Hemophilia

Overview and pathophysiology

• Congenital hemophilia: deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B), i.e. loss of the tenase complex (FIXa and FVIIIa).
• Without the tenase complex the patient is unable to adequately activate factor X, so there is a lack of adequate thrombin generation (deficient thrombin burst).
• Hem A → FVIII; Hem B → FIX. Both are X-linked recessive.

Epidemiology and carriers

• Hemophilia A (F8 gene): incidence in men about 1 in 5,000.
• Hemophilia B (F9 gene): about 1 in 20,000 to 30,000 male births, considerably rarer than hemophilia A.
• Carriers (females): depending on X-inactivation, carriers of F8/F9 defects associated with severe hemophilia can have factor VIII/IX levels ranging from as low as 1% to well within the normal range.
  • This is because of skewed X-inactivation: in every female cell there are two X chromosomes, one is inactivated and one is utilized; random inactivation follows a normal distribution, but skewing can leave a carrier with low factor levels.
  • Clinical manifestations in symptomatic carriers are similar to men with hemophilia, with the added issues of heavy menstrual bleeding and risk of postpartum hemorrhage.
  • About 50% of carriers have FVIII or FIX <50% due to lyonization and can have mild bleeding (especially menorrhagia, postpartum).

Clinical severity

• Severe (<1%): spontaneous bleeding; deep tissue bleeds and hemarthroses from infancy.
• Moderate (1 to 5%): variable bleeding, with minor trauma; occasional spontaneous bleeding.
• Mild (>5 to 40%): traumatic bleeding only (major trauma or surgery); may not be diagnosed until adulthood.

Diagnosis

• Clues: family history, abnormal bleeding, prolonged aPTT, low FVIII or FIX activity. Rule out other causes of factor deficiency.

Factor VIII and IX assay

• One-stage assay: similar to aPTT testing. Plasma, contact activator, phospholipid and calcium are mixed and the time to form a fibrin clot is measured. FVIII/FIX is measured by mixing serial dilutions of patient plasma with substrate plasma deficient in that factor, comparing clotting times to a reference calibration curve.
• Two-stage (chromogenic) assay: an incubation step generates FXa, and a second step measures the action of FXa by cleavage of a chromogenic substrate. The amount of FXa is proportional to the amount of FVIIIa/FIXa available.

Differential diagnosis of factor VIII deficiency

• Lab/analytic error (e.g. sample sits without being spun for too long).
• Von Willebrand disease, especially type 2N (isolated FVIII deficiency with normal VWF:Ag and VWF:RCo).
• Acquired hemophilia.
• Not causes of isolated FVIII deficiency: vitamin K deficiency lowers II, VII, IX, X;
• FVIII is normal or elevated in liver disease.

Clinical presentation

• Hemarthrosis: hallmark (not strictly pathognomonic); large joints (knee, ankle, elbow). Repeated bleeds → chronic synovitis → arthropathy; target joints emerge. Causes chronic pain and functional limitations.
• Intracranial bleeding: major cause of morbidity and mortality (death, functional limitations, cognitive deficits); prophylaxis prevents it.
• Soft tissue / muscle bleeding: iliopsoas (mimics hip pathology, femoral nerve compression), forearm (compartment syndrome); chronic neuropathic pain.
• Hematuria: common; usually self-limited.
• Post-surgical bleeding. Mucosal bleeding is less prominent than in VWD or platelet disorders.

Treatment: overview and timeline

• Replace the missing protein: factor concentrates (used for treatment and prophylaxis); gene therapy (prophylaxis only).
• Mimic FVIII in the tenase complex: emicizumab (prophylaxis only).
• Promote FXa generation independent of the tenase complex (bypassing agents): recombinant FVIIa (treatment and prophylaxis); activated prothrombin complex concentrate (aPCC) (treatment and prophylaxis).
• DDAVP: releases endothelial VWF/FVIII; used for treatment and short-term periprocedural prophylaxis in responsive nonsevere Hem A.
• Antifibrinolytics: stabilize clot by inhibiting fibrinolysis (treatment only).
• Rebalancing hemostasis: fitusiran and TFPI inhibitors (prophylaxis only).

