Kenneth A. Bauer

Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial

BACKGROUND Prophylaxis for venous thromboembolism is recommended for at least 10 days after total knee arthroplasty; oral regimens could enable shorter hospital stays. We aimed to test the efficacy and safety of oral rivaroxaban for the prevention of venous thromboembolism after total knee arthroplasty. METHODS In a randomised, double-blind, phase III study, 3148 patients undergoing knee arthroplasty received either oral rivaroxaban 10 mg once daily, beginning 6-8 h after surgery, or subcutaneous enoxaparin 30 mg every 12 h, starting 12-24 h after surgery. Patients had mandatory bilateral venography between days 11 and 15. The primary efficacy outcome was the composite of any deep-vein thrombosis, non-fatal pulmonary embolism, or death from any cause up to day 17 after surgery. Efficacy was assessed as non-inferiority of rivaroxaban compared with enoxaparin in the per-protocol population (absolute non-inferiority limit -4%); if non-inferiority was shown, we assessed whether rivaroxaban had superior efficacy in the modified intention-to-treat population. The primary safety outcome was major bleeding. This trial is registered with ClinicalTrials.gov, number NCT00362232. FINDINGS The primary efficacy outcome occurred in 67 (6.9%) of 965 patients given rivaroxaban and in 97 (10.1%) of 959 given enoxaparin (absolute risk reduction 3.19%, 95% CI 0.71-5.67; p=0.0118). Ten (0.7%) of 1526 patients given rivaroxaban and four (0.3%) of 1508 given enoxaparin had major bleeding (p=0.1096). INTERPRETATION Oral rivaroxaban 10 mg once daily for 10-14 days was significantly superior to subcutaneous enoxaparin 30 mg given every 12 h for the prevention of venous thromboembolism after total knee arthroplasty. FUNDING Bayer Schering Pharma AG, Johnson & Johnson Pharmaceutical Research & Development.

Activation of Coagulation after Administration of Tumor Necrosis Factor to Normal Subjects

Tumor necrosis factor has been implicated in the activation of blood coagulation in septicemia, a condition commonly associated with intravascular coagulation and disturbances of hemostasis. To evaluate the early dynamics and the route of the in vivo coagulative response to tumor necrosis factor, we performed a controlled study in six healthy men, monitoring the activation of the common and intrinsic pathways of coagulation with highly sensitive and specific radioimmunoassays. Recombinant human tumor necrosis factor, administered as an intravenous bolus injection (50 micrograms per square meter of body-surface area), induced an early and short-lived rise in circulating levels of the activation peptide of factor X, reaching maximal values after 30 to 45 minutes (mean +/- SEM increase after 45 minutes, 34.2 +/- 18.2 percent; tumor necrosis factor vs. saline, P = 0.015). This was followed by a gradual and prolonged increase in the plasma concentration of the prothrombin fragment F1+2, peaking after four to five hours (mean increase after five hours, 348.0 +/- 144.8 percent; tumor necrosis factor vs. saline, P less than 0.0001). These findings signify the formation of factor Xa (activated factor X) and the activation of prothrombin. Activation of the intrinsic pathway could not be detected by a series of measurements of the plasma levels of factor XII, prekallikrein, factor XIIa-C1 inhibitor complexes, kallikrein-C1 inhibitor complexes, and the activation peptide of factor IX. The delay between the maximal activation of factor X and that of prothrombin amounted to several hours, indicating that neutralization of factor Xa activity was slow. We conclude that a single injection of tumor necrosis factor elicits a rapid and sustained activation of the common pathway of coagulation, probably induced through the extrinsic route. Our results suggest that tumor necrosis factor could play an important part in the early activation of the hemostatic mechanism in septicemia.

Parenteral Anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

This chapter describes the pharmacology of approved parenteral anticoagulants, including the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin factor Xa and other clotting factors. Heparin also binds to cells and other plasma proteins, endowing it with unpredictable pharmacokinetic and pharmacodynamic properties, and can lead to nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and have a lower risk of nonhemorrhagic side effects. LMWHs can be administered once or twice daily by subcutaneous injection, without anticoagulant monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin; therefore, HIT and osteoporosis are unlikely to occur. Fondaparinux has excellent bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without anticoagulant monitoring. Three parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in HIT patients.

Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial

BACKGROUND Elective hip-replacement surgery carries significant risk of venous thromboembolism, despite use of thromboprophylaxis. We aimed to see whether the pentasaccharide fondaparinux, the first drug of a new class of synthetic antithrombotic agents, could reduce this risk to a greater extent than other available treatments. METHODS In a double-blind study, we randomly assigned 2275 consecutive patients aged 18 years or older who were undergoing elective hip-replacement surgery to receive postoperative subcutaneous injections of either 2.5 mg fondaparinux once daily or 30 mg enoxaparin twice daily. The primary efficacy outcome was venous thromboembolism to day 11. The main safety outcomes were bleeding and death. Patients were followed up for 6 weeks. FINDINGS We assessed venous thromboembolism to day 11 in 1584 (70%) of 2275 patients. By day 11, venous thromboembolisms were recorded in 48 (6%) of 787 patients on fondaparinux and in 66 (8%) of 797 patients on enoxaparin. The relative reduction in risk was 26.3% (95% CI -10.8 to 52.8, p=0.099). The two groups did not differ in the number of patients who died or in the number who had clinically relevant bleeding. INTERPRETATION In patients undergoing elective hip-replacement surgery, 2.5 mg fondaparinux once daily was not significantly more effective than 30 mg enoxaparin twice daily in reducing risk of venous thromboembolism. However, the lower risk recorded with fondaparinux than enoxaparin was clinically important, with no increase in clinically relevant bleeding.

Tumor-Derived Tissue Factor–Bearing Microparticles Are Associated With Venous Thromboembolic Events in Malignancy

Purpose: Despite the strong association between malignant disease and thromboembolic disorders, the molecular and cellular basis of this relationship remains uncertain. We evaluated the hypothesis that tumor-derived tissue factorbearing microparticles in plasma contribute to cancer-associated thrombosis. Experimental Design: We developed impedance-based flow cytometry to detect, quantitate, and size microparticles in platelet-poor plasma. We evaluated the number of tissue factorbearing microparticles in a cohort of cancer patients of different histologies (N = 96) and conducted a case-control study of 30 cancer patients diagnosed with an acute venous thromboembolic event (VTE) compared with 60 cancer patients of similar age, stage, sex, and diagnosis without known VTE, as well as 22 patients with an idiopathic VTE. Results: Tissue factorbearing microparticles were detected in patients with advanced malignancy, including two thirds of patients with pancreatic carcinoma. Elevated levels of tissue factorbearing microparticles were associated VTE in cancer patients (adjusted odds ratio, 3.72; 95 confidence interval, 1.18-11.76; P = 0.01). In cancer patients without VTE, a retrospective analysis revealed a 1-year cumulative incidence of VTE of 34.8 in patients with tissue factorbearing microparticles versus 0 in those without detectable tissue factorbearing microparticles (Gray test P = 0.002).The median number of tissue factorbearing microparticles in the cancer VTE cohort (7.1 104 microparticles/L) was significantly greater than both the idiopathic VTE and cancerno VTE groups (P = 0.002 and P = 0.03, respectively). Pancreatectomy in three patients eliminated or nearly eliminated these microparticles which coexpressed the epithelial tumor antigen, MUC-1. Conclusion: We conclude that tumor-derived tissue factorbearing microparticles are associated with VTE in cancer patients and may be central to the pathogenesis of cancer-associated thrombosis. (Clin Cancer Res 2009;15(22):683040)

BAY 59-7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study.

