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hemophilia A; factor VIII deficiency

Etiology: 1) inherited disorder 2) acquired due to autoantibody to coagulation factor VIII [3] Epidemiology: 1) occurs in men 2) 10-fold more common than hemophilia B 3) mean age of acquired form is 78 years of age 4) acquired form is rare Genetics: 1) X-linked recessive 2) transmitted from unaffected mother to male offspring Clinical manifestations: 1) excessive bleeding from minor trauma 2) excessive bleeding following surgery & dental procedures 3) recurrent hemarthrosis leading to contractures & crippling degenerative joint disease 4) deep ecchymoses & hemorrhages into muscle 5) visceral bleeding 6) easy bruising 7) no excessive bleeding after minor cuts 8) clinically indistinguishable from hemophilia B 9) female carriers are asymptomatic Laboratory: 1) complete blood count (CBC) - assess anemia 2) prothrombin time (PT) is normal 3) prolonged partial thromboplastin time (PTT) 4) mixing studies - correction of PTT with normal serum or factor VIII - PTT does not fully correct with acquired form (factor VIII inhibitor) [13] 5) plasma factor VIII activity level a) > 5%: mild disease b) < 1%: severe disease 6) F8 gene mutation 7) see ARUP consult [5] Complications: - factor VIII inhibitors - 30% of patients with hemophilia A develop factor VIII inhibitors (neutralizing antibodies) to factor VIII that render treatment with factor VIII concentrates futile [9] - incidence of inhibitors of factor VII is higher with recombinant factor VIII than with plasma-derived factor VIII (44% vs 27%) [9] - incidence of factor VIII inhibitors up to 25% [2] Management: 1) inherited form: a) mild disease: - DDAVP prior to dental work other minimally-invasive procedures [2] - DDAVP causes release of factor VIII & von Willebrand factor (vWF) from endothelial cells b) severe to moderate disease - recombinant human factor VIII* - treatment of choice - prophylactic factor VIII concentrate may prevent hemophilic arthropathy - recombinant factor VIII Fc fusion protein (Eloctate) with extended 1/2 life (3-5 days) - fresh frozen plasma - cryoprecipitate c) general - begin treatment with onset of symptoms, do not wait - early treatment prevents hemophilic arthropathy - 50-100% activity of factor VIII is required to control life-threatening hemorrhage 2) acquired form (factor VIII antibody) a) factor VIII concentrate if inhibitor titer is low b) if the inhibitor titer is high, prothrombin complex or recombinant factor VIIa bypasses the need for factor VIII in activating factor X & the coagulation cascade [2] - activated prothrombin complex 50-100 ug/kg - recombinant factor VIIa 270 ug/kg [11] c) consider tranexamic acid as adjunctive therapy [11] d) emicizumab is a bispecific antibody that binds to activated factor IX & factor X, substituting for factor VIII [10,12] - may be useful for prophylaxis [12] e) immunosuppression [3] - prednisone - cyclophosphamide or other cytotoxic agent f) relapse in 20% after discontinuation of immunosuppression g) clotting-factor concentrates (bypassing agents) that induce hemostasis through pathways that circumvent the need for factor VIII [4] 3) exercise reasonable for children with hemophilia [6] 4) gene therapy: valoctocogene roxaparvovec-rvox (Rocktavian) *Previously, human factor VIII concentrate carried a high risk of transmitting HIV & hepatitis due to pooling of blood from large numbers of individuals. Since 1985, specific procedures to inactivate HIV & hepatitis C have been implemented for blood products obtained by pooling blood from large numbers of individuals. Recombinant factor VIII carries no risk of transmitting HIV or hepatitis.

Related

coagulation factor VIII autoantibody (acquired hemophilia) coagulation factor VIII; antihemophilic factor; AHF; procoagulant component; contains: factor VIIIa heavy chain, 200 kD & 92 isoforms; factor VIII B chain; factor VIIIa light chain (F8, F8C) hemophilia B; factor IX deficiency ; Christmas disease

General

hemophilia X-linked disease

References

  1. DeGowin & DeGowin's Diagnostic Examination, 6th edition, RL DeGowin (ed), McGraw Hill, NY 1994, pg 893
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2012, 2015, 2018, 2022.
  3. Collins PVV et al, Acquired hemophilia A in the United Kingdom: A 2-year national surveillance study by the United Kingdom. Haemophila Centre Doctors' Organisation Blood 2007, 109:1870 PMID: 170047148
  4. Leissinger C et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med 2011 Nov 3; 365:1684 PMID: 22047559
  5. ARUP Consult: Hemophilia - Factor VIII or IX Deficiency The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/hemophilia
  6. Broderick CR et al Association Between Physical Activity and Risk of Bleeding in Children With Hemophilia JAMA. 2012;308(14):1452-1459 PMID: 23047359 http://jama.jamanetwork.com/article.aspx?articleid=1377921 - Manco-Johnson MJ Collision Sports and Risk of Bleeding in Children With Hemophilia JAMA. 2012;308(14):1480-1481 PMID: 23047364 http://jama.jamanetwork.com/article.aspx?articleid=1377908
  7. Franchini M, Mannucci PM. Acquired haemophilia A: a 2013 update. Thromb Haemost. 2013 Dec;110(6):1114-20 PMID: 24008306
  8. Sborov DW, Rodgers GM How I manage patients with acquired haemophilia A. Br J Haematol. 2013 Apr;161(2):157-65 PMID: 23373521
  9. Peyvandi F et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med 2016 May 26; 374:2054 PMID: 27223147 http://www.nejm.org/doi/10.1056/NEJMoa1516437 - DiMichele DM. Hemophilia therapy - navigating speed bumps on the innovation highway. N Engl J Med 2016 May 26; 374:2087 PMID: 27223151 http://www.nejm.org/doi/10.1056/NEJMe1603419
  10. Uchida N, Sambe T, Yoneyama K et al A first-in-human phase 1 study of ACE910, a novel factor VIII- mimetic bispecific antibody, in healthy subjects. Blood. 2016 Mar 31;127(13):1633-41. PMID: 26626991 Free PMC Article - Shima M et al. Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. N Engl J Med 2016 May 26; 374:2044. PMID: 27223146 http://www.nejm.org/doi/10.1056/NEJMoa1511769
  11. Anello J, Feinberg B, Heinegg J et al Hemophilia Guidelines on management of acute joint bleeds and chronic synovitis in hemophilia by the United Kingdom Haemophilia Centre Doctors' Organisation. Medscape: New Guidelines and Recommendations, August 2017. http://reference.medscape.com/viewarticle/884517
  12. Oldenburg J, Mahlangu JN, Kim B et al Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med 2017; 377:809-818. August 31, 2017 PMID: 28691557 Free Article http://www.nejm.org/doi/full/10.1056/NEJMoa1703068
  13. Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022