Platelet glycoprotein V spatio-temporally controls fibrin formation

Sarah Beck, Patricia Öftering, Renhao Li, Katherina Hemmen, Magdolna Nagy, Yingchun Wang, Alessandro Zarpellon, Michael K. Schuhmann, Guido Stoll, Zaverio M. Ruggeri, Katrin G. Heinze, Johan W.M. Heemskerk, Wolfram Ruf, David Stegner*, Bernhard Nieswandt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Pages (from-to)368-382
Number of pages15
JournalNature cardiovascular research
Volume2
Issue number4
DOIs
Publication statusPublished - 1 Apr 2023

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