Summary.  Background: BAY 59‐7939, a novel, oral, direct factor Xa inhibitor, is in clinical development for the prevention of venous thromboembolism (VTE), a frequent complication following orthopaedic surgery. Methods: In a multicenter, parallel‐group, double‐blind, double‐dummy study, 621 patients undergoing elective total knee replacement were randomly assigned to oral BAY 59‐7939 (2.5, 5, 10, 20, and 30 mg b.i.d., initiated 6–8 h postsurgery), or subcutaneous enoxaparin (30 mg b.i.d., initiated 12–24 h postsurgery). Treatment was continued until mandatory bilateral venography 5–9 days after surgery. The primary efficacy endpoint was a composite of any deep vein thrombosis (proximal and/or distal), confirmed non‐fatal pulmonary embolism and all‐cause mortality during treatment. The primary safety endpoint was major, postoperative bleeding during treatment. Results: Of the 613 patients treated, 366 (59.7%) were evaluable for the primary efficacy analysis. The primary efficacy endpoint occurred in 31.7%, 40.4%, 23.3%, 35.1%, and 25.4% of patients receiving 2.5, 5, 10, 20 and 30 mg b.i.d. doses of BAY 59‐7939, respectively (test for trend, P = 0.29), compared with 44.3% in the enoxaparin group. The frequency of major, postoperative bleeding increased with increasing doses of BAY 59‐7939 (test for trend, P = 0.0007), with no significant difference between any dose group compared with enoxaparin. Bleeding endpoints were lower for the 2.5–10 mg b.i.d. doses compared with higher doses of BAY 59‐7939. Conclusions: Oral administration of 2.5–10 mg b.i.d. of BAY 59‐7939, early in the postoperative period, showed potential efficacy and an acceptable safety profile, similar to enoxaparin, for the prevention of VTE in patients undergoing elective total knee replacement.

Population pharmacokinetics and pharmacodynamics of rivaroxaban - An oral, direct factor Xa inhibitor in patients undergoing major orthopaedic surgery

AbstractBackground: There is a clinical need for novel oral anticoagulants with predictable pharmacokinetics and pharmacodynamics. Rivaroxaban is an oral direct Factor Xa (FXa) inhibitor in clinical development for the prevention and treatment of thromboembolic disorders. This analysis was performed to characterize the population pharmacokinetics and pharmacodynamics of rivaroxaban in patients participating in two phase II, double-blind, randomized, active-comparator-controlled studies of twice-daily rivaroxaban for the prevention of venous thromboembolism after total hip- or knee-replacement surgery. Methods: Sparse blood samples were taken from all patients participating in the studies (n = 1009). In addition, a subset of patients in the hip study (n = 36) underwent full profiling. Rivaroxaban plasma concentrations, FXa activity and the prothrombin time were determined. Nonlinear mixed-effects modelling was used to model the population pharmacokinetics and pharmacodynamics of rivaroxaban. Results: An oral one-compartment model described the population pharmacokinetics of rivaroxaban well. On the first postoperative day only, categorization of patients as slow or fast absorbers as a tool to address variability in absorption improved the fit of the model. Clearance of rivaroxaban was lower and more variable on the first postoperative day, and so time was factored into the model. Overall, the only major difference between the models for the hip study and the knee study was that clearance was 26% lower in the knee study, resulting in approximately 30% higher exposure. Residual variability in the models was moderate (37% and 34% in the hip and knee studies, respectively). Plasma concentrations of rivaroxaban increased dose dependently. Pharmacokinetic parameters that were estimated using the models agreed closely with results from full-profile patients in the hip study, demonstrating that rivaroxaban pharmacokinetics are predictable. The pharmacokinetics of rivaroxaban were affected by expected covariates: age affected clearance in the hip study only, haematocrit (on the first postoperative day only) and gender affected clearance in the knee study only, and renal function affected clearance in both studies. Bodyweight affected the volume of distribution in both studies. However, the effects of covariates on the pharmacokinetics of rivaroxaban were generally small, and predictions of ‘extreme’ case scenarios suggested that fixed dosing of rivaroxaban was likely to be possible. FXa activity and the prothrombin time were both affected by surgery, probably because of perioperative bleeding and intravenous administration of fluids; therefore, time was included in the pharmacodynamic models. In both studies, FXa activity correlated with rivaroxaban plasma concentrations following a maximum effect model, whereas prothrombin time prolongation correlated following a linear model with intercept. The slope of the prothrombin time prolongation correlation was 3.2 seconds/(100 μg/L) in the hip study and 4.2 seconds/(100 μg/L) in the knee study. Both pharmacodynamic models in both studies demonstrated low residual variability of approximately 10%. Conclusion: This population analysis in patients undergoing major orthopaedic surgery demonstrated that rivaroxaban has predictable, dose-dependent pharmacokinetics that were well described by an oral one-compartment model and affected by expected covariates. Rivaroxaban exposure could be assessed using the prothrombin time, if necessary, but not the international normalized ratio. The findings suggested that fixed dosing of rivaroxaban may be possible in patients undergoing major orthopaedic surgery.

