Residency · Residency · Hematology Thrombosis

Hemophilia A and B

Introduction

Hemophilia A is caused by deficiency of factor VIII and is inherited in an X-linked recessive pattern, with an incidence of 1 in 5,000 male births. Hemophilia B is caused by deficiency of factor IX, also X-linked recessive, with an incidence of 1 in 30,000 male births. The two conditions are clinically indistinguishable, both presenting with deep tissue and joint bleeding that is the hallmark of the hemophilias. The treatment landscape has evolved dramatically from plasma-derived factor products to recombinant factors, extended half-life products, non-factor therapies including emicizumab and fitusiran, and most recently gene therapy.

Genetics and Pathophysiology

Molecular Basis

The F8 gene is located on Xq28 and is one of the largest human genes, with more than 2,000 mutations described. The intron 22 inversion is the most common mutation causing severe hemophilia A, accounting for approximately 45% of severe cases. The intron 1 inversion accounts for approximately 5% of severe cases, with point mutations, deletions, and insertions accounting for the remainder. The F9 gene is located on Xq27 and is a substantially smaller gene, with approximately 1,100 mutations described. Hemophilia B Leiden is an interesting variant caused by F9 promoter mutations that result in an androgen-responsive promoter, leading to spontaneous improvement in factor IX levels at puberty. Female carriers typically have factor levels of approximately 50%, though symptomatic carriers with levels below 40% exist due to skewed X-inactivation or, rarely, Turner syndrome.

Severity Classification

Clinical Manifestations

Joint Bleeding (Hemarthrosis)

Hemarthrosis is the hallmark clinical manifestation of severe hemophilia and accounts for 70 to 80% of all bleeding episodes. The most commonly affected target joints are the knees, elbows, and ankles. The pathologic mechanism begins with bleeding into the joint space, which triggers synovial hypertrophy and iron deposition as hemosiderin. This initiates a cycle of inflammatory synovitis that progressively destroys cartilage and leads to hemophilic arthropathy. Acute hemarthrosis presents with rapid-onset pain, swelling, warmth, and limited range of motion, and the cornerstone of management is early factor replacement. Chronic hemophilic arthropathy represents the end result of recurrent hemarthroses, characterized by joint destruction, flexion contractures, and significant disability. The prevention of arthropathy through prophylactic factor replacement is one of the most important therapeutic goals in hemophilia care.

Other Bleeding Sites

Muscle hematomas are a significant source of morbidity, with iliopsoas hematomas being particularly important because they can compress the femoral nerve and may clinically mimic appendicitis. Calf and forearm hematomas carry a risk of compartment syndrome. Intracranial hemorrhage is the leading cause of death in severe hemophilia, occurring in approximately 3 to 5% of patients. A critical management principle is that factor replacement must be administered immediately upon suspicion of intracranial hemorrhage, before imaging is performed. Gastrointestinal bleeding and hematuria may also occur; hematuria is usually self-limited, and antifibrinolytics should be avoided for urinary tract bleeding because the resulting clot may obstruct the ureter. Post-surgical and post-dental extraction bleeding are common in untreated patients. Mucosal bleeding is less common in hemophilia than in platelet or VWF disorders, reflecting the distinct pathophysiology of secondary versus primary hemostatic defects.

Diagnosis

Laboratory Findings

The characteristic laboratory profile of hemophilia includes a prolonged aPTT with normal PT, normal platelet count, and normal bleeding time. A mixing study demonstrates correction of the aPTT, indicating a factor deficiency rather than an inhibitor, unless an inhibitor has developed. Factor VIII activity is reduced in hemophilia A, and factor IX activity is reduced in hemophilia B. VWF levels are normal, which is the key distinguishing feature from type 3 von Willebrand disease, which also presents with low factor VIII levels. Clinicians should be aware that discrepancies between chromogenic and one-stage FVIII assays can occur with certain mutations and with extended half-life products, and it is important to know which assay the laboratory uses.

Genetic Testing

Genetic testing is confirmatory and is essential for carrier detection and prenatal diagnosis. Inversion PCR is used to detect intron 22 and intron 1 inversions, while gene sequencing identifies point mutations, small deletions, and insertions.

