Bernard–Soulier Syndrome and Other GPIb-IX-Related Receptor Defects

Bernard–Soulier Syndrome

Bernard–Soulier syndrome (BSS) is an autosomal recessive platelet disorder characterized by thrombocytopenia, the presence of giant platelets, and defective ristocetin-induced platelet agglutination.

BSS occurs when a mutation is present in both alleles of one of the components of the platelet receptor GPIb-IX. GPIb-IX is the receptor that is predominantly responsible for the VWF-dependent adhesion of platelets in damaged blood vessels. The absence of GPIb-IX results in greatly diminished platelet accumulation at sites of vessel injury and bleeding. GPIb-IX is a multimeric receptor complex composed of the products of three separate glycoprotein (GP) subunits (Ibα, Ibβ, IX), which are encoded by three different genes. Homozygous or compound heterozygous mutations responsible for BSS have been identified within each of these GPIbα, GPIbβ, and GPIX components. The absence of any one of component results in markedly decreased cell surface expression of the entire GPIb-IX complex because intracellular association of the GPIbα, GPIbβ, and GPIX subunits is necessary for the appropriate trafficking of GPIb-IX. Although classically associated with GPIb-IX, BSS caused by mutations in the gene-encoding Glycoprotein V has not been identified.

Giant platelets are a characteristic feature of BSS, and it is not uncommon to see platelets as large as 20 μm in diameter (RBCs are 8 μm). Platelet counts in individuals with BSS range from 20,000/μL to near normal. A normal interaction between GPIbα and the cytoskeletal protein filamin is an important determinant of platelet size, and its disruption leads to the production of abnormally large platelets. Platelet aggregation studies in patients with BSS demonstrate a poor agglutination response to ristocetin and botrocetin. Both ristocetin and botrocetin bind and activate the GPIb-IX receptor. In vivo the GPIb-IX receptor only binds VWF once the A1 domain of VWF has been functionally presented due to tensile forces imposed by shear within the vasculature. In vitro, the normally shear-induced conformational change in VWF that results in functional presentation of the A1 domain can be mimicked by allowing VWF to bind to ristocetin. In platelet-rich plasma absence of ristocetin-induced agglutination could either be due to a defect in GPIb-IX or decreased or dysfunctional VWF. To discern between these two possibilities the patient’s platelets are mixed with normal platelet-poor plasma and ristocetin. If the defect in ristocetin-induced agglutination persists, this would indicate a defect in the patient’s GPIb-IX receptor, and not absent or dysfunctional VWF. GPIb-IX levels determined by flow cytometry typically demonstrate the absence of the GPIb-IX receptor complex from the platelet surface. However, variant forms of BSS have been identified that have expression of a dysfunctional GPIb-IX complex on the platelet surface. Sequencing of the genes encoding for the molecular components of GPIb-IX may also assist in the diagnosis.

BSS patients most often have a clinically significant bleeding disorder. Mild to moderate bleeds might be adequately treated using desmopressin (DDAVP) and antifibrinolytic agents, and platelet transfusions are recommended for more severe bleeding manifestations. BSS patients with an absence of GPIb-IX can become refractory to platelet transfusion due to the development of GPIb-IX antibodies.