Why does Bernard-Soulier syndrome cause thrombocytopenia with large platelets?

From the Guidelines

Bernard Soulier syndrome causes large platelets due to a genetic defect in the glycoprotein (GP) Ib-IX-V complex on platelet membranes, leading to abnormal platelet formation and release. This condition is characterized by thrombocytopenia and macrothrombocytopenia, resulting from a defect in the GP Ib-IX-V complex, which normally functions as a receptor for von Willebrand factor and is essential for normal platelet adhesion to damaged blood vessels 1. The mutation affects platelet development during megakaryocyte maturation in the bone marrow, disrupting normal cytoskeletal organization and membrane assembly, and resulting in platelets that are fewer in number but significantly larger in size. Some key points to consider in the diagnosis of Bernard Soulier syndrome include:

• Flow cytometry screening should be carried out on resting platelets using antibodies against GPIIb/IIIa (CD41), GPIIIa (CD61), GPIb (CD42b) and GPIb/IX (CD42a), and on activated platelets using an antibody against a GPIIb/IIIa activation epitope (PAC-1) 1.
• Reduced glycoprotein expression suggests some well-defined inherited platelet function disorders (IPFD), including Bernard Soulier syndrome 1.
• The PFA-100 and the skin bleeding time test are not recommended due to insufficient specificity/sensitivity 1.
• Second-step tests for patients not diagnosed by the first-step tests include LTA with an expanded agonist panel, flow-cytometry with additional antibodies, clot retraction, the measurement of serum TxB2 and transmission electron microscopy (TEM) 1. The giant platelets in Bernard Soulier syndrome have impaired function and cannot properly adhere to injured vessel walls, leading to bleeding symptoms. Treatment focuses on platelet transfusions for severe bleeding episodes, as there is no specific therapy to correct the underlying genetic defect.

From the Research

Mechanism of Giant Platelet Formation in Bernard-Soulier Syndrome

• The formation of giant platelets in Bernard-Soulier syndrome (BSS) is attributed to defects in the glycoprotein (GP) Ib-IX-V complex, which is the platelet receptor for von Willebrand factor 2, 3.
• Studies have shown that mutations in the GPIbalpha, GPIbbeta, or GPIX genes can lead to quantitative or qualitative abnormalities in the GP Ib/IX/V complex, resulting in giant platelets and thrombocytopenia 4, 3, 5.
• The GP Ib-IX-V complex plays a crucial role in platelet production and function, and defects in this complex can lead to impaired proplatelet formation and platelet ultrastructure 2, 6.

Role of Glycoprotein Ib-IX-V Complex in Platelet Production

• The GP Ib-IX-V complex is essential for the regulation of platelet size and production, and defects in this complex can lead to the formation of giant platelets 2, 3.
• Studies have shown that the expression of the GP Ib-IX-V complex is critical for the stability and function of platelets, and that defects in this complex can lead to impaired platelet function and thrombocytopenia 4, 5, 6.
• The use of induced pluripotent stem cells (iPSCs) has provided a valuable tool for studying the molecular mechanisms of BSS and the role of the GP Ib-IX-V complex in platelet production 2.

Molecular Basis of Bernard-Soulier Syndrome

• BSS is a rare autosomal recessive bleeding disorder characterized by a prolonged bleeding time, giant platelets, thrombocytopenia, and normal platelet aggregation in response to ADP 4, 3, 6.
• The molecular basis of BSS involves mutations in the genes encoding the GP Ib-IX-V complex, which can lead to quantitative or qualitative abnormalities in the complex 4, 3, 5.
• Studies have identified over 30 mutations in the GPIbalpha, GPIbbeta, or GPIX genes that are associated with BSS, and have provided valuable insights into the molecular mechanisms of the disease 3, 6.