Hematology & Laboratory Medicine & Internal Medicine
Factor VIII (coagulation)
Factor VIII (FVIII) - also known as antihemophilic factor A - is a high-molecular-weight (330 kDa) plasma glycoprotein encoded by the F8 gene located on chromosome X (Xq28), synthesized mainly by hepatic sinusoidal cells and, to a lesser extent, by endothelial cells. In the circulation, FVIII circulates in inactive form, non-covalently bound to Willebrand factor (VWF), which protects it from premature proteolytic degradation and prolongs its half-life (from 1-2 hours free to 12 hours bound to VWF). During coagulation activation, FVIII is cleaved by thrombin and factor Xa, releasing FVIIIa - the active cofactor - which combines with factor IXa (FIXa), anionic membrane phospholipids and calcium ions to form the «intrinsic tenase» complex (FVIIIa-FIXa). This complex activates factor X into factor Xa with a catalytic efficiency some 200,000 times greater than that of FIXa alone, playing a central role in the amplification phase of coagulation. FVIII is therefore a cofactor of the intrinsic pathway (contact pathway), whose activity is measured in the APTT (activated partial thromboplastin time) - an isolated prolongation of the APTT (normal PT) points to a deficiency of intrinsic pathway factors: XII, XI, IX, VIII, or to the presence of an inhibitor. Normal FVIII values are 50 to 150 % of normal activity (0.5 to 1.5 IU/mL). FVIII deficiency is the cause of hemophilia A, the most common hereditary coagulopathy (1/5,000 male births), but FVIII can also be secondarily depleted in type 3 von Willebrand disease, acquired Willebrand syndrome, and certain liver diseases. Conversely, elevated FVIII is an independent venous thromboembolic risk factor.
Normal values, biology, and coagulation profile
- Normal values and physiological variations : normal adult value: 50-150 % (0.5-1.5 IU/mL) - measured by chromogenic assay (gold standard - measures FVIIIa functional activity) or by one-step coagulation test (aPTT-based assay) - both methods may give inconsistent results in certain forms of mild hemophilia A (specific mutations) - chromogenic assay is recommended as the reference method in 2024; physiological variations in FVIII : moderate acute-phase protein: FVIII increases during inflammatory responses, stress, pregnancy, intense physical exercise and estrogen administration (COC + HRT) - these increases may mask a moderate deficiency (mild hemophilia A + Von Willebrand disease type 2N) if the assay is performed in an inflammatory context; full-term newborn: FVIII normal at birth (unlike FIX, FII, FVII, FX which are physiologically low at birth) - the diagnosis of hemophilia A can therefore be made at birth by cordocentesis or from cord blood; blood group: group O individuals have a plasma FVIII naturally 20-30 % lower than groups A, B or AB (VWF also lower - faster degradation by ADAMTS13 in the absence of the ABH antigen on VWF) - the diagnostic threshold for certain type 1 Von Willebrand's diseases takes blood group into account; high FVIII (>150 % - hyperactivity) : independent venous thromboembolic risk factor - risk of DVT/PE multiplied by 5-11 according to studies - confirmed persistence at a distance of any inflammatory episode necessary before concluding to a constitutional elevation
- Interpretation of coagulation profile — role of FVIII: algorithm for interpreting an isolated prolonged aPTT (normal PT + normal fibrinogen + normal platelets) - systematic approach: step 1 - mixing test: mix equal parts of patient's plasma with normal plasma - aPTT correction (aPTT of mixture = normal aPTT) → factor deficiency → measure FVIII + FIX + FXI + FXII; no correction or partial correction → inhibitor present - lupus anticoagulant (LA) or specific acquired inhibitor; step 2 - if deficiency confirmed by mixing test: assay FVIII + FIX + FXI + FXII - FVIII is assayed in the first instance, as hemophilia A (FVIII deficiency) is the most common severe hereditary coagulopathy; step 3 - if FVIII low: assay VWF antigen (VWF:Ag) + VWF activity (VWF:RCo or VWF:GPIbM) → if VWF also low → Von Willebrand disease (VWD) type 1 or 3 → if VWF normal or only slightly lowered with very low FVIII → hemophilia A or VWD type 2N (mutation of VWF FVIII binding site); prolonged APTT with low FVIII + prolonged PT : combined deficiency (severe liver disease + DIC + rare combined FVII+FVIII deficiency); isolated low FVIII with prolonged APTT + inhibitor (anti-FVIII antibodies): acquired hemophilia A - diagnostic and therapeutic emergency
