Fibrin activates GPVI in human and mouse platelets

被引:184
作者
Alshehri, Osama M. [1 ]
Hughes, Craig E. [1 ]
Montague, Samantha [1 ]
Watson, Stephanie K. [1 ]
Frampton, Jon [1 ]
Bender, Markus [2 ,3 ]
Watson, Steve P. [1 ]
机构
[1] Univ Birmingham, Coll Med & Dent Sci, Inst Biomed Res, Ctr Cardiovasc Sci, Birmingham B15 2TT, W Midlands, England
[2] Univ Wurzburg, Univ Hosp Wurzburg, Dept Expt Biomed, Emmy Noether Grp DFG, D-97070 Wurzburg, Germany
[3] Univ Wurzburg, Rudolf Virchow Ctr Expt Biomed, D-97070 Wurzburg, Germany
基金
英国惠康基金;
关键词
C-TYPE LECTIN; GLYCOPROTEIN-VI DEFICIENCY; INTEGRIN ALPHA(IIB)BETA(3); ARTERIAL THROMBOSIS; IN-VIVO; COLLAGEN RECEPTOR; TYROSINE PHOSPHORYLATION; BLEEDING DISORDER; BINDING-SITES; ADHESION;
D O I
10.1182/blood-2015-04-641654
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The glycoprotein VI (GPVI)-Fc receptor gamma (FcR gamma) chain is the major platelet signaling receptor for collagen. Paradoxically, in a FeCl3 injury model, occlusion, but not initiation of thrombus formation, is delayed in GPVI-deficient and GPVI-depleted mice. In this study, we demonstrate that GPVI is a receptor for fibrin and speculate that this contributes to development of an occlusive thrombus. We observed a marked increase in tyrosine phosphorylation, including the FcR gamma chain and Syk, in human and mouse platelets induced by thrombin in the presence of fibrinogen and the alpha IIb beta 3 blocker eptifibatide. This was not seen in platelets stimulated by a protease activated receptor (PAR)-4 peptide, which is unable to generate fibrin from fibrinogen. The pattern of tyrosine phosphorylation was similar to that induced by activation of GPVI. Consistent with this, thrombin did not induce tyrosine phosphorylation of Syk and the FcR gamma chain in GPVI-deficient mouse platelets. Mouse platelets underwent full spreading on fibrin but not fibrinogen, which was blocked in the presence of a Src kinase inhibitor or in the absence of GPVI. Spreading on fibrin was associated with phosphatidylserine exposure (procoagulant activity), and this too was blocked in GPVI-deficient platelets. The ectodomain of GPVI was shown to bind to immobilized monomeric and polymerized fibrin. A marked increase in embolization was seen following FeCl3 injury in GPVI-deficient mice, likely contributing to the delay in occlusion in this model. These results demonstrate that GPVI is a receptor for fibrin and provide evidence that this interaction contributes to thrombus growth and stability.
引用
收藏
页码:1601 / 1608
页数:8
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