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In vivo relevance for platelet glycoprotein Ibα residue Tyr276 in thrombus formation
Author(s) -
GUERRERO J. A.,
SHAFIRSTEIN G.,
RUSSELL S.,
VARUGHESE K. I.,
KANAJI T.,
LIU J.,
GARTNER T. K.,
BÄUMLER W.,
JARVIS G. E.,
WARE J.
Publication year - 2008
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2008.02916.x
Subject(s) - platelet , von willebrand factor , in vivo , platelet glycoprotein gpib ix complex , glycoprotein ib , chemistry , glycoprotein , ristocetin , thrombin , microbiology and biotechnology , biochemistry , biology , immunology
Summary. 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 α‐subunit of GP (GPIbα) 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 GPIbα. Objectives: This study investigated the in vivo relevance of GPIbα residue Tyr276 in hemostasis and thrombosis. Methods: Transgenic mouse colonies expressing the normal human GPIbα subunit or a mutant human GPIbα containing a Phe substitution for Tyr276 (hTg Y276F ) were generated. Both colonies were bred to mice devoid of murine GPIbα. Results: Surface‐expressed GPIbα levels and platelet counts were similar in both colonies. hTg Y276F platelets were significantly impaired in binding α‐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 (FeCl 3 ) 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 GPIbα residue Tyr276 is physiologically important, supporting stable thrombus formation in vivo .