21 Hemophilia A & B
- Hem A: F8 mut, X-linked, ~1:5000 males; Hem B: F9 mut, X-linked, ~1:30,000 males
- Severity: severe (<1%), mod 1–5%, mild 5–40%; females rarely symptomatic unless skewed X-inactivation
- Defect: ↓ thrombin burst in tenase complex → delayed clot propagation; platelet plug normal
- Bleeding: spontaneous hemarthrosis/intramuscular, not mucosal; ↑ w/ trauma/surgery
- Prophylaxis: CFC (recombinant or EHL) q2–7d; nonfactor agents (desmopressin, tranexamic acid) adjuncts
- Inhibitors: Hem A ~30%, Hem B ~5% → bypass agents (rFVIIa, aPCC); ITI for eradication
- Gene therapy: etranacogene (Hem B), valoctocogene (Hem A) emerging options
- Acquired Hem A: autoAb to FVIII in elderly (60–80y); 30% malignancy-assoc, 50% idiopathic → immunosuppression + bypass agents
21.1 Genetics & Pathophysiology
- Hem A: F8 mut Xq28 → dysfunctional/absent FVIII
- Hem B: F9 mut Xq27 → dysfunctional/absent FIX
- Both X-linked recessive; spontaneous mutation ~30% (Hem A), ~20% (Hem B)
- Mechanism: FVIII/FIX cofactors in tenase complex (FVIII·IXa·PL·Ca²⁺)
- Catalyzes prothrombin → thrombin → fibrin clot
- Deficiency → ↓ thrombin burst, delayed propagation phase
- Platelet plug formation preserved (→ normal bleeding time)
21.2 Clinical Features
21.2.1 Severity & Presentation
| Severity | Activity | Features |
|---|---|---|
| Severe | <1% | Spontaneous hemarthrosis, intramuscular hematomas, CNS bleeds |
| Moderate | 1–5% | Rare spontaneous bleeding; bleeds w/ minor/moderate trauma |
| Mild | 5–40% | Bleeding only w/ surgery, dental, significant trauma |
Childhood (early): - Circumcision or tooth eruption hemorrhage - Hemarthrosis (knees, elbows, ankles) - Ecchymoses w/ minor trauma - Intramuscular hematoma → compartment syndrome risk
Adolescence & adulthood: - Recurrent hemarthrosis → hemophilic arthropathy (irreversible) - Muscle bleeds (psoas, neck, compartments) - Oral/GI bleeding (↑ w/ NSAIDs, H. pylori) - CNS hemorrhage (1–2% lifetime; catastrophic) - Pseudotumors (chronic encapsulated hematomas)
Female carriers: - Usually asymptomatic (~50% activity sufficient) - Skewed X-inactivation (>70% mutant) → symptomatic bleeding - Pregnancy: FVIII ↑, FIX unchanged → peripartum bleed risk persists
21.3 Diagnosis
| Test | Findings |
|---|---|
| PT, thrombin time, plt | Normal |
| aPTT | ↑; corrects w/ 1:1 mix (factor-dependent) |
| FVIII activity | ↓ (Hem A); normal (Hem B) |
| FIX activity | ↓ (Hem B); normal (Hem A) |
Mixing study (1:1 normal plasma): - aPTT corrects → factor deficiency - aPTT persists → inhibitor or other coagulation defect
Factor assays: - One-stage (aPTT) or two-stage (chromogenic); chromogenic ↑ sensitivity - Chromogenic preferred for monitoring; Xa inhibitors interfere w/ FIX assay
Genetics: - F8 or F9 sequencing confirms diagnosis - MLPA/NGS detect deletions/inversions - Predicts inhibitor risk (nonsense > missense) & family counseling
21.4 Management
21.4.1 Factor Replacement Targets & Dosing
- Prophylaxis: FVIII 30–50 IU/kg q2–3d; FIX 25–40 IU/kg q3–5d (varies by half-life, clearance)
- Minor bleed: Bolus to 20–40% (10–20 IU/kg)
- Major bleed/surgery: Bolus to 80–100% (40–50 IU/kg), maintain ≥50% × 5–7d
| Product | Half-Life | Dosing | Notes |
|---|---|---|---|
| Plasma-derived FVIII/FIX | 8–12h/18–24h | q12h/q3–5d | Historical; ↓ cost |
| Recombinant FVIII | 8–12h | q12h | Preferred monotherapy |
| Recombinant FIX | 18–24h | q3–5d | — |
| EHL FVIII/FIX (pegylated/Fc) | 1.5× baseline | q3–4d/q7d | ↓ frequency; ↑ cost |
| SC FVIII (antithrombin) | 19h | 2–3×/wk | Poor if ADAMTS13 def |
21.4.2 Nonfactor Agents (Adjuncts/Mild-Moderate)
Desmopressin (0.3 µg/kg IV/SC or 150 µg intranasal): - ↑ FVIII & vWF release (70% Hem A responders) - Effective if baseline FVIII >5–10% - Onset 30–60 min, duration 4–8h; tachyphylaxis w/ repeat dosing - CI: ADAMTS13 deficiency (TMA risk)
Tranexamic acid (10–15 mg/kg IV q6–8h or 25 mg/kg PO tid): - Inhibits fibrinolysis, stabilizes clots - Excellent for mucosal, dental, GI bleeding - ⚠ Thrombotic risk w/ prothrombin complex concentrates