The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor.

The human coagulation system continuously generates very small quantities of Factor Xa and thrombin. Current evidence suggests that basal level activation of the hemostatic mechanism occurs via Factor VIIa-dependent activation of Factor X, but direct proof has not been available for the participation of tissue factor in this pathway. To examine this issue, we infused relatively high concentrations of recombinant Factor VIIa (approximately 50 micrograms/kg body wt) into normal chimpanzees and observed significant increases in the plasma levels of Factor IX activation peptide, Factor X activation peptide, and prothrombin activation fragment F1+2. Metabolic turnover studies with radiolabeled Factor IX activation peptide, Factor X activation peptide, and F1+2 indicate that elevated levels of the activation peptides are due to accelerated conversion of the three coagulation system zymogens into serine proteases. The administration of a potent monoclonal antibody to tissue factor, which immediately neutralizes function of the Factor VIIa-tissue factor complex in vitro, abolishes the activation of Factor X and prothrombin mediated by the infused recombinant protein, and also suppresses basal level activation of Factor IX and Factor X. The above results suggest that recombinant Factor VIIa functions as a prohemostatic agent by interacting with endogenous tissue factor sites, but definitive proof will require studies in hemophilic animals using relevant hemostatic endpoints.

Thrombosis and ELISA optical density values in hospitalized patients with heparin-induced thrombocytopenia.

Summary.  The natural history of heparin‐induced thrombocytopenia (HIT) in the absence of thrombosis was previously established using functional assays for confirmation of diagnosis (e.g. 14C serotonin release assay). An enzyme‐linked immunosorbent assay (ELISA) that detects the presence of antibodies directed against the heparin–platelet factor‐4 (PF4) complex has largely replaced functional assays in many medical centers. Although the ELISA is highly sensitive for detecting HIT antibodies, its usefulness for predicting thrombotic outcomes has not been clearly established. We performed a retrospective chart review of all hospitalized patients at a university hospital who tested seropositive for HIT by a commercial ELISA during 2001 and 2002. A total of 63 inpatients were identified as HIT positive by ELISA. Forty‐eight patients had no apparent HIT‐associated thrombosis at the time of HIT seropositivity (i.e. isolated HIT) and only one was treated prophylactically with a direct thrombin inhibitor. The 30‐day thrombosis rate for patients with isolated HIT was 17% (eight of 48). Higher ELISA optical density (OD) measurements correlated significantly with thrombosis (1.41 ± 0.87 vs. 0.79 ± 0.46, P < 0.001). Patients with isolated HIT and an OD measurement of ≥ 1.0 demonstrated nearly a 6‐fold increased risk of thrombosis compared with those with OD values between 0.4 and 0.99 (odds ratio 5.74, 95% confidence interval 1.73, 19.0; absolute rate of thrombosis, 36% vs. 9%, respectively, P = 0.07). We conclude that in hospitalized patients with isolated HIT, the presence of heparin–PF4 antibodies detected by ELISA was associated with a significant risk of subsequent thrombosis and higher ELISA values were observed among patients suffering thrombotic events.

