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RGD‐ligand mimetic antagonists of integrin α IIb β 3 paradoxically enhance GPVI‐induced human platelet activation
Author(s) -
JONES M. L.,
HARPER M. T.,
AITKEN E. W.,
WILLIAMS C. M.,
POOLE A. W.
Publication year - 2010
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.1538-7836.2009.03719.x
Subject(s) - gpvi , integrin , tirofiban , platelet activation , chemistry , platelet , collagen receptor , phosphatidylserine , abciximab , tyrosine phosphorylation , microbiology and biotechnology , platelet glycoprotein gpiib iiia complex , eptifibatide , pharmacology , phosphorylation , biochemistry , biology , medicine , receptor , phospholipid , membrane , percutaneous coronary intervention , myocardial infarction , conventional pci
Summary. Background: The integrin α IIb β 3 is the major mediator of platelet aggregation and has, therefore, become an important target of antithrombotic therapy. Antagonists of α IIb β 3 , for example abciximab, tirofiban and eptifibatide, are used in the treatment of acute coronary syndromes. However, in addition to effective blockade of the integrin, binding of can induce conformational changes in the integrin and can also induce integrin clustering. This class effect of RGD‐ligand mimetics might, therefore, underlie paradoxical platelet activation and thrombosis previously reported. Objectives: To examine the components of signaling pathways and functional responses in platelets that may underlie this phenomenon of paradoxical platelet activation. Methods: We assessed the effect of lotrafiban, and other α IIb β 3 antagonists including the clinically used drug tirofiban, on tyrosine phosphorylation of key signaling proteins in platelets by immunoblotting and also platelet functional outputs such as cytosolic calcium responses, phosphatidylserine exposure (pro‐coagulant activity) and dense granule release. Results: In all cases, no effect of α IIb β 3 antagonists were observed on their own, but these integrin antagonists did lead to a marked potentiation of glycoprotein VI (GPVI)‐associated FcR γ‐chain phosphorylation, activation of Src family kinases and Syk kinase. This correlated with increased dense granule secretion, cytosolic calcium response and exposure of phosphatidylserine on the platelet surface. P2Y 12 antagonism abolished the potentiated phosphatidylserine exposure and dense granule secretion but not the cytosolic calcium response . Conclusions: These data provide a mechanism for enhancement of platelet activity by α IIb β 3 inhibitors, but also reveal a potentially important signaling pathway operating from the integrin to GPVI signaling.