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It is not known whether the synergistic effect of genetic markers, increasing the risk of venous thrombosis (VT), and combined oral contraceptives (COC) use varies between different types of progestogens in these preparations. We investigated the joint effect of genetic risk factor, that is, F5 rs6025, F2 rs1799963, and FGG rs2066865 mutations, and different progestogens on the risk of VT. The constrained maximum likelihood estimation (CMLE) method was used to calculate joint effects, expressed as odds ratio (OR) with 95% confidence intervals [CI]. As the dose of estrogen is known to be a risk factor for VT, analyses were restricted to COC with 30 mu g estrogen and each progestogen. Overall, the joint effect of COC and genetic variants was lowest for COC containing the progestogen levonorgestrel, albeit CIs were wide. The OR (95% CI) of the four different analyses (i.e. joint effect with F5 rs6025, F2 rs1799963, F5 rs6025 or F2 rs1799963 and FGG rs2066865) ranged between 7 center dot 4 (5 center dot 4-10 center dot 2) and 24 center dot 8 (12 center dot 3-50 center dot 0) for levonorgestrel. For gestodene the joint effect ranged between 11 center dot 7 (7 center dot 2-19 center dot 1) and 30 center dot 9 (10 center dot 6-89 center dot 9). Desogestrel and cyproterone acetate had the highest risk estimates: 14 center dot 6 (9 center dot 7-21 center dot 9) and 32 center dot 6 (13 center dot 2-80 center dot 6) and 15 center dot 5 (9 center dot 7-24 center dot 9) and 44 center dot 4 (16 center dot 9-116 center dot 3) respectively. In women with inherited thrombophilia, COC containing levonorgestrel were associated with the lowest risk of VT, albeit the CIs were wide.

The role of the fibrinolytic system in the development of venous thrombosis (VT) is unclear. We studied the risk of first and recurrent VT associated with reduced fibrinolysis, as measured by clot lysis time (CLT). We also studied the relationship between CLT and thrombin generation to determine if any relationship between CLT and VT was affected by thrombin generation. Analyses were performed in the Thrombophilia Hypercoagulability Environmental risk for Venous Thromboembolism Study, a two-centre population-based case-control study, including 579 patients and 338 controls, with patients followed from the event to determine incidence of recurrent VT. Hypofibrinolysis was associated with a 1·8-fold increased risk of a first VT [95% confidence interval (CI) 1·2-2·7]. Adjustment for sex, age, study location and Endogenous Thrombin Potential (ETP) did not change the result. The risk of VT was 2·9-fold increased when the 90th percentiles of prolonged CLT and high ETP were combined, with the highest risk for unprovoked first events (Odds Ratio = 4·2, 95% CI 1·3-13·5). In the follow-up study the Hazard Ratio for a recurrent VT associated with hypofibrinolysis was 1·5 (95% CI 0·9-2·6). A weak dose response effect was observed in relation to prolongation of CLT and recurrent VT. Although hypofibrinolysis constitutes a risk factor for a first VT, an association with recurrence is, at best, weak.

Venous thrombosis is common in older age, with an incidence of 0·5-1% per year in those aged >70 years. Stasis of blood flow is an important contributor to the development of thrombosis and may be due to venous insufficiency in the legs. The risk of thrombosis associated with clinical features of venous insufficiency, i.e., varicose veins, leg ulcers and leg oedema, obtained with a standardized interview was assessed in the Age and Thrombosis Acquired and Genetic risk factors in the Elderly (AT-AGE) study. The AT-AGE study is a case-control study in individuals aged 70 years and older (401 cases with a first-time venous thrombosis and 431 control subjects). We calculated odds ratios (ORs) and corresponding 95% confidence intervals (CI) adjusted for age, sex and study centre. Varicose veins and leg ulcer were associated with a 1·6-fold (95% CI 1·2-2·3) and 3·3-fold increased risk of thrombosis (95% CI 1·6-6·7), respectively, while the risk was increased 3·0-fold (95% CI 2·1-4·5) in the presence of leg oedema. The risk of thrombosis was highest when all three risk factors occurred simultaneously (OR: 10·5; 95% CI 1·3-86·1). In conclusion, clinical features of venous insufficiency, i.e., varicose veins, leg ulcers and leg oedema, are risk factors for venous thrombosis in older people.

Thrombophilia can be identified in about half of all patients presenting with venous thrombosis. Testing has increased tremendously for various indications, but whether the results of such tests help in the clinical management of patients has not been settled. Here, we review the most commonly tested thrombophilic abnormalities, i.e. protein C, protein S, and antithrombin deficiencies, the F5 R506Q (factor V Leiden) and F2 G20210A (prothrombin G20210A) mutations, and elevated levels of coagulation factor VIII, and their association with venous and arterial thrombosis as well as pregnancy complications. We conclude that testing for hereditary thrombophilia generally does not alter the clinical management of patients with venous or arterial thrombosis or pregnancy complications. Because testing for thrombophilia only serves limited purpose this should not be performed on a routine basis.

