Restricted accessReview articleFirst published online 2006-5
Molecular Mechanisms of Prothrombotic Risk Due to Genetic Variations in Platelet Genes: Enhanced Outside-In Signaling Through the Pro 33 Variant of Integrin β 3
In recent years inherited variations in platelet proteins have emerged as potential risk factors that could predispose individuals to arterial thrombosis. Although many studies have examined the association of platelet gene polymorphisms with particular disease states, the underlying mechanisms by which most of these polymorphisms contribute to the pathophysiology of thrombosis have remained largely unexplored. This review will focus on the cellular and molecular features by which these genetic changes affect platelet physiology. Although many genes have been investigated in this regard, only the genes encoding integrins β3 and α2, and the platelet Fc receptor, FcγRIIA, have been studied in any depth. In some cases (such as integrin α2), evidence supports a quantitative trait locus. For other genes, nonsynonymous nucleotide substitutions lead to structural and functional consequences. A large portion of this review will focus on the widely studied Leu33Pro (PIA) polymorphism of integrin β3, and will consider the potential mechanisms by which the Pro33 polymorphism could induce a prothrombotic risk. A detailed understanding of how polymorphisms modulate platelet physiology will be important for understanding individual differences in response to antiplatelet therapy.
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