Prophylaxis vs on-demand

• Continuous prophylaxis (prevention of bleeding):
  • Primary: started prior to the second joint bleed and before age 3. Standard half-life factor concentrates every other day for hemophilia A, or twice weekly for hemophilia B; continue long-term; discontinuation or tapering is individualized and not guideline-endorsed.
  • Secondary: after the second joint bleed but before the onset of joint disease; goal is to prevent joint disease.
  • Tertiary: after the onset of joint disease; goal is to decrease bleeding frequency and improve quality of life and joint function.
• Targeted prophylaxis: treatment prior to high-risk activities (surgery, sports).
• On-demand: treatment of bleeding after it occurs; can be the only treatment for some mild-to-moderate patients. Keep factor level 30 to 50% for mild bleeds and 80 to 100% for severe bleeds.

Trials supporting prophylaxis

• Joint Outcome Study (Manco-Johnson, NEJM 2007, PMID 17687129): boys <30 months with severe hemophilia A (FVIII <2 U/dL) randomized to prophylaxis vs episodic treatment at the time of hemarthrosis. Median annual joint bleed rate 0.2 vs 4.65 bleeds/year (p<0.001, prophylaxis vs on-demand). Weak correlation between MRI scores and clinically evident hemarthroses. Conclusion: rFVIII prophylaxis prevents joint damage and decreases hemorrhage in young boys with severe hemophilia A.
• SPINART Study (Manco-Johnson, J Thromb Haemost 2017, PMID 28836341): similar design in adults. Reduced median annualized joint bleeding 0.3 (prophylaxis) vs 27.3 (on-demand); improved joint exam and quality of life.

Factor replacement

• Standard half-life products (plasma-derived and recombinant): normal half-life FVIII about 12 h, FIX about 24 h.
• Extended half-life (EHL) technologies:
  • Fc-fusion: FVIII(BDD)-Fc (Eloctate) about 1.5× longer; FIX-Fc (Alprolix) about 2.5 to 3.0× longer.
  • Albumin-fusion (FIX): FIX-albumin (Idelvion) >5× longer.
  • Pegylation (reduces clearance): FVIII: Bax855 (Adynovate, half-life ×1.4), BAY94-9027 (Jivi, ×1.5), N8-GP (Esperoct, ×1.6); FIX: N9-GP (Rebinyn, ×5).
  • VWF-fusion (FVIII): BIVV001 (efanesoctocog alfa): fusion of the FVIII-binding D'D3 domains of VWF fused to a single-chain rFVIII-Fc plus two XTEN linkers; circulates independent of endogenous VWF:Ag; overcomes the VWF-imposed half-life ceiling, reaching about 40 hours (3 to 4× standard FVIII; FDA-approved as Altuviiio, February 2023). Phase 3 used weekly prophylaxis dosing with mean ABR 0.71.
• FVIII dosing: 1 IU/kg raises the FVIII level by about 2%, so an empiric dose of 50 IU/kg brings levels from <1% to 100%. Nonmodified FVIII given q8 to q12 h (EHL-FVIII dosing varies).
• FIX dosing: 1 IU/kg raises the FIX level by about 1% for plasma-derived FIX and FIX-Fc, so an empiric dose of 100 IU/kg raises levels from <1% to 100%. For recombinant FIX, 1 IU/kg raises the level by about 0.6 to 0.8%. Nonmodified FIX given q12 to q24 h for acute bleeds.

Gene therapy

• Adeno-associated virus (AAV) mediated, liver-directed gene therapy: the AAV vector delivers the FVIII or FIX gene to the liver and liver cells produce the factor. FVIII is a very large gene, so packaging it in the vector is challenging.
• In an early FIX-AAV trial (10 subjects), FIX activity ranged 1.4 to 7.2% over 5 years; at 7 years, improved bleeding frequency and reduced factor IX use with no significant long-term adverse events. Patients mainly improved from severe to moderate or mild deficiency.
• Gene therapy is prophylaxis only; a pre-existing factor inhibitor makes gene therapy ineffective.