<image>A clinical and diagnostic diagram for hemophilia. Show the X-linked inheritance pattern with a carrier mother and affected son pedigree, including the probability of each offspring genotype. Below, display the laboratory diagnostic pathway: prolonged aPTT with normal PT → mixing study corrects → specific factor assays (FVIII for hemophilia A, FIX for hemophilia B). Include a severity classification table with factor levels and bleeding phenotypes. On the right, show the clinical manifestations as an anatomical figure with arrows pointing to common bleeding sites: joints (hemarthrosis with inset showing synovial hypertrophy and iron deposition), muscles (iliopsoas hematoma), intracranial hemorrhage, and GI tract. Include a radiograph or diagram of hemophilic arthropathy showing joint space narrowing, erosions, and subchondral cysts. Medical textbook illustration style.</image>

Treatment - Factor Replacement

On-Demand Treatment

Acute bleeds should be treated as early as possible, and the guiding principle for suspected intracranial hemorrhage is "treat first, assess later." For hemophilia A, recombinant factor VIII (rFVIII) is the treatment of choice. Standard half-life rFVIII has a half-life of approximately 8 to 12 hours, requiring dosing every 8 to 12 hours. Target factor levels depend on bleed severity: 40 to 60% for minor bleeds such as joint hemorrhage, 80 to 100% for major bleeds, and 80 to 100% initially with 50 to 80% for maintenance after surgery. The dose calculation for factor VIII is: dose (IU) equals weight (kg) multiplied by the desired rise (%) multiplied by 0.5.

For hemophilia B, recombinant factor IX (rFIX) has a longer standard half-life of approximately 18 to 24 hours, allowing dosing every 12 to 24 hours. Target factor levels mirror those for factor VIII. The dose calculation differs: dose (IU) equals weight (kg) multiplied by the desired rise (%) multiplied by 1.0, reflecting the higher dose requirement per unit of desired rise due to the extravascular distribution of factor IX.

Extended Half-Life (EHL) Products

Extended half-life factor VIII products include Fc fusion (efmoroctocog alfa/Eloctate, half-life approximately 19 hours) and PEGylated products (damoctocog alfa pegol/Jivi, half-life approximately 17 hours; turoctocog alfa pegol/Esperoct, half-life approximately 19 hours). The half-life extension for factor VIII products is modest, at 1.5 to 1.8 times standard products, because factor VIII clearance is largely governed by the VWF clearance pathway, which limits the achievable half-life extension.

Extended half-life factor IX products achieve dramatically greater half-life extension of 3 to 5 times standard products because factor IX is not subject to VWF-mediated clearance. These include Fc fusion (eftrenonacog alfa/Alprolix, half-life approximately 82 hours), PEGylated (nonacog beta pegol/Rebinyn, half-life approximately 93 hours), and albumin fusion (albutrepenonacog alfa/Idelvion, half-life approximately 102 hours). These products allow once-weekly or every-10-to-14-day dosing, substantially reducing treatment burden for patients with hemophilia B.

Prophylaxis

Primary prophylaxis should begin before age 3 or after the first hemarthrosis and is the standard of care for preventing arthropathy. Standard prophylactic dosing consists of rFVIII at 25 to 40 IU/kg three times per week for hemophilia A and rFIX at 50 to 100 IU/kg one to two times per week for hemophilia B. Extended half-life products allow less frequent dosing. Pharmacokinetic-guided dosing, based on population PK models, allows individualized regimens with target trough levels of greater than 3 to 5% for standard prophylaxis or greater than 10 to 15% for intensive prophylaxis.

Non-Factor Therapies

Emicizumab (Hemlibra)

Emicizumab is a bispecific monoclonal antibody that mimics the cofactor function of factor VIIIa by bridging factor IXa and factor X, thereby restoring the function of the intrinsic tenase complex. It is administered subcutaneously and has a half-life of approximately 28 days. The loading dose is 3 mg/kg weekly for 4 weeks, followed by maintenance dosing of 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks.

The HAVEN clinical trial program established emicizumab as a transformative therapy. HAVEN 1 demonstrated an 87% reduction in treated bleeds compared to no prophylaxis in hemophilia A patients with inhibitors. HAVEN 3 showed a 68% reduction in bleeds compared to on-demand factor VIII in patients without inhibitors. HAVEN 4 confirmed the efficacy of every-4-week dosing. Emicizumab is now standard of care for prophylaxis in all patients with severe hemophilia A, regardless of inhibitor status.