- Hemophilia A — Classification and Genetics definition: constitutional deficiency in FVIII due to mutation of the F8 gene - X-linked recessive transmission - almost exclusively in men (carrier women generally asymptomatic unless unfavorable lyonization or Turner 45X0) - incidence: 1/5,000 male births - prevalence in Canada: approximately 3,000–4,000 known patients; classification according to residual FVIII activity: severe: FVIII <1 % (<0.01 IU/mL) - 50 % of hemophiliacs A - recurrent spontaneous hemarthroses + deep muscle bleeds + visceral hematomas - without prophylactic treatment: 2-4 bleeding episodes/month - long-term disabling hemophilic arthropathy; moderate: FVIII 1-5 % (0.01-0.05 IU/mL) - 10 % of cases - bleeding mainly post-traumatic + surgical - rare spontaneous bleeding; mild: FVIII 5-40 % (0.05-0.40 IU/mL) - 40 % of cases - bleeding only post-traumatic or surgical - diagnosis often late (incidental discovery on preoperative work-up or after unusual bleeding); F8 gene mutations: inversion of intron 22: most frequent in severe forms (40-45 % of severe hemophilia A) + inversion of intron 1 (5 %) + point mutations + deletions + insertions - large F8 gene deletions are associated with a higher risk of inhibitor development (neutralizing anti-FVIII antibodies) under replacement therapy
Treatment
| Treatment | Mechanism, molecules, and modalities | Efficacy, results and precautions |
|---|---|---|
| FVIII Concentrates — Replacement Therapy Hemophilia A - Prophylaxis and Treatment of Bleeding |
The reference treatment for hemophilia A remains FVIII substitution - administered either on demand (treatment of bleeding episodes) or prophylactically (prevention of bleeding); FVIII plasma concentrates (pdFVIII) : derived from fractionation of human plasma + double viral inactivation (solvent-detergent + heat) - excellent viral safety for HIV + HCV + HBV since the 1990s - less immunogenic than recombinant products according to some data - still used in some countries, but less and less as first-line treatment in high-income countries; recombinant FVIII concentrates (rFVIII): produced by genetic engineering (CHO or BHK cells) - successive generations: 1st generation (human plasma in culture media) + 2nd generation (human albumin as stabilizer) + 3rd generation (without added human protein - full-recombinant) - greater availability + no risk of viral transmission of plasma pathogens + repeatability of production; extended half-life FVIII (EHL-FVIII) : FVIII-Fc fusion (efmoroctocog alfa - Elocta): fusion of IgG1 Fc region - recycling by FcRn receptor - half-life 19 h (vs. 12 h for standard FVIII) → injections every 3-5 days instead of every 2 days; FVIII-PEGylated (rurioctocog alfa pegol - Adynovate + turoctocog alfa pegol - Esperoct): PEGylation reduces renal clearance - half-life 14-19 h → injections 2× per week; substitution dosing: formula: dose (IU) = weight (kg) × desired increase in FVIII (%) × 0.5 (volume of distribution = 50 mL/kg) - mild hemarthrosis: target FVIII 30-50 % - major surgery: target 80-100 % pre-operatively + maintain >50 % for 7-14 days post-operatively | Primary prophylaxis: standard of care treatment for severe hemophilia A since the 1990s - started before 2-3 years (before 2nd hemarthrosis) or as soon as diagnosis - reduction in hemarthroses of 90-95 % vs on-demand treatment - preservation of joint capital + normal quality of life + normal schooling and sports activity; results of extended half-life rFVIII (EHL) : ASPIRE + A-LONG studies: reduction in bleeding by 95 % vs. placebo + median annual bleeding rate (ABR) = 0 under prophylaxis with efmoroctocog every 3-5 days - improved comfort of life (fewer injections); prophylaxis in adults: personalized regimens according to individual pharmacokinetics (PK-guided dosing) - targeted FVIII nadir: >1-3 % (minimal nadir) + ideally >10-15 % for physically active patients; route of administration: IV (intravenous) - patients learn self-injection (or parents for children) - central catheter with implantable chamber (PAC or PICC) in pediatrics if difficult venous access; in Canada (Quebec) : FVIII concentrates are distributed to hemophilia patients by Canadian Blood Services (CBS) + Héma-Québec - available free of charge to patients registered at hemophilia treatment centers (HTCs) - mandatory follow-up at an accredited HTC (CHUM + Hôpital Sainte-Justine + CHU Sainte-Anne + CHU de Québec) |
| Emicizumab (Hemlibra) — non-replacement therapy Therapeutic Revolution — With or Without Inhibitors |
