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

Abstract

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.

Keywords

coagulation factors - collagen receptor - coagulation - activated platelets

Author Contributions

Contribution: L.L., D.H., M.R., R.T.U., P.G.d.G., and B.d.L. were involved in the conception and design of the experiments. J.C.M.M. was involved in the design of the experiments and provided essential reagents. L.L. performed the experiments. L.L. and D.H. interpreted the data and drafted the manuscript. M.R., P.G.d.G., B.d.L., R.T.U., and J.C.M.M. critically revised the manuscript. All authors approved the final version of the article.

Publication History

Received: 27 September 2021

Accepted: 03 February 2022

Article published online:
05 May 2022

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