High Levels of Coagulation Factor XI as a Risk Factor for Venous Thrombosis

Meijers, Joost C. M.; Tekelenburg, Winnie L.H.; Bouma, Bonno N.; Bertina, Rogier M.; Rosendaal, Frits R.

doi:10.1056/nejm200003093421004

Cited by 616 publications

(446 citation statements)

References 31 publications

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“…Risk estimates were adjusted by residual analysis for all factors that influenced thrombosis risk in LETS and were associated with fibrinogen levels. These factors were age, sex, diabetes mellitus, body mass index (BMI), 33 and high levels (higher than P90) of prothrombin, 34 factor VIII, 35 factor IX, 36 factor XI, 37 and C-reactive protein (CRP). 38 Separate analyses were performed for patients with (n ϭ 259) and without (n ϭ 215) idiopathic thrombosis, in whom idiopathic was defined as an initial thrombotic event that occurred in the absence of pregnancy, puerperium, oral contraceptive use within 30 days, trauma, surgery, immobilization, or use of a plaster cast within 3 months before the event.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels

Willige

Visser

Houwing-Duistermaat

et al. 2005

Blood

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230

260

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We investigated the association between haplotypes of fibrinogen alpha (FGA), beta (FGB), and gamma (FGG), total fibrinogen levels, fibrinogen ␥ (␥A/␥ plus ␥/␥) levels, and risk for deep venous thrombosis. In a population-based case-control study, the Leiden Thrombophilia Study, we typed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) in this gene cluster. None of these haplotypes was associated with total fibrinogen levels. In each gene, one haplotype increased the thrombosis risk approximately 2-fold. After adjustment for linkage disequilibrium between the genes, only FGG-H2 homozygosity remained associated with risk (odds ratio [OR], 2.4; 95% confidence interval [95% CI], 1.5-3.9). FGG-H2 was also associated with reduced fibrinogen ␥ levels and reduced ratios of fibrinogen ␥ to total fibrinogen. Multivariate analysis showed that reduced fibrinogen ␥ levels and elevated total fibrinogen levels were both associated with an increased risk for thrombosis, even after adjustment for FGG-H2. A reduced fibrinogen ␥ to total fibrinogen ratio (less than 0.69) also increased the risk (OR, 2.4; 95% CI, 1.7-3.5)

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Section: Discussionmentioning

confidence: 99%

Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels

Willige

Visser

Houwing-Duistermaat

et al. 2005

Blood

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230

260

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“…10,11 Compelling circumstantial evidence suggests a contributory role for FXI in the pathogenesis of thrombosis. An elevated plasma FXI level appears to be an independent risk factor for deep vein thrombosis (DVT), 12 ischemic stroke, 13 and myocardial infarction 14 in humans. While one study did not detect a reduced incidence of myocardial infraction in patients with severe factor XI deficiency, 15 the incidence of ischemic stroke appears to be significantly lower in FXI deficiency than in the general population.…”

Section: Introductionmentioning

confidence: 99%

Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI

Tucker¹,

Marzec²,

White³

et al. 2009

Blood

195

197

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The protease thrombin is required for normal hemostasis and pathologic thrombogenesis. Since the mechanism of coagulation factor XI (FXI)-dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombosis model. Pretreatment of baboons with a novel anti-human FXI monoclonal antibody (aXIMab; 2 mg/kg) inhibited plasma FXI by at least 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and ␤-thromboglobulin (␤TG) formation measured immediately downstream from thrombi forming within collagen-coated vascular grafts. FXI inhibition with aXIMab limited platelet and fibrin deposition in 4-mm diameter grafts without an apparent increase in D-dimer release from thrombi, and prevented the occlusion of 2-mm diameter grafts without affecting template bleeding times. In comparison, pretreatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, supporting the concept that FXI blockade may offer therapeutic advantages over other antithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagencoated flow chamber, independent of factor XII and factor VII. These data suggest that endogenous FXI contributes to arterial thrombus propagation through a striking amplification of thrombin generation at the thrombus luminal surface. (Blood. 2009;113:936-944) IntroductionBlood coagulation during hemostasis is initiated by the tissue factor (TF)/factor VIIa complex (the extrinsic pathway) that activates factors IX and X, and ultimately produces thrombin at sites of vascular injury. 1 In thrombosis, intravascular blood coagulation may also be initiated by the extrinsic pathway. 2,3 However, impairment of the TF/factor VIIa pathway does not provide full protection from thrombosis, since symptomatic factor VII deficient subjects can develop concurrent thrombosis and severe bleeding. 4 The functions of the contact proteins (factor XI, factor XII, prekallikrein, and high-molecular-weight kininogen) in hemostasis are less clear. The physiologic role of factor XI (FXI) has been difficult to determine because of the variable bleeding disorder associated with FXI deficiency, 5 and because monospecific FXI inhibitors have not been widely available for experimental investigation. FXI activation is thought to proceed through thrombin-and/or factor XIIdependent mechanisms, and activated FXI (FXIa) contributes to sustained thrombin generation after initiation of blood clotting by activating factor IX. These activities ultimately promote coagulation, platelet activation, and preservation of fibrin clot integrity. 6,7 Thrombin also increases the density of fibrin networks 8 and indirectly inhibits fibrinolysis through activation of carboxypeptidase B (thrombin-activatable fibrinolysis inhibitor, TAFI). 9 Thus, FXI may support thrombus propagation and clot stability by increasing thrombin generation. 10,11 Compelling circumstantial evidence suggests a contributory role for FXI in the p...

