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Impaired platelet function in a patient with P2Y 12 deficiency caused by a mutation in the translation initiation codon
Author(s) -
SHIRAGA M.,
MIYATA S.,
KATO H.,
KASHIWAGI H.,
HONDA S.,
KURATA Y.,
TOMIYAMA Y.,
KANAKURA Y.
Publication year - 2005
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.1538-7836.2005.01554.x
Subject(s) - translation (biology) , mutation , medicine , platelet , p2y12 , function (biology) , genetics , biology , platelet aggregation , gene , messenger rna
Summary. 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 (A T G to A G G) 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.