Variant Bernard-Soulier syndrome type Bolzano. A congenital bleeding disorder due to a structural and functional abnormality of the platelet glycoprotein Ib-IX complex

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.