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.     

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).     

Clotting activation after oral anticoagulant therapy discontinuation: a risk factor for recurrent venous thromboembolism.

A hypercoagulable state has been reported in some patients treated for venous thromboembolism (VTE) after oral anticoagulant treatment (OAT) discontinuation. It is unclear whether this is a risk factor for thrombosis recurrence. We investigated 139 patients with VTE and followed them up for a median of 20.5 months (6-90 months) to evaluate whether fragment 1 + 2 (F1 + 2) plasma levels are prognostic for VTE recurrence and to confirm clotting activation after OAT withdrawal. Fourteen patients had recurrences during the follow-up. F1 + 2 was measured the day before OAT withdrawal (T0) and 4 weeks later (T1) and its levels were similar in patients with spontaneous VTE versus those with transient risk factors for VTE. F1 + 2 levels increased from T0 to T1 (P < 0.0005). At T1, F1 + 2 values were significantly higher in patients with recurrence than in those without (P < 0.005). The negative predictive value of normal levels of F1 + 2 at T1 was 95%. In carriers of thrombophilic conditions no correlation was found between F1 + 2 levels and VTE recurrence. The results of this study confirm clotting activation after OAT discontinuation and suggest that higher F1 + 2 plasma levels are an independent risk factor for VTE recurrence.     

Testicular vein thrombosis: Incidence of recurrent venous thromboembolism and survival

Purpose

Testicular vein thrombosis (TVT) etiology, recurrence, and survival were compared with lower extremity deep vein thrombosis (DVT) in order to determine whether treatment guidelines for DVT could be applied to TVT.

Patients and Methods

An inception cohort of patients with confirmed TVT (January 1995‐October 2015) was compared to a control group of patients with lower extremity DVT matched by age, gender, and diagnosis date.

Results

Thirty‐nine men with TVT were identified; 15 (38%) with isolated TVT. Left testicular vein was affected in 77% patients; there were no cases of bilateral TVT. Cancer was over twofold more common in TVT patients (59% vs 28%, P = .01). Most cancers (78%) involved organs in proximity to the testicular vein. Although TVT patients were less frequently treated with anticoagulants (49% vs 97%, P = .0001), recurrence rates were similar to DVT group (TVT 4.2 vs DVT 1.1 per 100 patient‐years, P = .11). Despite higher cancer prevalence, survival rates were similar between groups (31% vs 28%; P = .34). Major bleeding events were rare (one patient per group).

Conclusions

Identifying TVT should prompt a search for a regional malignancy. Despite the high cancer prevalence and low utilization of anticoagulants, recurrent venous thrombosis and mortality rates are similar to DVT patients.     

HIV infection is a risk factor for venous thromboembolism

The reported incidence of venous thromboembolism (VTE) in patients with human immunodeficiency virus (HIV) infection has ranged from 0.25 to 0.96% in clinical studies, but up to 17% at autopsy. A preliminary analysis at our hospital suggested that the frequency of VTE among HIV-positive individuals might be higher than previously reported. To further evaluate this issue, we performed a retrospective study of patients with a diagnosis of VTE and/or HIV infection discharged from our hospital between July 1, 1998 and June 30, 1999. A total of 13,496 patients were discharged during the year of the study. There were 244 patients with VTE and 362 who were HIV-positive. Ten of the 244 patients with VTE were HIV-positive (4.1%). The frequency of VTE among HIV-positive individuals was 10/362 (2.8%) compared to 234/13134 (1.8%) in the non-HIV-positive group, but the difference is not statistically significant. However, in patients under age 50, the frequencies were significantly different: 10/302 (3.31%) versus 35/6594 (0.53%), respectively (p < 0.0001). The frequency of VTE in HIV-positive patients less than 50 years old (3.31%) was greater than in HIV-positive patients over 50 years of age (0/60), but the difference did not reach statistical significance. In contrast, in the non-HIV-positive group, VTE was significantly more frequent in those 50 and older compared to younger patients (3.04% versus 0.53%, p = 0.0001). Statistical analysis indicated that the direction of association between age and diagnosis of VTE differed for HIV-positive patients versus non-HIV-positive patients. Our results suggest that HIV-positive patients under age 50 are at increased risk for VTE compared with non-HIV-positive individuals.     

