrombolysis - A single genetic biomarker is unable to accurately predict the risk for venous thromboembolism (VTE) recurrence. We aimed to: (a) develop a multiple single...