Glanzmann Thrombasthenia

Definition and Genetics

• Goldman-Cecil Medicine, p. 1668
• Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 971

Pathophysiology

• Binding fibrinogen (and vitronectin, fibronectin, vWF) after platelet activation
• Cross-linking platelets to form the platelet plug (aggregation)
• Clot retraction via interaction with the platelet cytoskeleton

Classification

Clinical Features

• Onset: Bleeding typically presents from childhood, often severe
• Pattern: Mucocutaneous bleeding - epistaxis, gingival bleeding, easy bruising, menorrhagia (often severe at menarche), gastrointestinal bleeding
• Platelet count: Normal
• Platelet morphology: Normal size (not macrothrombocytopenic, unlike Bernard-Soulier)
• Bleeding time: Markedly prolonged
• PT/aPTT: Normal
• Clot retraction: Abnormal/absent

Laboratory Diagnosis

Platelet Aggregometry (Key Finding)

• Shape change (initial upward deflection) is preserved - platelets can still respond to activation signals
• Both primary AND secondary waves of aggregation are absent (unlike storage pool defects where only the secondary wave is lost)

Comparison with Bernard-Soulier Syndrome

Confirmatory Tests

• Flow cytometry - confirms absent/reduced surface GPIIb/IIIa (CD41/CD61)
• Genetic testing - ITGA2B and ITGB3 mutation analysis (database: https://glanzmann.mcw.edu/)
• Heterozygous carriers have ~50% of normal GPIIb/IIIa levels but no bleeding disorder and normal aggregation

Treatment

Acute Bleeding

• Platelet transfusion - first-line for significant bleeds; HLA-matched single-donor platelets preferred to limit alloimmunization
  • Repeated transfusions can induce anti-GPIIb/IIIa and anti-HLA antibodies, causing refractoriness
• Recombinant Factor VIIa (rFVIIa) - FDA-approved specifically for GT; bypasses the platelet aggregation defect by generating thrombin at the injury site; particularly useful when alloimmunization has made platelets ineffective

Adjunctive

• Antifibrinolytics (tranexamic acid, epsilon-aminocaproic acid) - especially effective for mucosal bleeding (epistaxis, menorrhagia, dental procedures); often used first-line for minor bleeds
• DDAVP - may provide some benefit, especially for milder bleeding; acts by releasing vWF and increasing platelet adhesion

Special Situations

• Pregnancy/delivery: Platelet transfusion is the primary treatment intrapartum; postpartum hemorrhage occurs in ~50% of pregnancies despite prophylaxis. Women who have previously received transfusions should be evaluated for HLA- and GP-specific antibodies before delivery.
• Dental procedures: Pre-procedure antifibrinolytics or platelet support are important
• Emerging therapies: Gene therapy and emicizumab (off-label) are being investigated per recent literature
• Harrison's Principles of Internal Medicine 22E, p. 1802
• Goldman-Cecil Medicine, p. 1668

Recent Literature (2023-2026)

• A 2025 review by Nurden & Nurden in Semin Thromb Hemost (PMID 38499192) reviewed 10 years of progress, highlighting advances in gene therapy, novel hemostatic agents, and molecular understanding of ITGA2B/ITGB3 mutations.
• A 2024 review in Br J Haematol (PMID 38744450) addressed pregnancy management specifically.
• A 2025 review on molecular pathogenesis (PMID 41301446) covers the full landscape of inherited platelet dysfunction including GT.

Key High-Yield Summary

Glanzmann Thrombasthenia - Pediatric Perspective

Library note: The textbook library contains two pediatrics references: The Harriet Lane Handbook (23rd ed.) and Red Book 2021. Harriet Lane lists Glanzmann thrombasthenia as a key inherited cause of platelet dysfunction (Table 14.10), but neither pediatric text has a dedicated chapter. The following answer integrates Harriet Lane's pediatric framework with content from Harrison's 22E, Goldman-Cecil, and Henry's Clinical Diagnosis, supplemented by current peer-reviewed literature (2021-2026).

1. Overview and Epidemiology in Children

• Harriet Lane Handbook, 23rd ed., Table 14.10 (platelet dysfunction causes in children)
• Nurden & Nurden, Semin Thromb Hemost 2025 (PMID 38499192)

2. Molecular Basis

3. Classification

4. Clinical Features in Children

Bleeding pattern

• Onset: Often at birth or in infancy (purpura neonatorum, umbilical stump bleeding, circumcision bleeding)
• Mucocutaneous dominant: Epistaxis (most common - often severe and recurrent), gingival bleeding, easy bruising, petechiae
• Dental eruption bleeding - characteristic in young children
• GI bleeding (less common)
• Intracranial hemorrhage - rare but life-threatening
• Menorrhagia - major problem at menarche; often the presenting symptom in adolescent girls

