CYS374TYR HOMOZYGOUS MUTATION OF PLATELET GLYCOPROTEIN IIIA (BETA(3))IN A CHINESE PATIENT WITH GLANZMANNS-THROMBASTHENIA

A 20-year-old woman from a consanguineous family in the Hunan Province of the People's Republic of China was diagnosed as having Glanzmann's thrombasthenia based on (1) nearly a lifelong history of epistaxis, g um bleeding, petechiae, and purpura; (2) severe menorrhagia resulting in anemia and need for whole-blood transfusion; (3) normal coagulation assays; (4) prolonged bleeding time; (5) absent clot retraction; (6) decreased glass bead retention: (7) absent platelet aggregation in res ponse to adenine diphosphate, epinephrine, and collagen; and (8) norma l initial slope of platelet aggregation in response to ristocetin, but with a diminished maximal extent. The patient's platelets had a decre ased level of platelet fibrinogen, but the deficiency was not as sever e as in other Glanzmann's thrombasthenia patients. As judged by monocl onal antibody binding studies, surface glycoprotein (GP) IIb/IIIa (alp ha(IIb)beta(3)) expression was less than 15% of normal and alpha(v) be ta(3) vitronectin receptor expression was 15% to 19% of normal, sugges ting that the defect was in GPIIIa (beta(3)). Immunoblotting of platel et lysates demonstrated decreased levels of GPIIb (similar to 30% to 3 5% of normal) and GPIIIa (similar to 10% of normal), and the GPIIb had undergone normal maturational processing into GPIIb heavy and light c hains, Sequence analysis of the patient's GPIIIa RNA identified a G to A mutation at nucleotide 1219, predicting a Cys to Tyr substitution a t residue 374, The patient's parents, who are first cousins, are asymp tomatic and have only minor reductions in platelet aggregation. Direct sequencing of polymerase chain reaction-amplified cDNA and GPIIIa exo n VIII indicated that the patient is homozygous and her parents are he terozygous for the mutation. Transient transfection studies in Chinese hamster ovary cells indicated that the mutation results in an 85% to 90% reduction in GPIIb/IIIa surface expression, but these cells retain the ability to mediate adhesion to immobilized fibrinogen. The relati ve preservation of platelet fibrinogen despite the very low level of p latelet surface GPIIb/IIIa expression in this patient raises some inte resting questions regarding the mechanism of fibrinogen uptake and the pathophysiology of Glanzmann's thrombasthenia. (C) 1996 by The Americ an Society of Hematology.