Defective thrombus formation in mice lacking coagulation factor XII

TLDR

Blood coagulation is generally initiated by factor VIIa–tissue factor, whereas factor XII–mediated fibrin formation has been considered negligible in vivo. The study aimed to determine the contribution of factor XII to thrombus formation in vivo using FXII‑deficient mice. The authors used FXII‑deficient mice and performed intravital fluorescence microscopy and blood‑flow measurements in three arterial beds to evaluate thrombus formation. Deficiency of FXII in mice causes a severe impairment of platelet‑rich thrombus formation and stabilization, protects against collagen‑ and epinephrine‑induced thromboembolism, and is reversed by human FXII infusion, demonstrating that FXII is essential for in vivo thrombus formation and a promising antithrombotic target.

Abstract

Blood coagulation is thought to be initiated by plasma protease factor VIIa in complex with the membrane protein tissue factor. In contrast, coagulation factor XII (FXII)–mediated fibrin formation is not believed to play an important role for coagulation in vivo. We used FXII-deficient mice to study the contributions of FXII to thrombus formation in vivo. Intravital fluorescence microscopy and blood flow measurements in three distinct arterial beds revealed a severe defect in the formation and stabilization of platelet-rich occlusive thrombi. Although FXII-deficient mice do not experience spontaneous or excessive injury-related bleeding, they are protected against collagen- and epinephrine-induced thromboembolism. Infusion of human FXII into FXII-null mice restored injury-induced thrombus formation. These unexpected findings change the long-standing concept that the FXII-induced intrinsic coagulation pathway is not important for clotting in vivo. The results establish FXII as essential for thrombus formation, and identify FXII as a novel target for antithrombotic therapy.