Important negatives

• Normal platelet count - this is a qualitative, not quantitative, defect
• Normal platelet size - distinguishes GT from Bernard-Soulier syndrome (which has macrothrombocytopenia)
• No joint bleeds - distinguishes from hemophilia

5. Diagnosis

Blood indices

Platelet aggregometry (gold standard functional test)

• Initial shape change is preserved (the tracing shows an upward deflection) but no subsequent aggregation follows
• This is the opposite pattern to Bernard-Soulier syndrome

• Henry's Clinical Diagnosis and Management by Laboratory Methods, p. 971

Confirmatory tests

1. Flow cytometry - absent or markedly reduced CD41 (GPIIb) and CD61 (GPIIIa) on platelet surface; this is particularly useful in neonates and infants where adequate PRP for aggregometry is hard to obtain
2. Genetic testing (ITGA2B, ITGB3) - confirms diagnosis; important for genetic counseling; mutations catalogued at https://glanzmann.mcw.edu/
3. Anti-GPIIb/IIIa antibody testing - critical before platelet transfusion; detects alloimmunization

• Rodriguez-Alen et al., Biomolecules 2025 (PMID 41301446)

6. Management in Children

A. First-line for minor/mucosal bleeding

• Antifibrinolytics - tranexamic acid (TXA) or epsilon-aminocaproic acid (EACA) are the first-line for epistaxis, gingival bleeding, and dental procedures in children
  • TXA: 15-25 mg/kg orally (or IV) every 8 hours; topical application in epistaxis
• Local measures - nasal packing, pressure, cauterization for nosebleeds

B. Desmopressin (DDAVP)

• 0.3 mcg/kg IV or intranasal; may augment platelet adhesion via vWF release; useful adjunct in moderate bleeding, though efficacy is variable in GT

C. Platelet transfusion

• First-line for significant or surgical bleeding
• HLA-matched, single-donor apheresis platelets preferred to minimize alloimmunization
• Risk: repeated transfusions cause anti-HLA and anti-GPIIb/IIIa (PIA1) antibody formation, which leads to platelet transfusion refractoriness - a major clinical challenge in children who will need lifelong management
• In children, limiting early platelet transfusions (by using rFVIIa when possible) is especially important to preserve transfusion efficacy for later life

D. Recombinant Factor VIIa (rFVIIa, NovoSeven)

• FDA-approved specifically for GT (and Bernard-Soulier) in patients with anti-GPIIb/IIIa antibodies or refractoriness
• Standard dose: 90 mcg/kg IV every 2-3 hours until hemostasis
• A 2025 systematic review of 100 subjects showed rFVIIa was effective in 93% of non-surgical bleeds, 91-92% of surgical procedures, with only 4 (2.7%) serious adverse events. The authors recommend considering rFVIIa as frontline even without antibodies, to prevent alloimmunization - especially relevant in children (Saultier et al., Haemophilia 2025, PMID 39604156)
• Mechanism: generates sufficient thrombin on the platelet surface even without GPIIb/IIIa-fibrinogen bridging

E. Emergency management consensus (2023)

• Minor bleeds: antifibrinolytics ± DDAVP
• Moderate bleeds with no refractoriness: platelets OR rFVIIa
• Severe/refractory bleeds: rFVIIa (90 mcg/kg) + antifibrinolytics
• Avoid unnecessary platelet exposure in children to preserve future options

F. Hematopoietic stem cell transplantation (HSCT)

• The only potentially curative treatment for severe GT
• Indicated in children with: life-threatening bleeding, refractoriness to platelets and rFVIIa, or severely impaired quality of life
• A 2025 pediatric report from J Pediatr Hematol Oncol (Al-Antary et al., PMID 40928240) documented successful allo-HSCT in 2 siblings with GT, supported by CIBMTR registry data (2008-2022), confirming HSCT prevents life-threatening bleeding
• Key post-HSCT monitoring: flow cytometric detection of GPIIb/GPIIIa on platelets to identify late graft rejection - particularly important when pre-transplant anti-GPIIb/IIIa antibodies are present

G. Emerging/future therapies

• Gene therapy using lentiviral vectors: preclinical stage; CRISPR/Cas9 approaches being explored
• Bispecific antibodies that link platelets to coagulation factors (e.g., emicizumab analogs) - under investigation
• Monoclonal antibodies to accelerate fibrin formation at injury sites - promising prophylactic approach
• Nurden & Nurden, Semin Thromb Hemost 2025 (PMID 38499192)

7. Perioperative and School/Activity Considerations

• Pre-procedural planning is critical - dental cleaning, tonsillectomy, and even minor procedures require hematology consultation
• Tranexamic acid mouthwash for dental procedures
• Children should wear medical alert identification
• Avoid aspirin, NSAIDs, and SSRIs (all impair residual platelet function)
• Contact sports restrictions based on severity

8. Differential Diagnosis in a Child with Mucocutaneous Bleeding + Normal Platelet Count

Summary Table