Hyperhomocysteinemia: a risk factor for arterial and venous thrombosis]

Homocysteine is a sulfur-containing amino acid intermediate involved in two metabolic pathways, in the remethylation to methionine and in the transsulfuration to cysteine. Severe hyperhomocysteinemia (> 100 mumol/l) is found in congenital homocystinuria. Moderate (15-30 mumol/l) or intermediate (> 30-100 mumol/l) hyperhomocysteinemia is caused by defects in genes encoding for enzymes of homocysteine metabolism or by inadequate intake of those vitamins that are involved in homocysteine metabolism (folic acid, cobalmin, and vitamin B6). Today, hyperhomocysteinemia should be considered an important risk factor for atherosclerotic vascular and venous thromboembolic diseases. Homocysteine-plasma levels above the 95th percentile were found to be associated with a 2 to 3-fold elevated relative risk for deep-vein thrombosis and pulmonary embolism. Moreover, mild hyperhomocysteinemia has been shown to be associated with a 2 to 4-fold increased relative risk for coronary artery disease, cerebrovascular disease, and peripheral arterial occlusive disease. Several mechanisms have been proposed by which hyperhomocysteinemia contributes to atherogenesis and thrombogenesis. Several studies have shown that hyperhomocysteinemia can be corrected by supplementation of folic acid, cobalamin and vitamin B6. Clinical trials are urgently needed which investigate the preventive effect of supplementation of these vitamins on thrombotic diseases.     

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.     

Obesity as a risk factor in venous thromboembolism

PURPOSE: Whether obesity is an independent risk factor for pulmonary embolism or deep venous thrombosis has not been fully determined. METHODS: We used the database of the National Hospital Discharge Survey to further investigate the potential risk of obesity in venous thromboembolic disease. RESULTS: The relative risk of deep venous thrombosis, comparing obese patients with non-obese patients, was 2.50 (95% confidence interval [CI] = 2.49-2.51). The relative risk of pulmonary embolism was 2.21 (95% CI = 2.20-2.23). Obese females had a greater relative risk for deep venous thrombosis than obese males, 2.75 (95% CI = 2.74-2.76) versus 2.02 (95% CI = 2.01-2.04). Obesity had the greatest impact on both men and women aged less than 40 years. CONCLUSION: The data indicate that obesity is a risk factor for venous thromboembolic disease in men as well as women.     

Antiphospholipid antibodies as risk factor for venous thromboembolism

The aim of the following study was to determine the prevalence of lupus anticoagulant (LA) and anticardiolipin antibodies (ACL) in patients with a history of venous thromboembolism (VTE). The patient group comprised 218 subjects with VTE before the age of 45, recurrent VTE or thrombosis in an unusual site. The control group consisted of 218 age, and sex-matched healthy individuals. LA and/or ACL were detected in 19 among 218 patients (8.7%). Lupus anticoagulant was found in 17 patients with VTE and in none out of 218 controls. The odds ratio for having venous thromboembolism was 14.1 (95% CI: 1.8-108.8) for patients with LA. Lupus anticoagulant is significantly associated with VTE. The prevalence of anticardiolipin was similar in patients and in controls. The results of our study indicate that anticardiolipin antibodies are not associated with venous thromboembolism.     

