Factor XI as a Therapeutic Target

Abstract

Factor XIa is a plasma serine protease that contributes to thrombin generation primarily through proteolytic activation of factor IX. Traditionally considered part of the intrinsic pathway of coagulation, several lines of evidence now suggest that factor XIa serves as an interface between the vitamin-K dependent thrombin generation mechanism and the pro-inflammatory kallikrein-kinin system, allowing the two systems to influence each other. Work with animal models and results from epidemiologic surveys of human populations support a role for factor XIa in thromboembolic disease. These data, and the clinical observation that deficiency of factor XI, the zymogen of factor XIa, produces a relatively mild bleeding disorder suggest that drugs targeting factor XI or XIa could produce an antithrombotic effect while leaving hemostasis largely intact. Results of a recent trial comparing antisense-induced factor XI reduction to standard dose low molecular weight heparin as prophylaxis for venous thrombosis during knee replacement are encouraging in these regards. Here we discuss recent findings on the biochemistry, physiology and pathology of factor XI as they relate to thromboembolic disease.

Fibrinogen and Fibrin in Hemostasis and Thrombosis

“…Since factor XI (FXI[a]) augments thrombin generation, in part by synergizing tissue factor-mediated procoagulant activity 50 , FXI inhibition strategies to reduce thrombosis have received considerable attention (reviewed in 51 ). These approaches include conventional anti-FXI inhibitory antibodies, as well as technology in which antisense oligonucleotides (ASOs) result in the specific degradation of a target mRNA and corresponding reduction in target protein level.…”

2017 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

“…Recent epidemiological and animal studies have suggested that FXI, a coagulation factor upstream to thrombin and FXa, is a potential target to achieve this goal. 11 This review outlines the rationale for targeting upstream coagulation factors, identifies FXI as the ideal candidate, summarizes current progress, and highlights what is in the pipeline for the next era of anticoagulants.…”

“…However, FXI-deficient individuals are more prone to bleeding in the nasopharyngeal and reproductive tracts than in other sites, suggesting that tissues with high fibrinolytic activity may be more dependent on FXI than others. 11 Furthermore, FXI levels are poorly correlated with the risk of bleeding. 65 Despite these limitations, however, FXI remains an attractive target for novel anticoagulant strategies.…”

Differential Roles for the Coagulation Factors XI and XII in Regulating the Physical Biology of Fibrin

“…Congenital FXI deficiency protects patients from stroke and venous thromboembolism, and is only associated with minor bleeding episodes. 9,10 Additionally, blockade of FXII might be protective in microorganism-driven thrombotic complications accompanying sepsis, as inhibition of FXII activation of FXI reduced thrombotic complications in animal models of sepsis. 5,9 Here, we sought to better understand whether FXII and FXI differentially regulate the physical biology of fibrin networks.…”