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“…Coagulation factor XI contributes to thrombin generation and is involved in both fibrin formation and protection against fibrinolysis (20,21), and the increase in its coagulant activity level also has been associated with increased VTE risk (22). Thus, it is possible that the increase in factor XI plasma levels associated with raloxifene use that is described in this study also may contribute to VTE risk in users of this medication.…”

Section: Discussionmentioning

confidence: 68%

Procoagulant state after raloxifene therapy in postmenopausal women

Azevedo

Franco

Baggio

et al. 2005

Fertility and Sterility

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Objective: To investigate the effects of raloxifene on the hemostatic system in postmenopausal women. Design: A prospective longitudinal study. Setting: Outpatient clinic of the Faculty of Medicine of Ribeirão Preto, Brazil. Patient(s): Sixteen postmenopausal women aged 56.8 Ϯ 5.9 years (mean Ϯ SD). Intervention(s): Raloxifene hydrochloride (60 mg once daily) was administered orally for a period of 6 months. Main Outcome Measure(s): Plasma activities of coagulation factors (II, V, VII, VIII, IX, X, XI, XII, and fibrinogen), prothrombin-derived fragment 1ϩ2, and activated protein C (APC) sensitivity ratio were measured at baseline and after 1, 3, and 6 months of treatment. Result(s): Factor VIII activity increased by 17.1% and 26.9% at 3 and 6 months of treatment, respectively, compared with baseline. Factor XI and FXII activities significantly increased by 10.9% and 43.1%, respectively, after 6 months compared with baseline. A significant reduction of APC sensitivity ratio also was observed after 6 months of treatment. Conclusion(s):A procoagulant state characterized by increased factor VIII, XI, and XII plasma levels and by reduced APC sensitivity was observed after raloxifene therapy in post-menopausal women. (Fertil Steril 2005; 84:1680 -4. ©2005 by American Society for Reproductive Medicine.)Key Words: Climacteric, hemostatic system, raloxifene, SERMs Raloxifene is a selective estrogen receptor modulator and exerts tissue-selective effects similar to those of estrogen (E) on bone and serum lipids, without any apparent stimulatory effect on mammary and uterine tissues (1-5). The effect of raloxifene on the cardiovascular system in postmenopausal women has been studied, and the favorable results have been explained mainly by its effects on metabolic changes in lipoproteins, homocysteine, and improved endothelium-dependent vasomotricity, preventing arteriosclerosis and acting as a vasodilating agent (6 -9).Despite these benefits, raloxifene therapy increases the risk of venous thromboembolism (VTE) by approximately threefold, a similar effect to that observed with hormone therapy (HT) (4). Although a large body of data supports a procoagulant state related to E administration, there are few published data on the effect of raloxifene on hemostatic parameters in postmenopausal women. In an article published elsewhere (10), we reported that raloxifene therapy is associated with a significant reduction in plasma antithrombin activity, suggesting that this effect may contribute to a procoagulant state and partly explain the increased risk of VTE in raloxifene users. Here, we report the results of a longitudinal study assessing the effects of raloxifene on other hemostatic parameters in healthy postmenopausal women. MATERIALS AND METHODS Study SubjectsSixteen postmenopausal women were enrolled in a prospective longitudinal study. General characteristics of the subjects were as follows (values given as mean Ϯ SD): age, 56.8 Ϯ 5.9 years; duration of menopause, 9.3 Ϯ 5.5 years; and body mass index, 25.8 Ϯ 3.7 kg/m 2 . ...

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High Levels of Coagulation Factor XI as a Risk Factor for Venous Thrombosis

Abstract: High levels of factor XI are a risk factor for deep venous thrombosis, with a doubling of the risk at levels that are present in 10 percent of the population.

Cited by 616 publications

References 31 publications

Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels

Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels

Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI

Procoagulant state after raloxifene therapy in postmenopausal women

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