• Valoctocogene roxaparvovec (Roctavian), phase 3, N=134: dose 6 × 10¹³ vg/kg; reactive glucocorticoids in 106 participants (median duration 230 days). At week 52 mean FVIII 41.9 IU/dL (median 22.9 IU/dL). At week 104 (n=17), FVIII was <5 IU/dL in 24% and >40 IU/dL in 18% of participants. Mean ABR 0.8 (after) vs 4.8 (before). About 10% of patients had no benefit and increased bleeding. Well tolerated. Ozelo MC et al, N Engl J Med 2022;386(11):1013 to 1025.
• Roctavian (Hem A) and Hemgenix (Hem B): gene therapies given as a one-time IV infusion. Roctavian FVIII levels tend to decline over time, and BioMarin withdrew Roctavian from the US market in 2026 (announced February, supplied through May); Hemgenix has shown durable effect with the majority off prophylaxis at 3+ years.

Complications of treatment: inhibitors

• Frequency: hemophilia A, 35% of severe and 13% of mild/moderate; hemophilia B, <5% of severe. In SIPPET (previously untreated children, severe Hem A), inhibitor incidence was 44.5% with recombinant vs 26.8% with VWF-containing plasma-derived FVIII; not a universal comparison. Typically develop within the first 50 exposure days.
• Inhibitors reduce or abolish factor efficacy: low-responding (low-titer) inhibitors can be overcome with higher factor doses, but high-responding inhibitors need bypassing agents. A pre-existing inhibitor makes gene therapy ineffective.
• Diagnosis: prolonged aPTT that does NOT correct on a mixing study. The Bethesda assay quantifies the titer (BU = Bethesda units).
• Low-responding inhibitor (<5 BU/mL): 25% of all inhibitors; no rise in titer with factor exposure; 10% are transient and resolve spontaneously despite continued replacement (typically within 6 months). Check inhibitor periodically; can increase the dose of factor replacement to overwhelm.
• High-responding inhibitor (peak ≥5 BU/mL ever, even if current titer is lower): 75% of all inhibitors; titer rises in response to factor exposure; the main cause of morbidity in US hemophilia patients.
  • Bleeding control: aPCC and rFVIIa have response rates of 70 to 90%. aPCC contains FIX; avoid it in hemophilia B with a FIX inhibitor plus FIX allergy/anaphylaxis (use rFVIIa). A FIX inhibitor alone is not a contraindication: FEIBA is indicated for hemophilia A or B with inhibitors.; aPCC may also have small amounts of FVIII and continue to stimulate the inhibitor titer in FVIII-deficient patients. rFVIIa contains no FVIII or FIX, does not cause anamnesis (rise in inhibitor titer), and may be preferred when trying to let the inhibitor fall to a low level before starting immune tolerance induction (ITI).
  • Bleeding prevention: aPCC 85 U/kg 3 to 3.5 times/week gives a 62 to 72.5% reduction in bleeding; rFVIIa prophylaxis at 90 and 270 mcg/kg daily gives 45% and 59% reductions respectively; or emicizumab (see below).
  • Inhibitor eradication with ITI (see below).

• All PCCs are plasma-derived and contain other proteins, including anticoagulant proteins C and S. Unactivated factors are proenzymes (inactive precursors); activated factors have higher enzymatic activity. Bebulin (a 3-factor PCC) was discontinued in 2018.

Inhibitor eradication

• Severe hemophilia: immune tolerance induction (ITI): frequent infusion of FVIII/FIX at higher doses to induce peripheral tolerance. The only effective eradication treatment; best done early after inhibitor onset. Effective in up to two-thirds of patients. Less effective in hemophilia B (risk of allergic reactions to FIX and nephrotic syndrome).
• Non-severe hemophilia: immunosuppressive therapy vs observation; best approach is unclear.

Bleeding treatment and prevention (bypassing agents)

• Bleeding treatment: aPCC (FEIBA) 50 to 100 U/kg q8h, not to exceed 200 U/kg/day; rFVIIa 90 to 120 mcg/kg q2 to 3 h, or a single 270 mcg/kg dose.
• Bleeding prevention: bypassing agents are not very effective for prophylaxis (FEIBA takes an hour to infuse, and 3 times/week was never a good option). The best option for bleeding prophylaxis is now emicizumab.

