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Hematology›Condition·Updated Jul 2, 2026·v1

Hemophilia A

Hemophilia A is an X-linked bleeding disorder due to FVIII deficiency, classified by baseline FVIII activity as severe (<1%), moderate (1-5%), or mild (>5-40%). Management involves factor VIII replacement for acute bleeds and prophylaxis, with non-factor therapies (emicizumab, concizumab, marstacimab) as first-line alternatives. Gene therapy (valoctocogene roxaparvovec) offers a one-time curative option for adults without inhibitors. Inhibitors develop in 25-35% of severe patients, requiring bypassing agents (rFVIIa or aPCC) and emicizumab. Early prophylaxis prevents hemophilic arthropathy, and comprehensive care at specialized centers improves outcomes.

High Evidence303 references·13,663 words·55 min read·v1
hemophilia Afactor VIII deficiencybleeding disorderhemarthrosisinhibitoremicizumabgene therapyhematology

Quick Reference

RxDrug of choiceFVIII concentrate (standard or extended half-life) for acute bleeds and prophylaxis in patients without inhibitors; emicizumab for prophylaxis in patients with or without inhibitors.
AltAlternativesDDAVP (0.3 mcg/kg IV or intranasal) for mild hemophilia A with known response; rFVIIa (90 mcg/kg IV q2-3h) or aPCC (50-100 U/kg IV q12h) for acute bleeding in patients with inhibitors; concizumab (0.15 mg/kg SC daily) or marstacimab (150 mg SC weekly) for prophylaxis.
⊘AvoidNSAIDs and aspirin (antiplatelet effects); desmopressin in severe hemophilia (FVIII <1%) or unknown response; aPCC in patients on emicizumab (risk of thrombotic microangiopathy); intramuscular injections during acute bleeding; concurrent aPCC and rFVIIa (thrombosis risk).
DxTest of choiceOne-stage clotting assay for FVIII activity (FVIII:C) for initial diagnosis; Nijmegen Bethesda assay for inhibitor detection; chromogenic FVIII assay if discrepant mild hemophilia suspected; F8 gene sequencing for confirmation, mutation type, and carrier testing.
ScKey scoreSeverity classification by baseline FVIII activity (<1% severe, 1-5% moderate, >5-40% mild); inhibitor risk stratification by F8 mutation type (null vs non-null) and product use (recombinant vs plasma-derived, HR 1.87).
→When to referAll patients with severe hemophilia A, moderate disease with severe bleeding, or any inhibitor; women with symptomatic hemophilia A carriers; patients considering gene therapy; recurrent bleeding despite prophylaxis.
Immediate factor replacement for acute bleeds; early primary prophylaxis with FVIII or emicizumab to prevent hemophilic arthropathy; inhibitor management with bypassing agents or emicizumab; gene therapy for eligible adults.
Hemophilia A is an X-linked inherited bleeding disorder caused by deficiency of coagulation factor VIII (FVIII), leading to spontaneous and trauma-related bleeding, particularly into joints. Severity is classified by baseline FVIII activity: severe (<1%), moderate (1-5%), and mild (>5-40%). Modern management includes prophylaxis with factor VIII concentrates, non-factor therapies like emicizumab, and, for eligible adults, gene therapy. Early diagnosis and treatment are essential to prevent life-threatening hemorrhage and progressive hemophilic arthropathy.

