VARIANT BERNARD-SOULIER SYNDROME TYPE BOLZANO - A CONGENITAL BLEEDING DISORDER DUE TO A STRUCTURAL AND FUNCTIONAL ABNORMALITY OF THE PLATELET GLYCOPROTEIN-IB-IX COMPLEX

被引:56
作者
DEMARCO, L
MAZZUCATO, M
FABRIS, F
DEROIA, D
COSER, P
GIROLAMI, A
VICENTE, V
RUGGERI, ZM
机构
[1] SCRIPPS CLIN & RES FDN,DEPT MOLEC & EXPTL MED,DIV EXPTL HEMOSTASIS & THROMBOSIS,LA JOLLA,CA 92037
[2] OSPED CIVILE,DIV EMATOL,BOLZANO,ITALY
[3] SCRIPPS CLIN & RES FDN,COMM VASC BIOL,LA JOLLA,CA 92037
[4] UNIV PADUA,IST PATOL MED 2,I-35100 PADUA,ITALY
[5] CTR RIFERIMENTO ONCOL,CTR TRANSFUS & CHIM CLIN,AVIANO,ITALY
关键词
Bernard-Soulier syndrome; platelet glycoproteins; thrombin; von Willebrand factor;
D O I
10.1172/JCI114692
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
We have studied a patient with a congenital bleeding disorder and phenotypic manifestations typical of Bernard-Soulier syndrome, including giant platelets with absent ristocetin-induced von Willebrand factor binding. Two monoclonal antibodies reacting with distinct epitopes in the amino-terminal domain of the α-chain of glycoprotein (GP) Ib were used to estimate the number of GP Ib molecules on the platelet membrane. In the patient, binding of one antibody (LJ-Ib10) was ~50% of normal, while binding of the other (LJ-Ib1) was absent. Binding of both antibodies was reduced to ~50% of normal in the mother and one sister of the propositus, and their platelets exhibited ~70% of normal von Willebrand factor binding. Immunoblotting studies confirmed the presence of GP IBα, as well as GP IX, in patient platelets. Antibody LJ-IB10, but not LJ-Ib1, could immunoprecipitate the patient's GP Ibα from surface-labeled proteins. Thus, platelets from the propositus contained a structurally and functionally altered GP Ib-IX complex lacking a specific antibody epitope and the ability to bind von Willebrand factor. In contrast, the binding of human α-thrombin to the patient's platelets was normal, and three classes of binding sites with high, intermediate, and low affinity could be detected. These studies define a distinct variant form of Bernard-Soulier syndrome and provide evidence, based on naturally occurring mutant molecule, that the amino-terminal region of GP Ibα contains a von Willebrand factor-binding domain distinct from the high affinity thrombin-binding site. Use of different monoclonal antibodies with distinct epitope specificities appears to be essential for a correct identification of variant Bernard-Soulier syndrome.
引用
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页码:25 / 31
页数:7
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