26 Hereditary Thrombocytopenia & Qualitative Platelet Disorders
- Platelet adhesion: vWF → GPIb-IX → GPIIb-IIIa binding collagen/fibrinogen
- Activation releases ADP, serotonin, TXA₂ → signal amplification
- Screening: PFA-100/200 have limited value; light transmission aggregometry = gold standard
- Electron microscopy: ID platelet ultrastructural defects
- Unresponsive ITP → suspect hereditary thrombocytopenia
- MYH9-related: most common hereditary macrothrombocytopenia, 1/3 de novo mutations
- Thrombocytopenia w/ normal plt size → ↑ MDS/AML risk (Wiskott-Aldrich)
- Genetic testing: guides therapy, counseling, cancer risk assessment
26.1 Platelet Function in Hemostasis
26.1.1 Overview
Adhesion (high shear stress): - vWF binds GPIb-IX-V → tether to vessel wall - GPV1 interacts collagen; GPIIb-IIIa (integrin αIIbβ3) binds fibrinogen
Activation (granule secretion): - ADP, serotonin, TXA₂ released - Bind GPCRs: purinergic P2Y₁, P2Y₁₂; TXA₂ receptor; PAR1, PAR4 - Phosphatidylserine exposure → procoagulant activity
26.2 Tests to Evaluate Platelet Function
| Test | Function |
|---|---|
| PFA-100/200 | High shear stress simulation; limited specificity |
| Light transmission aggregometry | Gold standard; patterns diagnostic |
| Flow cytometry | Quantify surface receptors (GPIb-IX, GPIIb-IIIa) |
| Electron microscopy | Identify granule defects (δ-SPD, gray platelet) |
| NGS panels | Genetic diagnosis; >560 genes implicated |
26.3 Hereditary Thrombocytopenia
26.3.1 Overview
- Up to 30% of “ITP” = undiagnosed congenital thrombocytopenia
- Misdiagnosis → unnecessary splenectomy, immunosuppression
- Consider hereditary: family hx, bleeding ↑ for plt count, refractory ITP
- Genetic testing essential → management, counseling, malignancy risk
26.3.2 Thrombocytopenia w/ Large Platelets (Macrothrombocytopenia)
26.3.2.2 Other Macrothrombocytopenias
Bernard-Soulier Syndrome (BSS): - AR deficiency GPIb-IX receptor complex - ↓↓↓ plt count, giant plt, impaired ristocetin agglutination - Mild-severe bleeding; biallelic worse - Flow cytometry confirms ↓ GPIb-IX expression
Gray Platelet Syndrome (GPS): - AR NBEAL2 mutation; α-granule deficiency - ↓↓ plt count, gray appearance on smear - Mild-mod bleeding; progressive BMF, MDS risk - ↑ serum B₁₂; absent/↓ α-granule contents on EM
Platelet-Type vWD (PT-vWD): - AD GP1BA mutation; ↑ vWF binding affinity - Normal plt count → may ↓ w/ stress (pregnancy, surgery, infection)
Other Variants: - GATA1 mutations: X-linked dyserthropoiesis, macrothrombocytopenia - FLI1 mutations: Paris-Trousseau/Jacobsen syndrome (AD)
26.3.3 Thrombocytopenia w/ Normal-Sized or Small Platelets
26.3.3.1 Wiskott-Aldrich Syndrome (WAS)
Gene: WAS (X-linked)
Classic Triad: - Severe immunodeficiency + eczema + thrombocytopenia - Normal-small plt; severe bleeding
Complications: - ↑↑ malignancy risk (acute leukemias, lymphomas) - Infections common
Prognosis: Better if recognized/treated early
Management: - Consider HSCT in severe phenotypes - DDAVP, plt transfusion PRN
26.3.3.2 Diagnosis & Management of Hereditary Thrombocytopenias
Diagnostic Approach: - Flow cytometry: ↓ GPIb-IX (BSS), ↓ GPIIb-IIIa (Glanzmann) - Immunofluorescence: myosin clustering in granulocytes (MYH9) - NGS genetic testing for definitive diagnosis & counseling
| Disorder | Inheritance | Gene | Plt Count/Size | Bleeding | Additional Features |
|---|---|---|---|---|---|
| Bernard-Soulier | AR | GP1BA, GPIB, GP9 | ↓↓↓/giant | Mod-severe | ↓ platelet fn, ↓ α-granules, RBC anisocytosis |
| Gray Platelet Syndrome | AR | NBEAL2 | ↓↓↓/large | Mild-mod | ↓↓ α-granules, BMF/MDS risk, ↑ B₁₂ |
| Platelet-type vWD | AD | GP1BA | Normal/normal | Absent-mild | ↓ plt w/ stress (pregnancy, surgery) |
| MYH9-related | AD | MYH9 | ↓↓/large | Mild-mod | ±nephritis, deafness, cataracts; Döhle bodies |
26.4 Inherited Disorders of Platelet Function
26.4.1 Overview
Classification: - Adhesion disorders: abnormal plt-vessel wall interaction (vWD, BSS) - Aggregation disorders: deficiency GPIIb-IIIa (Glanzmann) - Secretion/signal transduction: impaired granule release, G-protein coupling
Clinical: mild-mod bleeding (spontaneous ICH rare); normal aggregometry doesn’t rule out
26.4.2 von Willebrand Disease
See chapter 20.
