Bleeding in Factor XI Deficient Mice

Introduction:Factor XI (FXI) is a key component of the intrinsic or contact pathway of coagulation. It can be activated by either FXIIa or thrombin and amplifies thrombin generation during clot formation. Humans with congenital FXI deficiency, a rare bleeding disorder also referred to as hemophilia C, have a mild hemostatic defect with rare spontaneous bleeding but bleeding after hemostatic challenge, as occurs with some instances of surgery or trauma (e.g. dental surgery, tonsillectomy, prostate surgery or in the postpartum period). In previous studies, FXI deficient mice did not have increased bleeding in a tail transection model. In contrast, we observed increased surgical wound bleeding in FXI deficient mice compared to wild-type mice, which promted us to further investigate the effect of an absence of FXI in mice on bleeding in different models.

Methods:We assessed the hemostatic capacity of FXI^-/- mice using two quantitative bleeding models (tail transection and saphenous vein injury). In the saphenous vein bleeding model, the saphenous vein was partially transected, clots that formed were removed and the total number of clots formed within a 30 minutes period (i.e. number of hemostatic events) were recorded under the microscope. In this model, a larger number of reforming clots corresponds to a higher hemostatic capacity.

Results: We found that tail bleeding times of FXI^-/- mice were similar to wild-type mice (median [range]: 63 [42 - 90] vs. 70 [60 - 114] seconds, p=0.119), which is consistent with previous studies. In contrast, we observed an impaired hemostatic capacity in FXI^-/- mice compared with wild-type controls in the saphenous vein bleeding model (median number of hemostatic events [range]: (19 [9 - 26] vs. 25 [21 - 30], p=0.003). However, this phenotype was milder than the bleeding observed in FIX^-/- mice (median number of hemostatic events [range]: 2 [0 - 4], p<0.001).

Conclusions: Our results indicate that FXI^-/- mice have a mild hemostatic defect after laparotomy and injury to the saphenous vein but not after tail transection. The mild increase in bleeding in FXI deficient mice after hemostatic challenge is similar to the increased bleeding observed in patients with FXI deficiency. Therefore, these mice may be useful in studying bleeding associated with FXI deficiency and in the presence of FXIa inhibitors.