Platelets from a patient heterozygous for the defect of P2(CYC) receptors for ADP have a secretion defect despite normal thromboxane A(2) production and normal granule stores - Further evidence that some cases of platelet 'primary secretion defect' are heterozygous for a defect of P2(CYC) receptors

Two unrelated patients with a congenital bleeding diathesis associated with a severe defect of the platelet ADP receptor coupled to adenylate cyclase (P2(CYC)) have been described so far. In one of them, platelet secretion wa s shown to be abnormal. We recently showed that platelets with the primary secretion defect (PSD; characterized by abnormal secretion but normal granu le stores, thromboxane A(2) production, and ADP-induced primary wave of agg regation) have a moderate defect of P2(CYC). Therefore, the interaction of ADP with the full complement of its receptors seems to be essential for nor mal platelet secretion, and PSD patients may be heterozygotes for the conge nital severe defect of P2(CYC). In this study, we describe 2 new related pa tients with a severe defect of P2(CYC) and the son of one of them, who is t o be considered an obligate heterozygote for the defect. The 2 patients wit h the severe defect had lifelong histories of abnormal bleeding, prolonged bleeding times, abnormalities of platelet aggregation and secretion, lack o f inhibition of adenylate cyclase by ADP, and a deficiency of platelet-bind ing sites for [P-33]2 MeS-ADP (240 and 225 sites per platelet; normal range , 530 to 1102). The son of one of them had a mildly prolonged bleeding time and abnormalities of platelet aggregation and secretion similar to those f ound in patients with PSD. In addition, his platelets showed a moderate def ect of binding sites for [P-33]2 MeS-ADP (430 sites per platelet) and of ad enylate cyclase inhibition by ADP. This study of a family with the platelet disorder characterized by a defect of the platelet P2(CYC) receptor suppor ts our hypothesis that the full complement of the platelet ADP receptors is essential for normal platelet secretion and that some patients with the co mmon, ill-defined diagnosis of PSD are actually heterozygous for the defect .