Emicizumab (Hemlibra)

• A bispecific monoclonal antibody that binds factors IXa and X, bridging them together and replacing the role of missing factor VIIIa. Cannot be used in FIX deficiency (hemophilia B). Half-life 4 to 5 weeks. SC dosing q1, 2 or 4 weeks. Reduces annualized bleeding rate by >90%.
• Works for bleeding control and reduces annual bleeding in hemophilia A patients with inhibitors (HAVEN 1 and HAVEN 2: HAVEN 1: 87% ↓ treated bleeds (ABR 2.9 vs 23.3) vs no prophylaxis. HAVEN 2 (children, single-arm): ~99% intra-patient ↓ vs prior bypassing-agent prophylaxis. In HAVEN 1, TMA (thrombotic microangiopathy) occurred with concomitant aPCC/FEIBA >100 U/kg/24 h for >24 h) or without inhibitors (HAVEN 3: annual bleeding reduced 95%, 1.5 vs 38.2).
• If a patient on emicizumab is bleeding, do NOT use FEIBA/aPCC to stop the bleeding: use rFVIIa. The aPCC + emicizumab combination caused thrombotic microangiopathy (TMA) in the HAVEN trials.
• Lab pearl: emicizumab interferes with clot-based assays, causing a falsely shortened aPTT and a falsely elevated one-stage FVIII activity. Do NOT use aPTT to monitor coagulation while on emicizumab; use a bovine-reagent chromogenic FVIII assay (human-reagent chromogenic assays respond to emicizumab); quantify inhibitors with a bovine-reagent chromogenic Bethesda assay. (Board vignette: a bleeding hemophilia A patient with an inhibitor, a short aPTT and a very high one-stage FVIII is on emicizumab and should receive rFVIIa, not FVIII concentrate or 4F-PCC.)

Rebalancing hemostasis

• In hemophilia, hemostasis is imbalanced toward anticoagulation. The usual approach increases procoagulants (more FVIII/FIX, FEIBA, rFVIIa). An alternative is to rebalance by reducing natural anticoagulants (antithrombin, TFPI, protein C, protein S).
• Fitusiran (decreases antithrombin): an siRNA targeting antithrombin mRNA for degradation in liver cells. Decreased AT → decreased inhibition of Xa and IIa → increased fibrin clot formation. Phase 2 ABR 1.5. Phase 3: no-inhibitor population mean ABR 3.1 (SD 5.1) vs 29.6 (26.0); with-inhibitor population mean ABR 1.7 vs 18.1. Paused after a fatal cerebral venous sinus thrombosis (2017) and later thrombotic events of various types; AT-guided dosing (target AT 15 to 35%) adopted to reduce risk.
• Concizumab (TFPI inhibition): a monoclonal antibody against the Kunitz-2 domain of tissue factor pathway inhibitor (TFPI); the Kunitz-2 domain inhibits factor Xa, so inhibiting TFPI increases thrombin generation. Phase 2 (dose escalated 0.15 to 0.20 to 0.25 mg/kg daily for 24 weeks): Phase 2 estimated ABR ~4.5 (explorer4, Hem A/B with inhibitors) and ~7.0 (explorer5, Hem A without inhibitors) on concizumab. Phase 3 resumed after a hold for non-fatal thrombotic events; now FDA-approved (Alhemo, see below).

Recently approved non-factor and rebalancing agents

• Marstacimab (Hympavzi): anti-TFPI monoclonal antibody; FDA October 11, 2024 for hemophilia A or B without inhibitors (ages ≥12 y); expanded June 2026 to patients with inhibitors and to children 6 to 11 y; weekly SC (BASIS, Mancuso JTH 2024).
• Concizumab (Alhemo): anti-TFPI monoclonal antibody; FDA December 20, 2024 for hemophilia A or B with inhibitors; expanded July 31, 2025 to hemophilia A or B without inhibitors (ages ≥12 y); daily SC (explorer4/7).
• Fitusiran (Qfitlia): siRNA to hepatic antithrombin; lowers AT to rebalance hemostasis; FDA March 28, 2025 for hemophilia A or B, with or without inhibitors, ages ≥12 y; SC q2 months (AT-based dosing targeting AT 15 to 35%, introduced after the October 2020 dosing pause to reduce thrombosis; boxed warning for thrombotic events and gallbladder disease). ATLAS-INH / ATLAS-A/B (Young, Lancet 2023): median ABR 0 to 1 vs 21 with on-demand bypassing agent/factor; first non-factor therapy approved at launch for hemophilia A or B regardless of inhibitor status.
• For inhibitor prophylaxis: hemophilia A inhibitors, emicizumab is the gold standard; hemophilia B inhibitors, concizumab, marstacimab (since June 2026), or fitusiran.