vWF concentrates (40–80 IU/kg IV q12h): - Contains vWF + FVIII; for Hem A w/ low vWF - Improves platelet function
21.4.3 Inhibitor Management
Prevalence: - Hem A: ~30% severe (↑ w/ nonsense mutations, deletions, non-white) - Hem B: ~5% severe
Diagnosis: - Bethesda assay (BU); mixing study w/ persistent aPTT prolongation
Strategy by titer:
| Titer | Approach |
|---|---|
| <5 BU | Continue factor; monitor q2–4wk |
| ≥5 BU | Bypass agents; avoid factor infusion |
Bypass agents:
rFVIIa (NovoSeven): 90 µg/kg IV q2–3h (unlicensed: 270 µg/kg q2h severe) - TF-independent thrombin via Factor X - Half-life 2.3h; frequent dosing - Cost ~$1000–2000/dose
aPCC (FEIBA): 50–100 IU/kg IV q8–12h (max 200 IU/kg/d) - Factors II, VII, IX, X - Half-life 4–6h > rFVIIa - ↑ thrombotic risk; avoid repeat dosing
ITI (immune tolerance induction): - High-dose factor ≥100 IU/kg/d ± immunotherapy - Success: 50–80% Hem A, lower Hem B - Duration 6 mo–2 yr; central line required - Desensitization if low initial tolerance
- Start age 1–2y: prevents 90% spontaneous bleeds
- ↓ bleed rate 70% vs on-demand (intermediate dose)
- Early start & compliance essential → prevent irreversible joint damage
21.5 Acquired Hemophilia A
Epidemiology: - Spontaneous autoAb (IgG) to FVIII; rare (1–2 cases/million/yr) - Age 60–80y (older than congenital) - Assoc: malignancy (30%, lymphoproliferative), pregnancy, autoimmune (SLE, RA), drugs (PCN, sulfa) - ~50% idiopathic
Presentation: - Acute bleeding: spontaneous ecchymoses, hematomas, GI/GU, hemoptysis - Severe despite no prior bleed hx; misdiagnosed as DIC (25–50% delayed diagnosis)
Labs: - aPTT ↑; PT, fib, plt normal - Mixing study: aPTT persists (not corrected) → inhibitor - FVIII <1%; Bethesda titer typically 50–100 BU - Exclude: VTE, FIX inhibitor, antiphospholipid, factor deficiency
Management:
Acute bleed: - Bypass agents: rFVIIa 90 µg/kg q2–3h or aPCC 50–100 IU/kg q8–12h - Factor replacement ineffective (autoAb neutralizes) - Titrate to clinical response - Adjunct: tranexamic acid 10–15 mg/kg q6–8h
Eradication (goal: sustained remission): - Corticosteroids: prednisone 1 mg/kg/d, taper 4–8 wk if remission - Add cyclophosphamide, rituximab, or mycophenolate if needed - Response: 60–70% remission w/ steroids alone, 85% combo - Monitor: aPTT, FVIII, Bethesda q1–2 wk; if <5 BU, taper to FVIII monotherapy - Timing: median 4–8 wk, range 1–12 mo
- Elderly + new bleed + aPTT not corrected by mix → suspect acquired
- Do NOT assume DIC w/o thrombocytopenia
- Delay diagnosis ↑ morbidity; request Bethesda ASAP
21.6 Perioperative & Pregnancy
Surgery: - Baseline FVIII/FIX + inhibitor testing pre-op - Minor: target 50 IU/dL × 1–3d - Major: target 80–100 IU/dL × 5–7d post-op, then taper - Bolus vs continuous infusion (↓ total factor w/ continuous) - Inhibitor+ → bypass agents - Antifibrinolytic for mucosal surgery
Pregnancy/postpartum: - FVIII ↑ pregnancy (esp 3rd tri); FIX ↑ NOT → peripartum replacement FIX - Vaginal delivery if FVIII ≥50 IU/dL at labor - MDT planning (OB, heme, anesthesia) - Baseline FVIII/FIX at booking - FVIII: if ≥50 & ↑ trend, trial labor ok; <50 → infusions - FIX: ≥50 during labor, ≥30 post-op × 3d - Neuraxial safe if factor ≥50 & no anticoag - Antepartum prophylaxis (recurrent bleeds/low baseline): tranexamic acid 10–15 mg/kg q6–8h start 32–34 wk
21.7 Guidelines & Evidence
- 2021 ASH VTE: Individualize risk; anticoag prophylaxis high-risk (immobility, surgery, CA) if inhibitor risk low
- 2023 ASH Diagnosis/Mgmt: Trial desmopressin mild/mod Hem A before factor prophylaxis; outcome-based monitoring (joint, QOL, adherence) guides intensification
- Inhibitor prevention: RODIN, Branch trials suggest ↓ factor exposure high-risk genotypes (nonsense, deletions) may ↓ inhibitor rates; not universal
Knowledge gaps: - Optimal inhibitor eradication (rituximab role, timing) acquired Hem A - Long-term safety SC FVIII (antithrombin) if ADAMTS13 replete - Inhibitor predictors Hem B (genotype poorly characterized) - Joint outcomes mod Hem A (targeted prophylaxis vs on-demand, biomarker dosing)