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Spatio-temporal control of fibrin formation by platelet glycoprotein V

1 University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Bayern, Germany, 2University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Germany, Würzburg, Bayern, Germany, 3Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, USA, Atlanta, Georgia, United States, 4Rudolf Virchow Center, University of Würzburg, Würzburg, Bayern, Germany, 5Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands, Maastricht, Limburg, Netherlands, 6Department of Molecular Medicine, Scripps Research, La Jolla, CA, USA, La Jolla, California, United States, 7University Hospital Würzburg, Würzburg, Bayern, Germany, 8Rudolf Virchow Center for Integrative and Translational Biomaging University of Würzburg, Würzburg, Bayern, Germany, 9Department of Biochemistry, CARIM, Maastricht University, Maastricht, the Netherlands; Synapse Research Institute Maastricht, The Netherlands, Maastricht, Limburg, Netherlands, 10Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, Mainz, Rheinland-Pfalz, Germany, 11University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Biomaging University of Würzburg, Würzburg, Bayern, Germany, 12Institute of Experimental Biomedicine, University Hospital Würzburg and Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Bayern, Germany

Abstract Number: OC 49.2

Meeting: ISTH 2022 Congress

Theme: Platelets and Megakaryocytes » Platelet Function and Interactions

Background: Platelet activation and coagulation at sites of vascular injury are crucial for hemostasis but can promote thrombosis in vascular pathologies. During platelet activation, the abundant platelet glycoprotein (GP)V is cleaved by thrombin, however the function of membrane-bound as well as cleaved GPV remains unknown.

Aims: To elucidate the role of platelet GPV cleavage and its functional relevance at sites of vascular injury.

Methods: We used genetic and pharmacological approaches (Gp5-/- and Gp5dThr mice – thrombin-insensitive GPV, new anti-GPV antibodies, recombinant GPV ectodomain) to assess thrombus formation, thrombin generation and fibrin formation in vitro and in vivo.

Results: Platelets of Gp5-/- mice were hyperreactive to low thrombin concentrations under conditions where GPIbα was required for platelet responsiveness to thrombin. In contrast to Gp5-/- platelets, Gp5dThr platelets or blockade of thrombin-mediated GPV cleavage were not hyperreactive, indicating a key regulatory role of membrane-bound GPV for thrombin-dependent platelet activation.

Surprisingly, both Gp5-/- and Gp5dThr mice showed accelerated thrombus formation following vascular injury in vivo, suggesting that cleaved GPV controls thrombus formation by a mechanism unrelated to regulation of platelet activation. We uncovered that soluble (s)GPV regulates thrombin-dependent fibrin formation under flow. Specifically, we demonstrated (I) direct interaction of sGPV with thrombin in a pulldown assay, (II) accumulation of sGPV with fibrin in platelet-free areas of thrombi by super-resolution microscopy, (III) increased availability of free thrombin and fibrin formation in Gp5-/- and Gp5dThr mice and after blockade of GPV cleavage, and (IV) inhibition of thrombus formation by sGPV. Thus, sGPV localized to growing thrombi, limited thrombin-dependent fibrin formation and protected from arterial thrombosis without interfering with initial hemostatic platelet adhesion. Accordingly, genetic or pharmacologic defects in hemostatic platelet function were rescued by blockade of GPV cleavage.

Conclusion(s): GPV spatio-temporally controls fibrin formation and thereby provides a platelet-based mechanism that locally limits excessive fibrin formation and thrombus growth.

To cite this abstract in AMA style:

Beck S, Öftering P, Li R, Hemmen K, Nagy M, Wang Y, Zarpellon A, Schuhmann M, Stoll G, Ruggeri Z, Heinze K, Heemskerk J, Ruf W, Stegner D, Nieswandt B. Spatio-temporal control of fibrin formation by platelet glycoprotein V [abstract]. https://abstracts.isth.org/abstract/spatio-temporal-control-of-fibrin-formation-by-platelet-glycoprotein-v/. Accessed September 29, 2023.

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