Overview and Recommendations

Background

  • •Hemophilia A is an X-linked recessive bleeding disorder caused by pathogenic variants in the F8 gene, leading to deficient or dysfunctional coagulation factor VIII (FVIII). This impairs the intrinsic tenase complex, reducing thrombin generation by 10⁵-fold and predisposing to spontaneous and trauma-related bleeding, particularly into joints and soft tissues [1].
  • •The disease affects approximately 1 in 5,000 to 10,000 male births worldwide, making it one of the most common inherited bleeding disorders. Up to 75% of affected individuals globally remain undiagnosed, especially in resource-limited settings, underscoring the need for targeted screening of at-risk families [1].
  • •Severity is dichotomized by baseline FVIII activity: severe (<1 IU/dL) with spontaneous bleeding, moderate (1-5 IU/dL) with occasional spontaneous or trauma-related bleeds, and mild (>5 to <40 IU/dL) with bleeding only after significant injury or surgery. FVIII activity ≥40 IU/dL is generally asymptomatic [1, 10].
  • •The underlying F8 mutation type is the primary determinant of clinical severity and inhibitor risk. Intron 22 inversion accounts for 40-45% of severe cases, while missense mutations predominate in mild/moderate disease. Neutralizing anti-FVIII antibodies (inhibitors) develop in 25-35% of patients with severe hemophilia A and are the most significant treatment-related complication [13, 28].
  • •The 2021 ISTH nomenclature reclassified female F8 variant carriers into five distinct categories (asymptomatic, symptomatic, mild, moderate, severe) based on personal bleeding history and FVIII level, replacing the historical 'carrier' label and acknowledging that many females experience clinically significant bleeding [6, 7].
  • •A subset of patients exhibit 'discrepant hemophilia A,' where FVIII activity differs between one-stage clotting and chromogenic assays due to specific F8 missense mutations. Chromogenic assay is the confirmatory test and better reflects true bleeding risk, preventing underdiagnosis or misclassification [10].

Evaluation

  • •Suspect hemophilia A in any male with a history of spontaneous hemarthroses (especially ankles, knees, elbows), easy bruising, prolonged bleeding after dental extraction or surgery, or intracranial hemorrhage (ICH) in infancy. A three-generation family history revealing X-linked inheritance is highly suggestive [88, 111].
  • •Ask about the age at first significant bleed: severe disease often presents in infancy with excessive bruising after crawling or ICH after birth. Moderate disease may present in childhood with bleeding after minor trauma, while mild disease can remain undiagnosed until adulthood after a surgical challenge [81].
  • •Examine for joint swelling, warmth, and limited range of motion in acute hemarthrosis. Chronic arthropathy presents with fixed flexion deformities, crepitus, muscle atrophy, and reduced gait. In neonates, ICH may manifest as lethargy, seizures, vomiting, or bulging fontanelles [88, 111].
  • •Order a complete blood count (CBC), prothrombin time (PT), and activated partial thromboplastin time (aPTT). An isolated prolonged aPTT with normal PT is the classic screening abnormality. A mixing study (1:1 with normal plasma) that corrects immediately suggests a factor deficiency; failure to correct after incubation indicates an inhibitor [124, 96].
  • •Perform a one-stage clotting assay for FVIII activity (FVIII:C) as the initial gold-standard diagnostic test. A level <40 IU/dL confirms the diagnosis and defines severity: <1 IU/dL (severe), 1-5 IU/dL (moderate), >5 to <40 IU/dL (mild). Normal FVIII:C essentially excludes hemophilia A [124].
  • •In mild hemophilia A (FVIII:C 5-40 IU/dL), perform a chromogenic FVIII:C assay to detect discrepant hemophilia A, where the one-stage assay may overestimate FVIII activity. The chromogenic assay is the confirmatory test and better predicts bleeding risk [70].
  • •Measure von Willebrand factor (VWF) antigen and activity (ristocetin cofactor) to exclude von Willebrand disease type 2N, which also causes low FVIII:C due to defective VWF binding. This is essential in any patient with low FVIII and normal VWF levels to confirm true hemophilia A [33].
  • •If the mixing study fails to correct after 2-hour incubation, perform the Nijmegen-modified Bethesda assay to detect and quantify FVIII inhibitors (neutralizing antibodies). A titer ≥0.6 Bethesda units (BU) is considered positive; >5 BU defines high-titer inhibitors [118].
  • •Offer genetic counseling and F8 gene sequencing for confirmation of the diagnosis, determination of mutation type (critical for inhibitor risk stratification), carrier testing in female relatives, and prenatal diagnosis. The mutation type predicts inhibitor risk: null mutations (large deletions, nonsense) carry the highest risk [13, 18, 126].
  • •In female patients with low FVIII:C, assess for skewed X-inactivation, Turner syndrome mosaicism, or von Willebrand disease type 2N. A three-generation pedigree and evaluation of personal bleeding history with menstrual and postpartum bleeding are essential [6, 33, 129].
  • •Diagnostic criteria for acquired hemophilia A (AHA) include new-onset bleeding in an older adult without prior bleeding history, isolated prolonged aPTT that does not correct on mixing study, low FVIII:C, and a positive Bethesda assay for anti-FVIII autoantibodies. Unlike congenital disease, AHA often presents with ecchymoses and muscle hematomas rather than hemarthroses [20, 75, 98].
  • •Also consider other causes of isolated prolonged aPTT: lupus anticoagulant (does not correct with mixing but may show prolonged dilute Russell viper venom time), factor IX deficiency (hemophilia B), and factor XI deficiency. Specific factor assays for FIX and FXI should be performed if FVIII is normal and clinical suspicion remains high [124].