Emicizumab (Hemlibra) is a humanized bispecific monoclonal antibody that mimics the function of FVIIIa by simultaneously bridging FIXa and FX, thus reconstituting the activity of the intrinsic tenase complex - without itself being FVIII or being recognized by anti-FVIII inhibitors; major advantages over FVIII concentrates: subcutaneous route (vs. IV mandatory for FVIII) + long half-life (>4 weeks) → weekly (1.5 mg/kg SC/week) or fortnightly (3 mg/kg SC every 2 weeks) or monthly (6 mg/kg SC every 4 weeks) injection schedules - not recognized by anti-FVIII inhibitor antibodies → effective in patients with inhibitors; Health Canada-approved indications: hemophilia A with inhibitors (all severities) - hemophilia A without inhibitors (all severities - extended approval) - prophylaxis in adults and children (including infants); dosage: loading phase: 3 mg/kg SC × 1/week × 4 weeks → maintenance according to regimen chosen with patient and hematologist; adverse effects: injection site reactions (mild - erythema + pain) - no significant immunogenicity documented long-term - critical interaction with bypassing agents (see precautions); major precaution - interaction with bypassing agents (BPA): in case of intercurrent bleeding under emicizumab + need for rescue haemostatic treatment → use recombinant FVIII as 1st line (if without inhibitors) or recombinant FVIIa (NovoSeven) at low doses - never use FEIBA (activated prothrombin complex concentrate - see precautions) complex concentrate - aPCC) in combination with emicizumab → risk of thrombotic microangiopathy (TMA) + severe thromboembolic events documented in HAVEN trials (3 cases of TMA + 3 thromboses in HAVEN 1 trial when using FEIBA >100 IU/kg/24h) | Results of HAVEN trials (1 to 4): HAVEN 1 (severe hemophilia A with inhibitors): reduction in treated bleeds of 87 % vs no prophylaxis + median ABR = 0 under weekly emicizumab vs 23.3 under prophylaxis with BPA (FEIBA); HAVEN 3 (severe hemophilia A without inhibitors): reduction in treated bleeds by 96 % vs. no prophylaxis - median ABR = 0 in 55 % of patients on emicizumab; HAVEN 4 (monthly regimen): non-inferiority vs. weekly regimen + median ABR = 0; real-life data: INHIBIT-Q registry (Canada) + PedNet Europe: efficacy maintained at 3-5 years + reduction in hospitalizations for hemarthrosis + improvement in joint capital measured by MRI + significantly improved quality of life (HAL score + Haem-A-QoL); reimbursement in Canada: emicizumab reimbursed by Canadian provinces (including Quebec - RAMQ formulary exception) for hemophilia A with inhibitors + without severe inhibitors - prescribed by accredited HTCs - mandatory quarterly follow-up; biological monitoring under emicizumab: standard coagulation tests (APTT + chromogenic FVIII tests) are interfered with by emicizumab → mandatory use of bovine chromogenic test (bovine substrate not recognized by emicizumab) to monitor residual FVIII + specialized HTC tests |
| Management of anti-FVIII inhibitors Major complication of replacement therapy |
Anti-FVIII inhibitors are neutralizing autoantibodies (mainly IgG4) directed against functional epitopes of FVIII (domains A2, A3, C2) that neutralize the hemostatic activity of infused exogenous FVIII - most serious complication of hemophilia A treatment; incidence: 25-35 % of severe hemophilia A patients after cumulative exposure to FVIII - 5-10 % of moderate and mild forms - higher risk : large F8 gene deletions + nonsense mutations + first intensive exposure to FVIII (surgery + major bleeding + high initial dose) + age <6 years at 1st exposure + black race; inhibitor classification: low titer (<5 BU - Bethesda Units): low-titer inhibitor - may be transient - high-dose FVIII may still be effective with increasing doses; high titer (≥5 BU): high titer inhibitor - standard FVIII is ineffective → mandatory use of bypassing agents (BPA) or emicizumab; bypassing agents (BPA) for treatment of bleeding in inhibitors: Recombinant FVIIa (rFVIIa - NovoSeven): 90-270 µg/kg IV bolus every 2-3h until hemostasis (mechanism: direct activation of FX on platelet surfaces); FEIBA (activated prothrombin complex concentrate - aPCC): 50-100 IU/kg IV every 8-12h maximum 200 IU/kg/24h - DO NOT combine with fitusiran or emicizumab (thromboembolic risk + MAT); immune tolerance induction (ITI): repeated administration of high-dose FVIII (Malmo: 200 IU/kg/d) or low doses (Utrecht: 25 IU/kg × 3/wk) aimed at eradicating the inhibitor - success: 60-80 % if low historical titer + short time