Summary

To account for the variable hemostatic defect in patients with factorXI (FXI) deficiency, with normal hemostasis in contact factor deficiencies,a coagulation paradigm is presented whereby trace quantitiesof thrombin, generated transiently by exposure of tissue factor at sitesof vascular injury, activates FXI bound to the platelet surface in thepresence of prothrombin or high Mr kininogen (HK). Tissue factorpathway inhibitor (TFPI) limits the flux of thrombin generated by thetissue factor pathway, and protease nexin II (PNII), released fromactivated platelets, inhibits solution phase FXIa and localizes FIXactivation to the platelet surface where FXIa is protected from inactivationby PNII. Either prothrombin or HK binds to the Apple 1 (A1)domain of FXI, thereby exposing a platelet-binding site in the FXI A3domain. Dimeric FXI binds to activated platelets directly through theA3 domain of one monomer. After proteolytic activation of platelet-boundFXI by thrombin (or FXIIa), a substrate binding site for FIX isexposed in the opposite monomer that promotes FIX activation on theplatelet surface resulting in the local explosive generation of thrombinand the formation of hemostatic thrombi at sites of vascular injury.