Desmopressin (DDAVP)

• Increases VWF and FVIII by release from endothelial cells. Potential use in mild and moderate hemophilia A only; works via release of stored vWF/FVIII, so it is ineffective in severe hemophilia A or any hemophilia B.
• Assess response before use during a bleed or surgery: expect at least a 2-fold increase in FVIII and target levels >50%.
• Dosing: IV 0.3 mcg/kg; intranasal 1.5 mg/mL (<50 kg, 1 spray = 150 mcg; >50 kg, 2 sprays = 300 mcg); or SC.
• Side effects: facial flushing, headache, nausea, fluid retention leading to hyponatremia. Restrict free water while using it. Tachyphylaxis after 2 to 3 doses; limit use to 3 days if dosing q24 h.

Antifibrinolytics (aminocaproic acid, tranexamic acid)

• Lysine analogues: inhibit plasminogen binding to fibrin (where it is converted to plasmin), stabilizing the clot.
• Useful for GI and lower GU-tract bleeds and the mouth (high levels of fibrinolytic enzymes).
• Contraindicated in renal (upper urinary tract) bleeding. Do not combine with FEIBA. Used alone for minor mucosal/oral bleeds or as an adjunct; also for periprocedural (dental) prophylaxis.

Acquired hemophilia A

• Pathophysiology: autoantibody to factor VIII reducing FVIII activity and causing bleeding, with no prior personal or family history. Rare (about 1 per 1,000,000).
• Demographics: typically older adults (autoimmune disease, malignancy) and postpartum (pregnancy-associated); females and the elderly at higher risk.
• Presentation: more subcutaneous and muscle bleeding (mucocutaneous bleeding, soft tissue hematomas) than congenital hemophilia; NOT typically hemarthrosis.
• Labs: prolonged aPTT with an incubated mixing study (about 2 h at 37C) that fails to correct; immediate correction does not exclude acquired hemophilia A, low FVIII activity, and a FVIII inhibitor titer (Bethesda). Suspect when the aPTT is prolonged; do not wait for the titer to return before treating.
• Bleeding treatment: bypassing agents (rFVIIa or FEIBA). Recombinant porcine FVIII (susoctocog alfa, Obizur) is an option because anti-human FVIII autoantibodies usually do not cross-react with it (cross-reactivity ~one-third (10/28 in the pivotal study, up to ~44% elsewhere); test anti-porcine FVIII and monitor recovery). Adjunct antifibrinolytics.
• Inhibitor eradication: immunosuppression with combinations of corticosteroids, rituximab and cyclophosphamide. Most respond within about 5 weeks; mortality ~15 to 20%; in modern cohorts deaths are more often from infection (immunosuppression-related) and comorbidities than from bleeding.

High yield

• Hem A → FVIII; Hem B → FIX. Both X-linked recessive.
• Hemarthrosis is the hallmark of inherited hemophilia.
• DDAVP for responsive mild or moderate hemophilia A; works via release of stored vWF/FVIII; ineffective in severe Hem A or any Hem B.
• 1 IU/kg FVIII raises the level by 2%; 1 IU/kg FIX raises it by 1% (for plasma-derived FIX and FIX-Fc).
• Emicizumab transformed Hem A management: SC, q1 to 4 weeks, with or without inhibitors; falsely shortens the aPTT.
• AVOID aPCC + emicizumab (TMA risk in HAVEN); use rFVIIa for breakthrough.
• Inhibitor screening periodically with factor exposure (especially the first 50 exposures); mixing study fails to correct; quantify with the Bethesda assay.
• Acquired Hem A in the elderly or postpartum: autoantibody to FVIII; treat with bypassing agents plus immunosuppression. Postpartum bleeding with a new aPTT prolongation should prompt work-up for acquired hemophilia A.