期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 3, 期 10, 页码 2315-2323出版社
WILEY
DOI: 10.1111/j.1538-7836.2005.01554.x
关键词
alpha(IIb)beta(3); initiation codon; mutation; P2Y(12) deficiency; platelets; thrombogenesis
In this study, we have identified a patient (OSP-1) with a congenital P2Y(12) deficiency showing a mild bleeding tendency from her childhood and examined the role of P2Y(12) in platelet function. At low concentrations of agonists OSP-1 platelets showed an impaired aggregation to several kinds of stimuli, whereas at high concentrations they showed a specifically impaired platelet aggregation to adenosine diphosphate (ADP). ADP normally induced platelet shape change and failed to inhibit PGE(1)-stimulated cAMP accumulation in OSP-1 platelets. Molecular genetic analysis revealed that OSP-1 was a homozygous for a mutation in the translation initiation codon (ATG to AGG) in the P2Y(12) gene. Heterologous cell expression of wild-type or mutant P2Y(12) confirmed that the mutation was responsible for the deficiency in P2Y(12). OSP-1 platelets showed a markedly impaired platelet spreading onto immobilized fibrinogen. Real-time observations of thrombogenesis under a high shear rate (2000 s(-1)) revealed that thrombi over collagen were small and loosely packed and most of the aggregates were unable to resist against high shear stress in OSP-1. Our data suggest that secretion of endogenous ADP and subsequent P2Y(12)-mediated signaling are critical for platelet aggregation, platelet spreading, and as a consequence, for stabilization of thrombus.
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