The Thrombophilias: Well-Defined Risk Factors with Uncertain Therapeutic Implications

Before 1993, a heritable cause of thrombophilia was detectable in a relatively small percentage (5% to 15%) of patients presenting with venous thromboembolism. Such abnormalities were confined to deficiencies of antithrombin, protein C, and protein S (1). However, the recent discovery of two prothrombotic mutations prevalent in white populations, the factor V Arg506Gln, or factor V Leiden, mutation (2) and the prothrombin G20210A mutation (3), has kindled renewed interest in this area of research. The factor V Leiden mutation causes resistance to activated protein C (4); both prothrombin antigen and activity are elevated by approximately 30% in heterozygotes with the prothrombin G20210A mutation compared with normal persons (3). Elevated plasma homocysteine levels also constitute a risk factor for venous as well as arterial thrombosis, sometimes on an inherited basis (5). One or more of these abnormalities, or the antiphospholipid antibody syndrome (a lupus anticoagulant or elevated cardiolipin antibody titers), can be identified in a substantial percentage of patients presenting with a first episode of idiopathic venous thromboembolism (that is, venous thromboembolism in the absence of a triggering risk factor, such as surgery, immobilization, or active malignancy). However, with the exception of the antiphospholipid antibody syndrome (6), the available data do not indicate that most patients with defined thrombophilias should be managed any differently than patients without identifiable abnormalities. The following discussion will therefore focus on the question of who should be screened for hereditary and other thrombophilias and the implications of such a diagnosis on patient management. Is There a Rationale for Screening? Among unselected white patients presenting with an initial symptomatic episode of deep venous thrombosis, 12% to 20% will be heterozygous for the factor V Leiden mutation and 6% will be heterozygous for the prothrombin G20210A mutation, compared with 6% and 2%, respectively, of asymptomatic control populations (3, 7, 8). The relative and absolute risks for a first episode of deep venous thrombosis in persons carrying these abnormalities, along with the risk associated with oral contraceptive use, are shown in Table 1. The identification of either mutation in the setting of acute thrombosis does not alter the initial anticoagulant regimen. Similarly, the initial management of thrombotic patients with a diagnosis of one of the less common thrombophiliasdeficiencies of antithrombin, protein C, or protein Sis generally identical to that of patients without one of these defects. Also, these conditions can easily be misdiagnosed when testing is done in the acute setting. Therefore, it can be argued that there is little to be gained by immediate evaluation for the hereditary thrombophilias when patients present with their first thrombotic episodes. Table 1. Risks for and Incidence of a First Episode of Venous Thrombosis Standard therapy for patients with deep venous thrombosis and pulmonary embolism typically includes anticoagulation with warfarin for 3 to 6 months, with the international normalized ratio maintained between 2 and 3. However, Prandoni and colleagues (12) found that in patients who presented with a first episode of symptomatic venous thromboembolism, the cumulative incidence of recurrent venous thrombosis after the cessation of initial therapy was 24.8% at 5 years and 30.3% at 8 years. Recurrences are less common when the initial event is associated with surgery or trauma. Other groups have shown that the recurrence rate is approximately 5% per year after standard therapy. However, a recent clinical trial in patients with a first episode of idiopathic venous thromboembolism (that is, thromboembolism without a major precipitating factor) found that persons randomly assigned to 3 months of anticoagulation had a much higher risk for recurrence (27% per patient-year) (13). Patients in that study who were randomly assigned to continue warfarin at an international normalized ratio of 2 to 3 experienced a 95% reduction in risk for recurrent venous thromboembolism. Testing for prothrombotic abnormalities would clearly be helpful if it identified patients who are particularly prone to recurrences and thus are candidates for long-term antithrombotic prophylaxis. Unfortunately, the data disagree on whether the recurrence risk is higher among patients with first episodes of venous thromboembolism associated with the factor V Leiden or prothrombin G20210A mutations than in those without a prothrombotic mutation (13-20). However, the risk for recurrence seems to be statistically significantly higher in the small subset of patients who are heterozygous for both mutations (21, 22). In other clinical settings, such as arterial thrombosis, the data are unclear about whether hereditary thrombophilia constitutes a risk factor. The ascertainment of