In vivo relevance for platelet glycoprotein Ib alpha residue Tyr276 in thrombus formation

J.A. Guerrero, G. Shafirstein, S. Russell, K.I. Varughese, T. Kanaji, J. Liu, T.K. Gartner, W. Baumler, Gavin Jarvis, J. Ware

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Background: Platelet glycoprotein (GP) Ib-IX-V supports platelet adhesion on damaged vascular walls by binding to von Willebrand factor (VWF). For several decades it has been recognized that the alpha-subunit of GP (GPIb alpha) also binds thrombin but the physiological relevance, if any, of this interaction was unknown. Previous studies have shown that a sulfated tyrosine 276 (Tyr276) is essential for thrombin binding to GPIb alpha.Objectives: This study investigated the in vivo relevance of GPIb alpha residue Tyr276 in hemostasis and thrombosis.Methods: Transgenic mouse colonies expressing the normal human GPIb alpha subunit or a mutant human GPIb alpha containing a Phe substitution for Tyr276 (hTg(Y276F)) were generated. Both colonies were bred to mice devoid of murine GPIb alpha.Results: Surface-expressed GPIb alpha levels and platelet counts were similar in both colonies. hTg(Y276F) platelets were significantly impaired in binding alpha-thrombin but displayed normal binding to type I fibrillar collagen and human VWF in the presence of ristocetin. In vivo thrombus formation as a result of chemical damage (FeCl3) demonstrated that hTg(Y276F) mice have a delayed time to occlusion followed by unstable blood flow indicative of embolization. In models of laser-induced injury, thrombi developing in hTg(Y276F) animals were also less stable.Conclusions: The results demonstrate that GPIb alpha residue Tyr276 is physiologically important, supporting stable thrombus formation in vivo.
Original languageEnglish
Pages (from-to)684-691
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume6
Issue number4
DOIs
Publication statusPublished - Apr 2008

ASJC Scopus subject areas

  • Medicine(all)

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