A role for factor XIIa–mediated factor XI activation in thrombus formation in vivo

Abstract

Mice lacking factor XII (fXII) or factor XI (fXI) are resistant to experimentallyinduced thrombosis, suggesting fXIIa activation of fXI contributes to thrombus formation in vivo. It is not clear whether this reaction has relevance for thrombosis in primates. In 2 carotid artery injury models (FeCl 3 and Rose Bengal/laser), fXII-deficient mice are more resistant to thrombosis than fXI-or factor IX (fIX)-deficient mice, raising the possibility that fXII and fXI function in distinct pathways. Antibody 14E11 binds fXI from a variety of mammals and interferes with fXI activation by fXIIa in vitro. In mice, 14E11 prevented arterial occlusion induced by FeCl 3 to a similar degree to total fXI deficiency. 14E11 also had a modest beneficial effect in a tissue factor-induced pulmonary embolism model, indicating fXI and fXII contribute to thrombus formation even when factor VIIa/tissue factor initiates thrombosis. In baboons, 14E11 reduced plateletrich thrombus growth in collagen-coated grafts inserted into an arteriovenous shunt. These data support the hypothesis that fXIIa-mediated fXI activation contributes to thrombus formation in rodents and primates. Since fXII deficiency does not impair hemostasis, targeted inhibition of fXI activation by fXIIa may be a useful antithrombotic strategy associated with a low risk of bleeding complications. (Blood. 2010;116(19):3981-3989) IntroductionInitiation of fibrin formation by contact activation requires proteolytic conversion of plasma factor XII (fXII) to the protease factor XIIa (fXIIa) on a surface. 1-3 FXIIa activates the next zymogen in the coagulation cascade, factor XI (fXI), to factor XIa (fXIa), which in turn converts factor IX (fIX) to factor IXa␤ (fIXa␤). This series of reactions, referred to as the intrinsic pathway of coagulation, drives thrombin generation and fibrin formation in the activated partial thromboplastin time (aPTT) assay used by clinical laboratories. A role for fIX in hemostasis is not in question, as its deficiency causes the severe bleeding disorder hemophilia B. However, the importance of the intrinsic pathway, as a whole, to clot formation and stability at a site of injury is probably limited, as fXII deficiency is not associated with abnormal bleeding, 1,2 and fXI-deficient patients have a variable hemorrhagic disorder with milder symptoms than hemophiliacs. 2,4 Current models of thrombin generation address these phenotypic differences by incorporating additional mechanisms for protease activation. Thus, fIX is activated by the factor VIIa/tissue factor complex in addition to fXIa, 3,5 while fXI can be activated by thrombin. 3,6 Mice lacking fXII, like their human counterparts, do not have a demonstrable bleeding abnormality, 7 supporting the premise that fXIIa activation of fXI is not required for hemostasis. 8 Given this, it was surprising to observe that mice lacking fXII 9 or fXI 10 were resistant to arterial thrombotic occlusion. While this suggested contact activation might play an important role in pathologic coagulation, if not hemostasis...

Coagulation and the Vessel Wall in Pulmonary Embolism

“…However, thrombus formation in FXII −/− mice is defective in venous stasis models, arterial thrombosis and stroke models, and models for PE. [23][24][25][26] Therefore, FXII may become a target for safe anticoagulation with thromboprotective but sustained hemostatic properties. FXII seems to be important for thrombus stability.…”

Recent insights into the role of the contact pathway in thrombo-inflammatory disorders

“…[22][23][24][25][26] For example, inhibitory factor XI antibodies, which prevent the activation of factor XI by factor XII, protected mice from ferric chloride-induced arterial and venous thrombosis. 27,28 Furthermore, factor XI and factor XI antisense oligonucleotides have been studied in higher species using a vascular graft occlusion model in primates, 29,30 which paved the way for human studies using factor XI antisense oligonucleotides. Human data from patients undergoing total knee replacement surgery are expected this year.…”

Targeting coagulation factor XII as a novel therapeutic option in brain trauma

“…In recent years, however, it has been shown that FXII −/− mice are resistant to experimentally induced thrombosis34, 35 and ischemic brain injury 19. As deficiency of FXII is not associated with abnormal hemorrhaging from injury sites (hemostasis) either in patients or in animals,19, 34 inhibition of activated FXII prevented arterial thrombosis and ischemic brain injury20, 36 without affecting hemostasis 20, 37.…”