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 alpha-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 approximately 50% of normal, while binding of the other (LJ-Ib1) was absent. Binding of both antibodies was reduced to approximately 50% of normal in the mother and one sister of the propositus, and their platelets exhibited approximately 70% of normal von Willebrand factor binding. Immunoblotting studies confirmed the presence of GP Ib alpha, as well as GP IX, in patient platelets. Antibody LJ-Ib10, but not LJ-Ib1, could immunoprecipitate the patient's GP Ib alpha 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 alpha-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 a naturally occurring mutant molecule, that the amino-terminal region of GP Ib alpha 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.
De Marco
L
L
Centro Trasfusionale e Chimica Clinica, C.R.O. Aviano, Pordenone, Italy.
Mazzucato
M
M
Fabris
F
F
De Roia
D
D
Coser
P
P
Girolami
A
A
Vicente
V
V
Ruggeri
Z M
ZM
D000911:Antibodies, Monoclonal; D001606:Bernard-Soulier Syndrome / Q000503:physiopathology*; D001791:Blood Platelet Disorders / Q000503:physiopathology*; D015153:Blotting, Western; D000939:Epitopes; D006801:Humans; D008970:Molecular Weight; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D011233:Precipitin Tests; D011487:Protein Conformation; D013917:Thrombin / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000939:Epitopes; D010980:Platelet Membrane Glycoproteins; D014841:von Willebrand Factor; D013917:Thrombin