Factor XI localization in human deep venous thrombus and function of activated factor XI on venous thrombus formation and hemostasis in rabbit

BackgroundNovel anticoagulants targeting coagulation factor XI (FXI)/activated FXI (FXIa) are under development. However, whether FXI is present in human deep vein thrombosis (DVT) and whether FXIa and activated factor X (FXa) play different roles in venous thrombus formation and hemostasis remain unclear. This study aimed to determine the presence of FXI in DVT and the effects of direct oral FXIa and FXa inhibitors on venous thrombus formation and hemostasis in rabbits and mural thrombus formation in flow chamber system. MethodsWe immunohistochemically assessed FXI localization in human aspirated DVT (n=15). Additionally, we compared thrombus formation induced by endothelial denudation and stenosis in jugular vein, and skin bleeding time and volume between rabbits treated with direct FXIa inhibitors (ONO-1600586) and FXa inhibitors (rivaroxaban). Ex vivo rabbit and human blood were perfused on a flow chamber under low shear rates (70/s). ResultFXI was localized in all DVT, predominantly in fibrin-rich areas. The FXI-immunopositive area in the non-organizing area was greater than that in the organizing area. Although FXIa and FXa inhibitors comparably inhibited venous thrombus formation, FXIa inhibitors did not affect bleeding time or volume in rabbits. FXIa or FXa inhibitors mildly or strongly inhibited fibrin formation at low shear rates respectively. Furthermore, the FXIa inhibitor suppressed human FXIa activity, thrombin generation, and fibrin formation during perfusion. ConclusionThe pathological findings of human DVT suggest FXIs role in human DVT. FXIa inhibitors may inhibit less fibrin formation than FXa inhibitors, and may explain the minor role of FXIa in hemostasis. EssentialO_LIPresence of factor XI (FXI) in venous thrombus and less bleeding in its inhibition are unclear. C_LIO_LIWe assessed FXI localization in deep vein thrombosis (DVT) and function of FXIa in rabbit. C_LIO_LIFXI localized in human DVT that provide a rationale for FXI inhibition in human DVT. C_LIO_LIFXIa inhibitor inhibited less fibrin formation than factor Xa inhibitor under low-shear rate. C_LI