Elevated Factor XI Activity Levels Are Associated With an Increased Odds Ratio for Cerebrovascular Events

Yang, David T.; Flanders, Michele M.; Kim, Hyunhee; Rodgers, George M.

doi:10.1309/qc259f09unmkvp0r

Cited by 125 publications

(63 citation statements)

References 18 publications

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“…Patients with severe FXI deficiency were reported to exhibit protection from ischemic stroke and a lower incidence of venous thromboembolism (VTE) [24,25]. Conversely, higher levels of FXI were associated with increased risk of VTE and ischemic stroke [26,27]. Reducing factor XI levels in patients undergoing unilateral total knee arthroplasty has been shown to be an effective method for the prevention of postoperative VTE, suggesting FXI inhibition as an effective method of anticoagulation in surgery [28].…”

Section: Fxi and Thrombosismentioning

confidence: 99%

The hemostatic role of factor XI

Puy

Rigg

McCarty

2016

Thrombosis Research

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Coagulation factor (F)XI has been described as a component of the early phase of the contact pathway of blood coagulation, acting downstream of factor XII. However, patients deficient in upstream members of the contact pathway, including FXII and prekallikrein, do not exhibit bleeding complications, while FXI-deficient patients sometimes experience mild bleeding, suggesting FXI plays a role in hemostasis independent of the contact pathway. Further complicating the picture, bleeding risk in FXI-deficient patients is difficult to predict because bleeding symptoms have not been found to correlate with FXI antigen levels or activity. However, recent studies have emerged to expand our understanding of FXI, demonstrating that activated FXI is able to activate coagulation factors FX, FV, and FVIII, and inhibit the anti-coagulant tissue factor pathway inhibitor (TFPI). Understanding these activities of FXI may help to better diagnose which FXI-deficient patients are at risk for bleeding. In contrast to its mild hemostatic activities, FXI is known to play a significant role in thrombosis, as it is a demonstrated independent risk factor for deep vein thrombosis, ischemic stroke, and myocardial infarction. Recent translational approaches have begun testing FXI as an antithrombotic, with one promising clinical study showing that an anti-sense oligonucleotide against FXI prevented venous thrombosis in elective knee surgery. A better understanding of the varied and complex role of FXI in both thrombosis and hemostasis will help to allow better prediction of bleeding risk in FXI-deficient patients and also informing the development of targeted agents to inhibit the thrombotic activities of FXI while preserving hemostasis.

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Section: Fxi and Thrombosismentioning

confidence: 99%

The hemostatic role of factor XI

Puy

Rigg

McCarty

2016

Thrombosis Research

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“…Notably, high levels of FXI are associated with increased risk of stroke and associated marginally with myocardial infarction. 19,20 However, in patients with severe FXI deficiency, a reduced incidence of ischemic stroke but not of myocardial infarction was observed. 21,22 In animal models, it was shown that deprivation of FXI did protect against injury-induced thrombosis 23,24 and that apoE knockout mice treated with FXI antisense oligonucleotides were protected from thrombosis on acutely ruptured atherosclerotic plaques.…”

mentioning

confidence: 99%

Factor XI Deficiency Protects Against Atherogenesis in Apolipoprotein E/Factor XI Double Knockout Mice

Ganor

Harats

Gailani

et al. 2016

ATVB

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Objective Atherosclerosis and atherothrombosis are still major causes of mortality in the Western world, even after the widespread use of cholesterol-lowering medications. Recently, an association between local thrombin generation and atherosclerotic burden has been reported. Here, we studied the role of factor XI (FXI) deficiency in the process of atherosclerosis in mice. Approach and Results Apolipoprotein E/FXI double knockout mice, created for the first time in our laboratory. There was no difference in cholesterol levels or lipoprotein profiles between apolipoprotein E knockout and double knockout mice. Nevertheless, in 24-week-old double knockout mice, the atherosclerotic lesion area in the aortic sinus was reduced by 32% (P=0.004) in comparison with apolipoprotein E knockout mice. In 42-week-old double knockout mice, FXI deficiency inhibited atherosclerosis progression significantly in the aortic sinus (25% reduction, P=0.024) and in the aortic arch (49% reduction, P=0.028), with a prominent reduction of macrophage infiltration in the atherosclerotic lesions. Conclusions FXI deprivation was shown to slow down atherogenesis in mice. The results suggest that the development of atherosclerosis can be prevented by targeting FXI.

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“…This is comparable to the risk in people with high-normal plasma fIX levels [15]. Subsequent work demonstrated that high plasma fXI levels are associated with increased incidences of myocardial infarction and ischemic stroke [16,17], whereas severe fXI deficiency lowers risk for ischemic stroke and venous thrombosis [18,19]. …”

Section: Rationale For Inhibiting Factor Xia To Treat or Prevent Thromentioning

confidence: 99%

Factor XI as a target for antithrombotic therapy

Bane

Gailani

2014

Drug Discovery Today

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Anticoagulants currently used in clinical practice to treat thromboembolic disorders are effective but increase the risk of severe bleeding because they target proteins that are essential for normal coagulation (hemostasis). Drugs with better safety profiles are required for prevention and treatment of thromboembolic disease. Coagulation factor XIa has emerged as a novel target for safer anticoagulant therapy because of its role in thrombosis and its relatively small contribution to hemostasis.

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Elevated Factor XI Activity Levels Are Associated With an Increased Odds Ratio for Cerebrovascular Events

Cited by 125 publications

References 18 publications

The hemostatic role of factor XI

The hemostatic role of factor XI

Factor XI Deficiency Protects Against Atherogenesis in Apolipoprotein E/Factor XI Double Knockout Mice

Factor XI as a target for antithrombotic therapy

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