Minor injuries as a risk factor for venous thrombosis

BACKGROUND: Injuries increase the risk of venous thrombosis. So far, most research has focused on major injuries that are accompanied by other risk factors for venous thrombosis, such as plaster casts and surgery. We studied the association of venous thrombosis with common minor injuries, such as minor sural muscle ruptures and ankle sprains. METHODS: We performed a large, population-based, case-control study (the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA] study), including consecutive patients with a first deep venous thrombosis of the leg or pulmonary embolism and control subjects. Participants with malignant neoplasms, those who underwent surgery, and those who had a plaster cast or extended bed rest were excluded. RESULTS: Of 2471 patients, 289 (11.7%), and of 3534 controls, 154 (4.4%) had a minor injury in the 3 months preceding the venous thrombosis (patients) or completion of the questionnaire (controls). Venous thrombosis was associated with previous minor injury (odds ratio adjusted for sex and age, 3.1; 95% confidence interval, 2.5-3.8). The association was strongest for injuries that occurred in the 4 weeks before thrombosis and was not apparent before 10 weeks. Thrombosis was more strongly associated with minor injuries located in the leg (odds ratio adjusted for sex and age, 5.1; 95% confidence interval, 3.9-6.7), while those located in other body parts were not associated. A 50-fold increased risk was found in factor V Leiden carriers with a leg injury compared with noncarriers without injury (odds ratio, 49.7; 95% confidence interval, 6.8-362.7). CONCLUSIONS: Minor injuries in the leg are associated with greater risk of venous thrombosis. Because minor injuries are common, they could be major contributors to the occurrence of venous thrombosis.     

Clinical implications of different risk factor profiles in patients with mesenteric venous thrombosis and systemic venous thromboembolism: a population-based study

Journal of Thrombosis and Thrombolysis - It is unknown whether the risk factor profile for mesenteric venous thrombosis (MVT) is different from systemic venous thromboembolism (VTE). The aim of the...     

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...     

Usefulness of antithrombin deficiency phenotypes for risk assessment of venous thromboembolism: type I deficiency as a strong risk factor for venous thromboembolism

Inherited antithrombin deficiency, an established risk factor for venous thromboembolism (VTE), can be classified into type I (quantitative deficiency) or type II (qualitative deficiency). In the present study, we assessed the VTE risk associated with the phenotypes of antithrombin deficiency in patients admitted to our hospital. We found that patients with type I deficiency (n = 21) had more VTE events and earlier onset of VTE than those with type II deficiency (n = 10). The VTE-free survival analysis showed that the risk for VTE in patients with type I deficiency was sevenfold greater than that in patients with type II deficiency (hazard ratio: 7.3; 95% confidence interval: 1.9–12.2; P = 0.0009). The prevalence of type I deficiency in the VTE group (5.6%, 6/108) was higher than that in the general population (0.04%, 2/4,517) (odds ratio: 132.8; 95% confidence interval: 26.5–666.1; P < 0.0001). However, the prevalence of type II deficiency was not different between the VTE group and the general population. Our study indicated that the risk for VTE in patients with type I deficiency was much higher than that in patients with type II deficiency. Thus, simple phenotypic classification of antithrombin deficiency is useful for assessment of VTE risk in Japanese.     

Deep venous thrombosis and previous myocardial infarction in mild factor XII deficiency: a risk factor for both venous and arterial thrombosis

Factor XII deficiency is associated with increased risk for both arterial and venous thrombosis. We describe a case of DVT involving superficial femoral and popliteal vein occurred following total hip replacement and despite prophylaxis with low molecular weight heparin in a subject with previous acute myocardial infarction (AMI). Tests of haemostasis documented a slightly prolonged activated partial thromboplastin time (APTT) (45′′) due to mild factor XII deficiency (clotting activity 32%). A therapeutic dose of enoxaparin was started, together with warfarin therapy. The patient was advised to continue oral anticoagulation indefinitely. Although cases of both venous and arterial thrombosis in carriers of severe factor XII deficiency have been already reported, to our knowledge this is the first case in the literature occurred in a carrier of partial factor XII deficiency. In conclusion, factor XII deficiency should be suspected if a patient presents with recurrent arterial and/or venous thrombosis and prolonged APTT. If this defect is diagnosed, in the presence of a history of thrombotic events, lifelong anticoagulation could be considered.