Management

  • •For acute major bleeds (intracranial hemorrhage, retroperitoneal, gastrointestinal, large muscle with compartment syndrome) in patients without inhibitors: administer FVIII concentrate 50 IU/kg IV bolus immediately, followed by 25 IU/kg every 8-12 hours. For life-threatening bleeds, give initial bolus of 50-100 IU/kg and maintain FVIII activity >80% for 7-14 days [148].
  • •For acute minor bleeds (hemarthroses, superficial hematomas) in patients without inhibitors: administer FVIII concentrate 25-40 IU/kg IV; a single dose may suffice. For hemarthroses, rest, immobilize the joint, and apply ice. Avoid weight-bearing until pain and swelling resolve, typically 24-48 hours [148].
  • •For patients with inhibitors who present with an acute bleed: use a bypassing agent. First-line options are recombinant activated factor VII (rFVIIa) 90 mcg/kg IV every 2-3 hours or activated prothrombin complex concentrate (aPCC, FEIBA) 50-100 U/kg IV every 12 hours (maximum 200 U/kg/day). Do not administer aPCC and rFVIIa concurrently due to additive thrombosis risk [143].
  • •In patients with inhibitors who are on emicizumab prophylaxis: rFVIIa 90 mcg/kg is the preferred first-line bypassing agent for acute bleeding. Avoid aPCC in this setting if possible, as the combination has been associated with thrombotic microangiopathy and thromboembolic events [144, 154, 169].
  • •For mild hemophilia A (FVIII >5 IU/dL) with a known response to desmopressin (DDAVP test dose): administer DDAVP 0.3 mcg/kg IV (over 15-30 minutes) or intranasal (1.5 mg/mL, 150 mcg per spray, 1 spray for <50 kg, 2 sprays for ≥50 kg). DDAVP raises FVIII 2-4 fold; repeat every 12-24 hours but limit to 2-3 doses to avoid tachyphylaxis and hyponatremia [124, 283].
  • •Initiate primary prophylaxis for all patients with severe hemophilia A (FVIII <1 IU/dL) starting before age 2 years, ideally by 12 months, to prevent joint damage. Standard regimens include FVIII concentrate 25-40 IU/kg three times weekly (or every other day), or extended half-life products like efanesoctocog alfa 50 IU/kg IV once weekly [45, 76, 165, 169].
  • •For patients without inhibitors, non-factor prophylaxis with emicizumab (Hemlibra) is a first-line alternative to FVIII concentrates: loading dose 3 mg/kg subcutaneously weekly for 4 weeks, then maintenance 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. In HAVEN 3, emicizumab reduced annualized bleeding rate (ABR) by 96% vs on-demand therapy [156, 169].
  • •For patients with inhibitors, first-line prophylaxis is emicizumab (same loading and maintenance dosing as above), which reduced ABR by 87% in HAVEN 1 vs no prophylaxis. Immune tolerance induction (ITI) with daily high-dose FVIII should also be considered to eradicate the inhibitor; success rates are 60-80% [154, 169, 181].
  • •For patients with severe hemophilia A without inhibitors or anti-AAV5 antibodies, gene therapy with valoctocogene roxaparvovec (Roctavian) is an option: single IV infusion of 6×10¹³ vg/kg. Pre-treatment evaluation includes screening for anti-AAV5 antibodies, liver fibrosis (transient elastography <8 kPa), and active hepatitis. Post-infusion, monitor ALT weekly for 12 weeks; ALT elevation >1.5× baseline triggers corticosteroid therapy [183, 167, 186].
  • •Newer non-factor agents for prophylaxis include concizumab (anti-TFPI, 0.15 mg/kg SC once daily) and marstacimab (anti-TFPI, 150 mg SC once weekly). In the explorer7 and BASIS trials, these agents reduced ABR by 86-92% vs on-demand therapy and are emerging as alternatives for patients with and without inhibitors [155, 158, 159].
  • •What NOT to do: avoid NSAIDs (ibuprofen, naproxen) and aspirin in all patients with hemophilia A due to antiplatelet effects. Avoid intramuscular injections unless absolutely necessary. Do not use desmopressin for acute bleeding in patients with severe hemophilia A (FVIII <1 IU/dL) or in those with unknown DDAVP response. Do not combine aPCC and rFVIIa [148].
  • •Refer all patients with severe hemophilia A, moderate disease with a severe bleeding phenotype, or any patient with an inhibitor to a specialized hemophilia treatment center (HTC). Referral is also indicated for women with symptomatic hemophilia A carriers, patients considering gene therapy, or those with recurrent bleeding despite adequate prophylaxis [169].
  • •Discharge criteria after a treated acute bleed: cessation of bleeding (no further swelling, pain controlled, stable hemoglobin), ability to ambulate or use joint without severe pain, and a plan for transition to or continuation of prophylaxis. Ensure outpatient follow-up with hematology within 1-2 weeks [148].
  • •For major surgery or invasive procedures, achieve FVIII trough >80-100% on day of surgery and maintain >50% for 5-10 days postoperatively. Administer a bolus of FVIII concentrate 50 IU/kg immediately before incision, then continue with 25-40 IU/kg every 8-12 hours or continuous infusion. Mechanical thromboprophylaxis is preferred; pharmacologic prophylaxis is not routinely indicated [148, 209].

