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A Cys374Tyr homozygous mutation of platelet glycoprotein IIIa (beta 3) in a
Chinese patient with Glanzmann's thrombasthenia
CM Grimaldi, F Chen, LE Scudder, BS Coller and DL French
Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029,
USA.
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, gum
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 response to
adenine diphosphate, epinephrine, and collagen; and (8) normal initial
slope of platelet aggregation in response to ristocetin, but with a
diminished maximal extent. The patient's platelets had a decreased level of
platelet fibrinogen, but the deficiency was not as severe as in other
Glanzmann's thrombasthenia patients. As judged by monoclonal antibody
binding studies, surface glycoprotein (GP) IIb/IIIa (alpha IIb beta 3)
expression was less than 15% of normal and alpha v beta 3 vitronectin
receptor expression was 15% to 19% of normal, suggesting that the defect
was in GPIIIa (beta 3). Immunoblotting of platelet lysates demonstrated
decreased levels of GPIIb (approximately 30% to 35% of normal) and GPIIIa
(approximately 10% of normal), and the GPIIb had undergone normal
maturational processing into GPIIb heavy and light chains. Sequence
analysis of the patient's GPIIIa RNA identified a G to A mutation at
nucleotide 1219, predicting a Cys to Tyr substitution at residue 374. The
patient's parents, who are first cousins, are asymptomatic and have only
minor reductions in platelet aggregation. Direct sequencing of polymerase
chain reaction-amplified cDNA and GPIIIa exon VIII indicated that the
patient is homozygous and her parents are heterozygous 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 relative preservation of platelet fibrinogen
despite the very low level of platelet surface GPIIb/IIIa expression in
this patient raises some interesting questions regarding the mechanism of
fibrinogen uptake and the pathophysiology of Glanzmann's thrombasthenia.
Volume 88,
Issue 5,
pp. 1666-1675,
09/01/1996
Copyright © 1996 by The American Society of Hematology
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