RGD-ligand mimetic antagonists of integrin alphaIIbbeta3 paradoxically enhance GPVI-induced human platelet activation

ML Jones, MT Harper, EW Aitken, CM Williams, AW Poole

Research output: Contribution to journalArticle (Academic Journal)peer-review

22 Citations (Scopus)

Abstract

BACKGROUND: The integrin alpha(IIb)beta(3) is the major mediator of platelet aggregation and has, therefore, become an important target of antithrombotic therapy. Antagonists of alpha(IIb)beta(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 alpha(IIb)beta(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 alpha(IIb)beta(3) antagonists were observed on their own, but these integrin antagonists did lead to a marked potentiation of glycoprotein VI (GPVI)-associated FcR gamma-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 alpha(IIb)beta(3) inhibitors, but also reveal a potentially important signaling pathway operating from the integrin to GPVI signaling.
Translated title of the contributionRGD-ligand mimetic antagonists of integrin alphaIIbbeta3 paradoxically enhance GPVI-induced human platelet activation
Original languageEnglish
Pages (from-to)567 - 576
JournalJournal of Thrombosis and Haemostasis
Volume8(3)
Publication statusPublished - Mar 2010

Bibliographical note

Author of Publication Reviewed: Jones ML, Harper MT, Aitken EW, Williams CM, Poole AW

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