Hemophilia A and B

Factor deficiency, prophylaxis strategies, inhibitor management, non-factor therapies, and curative gene therapy for X-linked bleeding disorders

Key Points

• Hemophilia A (factor VIII deficiency) affects ~1:5,000 males; Hemophilia B (factor IX deficiency) ~1:30,000 males. Both are X-linked recessive — females are typically carriers but can have bleeding symptoms with lyonization.
• Prophylactic factor replacement starting in infancy is the standard of care, preventing hemarthrosis, joint destruction, and intracranial hemorrhage in severe disease.
• Inhibitor development (neutralizing anti-factor antibodies) occurs in 25–30% of severe Hemophilia A and 1–3% of Hemophilia B — it is the most challenging treatment complication and requires immune tolerance induction or bypass agents.
• Emicizumab (Hemlibra) is approved for Hemophilia A with or without inhibitors: a bispecific antibody bridging FIXa and FX that mimics FVIII cofactor function, administered subcutaneously weekly, biweekly, or monthly.
• FDA-approved gene therapies: Beqvez (fidanacogene elaparvovec, AAV-B hemophilia B, 2024) and Hemgenix (etranacogene dezaparvovec, AAV5-hFIX, 2022) for Hemophilia B; Roctavian (valoctocogene roxaparvovec, AAV5-hFVIII) for Hemophilia A — one-time IV infusions providing durable factor activity.
• Fitusiran (Alhemo, antithrombin-targeting siRNA) is approved for prophylaxis in adults with Hemophilia A or B with or without inhibitors — subcutaneous once monthly, rebalancing hemostasis by reducing antithrombin.

Pathophysiology and Diagnosis

Hemostasis requires a properly assembled intrinsic tenase complex: factor IXa (FIXa) bound to its cofactor FVIIIa on the platelet surface activates factor X (FX), which in turn generates thrombin and a fibrin clot. Deficiency of either FVIII (Hemophilia A) or FIX (Hemophilia B) disrupts this amplification step, producing inadequate thrombin generation and a tendency for prolonged, recurrent bleeding. **Severity classification (based on residual factor activity):** - **Severe:** <1 IU/dL (<1%) — spontaneous hemarthroses, muscle hematomas, life-threatening bleeds. Accounts for ~50% of cases. -…

Factor Replacement Therapy — Prophylaxis and On-Demand

**On-demand (episodic) treatment** is reserved for mild–moderate disease or acute bleeds in patients on prophylaxis who break through. The goal is to raise factor levels to hemostatic ranges as quickly as possible after a bleed is recognized. **Prophylaxis** is the standard of care for severe (and most moderate) Hemophilia and dramatically reduces hemarthrosis, joint destruction, and intracranial hemorrhage compared to on-demand therapy. The landmark Joint Outcomes Study demonstrated that prophylaxis starting before age 2.5 (before the first joint bleed) prevents hemophilic arthropathy — the…

Inhibitor Development and Management

Inhibitors are IgG antibodies that neutralize infused factor, rendering standard replacement therapy ineffective. They are the most serious complication of hemophilia treatment. **Epidemiology:** Inhibitors develop in 25–30% of patients with severe Hemophilia A (highest risk with large deletions, inversions of intron 22 — the most common severe mutation — and non-white race) and 1–3% of severe Hemophilia B. Risk is highest during the first 50–75 exposure days in previously untreated patients. **Detection:** Bethesda assay (modified Nijmegen method) quantifies inhibitor titer: - Low titer: <5…

Non-Factor Therapies — Emicizumab and Fitusiran

The therapeutic landscape for hemophilia has been transformed by non-factor therapies that rebalance hemostasis without requiring factor infusion: **Emicizumab (Hemlibra) — the paradigm shift for Hemophilia A:** Emicizumab is a humanized bispecific antibody engineered to simultaneously bind FIXa and FX, mimicking the cofactor function of FVIIIa. This restores adequate FX activation and thrombin generation without replacing FVIII. Because it is structurally unrelated to FVIII, it does not stimulate FVIII inhibitor production and is fully active in the presence of inhibitors. FDA-approved for…

Gene Therapy — Beqvez, Hemgenix, and Roctavian

Gene therapy for hemophilia aims to provide one-time, durable correction of factor deficiency by delivering a functional copy of the FVIII or FIX gene to hepatocytes using an adeno-associated viral (AAV) vector. Hepatocytes are ideal target cells — they naturally secrete FVIII and FIX into the bloodstream. **Hemophilia B — FDA-approved gene therapies:** *Hemgenix (etranacogene dezaparvovec-drlb) — FDA-approved November 2022:* - AAV5 vector carrying a Padua variant FIX transgene (FIX-Padua R338L has ~8× higher specific activity than wild-type FIX) - Single IV infusion: 2 × 10¹³ gc/kg -…

Musculoskeletal Care and Comprehensive Management

Hemophilic arthropathy — progressive, degenerative joint disease caused by recurrent hemarthrosis — is the leading cause of morbidity and disability in hemophilia. Blood in the joint space triggers synovial inflammation, angiogenesis, and iron deposition, ultimately leading to cartilage destruction and subchondral bone erosion. **Target joints** (joints with ≥3 spontaneous bleeds in 6 months): require intensified prophylaxis, synovial evaluation, and possibly synovioarthesis (radioactive synovectomy or rifampicin injection for chemical synovectomy) or arthroscopic synovectomy.…