Novel molecular defect in the platelet ADP receptor P2Y12 of a patient with haemorrhagic diathesis

Background: The platelet adenosine 5'-diphosphate (ADP) receptor P2Y 12 plays a crucial role in haemostasis. Only a few patients with haemorrhagic diathesis due to molecular defects in the P2Y 12 receptor have been described so far. We report a novel molecular defect in the gene coding for P2Y 12 in a patient with a history of epistaxis, easy bruising and excessive posttraumatic blood loss. Methods: Platelet aggregation studies, perfusion studies, in which patient blood was perfused over collagen surfaces at arterial shear rates, and PCR and sequencing were used. Results: Platelet aggregation studies showed impaired ADP and collagen-induced aggregation for patient G.S. Perfusion of patient blood over collagen surfaces showed small thrombi consisting of spread platelets overlayered with non-spread platelets. These thrombi were identical to control thrombi formed in the presence of a P2Y 12 antagonist. DNA analysis of the P2Y 12 gene revealed a novel heterozygous base pair C→A substitution in exon 3, changing codon 258 from proline to threonine in the third extracellular loop of the P2Y 12 receptor. Conclusions: We conclude that perfusion studies with patient blood are of added value in the diagnostic process, which resulted in identification of a novel molecular defect in the P2Y 12 gene of a patient with haemorrhagic diathesis.