26.4.3 Disorders of Platelet Aggregation
26.4.3.1 Glanzmann Thrombastenia
Gene: Defect ITGA2B, ITGB3 (chromosome 17); codes GPIIb/IIIa
Pathophysiology: - AR ↓ qualitative/quantitative GPIIb-IIIa complex (50K-80K copies/plt normal) - Loss fibrinogen binding → ↓↓ platelet aggregation
Clinical: - Severe mucocutaneous bleeding (much worse than other plt function disorders) - Epistaxis, menorrhagia, GI bleeding common - More common in consanguineous populations
Diagnosis: - Flow cytometry: ↓↓ GPIIb-IIIa expression (pathognomonic) - Aggregometry: absent aggregation w/ ADP, epinephrine, collagen
Variants: - Some patients: residual aggregation via GPIIb-IIIa-cytoskeleton interactions preserved - Variant forms (less severe phenotype) rare
26.4.4 Disorders of Platelet Secretion & Signal Transduction
26.4.4.1 Overview
Heterogeneous group: ↓ dense granule/α-granule secretion; absent 2nd-wave aggregation w/ ADP/epinephrine
Diagnosis: Difficult (often multiple minor abnormalities); aggregometry shows ↓ response to agonists
26.4.4.2 Defects of Granule Biogenesis
Storage Pool Deficiency (SPD):
δ-SPD (dense body deficiency): - Mild-mod bleeding; ↓ aggregation ADP/epinephrine (2nd wave absent) - Normal plt store 3-8 dense granules; ↓/absent on EM - Associated w/ Hermanski-Pudlak syndrome (HPS): oculocutaneous albinism, retinal accumulation
Gray Platelet Syndrome (α-granule SPD): - Platelet gray appearance on smear - ↓ α-granule proteins: fibrinogen, vWF, thrombospondin, PF4, factor V, PDGF - AR NBEAL2 mutation; X-linked GATA1 variant - Risk: progressive BMF, MDS - Plt aggregation variable; normal ADP/epinephrine response in most
Quebec Platelet Disorder: - AD tandem duplication PKG1 region chromosome - Abnormal proteolysis α-granule proteins (fibrinogen, factor V, thrombospondin, multimerin) - ↑ platelet uPA; normal-↓ plt count - Selective epinephrine aggregation response impaired
26.4.4.3 Signal Transduction Defects
Mechanisms: - G-protein coupling defects: impaired agonist response (ADP, TXA₂ receptors) - P2Y₁₂ deficiency: rare; impaired purinergic receptor coupling - Phospholipase C activation: defects → ↓ TXA₂ liberation - Scott syndrome: impaired phosphatidylserine exposure
Syndromic phenotypes: often associated w/ neural dysfunction
26.4.5 Treatment of Hereditary Platelet Disorders
First-line: - TXA (aspirin, NSAIDs): may worsen bleeding; use cautiously - DDAVP (desmopressin): ↑ vWF & FVIII; trial in congenital disorders - Route: IV, SC, intranasal - Use: heavy menses, epistaxis, minor surgery - SE: flushing, headache, hyponatremia (fluid restrict 18-24h post-dose)
Supportive: - Platelet transfusion: PRN major bleeding - Avoid antiplatelet agents (aspirin, NSAIDs, SSRIs) if possible
26.5 Acquired Disorders of Platelet Function
26.5.1 Overview
Etiologies: drugs (most common), MPNs, acute leukemias, MDS, liver disease, uremia
Pathophysiology: poorly understood; variable severity
26.5.2 Drugs That Inhibit Platelet Function
| Drug Class | Mechanism |
|---|---|
| Aspirin | Irreversibly inhibits COX → ↓ TXA₂ |
| Clopidogrel, ticlopidine | Irreversibly inhibit P2Y₁₂ → ↓ ADP response |
| SSRIs | ↓ serotonin reuptake → ↓ plt serotonin pool |
| Antiplatelet agents (above) | Effective in thromboembolism prevention; ↑ bleeding risk |
| NSAIDs, acetaminophen | Variable effects on plt function |
Key: Cumulative effect of multiple agents unknown
26.5.3 Myeloproliferative Neoplasms
Manifestations: - Thrombocytosis w/ bleeding & thrombosis paradoxically - Qualitative defects: ↓ dense/α-granules, altered canalicular system, ↓ mitochondria on EM
Aggregation: highly variable; some ↑ response, others ↓
26.5.4 Acute Leukemias & Myelodysplastic Syndromes
- Major bleeding cause: thrombocytopenia
- W/ normal-↑ plt count: plt dysfunction possible
- More common: AML, hairy cell leukemia, MDS
26.5.5 Acquired Storage Pool Disease
Mechanism: loss of dense granules in vivo platelet activation/abnormal plt production
Associations: liver disease, acute leukemias, severe vasculitis, cardiopulmonary bypass
26.5.6 Acquired von Willebrand Syndrome
See chapter 20.
26.5.7 Platelet Autoantibodies & Platelet Function
Mechanisms: - Accelerated plt destruction, cell lysis, aggregation, granule secretion - Phosphatidylserine outward expansion
In ITP: proportion of patients w/ platelet-directed antibodies → impaired plt function
| Uremia |
|---|
| Myeloproliferative neoplasms |
| Acute leukemia & myelodysplastic syndrome |
| Dysproteinemias, dyscrasias |
| Acquired vWD syndrome |
| Antiplatelet antibodies |
| Drugs & other agents |
Hereditary vs. Acquired Thrombocytopenia
- Suspect hereditary: family hx, bleeding ↑ for plt count, ITP-refractory
- NGS panels definitive; guides therapy & counseling
- ~30% of ITP diagnoses = missed hereditary thrombocytopenia
Screening Approach
- Bleeding hx & family hx
- Aggregometry if normal plt count w/ bleeding tendency
- Genetic testing for syndromic forms: assess malignancy risk, counseling