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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:e101.)
© 2000 American Heart Association, Inc.

Thrombosis

Platelets From a Patient Heterozygous for the Defect of P2_CYC Receptors for ADP Have a Secretion Defect Despite Normal Thromboxane A₂ Production and Normal Granule Stores

Further Evidence That Some Cases of Platelet ‘Primary Secretion Defect’ Are Heterozygous for a Defect of P2_CYC Receptors

Marco Cattaneo; Anna Lecchi; Rossana Lombardi; Christian Gachet; Maddalena L. Zighetti

From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center (M.C., A.L., R.L., M.L.Z.), Department of Internal Medicine. IRCCS Ospedale Maggiore. University of Milan, Milan, Italy and INSERM U.311 (C.G.), Biologie et Pharmacologie de l’Hémostase et de la Thrombose, Etablissement Français du Sang-Alsace, Strasbourg, France.

Correspondence to M. Cattaneo, MD, Hemophilia and Thrombosis Center, Via Pace 9, 20122 Milano, Italy. E-mail marco.cattaneo{at}unimi.it

Abstract—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 was shown to be abnormal. We recently showed that platelets with the primary secretion defect (PSD; characterized by abnormal secretion but normal granule stores, thromboxane A₂ production, and ADP-induced primary wave of aggregation) have a moderate defect of P2_CYC. Therefore, the interaction of ADP with the full complement of its receptors seems to be essential for normal platelet secretion, and PSD patients may be heterozygotes for the congenital severe defect of P2_CYC. In this study, we describe 2 new related patients with a severe defect of P2_CYC and the son of one of them, who is to be considered an obligate heterozygote for the defect. The 2 patients with the severe defect had lifelong histories of abnormal bleeding, prolonged bleeding times, abnormalities of platelet aggregation and secretion, lack of inhibition of adenylate cyclase by ADP, and a deficiency of platelet-binding sites for [³³P]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 found in patients with PSD. In addition, his platelets showed a moderate defect of binding sites for [³³P]2 MeS-ADP (430 sites per platelet) and of adenylate cyclase inhibition by ADP. This study of a family with the platelet disorder characterized by a defect of the platelet P2_CYC receptor supports our hypothesis that the full complement of the platelet ADP receptors is essential for normal platelet secretion and that some patients with the common, ill-defined diagnosis of PSD are actually heterozygous for the defect.

Key Words: ADP • purinoceptors • platelet secretion • congenital disorders of platelet function • thromboxane A₂

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