Bernard-Soulier

Overview of Bernard-Soulier Syndrome (BSS)

Definition: A rare, inherited bleeding disorder characterized by:
- Thrombocytopenia (low platelet count)
- Giant platelets (macrothrombocytes)
- Dysfunctional platelet adhesion
Genetic Basis: Autosomal recessive inheritance of mutations in genes encoding components of the platelet glycoprotein Ib/IX/V (GPIb/IX/V) complex
Key Feature: Impaired platelet adhesion to damaged blood vessel walls due to a defect in the GPIb/IX/V receptor
Clinical Significance: Leads to mucocutaneous bleeding tendencies, such as easy bruising, nosebleeds, and prolonged bleeding after trauma or surgery

Structure: A complex of four transmembrane glycoproteins:
- GPIbα: The primary vWF-binding subunit
- GPIbβ
- GPIX
- GPV
Function:
- Mediates the initial adhesion of platelets to damaged blood vessel walls by binding to von Willebrand factor (vWF)
- This interaction is essential for platelet plug formation, especially under high shear stress conditions
- Also involved in platelet signaling and activation

Pathophysiology of Bernard-Soulier Syndrome {-}

Genetic Mutations: Mutations in genes encoding GPIbα (CD42b), GPIbβ (CD42c), or GPIX (CD42a) lead to:
- Decreased expression of the GPIb/IX/V complex on the platelet surface
- Abnormal structure or function of the GPIb/IX/V complex
Impaired Platelet Adhesion:
- Defective GPIb/IX/V complex impairs platelet adhesion to vWF, particularly under high shear stress conditions
- This impairs the ability of platelets to form a stable plug at sites of vascular injury, leading to a prolonged bleeding time
Macrothrombocytopenia:
- Megakaryocytes in the bone marrow may be enlarged and have abnormal morphology due to impaired platelet shedding
- The released platelets are often abnormally large (macrothrombocytes)

Bleeding Manifestations: Severity varies, but most patients have moderate to severe mucocutaneous bleeding:
- Easy bruising
- Nosebleeds (epistaxis)
- Gum bleeding
- Prolonged bleeding after minor cuts or dental procedures
- Menorrhagia (heavy menstrual bleeding) in women
- Gastrointestinal bleeding (less common)
Splenomegaly: Enlargement of the spleen may be present in some cases
Thrombocytopenia: Platelet counts are often mildly to moderately decreased, but can be normal in some cases

Complete Blood Count (CBC):
- Platelet count: Often mildly decreased (thrombocytopenia), typically in the range of 50-150 x 10^9/L, but can be normal in some cases
- RBC and WBC counts: Usually normal
Peripheral Blood Smear:
- Macrothrombocytes (Giant Platelets):
  - Characteristically large platelets (often as large as or larger than red blood cells)
  - Essential for diagnosis
- Decreased platelet number
Bleeding Time:
- Prolonged (often significantly prolonged)
- Note: The bleeding time is not a very specific or sensitive test and is rarely used now. PFA testing has taken its place.
Platelet Function Analyzer (PFA-100):
- Prolonged closure time with both epinephrine and ADP cartridges
- Suggests a platelet adhesion defect
Platelet Aggregation Studies:
- Normal Aggregation with ADP, Collagen, and Epinephrine
- These agonists stimulate platelet aggregation via pathways independent of GPIb/IX/V
- Absent Aggregation with Ristocetin
  - Ristocetin requires vWF and GPIb/IX/V to cause platelet aggregation
  - Even with the addition of normal plasma (to provide vWF), aggregation remains absent
Flow Cytometry Immunophenotyping:
- Decreased or Absent Expression of GPIbα (CD42b), GPIbβ (CD42c), and GPIX (CD42a) on Platelets
  - This confirms the defect in the GPIb/IX/V complex
  - Essential for definitive diagnosis

Suspect BSS: In a patient with:
- History of mucocutaneous bleeding
- Thrombocytopenia
- Large platelets on peripheral blood smear
Perform Platelet Aggregation Studies: Absent ristocetin-induced platelet aggregation that is not corrected by the addition of normal plasma is a key finding
Confirm Diagnosis with Flow Cytometry: Demonstrate decreased or absent expression of GPIbα, GPIbβ, and GPIX on platelets
Rule Out Other Causes of Thrombocytopenia with Giant Platelets:
- May-Hegglin Anomaly: Döhle bodies in neutrophils, normal GPIb/IX/V expression
- Gray Platelet Syndrome: Alpha-granule deficiency, normal GPIb/IX/V expression
- Inherited thrombocytopenias (e.g., Wiskott-Aldrich syndrome, MYH9-related disorders): Variable clinical features and lab findings

No Specific Cure: Treatment is primarily supportive
Avoid Aspirin and NSAIDs: These medications can further impair platelet function and increase the risk of bleeding
Minimize Trauma: Avoid activities that could lead to injury
Platelet Transfusions:
- Used to treat significant bleeding episodes or before surgery
- Patients may develop alloantibodies (antibodies against foreign platelets) with repeated transfusions, making subsequent transfusions less effective
- HLA-matched platelets may be required in patients who have become alloimmunized
Recombinant Factor VIIa (rFVIIa):
- May be used to control bleeding in some patients with BSS
- Mechanism of action is not fully understood
Antifibrinolytic Agents:
- Tranexamic acid or aminocaproic acid may be used to control mucosal bleeding (e.g., nosebleeds, menorrhagia)
- These medications inhibit fibrinolysis (the breakdown of blood clots)
Hematopoietic Stem Cell Transplantation (HSCT):
- Potentially curative option for severe cases of BSS
- Involves replacing the patient’s damaged bone marrow with healthy stem cells from a donor

Bernard-Soulier Syndrome (BSS): Rare inherited bleeding disorder characterized by thrombocytopenia, giant platelets, and dysfunctional platelet adhesion
GPIb/IX/V: Platelet glycoprotein receptor for von Willebrand factor (vWF)
Macrothrombocytes: Abnormally large platelets
Ristocetin: An antibiotic that induces vWF-dependent platelet agglutination
Platelet Aggregation Studies: Tests that measure the ability of platelets to clump together
Flow Cytometry: Technique to identify cell surface markers
Alloantibodies: Antibodies against foreign antigens (e.g., transfused platelets)