Several critical considerations govern the safe use of emicizumab. The drug does not normalize the aPTT but is providing hemostatic protection; consequently, the aPTT is artificially shortened and cannot be used for monitoring. Concurrent use of activated prothrombin complex concentrate (aPCC/FEIBA) must be avoided, as this combination has caused thrombotic microangiopathy and thrombosis. For breakthrough bleeds or surgical coverage in inhibitor patients, recombinant factor VIIa (rFVIIa) should be used preferentially. In non-inhibitor patients, factor VIII can be administered. Emicizumab does not affect the chromogenic (bovine) FVIII assay, which should be used to monitor factor VIII levels when factor VIII is administered concomitantly.

Fitusiran (Alhemo)

Fitusiran is a small interfering RNA (siRNA) directed against antithrombin messenger RNA that reduces antithrombin levels, thereby rebalancing hemostasis by enhancing thrombin generation. It is administered subcutaneously on a monthly basis. The ATLAS clinical trial program demonstrated significant reductions in bleeding events in patients with hemophilia A and B, both with and without inhibitors. Fitusiran is the first non-factor therapy effective for both hemophilia A and hemophilia B, a significant advantage over emicizumab, which is active only in hemophilia A. It received FDA approval in 2024. The principal risk is thrombosis, which is dose-dependent; target antithrombin levels are maintained at approximately 15 to 25%, and concurrent high-dose factor replacement should be avoided.

Concizumab (Anti-TFPI Antibody)

Concizumab is a monoclonal antibody directed against tissue factor pathway inhibitor (TFPI) that enhances coagulation by removing the TFPI-mediated brake on the initiation phase. The explorer clinical trial program demonstrated efficacy in reducing bleeding events in hemophilia A and B with and without inhibitors. It is administered as a daily subcutaneous injection and received FDA approval for hemophilia A and B with inhibitors in 2024.

Inhibitor Development

Epidemiology

Factor VIII inhibitors develop in 25 to 30% of patients with severe hemophilia A, typically within the first 50 exposure days. Factor IX inhibitors are much less common, developing in only 1 to 5% of patients with severe hemophilia B, but they carry a higher risk of anaphylaxis to factor IX products and nephrotic syndrome. Risk factors for inhibitor development include severe genotype (inversions, large deletions, nonsense mutations), family history, African American race, and intensive early exposure to factor concentrates.

Diagnosis and Quantification

Inhibitor development should be suspected when factor replacement fails to achieve the expected factor levels or clinical response. The Bethesda assay quantifies the inhibitor titer in Bethesda Units (BU). Low-titer inhibitors (below 5 BU) may be overcome with high-dose factor replacement. High-titer inhibitors (5 BU or greater) render standard factor replacement ineffective, and bypassing agents must be used.

Acute Bleeding in Inhibitor Patients

Bypassing agents are the mainstay of hemostatic treatment in patients with high-titer inhibitors. Recombinant factor VIIa (NovoSeven) is administered at 90 to 120 mcg/kg every 2 hours as a bolus or by continuous infusion. Activated prothrombin complex concentrate (aPCC/FEIBA) is given at 50 to 100 IU/kg every 8 to 12 hours, with a maximum daily dose of 200 IU/kg; it contains activated forms of factors II, VII, IX, and X. aPCC must not be used concurrently with emicizumab due to the risk of thrombotic microangiopathy and thrombosis. For patients with low-titer inhibitors below 5 BU, high-dose factor VIII may be used, with dosing calculated to neutralize the inhibitor and provide a hemostatic factor level.

Immune Tolerance Induction (ITI)

The goal of immune tolerance induction is to eradicate the inhibitor and restore normal factor pharmacokinetics. The standard protocol involves high-dose factor VIII at 100 to 200 IU/kg daily until the inhibitor becomes undetectable and FVIII pharmacokinetics normalize. The overall success rate is 60 to 80%, with higher success rates observed in patients with lower peak inhibitor titers and earlier initiation of ITI. The duration of treatment ranges from months to years and is expensive. The Bonn protocol (200 IU/kg daily) is the historical gold standard, while the International ITI study (I-ITI) demonstrated that low-dose treatment (50 IU/kg three times per week) achieved similar outcomes but required a longer time to response.

