Platelet Activation via Glycoprotein VI Initiates Thrombin Generation: A Potential Role for Platelet-Derived Factor IX?

Collagen triggers coagulation via activation of factor (F) XII. In a platelet-rich environment, collagen can also trigger coagulation independently of FXII. We studied a novel mechanism of coagulation initiation via collagen-dependent platelet activation using thrombin generation (TG) in platelet-rich plasma. Collagen-induced coagulation is minimally affected by active-site inactivated FVIIa, anti-FVII antibodies, or FXIIa inhibition (corn trypsin inhibitor). Activation of platelets via specific glycoprotein (GP) VI agonists initiates TG, FX activation, and fibrin formation. To determine the platelet-derived trigger of coagulation, we systematically reconstituted factor-deficient plasmas with washed platelets. TG triggered by GPVI-activated platelets was significantly affected in FIX- and FVIII-deficient plasma but not in FVII- and FXII-deficient plasma. In a purified system composed of FX and FVIII, we observed that absence of FIX was compensated by GPVI-activated platelets, which could be inhibited by an anti-FIX antibody, suggesting FIXa activity from activated platelets. Furthermore, with the addition of FVIII in FIX-deficient plasma, TG induced by GPVI-activated platelets was restored, and was inhibited by the anti-FIX antibody. In conclusion, GPVI-activated platelets initiate TG, probably via platelet-derived FIXa activity.