Thromb Haemost 2022; 122(09): 1502-1512
DOI: 10.1055/s-0042-1744379
Cellular Haemostasis and Platelets

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

Li Li
1   Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands
2   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
,
Mark Roest
1   Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands
2   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
,
Joost C. M. Meijers
3   Department of Molecular Hematology, Sanquin Research, Amsterdam, The Netherlands
4   Department of Experimental Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
,
Bas de Laat
1   Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands
2   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
,
Rolf T. Urbanus
5   Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands
,
Philip G. de Groot
1   Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands
,
1   Department of Platelet Pathophysiology, Synapse Research Institute, Maastricht, The Netherlands
2   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
› Author Affiliations
Funding Li Li is supported by a scholarship (No. 201706230245) from the China Scholarship Council.

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.

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.


Supplementary Material



Publication History

Received: 27 September 2021

Accepted: 03 February 2022

Article published online:
05 May 2022

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