Glanzmann

Overview of Glanzmann Thrombasthenia (GT)

Definition: A rare, inherited bleeding disorder characterized by:
- Normal platelet count
- Defective platelet aggregation
- Absent or severely reduced expression of the platelet glycoprotein IIb/IIIa (GPIIb/IIIa) complex (also known as αIIbβ3 integrin)
Genetic Basis: Autosomal recessive inheritance of mutations in the genes encoding GPIIb (ITGA2B) or GPIIIa (ITGB3)
Key Feature: Impaired platelet aggregation due to a defect in the fibrinogen receptor (GPIIb/IIIa), which is essential for platelet cross-linking and thrombus formation
Clinical Significance: Leads to mucocutaneous bleeding tendencies, such as easy bruising, nosebleeds, gum bleeding, and prolonged bleeding after trauma or surgery

Structure: A heterodimeric complex consisting of two transmembrane glycoproteins:
- GPIIb (αIIb or CD41)
- GPIIIa (β3 or CD61)
Function:
- Major Integrin on Platelets: GPIIb/IIIa is the most abundant integrin on the platelet surface
- Fibrinogen Receptor: It acts as a receptor for fibrinogen, von Willebrand factor (vWF), fibronectin, and other adhesive ligands
- Platelet Aggregation: GPIIb/IIIa mediates platelet aggregation by binding to fibrinogen, which forms bridges between adjacent platelets, leading to thrombus formation
- Inside-Out Signaling: Platelet activation triggers a conformational change in GPIIb/IIIa that increases its affinity for fibrinogen
- Outside-In Signaling: Binding of fibrinogen to GPIIb/IIIa triggers intracellular signaling pathways that stabilize platelet aggregates and promote clot retraction

Genetic Mutations: Mutations in the genes encoding GPIIb (ITGA2B) or GPIIIa (ITGB3) lead to:
- Decreased Expression of GPIIb/IIIa on the Platelet Surface:
  - Type I GT: Severely reduced or absent GPIIb/IIIa expression (<5% of normal)
  - Type II GT: Reduced GPIIb/IIIa expression (5-20% of normal)
- Dysfunctional GPIIb/IIIa Complex:
  - Abnormal structure of the GPIIb/IIIa complex, impairing its ability to bind to fibrinogen and other ligands
Impaired Platelet Aggregation:
- Deficiency or dysfunction of GPIIb/IIIa impairs platelet aggregation, preventing platelets from forming stable clots
- Leads to a prolonged bleeding time and increased susceptibility to bleeding

Mucocutaneous Bleeding: The hallmark of GT
- Easy bruising (purpura)
- Nosebleeds (epistaxis)
- Gum bleeding (gingival bleeding)
- Menorrhagia (heavy menstrual bleeding) in women
- Prolonged bleeding after minor cuts or dental procedures
Severity:
- Severity of bleeding varies among patients, even within the same type of GT
- Bleeding episodes can be spontaneous or triggered by trauma or surgery
Joint Bleeds (Hemarthrosis): Rare in GT, unlike hemophilia

Complete Blood Count (CBC):
- Platelet count: Usually normal
- RBC and WBC counts: Normal
Peripheral Blood Smear:
- Normal platelet morphology and number (except for possible macroplatelets)
- No platelet clumps
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 global platelet dysfunction
Platelet Aggregation Studies: The key diagnostic test for GT
- Absent or Severely Reduced Aggregation with ADP, Collagen, Epinephrine, and Thrombin
  - These agonists require functional GPIIb/IIIa to induce platelet aggregation
- Normal Aggregation with Ristocetin
  - Ristocetin induces platelet aggregation by binding vWF to GPIb/IX/V (which is normal in GT)
  - Since the GPIIb/IIIa complex is not required for this interaction, ristocetin-induced aggregation is normal in GT
Clot Retraction:
- Absent or Impaired
- GPIIb/IIIa is required for clot retraction, so this process is abnormal in GT
Flow Cytometry Immunophenotyping:
- Decreased or Absent Expression of GPIIb (CD41) and/or GPIIIa (CD61) on Platelets
  - Confirms the defect in the GPIIb/IIIa complex
  - Can differentiate between Type I (severely reduced expression) and Type II (reduced expression) GT

Suspect GT: In a patient with:
- Lifelong history of mucocutaneous bleeding
- Normal platelet count
- Prolonged bleeding time (or abnormal PFA result)
Perform Platelet Aggregation Studies: Absent aggregation with ADP, collagen, epinephrine, and thrombin, but normal aggregation with ristocetin, is highly suggestive of GT
Confirm Diagnosis with Flow Cytometry: Demonstrate decreased or absent expression of GPIIb (CD41) and/or GPIIIa (CD61) on platelets
Rule Out Other Platelet Function Disorders:
- Acquired platelet dysfunction (e.g., drug-induced): Recent exposure to aspirin or other antiplatelet medications
- Bernard-Soulier Syndrome: Giant platelets, absent ristocetin-induced aggregation that is not corrected by normal plasma, abnormal GPIb/IX/V expression

No Specific Cure: Treatment is primarily supportive and aimed at controlling bleeding episodes
Avoid Platelet Inhibitors: Aspirin and other antiplatelet medications are contraindicated
Local Hemostatic Measures:
- Topical thrombin or fibrin sealants to control minor bleeding
- Pressure dressings to control bleeding from cuts or wounds
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)
Recombinant Factor VIIa (rFVIIa):
- May be used to control bleeding in patients with GT
- Mechanism of action is not fully understood, but it may promote thrombin generation and platelet activation
Platelet Transfusions:
- Used to treat severe 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
Hematopoietic Stem Cell Transplantation (HSCT):
- Potentially curative option for severe cases of GT
- Involves replacing the patient’s damaged bone marrow with healthy stem cells from a donor

Glanzmann Thrombasthenia (GT): Rare inherited bleeding disorder characterized by defective platelet aggregation
GPIIb/IIIa (αIIbβ3 Integrin): Platelet glycoprotein complex that binds to fibrinogen and mediates platelet aggregation
Platelet Aggregation Studies: Tests that measure the ability of platelets to clump together
Ristocetin: An antibiotic that induces vWF-dependent platelet agglutination
Alloantibodies: Antibodies against foreign antigens (e.g., transfused platelets)