thrombophilic genetic risk factors in these situations therefore often proves problematic because hereditary thrombophilia may be inappropriately interpreted as requiring anticoagulation, with its attendant bleeding risk, when it might not otherwise be prescribed. It is therefore advisable not to investigate for the hereditary thrombophilias in most patients who have only arterial thrombosis, particularly if they have other independent risk factors for arterial disease, such as hypertension, diabetes mellitus, smoking, or hyperlipidemia. Several arguments, however, can be advanced in favor of screening for the hereditary thrombophilias in appropriate patients with venous thromboembolism. These include the benefits, for both patient and treating physician, of an improved understanding of the pathogenesis of deep venous thrombosis or pulmonary embolism when a specific prothrombotic abnormality is identified. The discovery can benefit the patients family by leading to the identification of other affected relatives. It also focuses attention on antithrombotic prophylaxis during temporary periods of increased thrombotic risk (for example, during surgery or immobilization). In women with the factor V Leiden or prothrombin G20210A mutations, oral contraceptive use and pregnancy increase the risk for venous thrombosis another fourfold to eightfold (10, 23). Women with these mutations are also at increased risk for venous thrombotic complications associated with hormone replacement therapy and, very likely, tamoxifen and selective estrogen-receptor modulators (24-27). In healthy older patients with idiopathic deep venous thrombosis, the identification of a hereditary prothrombotic abnormality helps mitigate concern about an underlying occult malignancy and minimize the resulting tendency to order expensive diagnostic tests. Several other coagulation abnormalities have been implicated as risk factors for venous thrombosis. In the Leiden Thrombophilia Study, 25% of patients with a first episode of venous thrombosis and 11% of healthy controls had a factor VIII coagulant activity level greater than 150% of normal (28) at least 3 months after completing treatment with an oral anticoagulant. Persons with factor VIII coagulant activity levels greater than 150% of normal had a 4.8-fold increased risk for venous thrombosis compared with persons whose levels of factor VIII coagulant activity were under 100% of normal. The increased factor VIII coagulant activity levels were not associated with elevations in levels of acute-phase reactants (29). Several other groups (30, 31) have confirmed that high levels of factor VIII coagulant activity are a risk factor for venous thrombosis, and Austrian investigators (32) recently reported that the probability of thrombosis recurrence at 2 years in persons with factor VIII coagulant activity levels greater than 234% of normal (the 90th percentile of the values for the study sample) was 37% (95% CI, 16% to 57%), compared with 5% (CI, 2% to 8%) in patients with levels less than 120% of normal. Corroborating studies will be required before routine measurement of factor VIII coagulant activity levels can be recommended in patients with a previous venous thrombotic event. Elevated antigenic levels of several other coagulation factors, including factor XI (33), factor IX (34), and thrombin-activatable fibrinolysis inhibitor (35), also independently confer a significantly increased, albeit modest, risk for an initial episode of deep venous thrombosis. The mechanisms responsible for high levels of factor VIII coagulant activity and these other factors have yet to be explained, but family studies suggest that high factor VIII levels are often genetically determined (36). In the absence of the factor V Leiden mutation, a significantly increased risk for venous thrombosis is associated with a reduced sensitivity to activated protein C, as measured by a clotting assay that does not mix patient plasma with factor Vdeficient plasma (37). However, this risk is lower than that in carriers of the factor V Leiden mutation. This increased risk remains after adjustment for elevated levels of factor VIII coagulant activity and oral contraceptive use, both of which are known to lead to a reduced response to activated protein C. Most clinical laboratories test for activated protein C resistance by mixing patient plasma with factor Vdeficient plasma, a method that is highly sensitive and specific for the factor V Leiden mutation, or by using a genetic assay. Because commercially available assays for activated protein C resistance that do not mix the patients plasma with factor Vdeficient plasma fail to replicate the performance characteristics of the assay used by de Visser and coworkers (37), such assays are not recommended as part of the laboratory evaluation. Several hemostatic gene polymorphisms besides factor V Leiden and the prothrombin G20210A mutation have been investigated as risk factors for venous or arterial thrombosis, but the data supporting