Activated protein C (APC) resistance, determined with a thrombin-generation-based APC resistance test, may explain risk differences of venous thrombosis in users of second- and third-generation oral contraceptives (OC). To clinically validate this test, we analysed the Leiden thrombophilia case-control study (474 patients with a first episode of deep vein thrombosis and 474 age- and sex-matched control subjects). Data for men and women were analysed separately. As hormonal status in women is known to strongly influence the APC sensitivity ratio (APCsr), additional strata (OC use and menopausal state) were defined. The APCsr was higher in all patients than in control subjects. Odds ratios (OR), using the 90th percentile of all control subjects (APCsr > 4.5) as cut-off, were: 7.5 [95% confidence interval (CI) 1.6-33.8] for men, 3.0 (95% CI 1.0-8.8) for premenopausal women not using OC, 4.8 (95% CI 1.6-14.7) for premenopausal women using OC and 4.7 (95% CI 1.4-15.6) for postmenopausal women. After excluding the carriers of factor V Leiden, the OR became infinite for men (no control had an APCsr > 4.5), 1.4 (95% CI 0.2-8.2) for premenopausal women not using OC, 3.4 (95% CI 1.1-10.8) for premenopausal women using OC and 3.6 (95% CI 0.6-20.5) for postmenopausal women. A high APCsr, determined with the thrombin-generation-based APC resistance test, predicts venous thrombotic risk, in populations with and without factor V Leiden. In addition, acquired APC resistance resulting from OC use predicts an increased risk for venous thrombosis independent of factor V Leiden.

P>Venous thrombosis of the upper extremity is a rare form of thrombosis, accounting for around 4% of all venous thromboses, and for which only a few risk factors are known. This case-control study investigated the effect of coagulation factors on risk of venous thrombosis of the upper extremity. Patients with venous thrombosis of the arm and partner controls were selected from the Multiple Environmental and Genetic Assessment study, a large population-based case-control study. Participants with a malignancy were excluded. Odds ratios (OR) were estimated for elevated levels of factor II, VII, VIII, IX, X, XI, von Willebrand Factor (VWF), and fibrinogen, low levels of protein C, protein S, and antithrombin, and for blood group non-O. Substantially increased risks of venous thrombosis of the upper extremity were found for patients with high levels (above 90th percentile versus below) of factor VIII (OR: 4 center dot 2, 95% confidence interval (CI): 2 center dot 2-7 center dot 9), VWF (OR: 4 center dot 0, 95% CI: 2 center dot 1-7 center dot 8), fibrinogen (OR: 2 center dot 9, 95% CI, 1 center dot 5-5 center dot 7), and for blood group non-O compared to O (OR: 2 center dot 1, 95% CI, 1 center dot 3-3 center dot 6). The other factors were not associated with an increased risk. Elevated levels of several procoagulant factors are associated with a strongly increased risk of venous thrombosis of the upper extremity.

Activated protein C (APC) resistance, determined with a thrombin-generation-based APC resistance test, may explain risk differences of venous thrombosis in users of second- and third-generation oral contraceptives (OC). To clinically validate this test, we analysed the Leiden thrombophilia case-control study (474 patients with a first episode of deep vein thrombosis and 474 age- and sex-matched control subjects). Data for men and women were analysed separately. As hormonal status in women is known to strongly influence the APC sensitivity ratio (APCsr), additional strata (OC use and menopausal state) were defined. The APCsr was higher in all patients than in control subjects. Odds ratios (OR), using the 90th percentile of all control subjects (APCsr4.5) as cut-off, were: 7.5 [95% confidence interval (CI) 1.6-33.8] for men, 3.0 (95% CI 1.0-8.8) for premenopausal women not using OC, 4.8 (95% CI 1.6-14.7) for premenopausal women using OC and 4.7 (95% CI 1.4-15.6) for postmenopausal women. After excluding the carriers of factor V Leiden, the OR became infinite for men (no control had an APCsr4.5), 1.4 (95% CI 0.2-8.2) for premenopausal women not using OC, 3.4 (95% CI 1.1-10.8) for premenopausal women using OC and 3.6 (95% CI 0.6-20.5) for postmenopausal women. A high APCsr, determined with the thrombin-generation-based APC resistance test, predicts venous thrombotic risk, in populations with and without factor V Leiden. In addition, acquired APC resistance resulting from OC use predicts an increased risk for venous thrombosis independent of factor V Leiden.

Varying results on the effect of factor XIII (FXIII) Val34Leu on venous thrombotic risk have been reported. The probability of a true association between this polymorphism and venous thrombotic risk would be enhanced by a laboratory phenotype associated with this polymorphism and with the thrombotic risk. The aim of this study was to assess the effect of FXIII Val34Leu, FXIII activity and subunit levels on venous thrombotic risk in a large case-control study, The Leiden Thrombophilia study (LETS). We found higher FXIII activity for 34Leu carriers (Leu/Leu: 158.0, Val/Val: 95.0). FXIII subunit levels were not associated with genotype. Higher FXIII activity was associated with a slightly decreased thrombotic risk [Odds ratio (OR): 0.8, 95% confidence intervals (CI): 0.5-1.3]. This effect was not present for elevated FXIII subunit levels. Higher FXIII activity was also associated with a higher dissociation index (percentage A2B2 complex dissociated after activation by thrombin for a fixed time interval). This index was higher for FXIII 34Leu carriers. The risk of deep venous thrombosis was slightly decreased for carriers of the 34Leu allele [OR: 0.9 (95%CI: 0.7-1.1)]. For homozygous 34Leu carriers the OR was 0.7 (95%CI: 0.4-1.3). This finding, suggesting a weak protective effect, was completely restricted to men. An overall estimate of thrombotic risk was calculated by using earlier reports on the risk of FXIII Val34Leu. The overall risk estimate for homozygous 34Leu carriers was 0.8 (95%CI: 0.6-1.0). In this study, a weak protective effect against venous thrombosis was found, of FXIII 34Leu as well as of increased FXIII activity.