Platelet glycoprotein V spatio-temporally controls fibrin formation

• Type of Material: Article
• Authors: Sarah Beck, Julius-Maximilians-Universität Würzburg; Patricia Öftering, Julius-Maximilians-Universität Würzburg; Renhao Li, Emory University; Katherina Hemmen, Julius-Maximilians-Universität Würzburg; Magdolna Nagy, Universiteit Maastricht; Yingchun Wang, Emory University; Alessandro Zarpellon, Scripps Research; Michael K Schuhmann, Universitätsklinikum Würzburg; Guido Stoll, Universitätsklinikum Würzburg; Zaverio M Ruggeri, Scripps Research; Katrin G Heinze, Julius-Maximilians-Universität Würzburg; Johan WM Heemskerk, Universiteit Maastricht; Wolfram Ruf, Universitätsmedizin Mainz; David Stegner, Julius-Maximilians-Universität Würzburg; Bernhard Nieswandt, Julius-Maximilians-Universität Würzburg
• Language: English
• Date: 2023-04-01
• Publisher: Springer Nature Limited
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2023, The Author(s)
• Final Published Version (URL): http://dx.doi.org/10.1038/s44161-023-00254-6
• Title of Journal or Parent Work: Nature Cardiovascular Research
• Volume: 2
• Issue: 4
• Start Page: 368
• End Page: 382
• Grant/Funding Information: European Union (Thrombo-Inflame, EFRE–Europäischer Fonds für regionale Entwicklung, Bavaria); National Institutes of Health grant HL082808 (RL) and UM1 HL120877 (WR); German Research Foundation (SFB 1525, project number: 453989101); German Research Foundation (TR240, project number: 374031971); German Research Foundation Ni556/14-1 (BN); Rudolf Virchow Centre for Integrative and Translational Bioimaging; German Research Foundation INST 93/1022-1
• Keywords: fibrin formation

Abstract

The activation of platelets and coagulation at vascular injury sites is crucial for hemostasis but can promote thrombosis and inflammation in vascular pathologies. Here, we delineate an unexpected spatio-temporal control mechanism of thrombin activity that is platelet orchestrated and locally limits excessive fibrin formation after initial hemostatic platelet deposition. During platelet activation, the abundant platelet glycoprotein (GP)V is cleaved by thrombin. We demonstrate, with genetic and pharmacological approaches, that thrombin-mediated shedding of GPV does not primarily regulate platelet activation in thrombus formation but rather has a distinct function after platelet deposition and specifically limits thrombin-dependent generation of fibrin, a crucial mediator of vascular thrombo-inflammation. Genetic or pharmacologic defects in hemostatic platelet function are unexpectedly attenuated by specific blockade of GPV shedding, indicating that the spatio-temporal control of thrombin-dependent fibrin generation also represents a potential therapeutic target to improve hemostasis.