Why does Bernard-Soulier syndrome present with macrocythrombocytopenia (large platelet disorder characterized by thrombocytopenia and large platelets)?

From the Guidelines

Bernard Soulier Syndrome (BSS) is characterized by macrothrombocytopenia due to a genetic defect in the GPIb-IX-V complex, leading to impaired platelet production, abnormal development, and reduced survival, as supported by the study published in the Journal of Thrombosis and Haemostasis 1. The genetic mutation affects the expression of glycoproteins on the platelet surface, including GPIb and GPIb/IX, which can be detected by flow cytometry screening using specific antibodies against these glycoproteins, such as CD42b and CD42a 1. Key features of BSS include:

• Macrothrombocytopenia, which is a direct result of the defective GPIb-IX-V complex disrupting normal cytoskeletal organization and membrane development during platelet formation
• Impaired platelet adhesion to damaged blood vessels due to the reduced expression of the GPIb-IX-V complex, which serves as the receptor for von Willebrand factor
• Abnormal megakaryocyte fragmentation in the bone marrow, leading to reduced platelet production
• Reduced platelet survival in circulation, further contributing to thrombocytopenia The diagnosis of BSS can be guided by first-step tests, including flow cytometry screening, which can diagnose up to ~40% of all inherited platelet function disorders, including BSS 1. Second-step tests, such as light transmission aggregometry (LTA) with an expanded agonist panel and transmission electron microscopy (TEM), may be necessary to confirm the diagnosis in patients not diagnosed by first-step tests 1. Overall, the macrothrombocytopenia observed in BSS patients is a result of the complex interplay between impaired platelet production, abnormal development, and reduced survival, all of which are consequences of the genetic defect in the GPIb-IX-V complex.

From the Research

Bernard-Soulier Syndrome and Macrocythrombocytopenia

• Bernard-Soulier syndrome (BSS) is a rare inherited platelet bleeding disorder characterized by low platelet count and abnormally large platelets (macrothrombocytopenia) 2.
• The syndrome is caused by defects in the glycoprotein (GP)Ib-IX-V complex, a platelet-specific adhesion-signaling complex that binds to von Willebrand factor (VWF) 3.
• The GPIb-IX-V complex is composed of four subunits: GPIbα, GPIbβ, GPIX, and GPV, and defects in any of these subunits can lead to BSS 4.
• The macrocythrombocytopenia seen in BSS is thought to be due to the defective expression or function of the GPIb-IX-V complex, which is essential for normal platelet production and function 5.
• Studies have identified a wide spectrum of mutations in the genes encoding the GPIb-IX-V complex, including novel nonsense mutations that affect the expression of the complex on the platelet surface 6.

Genetic Basis of Macrocythrombocytopenia in BSS

• The genetic defects that cause BSS can lead to a range of phenotypes, from isolated giant platelet disorders to full-blown BSS and platelet-type von Willebrand disease 3.
• The severity of the bleeding tendency in BSS patients does not correlate with the degree of thrombocytopenia or platelet GPIbα expression, suggesting that other factors may contribute to the clinical phenotype 4.
• Further studies are needed to understand the genotype-phenotype correlations in BSS and to develop effective diagnostic and therapeutic strategies for this rare and underestimated disease 5.