Board Review — High Yield

  • •Intron 22 inversion, most common F8 mutation in severe hemophilia A (40-45%); causes complete FVIII deficiency due to homologous recombination.
  • •One-stage clotting assay, gold-standard initial diagnostic test for FVIII activity; chromogenic assay needed for discrepant mild hemophilia.
  • •Bethesda assay, detects and quantifies FVIII inhibitors (≥0.6 BU positive; >5 BU high-titer); essential before surgery or for unexplained bleeding.
  • •SIPPET trial, recombinant FVIII carries 1.87-fold higher risk of inhibitors vs plasma-derived FVIII/VWF in previously untreated patients with severe hemophilia A.
  • •Emicizumab, bispecific monoclonal antibody mimicking FVIIIa; given subcutaneously weekly to monthly; reduces ABR by 87-96% in patients with and without inhibitors.
  • •HAVEN 1 and 3 trials, established emicizumab prophylaxis vs on-demand in inhibitor (87% ABR reduction) and non-inhibitor (96% ABR reduction) patients.
  • •Efanesoctocog alfa (Altuviiio), once-weekly extended half-life FVIII; XTEND-1 trial showed mean ABR 0.7 and 86% zero bleeds; maintains FVIII >40% for most of the week.
  • •Valoctocogene roxaparvovec (Roctavian), AAV5-based gene therapy for adults without inhibitors or anti-AAV5 antibodies; single IV infusion sustains median FVIII 5.8 IU/dL at 5 years, eliminating need for prophylaxis in 88%.
  • •Hemophilic arthropathy, results from recurrent hemarthrosis driving synovial inflammation and cartilage destruction; prevented by early prophylaxis (Joint Outcome Study: 93% normal MRI vs 55% with episodic therapy).
  • •Acquired hemophilia A, autoantibodies against FVIII cause bleeding in older adults without prior history; treated with bypassing agents, emicizumab, and immunosuppression (steroids ± cyclophosphamide or rituximab).

Deep Dive — Evidence Details

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