FACTOR XI ACTIVATION AND INHIBITION IN CATHETER-INDUCED CLOTTING

Abstract

Thrombosis, or blood clot formation in vessels, is responsible for 1 in 4 deaths in Canada and worldwide. Patients with acute coronary syndrome (ACS), atrial fibrillation (AF), or cancer often require central venous catheters (CVCs) for medical access, such as receiving chemotherapy, drugs, and nutrition. These catheters, like peripherally inserted central catheters (PICC) and implanted ports, are associated with an increased risk of thrombosis, as clots tend to form inside the catheters and block the vessels. Vascular blockages cause severe complications like deep vein thrombosis (DVT) and pulmonary embolism (PE). Therefore, effective and safe anticoagulants are essential to manage and prevent catheter-induced clotting. Factor (F) XI in the contact pathway of coagulation has emerged as a promising target for anticoagulant therapy because FXI is key for blood clot formation but is not essential in normal blood clotting. Consequently, FXI inhibitors have become a safer alternative to currently available anticoagulants. FXI can be autoactivated by negatively charged surfaces like polyphosphate (polyP), released from activated platelets, or synthetic surfaces like catheters. Thus, FXI is a root cause of catheter- and polyP-induced clotting. Milvexian and abelacimab, both FXI inhibitors, are currently undergoing large phase 3 trials in patients with ACS, AF, or cancer. However, the effect of these FXI inhibitors on catheter-induced clotting has not been explored. We previously demonstrated that inhibiting FXI reduces catheter-induced clotting in rabbits. This thesis aims to investigate the role of catheters and polyP in FXI activation and to explore the anticoagulant effects of FXI inhibitors in catheter-induced thrombosis using our established plate-based assays. We found that catheters and polyP activate clotting at the level of FXI, bypassing FXII. Both milvexian and abelacimab attenuate catheter-induced clotting. These findings suggest that FXI inhibitors could be a potential therapeutic option for catheter- and polyP-induced thrombosis without increasing bleeding risk.