<image>A treatment landscape diagram for hemophilia A showing the evolution from on-demand factor replacement to modern prophylaxis options. Arrange treatments on a timeline from left to right: plasma-derived FVIII → recombinant FVIII (standard half-life) → extended half-life FVIII (Fc fusion, PEGylated) → emicizumab (bispecific antibody) → fitusiran (anti-AT siRNA) → gene therapy (valoctocogene roxaparvovec). For each therapy, show: route of administration (IV vs. SC), dosing frequency (daily to monthly to one-time), mechanism (with a small molecular diagram), and key clinical trial. At the bottom, show a separate track for inhibitor patients: bypassing agents (rFVIIa, aPCC) and immune tolerance induction, with emicizumab and fitusiran bridging both inhibitor and non-inhibitor pathways. Modern pharmaceutical timeline infographic style.</image>

Gene Therapy

Hemophilia A Gene Therapy

Valoctocogene roxaparvovec (Roctavian) is an AAV5-based gene therapy for hemophilia A that received FDA approval in 2023. The phase 3 GENEr8-1 trial demonstrated a median factor VIII activity of 23% at one year, with a significant reduction in bleeding events. However, factor VIII expression wanes over time, with approximately 50% decline per year observed in some patients. The therapy is administered as a single intravenous infusion and requires monitoring for transaminase elevation, with immunosuppression potentially needed. Eligibility criteria include severe hemophilia A, no history of factor VIII inhibitor, and no pre-existing AAV5 antibodies. Long-term durability remains uncertain, and follow-up is ongoing.

Hemophilia B Gene Therapy

Etranacogene dezaparvovec (Hemgenix) is an AAV5-based gene therapy using the FIX Padua variant that received FDA approval in 2022. The phase 3 HOPE-B trial demonstrated a mean factor IX activity of 36.9% at 18 months, with a 54% reduction in annualized bleeding rate. Factor IX gene therapy has shown more durable expression than factor VIII gene therapy, reflecting the smaller transgene size and different biological properties. The FIX Padua variant is a naturally occurring gain-of-function mutation that confers 5 to 8 times higher specific activity than wild-type factor IX. The cost of this therapy is approximately 3.5 million dollars as a one-time treatment.

Considerations

AAV antibody pre-screening is required before gene therapy, as 30 to 50% of patients may have pre-existing AAV5 antibodies that exclude them from treatment. Hepatotoxicity manifested as transaminase elevation may require corticosteroid management. Patients cannot be re-dosed with the same AAV serotype because anti-capsid antibodies develop after the initial infusion. The theoretical risk of insertional mutagenesis exists, though no hepatocellular carcinoma has been reported in hemophilia gene therapy trials to date. The decision to pursue gene therapy requires shared decision-making, weighing the appeal of a one-time treatment against the established safety profiles of non-factor therapies with proven long-term efficacy.

Key Clinical Pearls

• For suspected intracranial hemorrhage in hemophilia, administer factor replacement IMMEDIATELY before imaging; treat first, diagnose second
• Emicizumab has revolutionized hemophilia A prophylaxis; it is now standard of care for severe hemophilia A regardless of inhibitor status
• DO NOT use aPCC (FEIBA) concurrently with emicizumab; this combination has caused fatal TMA and thrombosis
• Fitusiran is the first non-factor therapy effective for BOTH hemophilia A and B; it works by reducing antithrombin levels
• Factor IX extended half-life products achieve much greater half-life extension (3-5x) than FVIII EHL products (1.5-1.8x) because FIX is not cleared via VWF
• Gene therapy for hemophilia B (etranacogene dezaparvovec) appears more durable than hemophilia A gene therapy; FIX Padua variant provides supraphysiologic specific activity
• Female carriers with factor levels <40% can have clinically significant bleeding and deserve assessment and management

References

1. Srivastava A, et al. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020;26(Suppl 6):1-158.
2. Oldenburg J, et al. Emicizumab prophylaxis in hemophilia A with inhibitors (HAVEN 1). N Engl J Med. 2017;377(9):809-818.
3. Mahlangu J, et al. Emicizumab prophylaxis in patients with hemophilia A without inhibitors (HAVEN 3). N Engl J Med. 2018;379(9):811-822.
4. Pipe SW, et al. Gene therapy with etranacogene dezaparvovec for hemophilia B (HOPE-B). N Engl J Med. 2023;388(8):706-718.
5. Mahlangu J, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A (GENEr8-1). N Engl J Med. 2023;388(8):694-705.

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