since onset of inhibitor - duration: 12-33 months | ITI results: RESIST randomized trial (Low vs High dose ITI): no significant difference in success between the two dose regimens (60 % success rate at 3 years) - low dose regimen preferred for lower cost + reduced infectious risk (fewer injections); impact of emicizumab on inhibitor management: emicizumab SC has revolutionized prophylaxis in patients with inhibitors - it is now started as soon as the inhibitor is confirmed, enabling effective prophylaxis for the duration of the ITI (which can last for years) - this emicizumab + ITI combination is the current standard of care in the majority of Canadian HTCs; systematic screening for inhibitors: screening by Bethesda test (or Nijmegen-Bethesda test - more specific) recommended: at each consultation (every 3-6 months) during the first 50-75 days of exposure + after any intensive exposure (surgery + major bleeding treated) + if insufficient clinical response to usual replacement therapy; acquired hemophilia A (non-congenital - anti-FVIII inhibitor without underlying hemophilia): see dedicated section - diagnostic and therapeutic urgency |
| FVIII and von Willebrand disease VWF-FVIII Linkage — Types 3 and 2N |
Von Willebrand disease (VWD) indirectly affects FVIII, as VWF is the physiological protector of FVIII in the circulation - a reduction or dysfunction of VWF leads to accelerated degradation of free FVIII and hence a lowering of plasma FVIII; VWD type 3 (total VWF deficiency) : most severe form - VWF antigen and activity undetectable - very low FVIII (1-10 %) - clinical phenotype similar to severe hemophilia A (hemarthrosis + deep hematomas) + severe mucosal bleeding (characteristics of VWD: epistaxis + menorrhagia + gastrointestinal bleeding) - autosomal recessive transmission - treatment: VWF/FVIII concentrates (Wilate + Humate-P) ± desmopressin (ineffective in type 3 as no VWF reserves); VWD type 2N (Normandy) : rare qualitative variant - mutations in the VWF-FVIII binding domain (D' and D3) → VWF can no longer protect FVIII → low FVIII (5-40 %) + normal or slightly reduced VWF antigen and activity → clinical mimicry of mild to moderate hemophilia A → important to distinguish as treatment differs (VWF/FVIII concentrates + no desmopressin effective on FVIII in 2N) - diagnosed by VWF genotyping (D'D3 mutations) + VWF- binding testFVIII binding assay ; desmopressin (DDAVP) in VWD type 1 : releases VWF and FVIII stocks from endothelial cells (Weibel-Palade bodies) → 2-5× increase in FVIII and VWF in 30-60 min - IV 0.3 µg/kg or intranasal (Octostim) - useful for minor surgery + dental care + DDAVP-mandatory test before any use to check individual response | Differential diagnosis between mild hemophilia A and MVW type 2N: clinically superimposable (FVIII 5-40 % + isolated prolonged APTT) - essential distinction because genetic transmission differs (X-linked for hemophilia A + autosomal recessive for 2N - women also affected in 2N) and treatment differs; differential diagnostic work-up: FVIII + VWF:Ag + VWF:RCo + VWF-FVIII binding test + F8 genotyping (hemophilia) + VWF (MVW 2N) - ask the specialized medical laboratory (CHU); acquired Willebrand syndrome (SVWA): acquired VWF loss or dysfunction + secondarily lowered FVIII - causes: lymphoid hemopathies (IgM monoclonal gammopathy + lymphoma + CLL) + cardiopathies with high shear stress (severe aortic stenosis + LVAD + CIA) + hypothyroidism + drugs (valproate) + autoimmune diseases - low FVIII + low VWF + FVIII:VWF ratio sometimes normal + high molecular weight VWF multimers absent - treatment of cause + IVIG if anti-VWF antibodies + DDAVP + VWF/FVIII concentrates for acute bleeding |
| Acquired hemophilia A (AHA) Emergency — Spontaneous anti-FVIII autoantibodies |
Acquired hemophilia A (HAA) is a rare but potentially fatal autoimmune disease - characterized by the spontaneous development of anti-FVIII autoantibodies in a patient with no personal or family history of coagulopathy - incidence: 1.5/1,000,000/year - average age at diagnosis: 60-80 years + secondary peak in post-partum (young women); clinical presentation: extensive cutaneous bleeding (giant spontaneous ecchymoses - without trauma) + deep muscle hematomas + mucous membrane bleeding (gastrointestinal + genitourinary) + postoperative hemorrhages - spontaneous hemarthroses, characteristic of congenital hemophilia A, are RARE in HAA (important clinical distinction); biology: very prolonged APTT + very low FVIII (<5 % in 60 % of cases) + anti-FVIII inhibitor