Glanzmann thrombasthenia

Rare autosomal recessive platelet function disorder where platelets cannot aggregate due to an absence or defect of the GpIIb/IIIa receptor (integrin αIIbβ3). Without this fibrinogen receptor, platelets fail to form clots, causing lifelong mucosal bleeding and a markedly prolonged bleeding time despite a normal platelet count.

• Though uncommon (≈1 in 1 million), GT is a classic prototype of inherited platelet disorders. It frequently appears in exams to test understanding of primary hemostasis – contrasting with other bleeding disorders (e.g., Bernard-Soulier, von Willebrand disease). Clinically, patients can have severe bleeding (e.g. after surgery or childbirth) requiring transfusions, and management challenges like platelet alloantibodies make it a high-yield topic.

• Typically presents in infancy or childhood with excessive mucosal bleeding: parents may report prolonged bleeding after birth (e.g., umbilical stump or circumcision) and frequent nosebleeds, easy bruising, or bleeding from the gums with teeth eruption. Adolescent girls often have heavy menstrual bleeding (menorrhagia).
• Bleeding is usually superficial (skin and mucous membranes); hemarthroses or deep muscle bleeds are extremely rare (unlike hemophilias). Severity ranges from mild bruising to severe hemorrhage. Many patients have bleeding with minor procedures (e.g., dental work). In women, postpartum hemorrhage is a major concern.
• Physical exam may show petechiae or purpura after minor trauma. Importantly, platelet count is normal, and the platelets appear morphologically normal. (Labs will reveal an isolated prolonged bleeding time or abnormal platelet function test, rather than thrombocytopenia or coagulation factor abnormality.)

1. Suspect a platelet function disorder like GT when a patient has significant mucocutaneous bleeding but normal platelet count and normal PT/PTT (ruling out thrombocytopenia and clotting factor disorders).
2. Order platelet function testing (aggregometry): GT shows absent platelet aggregation in response to ADP, epinephrine, collagen, etc., while aggregation with ristocetin is normal (since the GpIb–vWF adhesion pathway is intact). This pattern – "no aggregation except with ristocetin" – is classic for GT.
3. Confirm the diagnosis with flow cytometry or platelet immunophenotyping: GT platelets will have markedly reduced or absent GpIIb/IIIa expression on their surface. Monoclonal antibody binding to GpIIb/IIIa is reduced.
4. Genetic testing can identify biallelic mutations in the genes ITGA2B or ITGB3 (encoding the GpIIb and GpIIIa integrin subunits). Finding pathogenic variants confirms inherited GT and can be useful for family counseling.
5. Historical clue: the old clot retraction test is abnormal in GT (clot fails to retract in a test tube due to the loss of fibrinogen-platelet bridging). While not commonly used now, it's a classic teaching point.

1. Preventive measures: avoid any aspirin, NSAIDs, or other platelet-inhibiting medications (they can unmask or worsen bleeding); for women with GT, hormonal therapy (e.g. oral contraceptives) can help reduce menorrhagia.
2. For mild bleeding episodes: use local hemostatic measures (pressure, topical thrombin or fibrin sealants) and give antifibrinolytic agents (e.g., tranexamic acid) to stabilize clots on mucosal surfaces.
3. For severe bleeding or high-risk situations (surgery, childbirth): transfuse platelet concentrates to provide functional platelets. Platelet transfusion is usually effective short-term, but use it judiciously to minimize development of alloantibodies.
4. If a patient becomes refractory to platelet transfusions (due to anti-platelet antibodies) or platelets are unavailable, administer recombinant factor VIIa (rFVIIa) to bypass the platelet defect and promote clotting.
5. Definitive therapies: Hematopoietic stem cell transplant can cure GT by establishing donor-derived platelets with normal GpIIb/IIIa (reserved for only the most severe cases due to transplant risks). Gene therapy for GT is experimental but holds future promise as a curative approach.

• Peripheral smear in GT often shows platelets that are not clumped together (since they can't bind fibrinogen). By contrast, in many other conditions platelets may clump on smears.
• Use the B versus G trick: Bernard-Soulier = Big platelets + problem with platelet binding to vWF (adhesion, GpIb defect), whereas Glanzmann = problem with platelet Grouping (aggregation, GpIIb/IIIa defect).
• The ristocetin cofactor test is a key distinguisher: it's normal in Glanzmann thrombasthenia (because platelet adhesion via vWF is intact), but markedly abnormal in Bernard-Soulier syndrome and von Willebrand disease.

• Major hemorrhages (e.g., intracranial bleed, massive gastrointestinal bleed, or postpartum hemorrhage) in GT require emergency management – prompt platelet transfusions (and rFVIIa if needed) are critical to prevent mortality.
• If platelet transfusions fail to stop bleeding, suspect alloimmune platelet refractoriness – GT patients can develop anti-GpIIb/IIIa antibodies after repeated transfusions. In this scenario, switching to rFVIIa or other interventions immediately can be lifesaving.

1. Patient with mucosal bleeding but normal platelet count and normal PT/PTT → consider inherited platelet function disorder (suspect GT or Bernard-Soulier).
2. Initial workup: obtain CBC and peripheral smear (platelet count and morphology will be normal in GT) and perform platelet function analysis (e.g., PFA-100 or bleeding time – likely prolonged). Rule out von Willebrand disease with appropriate studies if indicated.
3. Platelet aggregation studies: if platelets fail to aggregate with multiple agonists (ADP, epinephrine, collagen) but aggregate normally with ristocetin, this pattern is virtually diagnostic of Glanzmann thrombasthenia (vs. the opposite pattern in Bernard-Soulier).
4. Confirm the diagnosis: perform flow cytometry for platelet GpIIb/IIIa expression or sequence the ITGA2B/ITGB3 genes. A significant decrease in GpIIb/IIIa receptors or biallelic pathogenic mutations confirms GT.
5. Management plan: counsel avoidance of platelet-inhibiting drugs; arrange blood bank support (platelet units) for procedures or bleeding; if bleeding occurs, escalate from local measures to platelet transfusion, and use rFVIIa if transfusions are ineffective. Refer to a hematologist for consideration of stem cell transplant in very severe cases.

• Newborn boy with severe bleeding after circumcision but normal platelet count and normal coagulation studies → Glanzmann thrombasthenia.
• Teenage girl with lifelong epistaxis and unusually heavy periods; labs show normal platelet count and platelets that fail to aggregate with ADP but do aggregate with ristocetin → Glanzmann thrombasthenia.