detectable in Bethesda test - mixing test: absence of correction (inhibitor); associated causes: idiopathic in 50 % of cases - autoimmune diseases (RA + SLE + Sjögren's syndrome + IBD) + neoplasia (solid + hemopathies) + drugs (interferon + penicillins + phenytoin) + postpartum (3-12 months postpartum) + bullous dermatoses (pemphigus + pemphigoid); hemostatic treatment of acute bleeding: rFVIIa (NovoSeven) 90 µg/kg IV every 2-3h until hemostasis (bypassing agent of choice - no interaction with inhibitor) + FEIBA 50-100 IU/kg IV every 8-12h alternative - very high-dose FVIII if low titer inhibitor (<5 BU): 100-200 IU/kg to saturate inhibitor; immunosuppressive treatment to eradicate inhibitor: prednisolone 1 mg/kg/d PO × 3-6 wks (1st line - success 60-70 %) - rituximab 375 mg/m² IV × 4 (in combination if corticosteroids fail or relapse) + cyclophosphamide 1-2 mg/kg/d PO alternative; emicizumab : increasing data on its use in HAA (EACH2 registry studies + retrospective series) - used off-label in Canada as haemostatic prophylaxis for the duration of immunosuppression | HAA prognosis: overall mortality 8-22 % at 1 year (bleeding + complications of immunosuppression) - inhibitor eradication (complete remission) achieved in 70-90 % of cases with immunosuppressive therapy - median time to remission: 4-6 weeks - relapses: 10-20 % at 2 years - quarterly follow-up of FVIII + Bethesda after remission for 12-24 months; EACH2 registry (European Acquired Haemophilia Registry): the largest HAA cohort - 501 patients - prednisone alone : remission 70 % - prednisone + cyclophosphamide: 89 % - shorter remission time with combination; HAA emergency: any patient presenting with extensive spontaneous ecchymoses + isolated very prolonged aPTT + collapsed FVIII must be admitted to hospital as an emergency - without rapid hemostatic treatment, mortality from bleeding is high (intracranial + retroperitoneal + gastrointestinal); reference: Canadian Haemophilia Society (www.hemophilia.ca) + Association des hémophiles du Québec (AHQ - www.hemophilieqc.ca) |
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Gene Therapy for Hemophilia A — Canadian Perspectives: Gene therapy for hemophilia A has reached a historic milestone with the FDA (2023) and Health Canada (2024) approval of valoctocogene roxaparvovec (Roctavian — BioMarin), an AAV5 vector delivering a functional copy of the F8 gene into hepatocytes. 5-year results (GENEr8-1 trial) show an average increase in FVIII of 40–50 % at 1 year, with an 80–90 % reduction in bleeding and elimination of prophylaxis in 55 % of patients. FVIII activity gradually decreases over time (approximately 50 % annual decline) but generally remains protective. Fitusiran (antithrombin inhibitor — monthly SC siRNA) is another non-replacement option under evaluation, approved in Europe but not yet in Canada in 2024. These innovations are transforming the management of severe hemophilia A.
Hemorrhagic Emergencies — Hemophilia A and Acquired Inhibitors
Hemophiliac A known with joint pain + sudden swelling → hemarthrosis → immediate replacement therapy (FVIII or emicizumab + rescue FVIII depending on inhibitor status) — do not wait for biological confirmation.
Hemophilia A with severe headaches and vomiting → intracranial hemorrhage → 911 + IV FVIII emergently (target FVIII 100 %) + urgent head CT — intracranial hemorrhage is the leading cause of death in hemophilia.
Patient with no hematological history presenting with extensive spontaneous ecchymoses + very prolonged aPTT → acquired hemophilia A → urgent hospitalization + FVIII assay + Bethesda inhibitor + hemostatic treatment with bypassing agents.
Consult at Clinique Omicron
Clinique Omicron physicians participate in the front-line management of hemophilia patients, including prescription renewals for FVIII concentrates, management of minor bleeds, coordination with Hemophilia Treatment Centers (HTCs) for specialized decisions, and inhibitor screening. The initial prescription of emicizumab and the management of acquired hemophilia A are the responsibility of the specialized hematologist. Consultations are available at various service points across Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The content on this page is for informational purposes only and does not substitute the advice of a hematologist specializing in bleeding disorders. The management of hemophilia A should be coordinated by an accredited hemophilia treatment center (HTC).
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