Acquired haemophilia A: A 2013 update

Massimo Franchini; Pier Mannuccio Mannucci

doi:10.1160/TH13-05-0363

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 110(06): 1114-1120
DOI: 10.1160/TH13-05-0363

Review Article

Schattauer GmbH

Acquired haemophilia A: A 2013 update

Massimo Franchini

¹Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy

,

Pier Mannuccio Mannucci

²Scientific Direction, IRCCS Cà Granda Foundation Maggiore Hospital, Milan, Italy

› Author Affiliations

Abstract

Summary

Acquired haemophilia A (AHA) is a rare but often severe bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). AHA occurs more frequently in the elderly and in association with several conditions, such as the post-partum period, malignancies, autoimmune diseases or drug exposure; however, approximately 50% of reported cases are apparently idiopathic. Beside the elimination of the underlying disorder, the therapeutic approach to AHA should be directed toward the control of acute bleed and the eradication of FVIII autoantibody production. In this narrative review, we summarise the current knowledge on the epidemiology, diagnosis and clinical features of AHA, focusing in particular on advances in the management of this challenging bleeding disorder.

Keywords

Acquired haemophilia A - FVIII - auto-antibodies - bleeding - inhibitors - therapy

Full Text

References

References
1 Cohen AJ, Kessler CM. Acquired inhibitors. Bailleres Clin Haematol 1996; 9: 331-354.
2 Delgado J. et al. Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003; 121: 21-35.
3 Franchini M, Lippi G. Acquired haemophilia A. Adv Clin Chem 2011; 54: 71-80.
4 Collins PW, Percy CL. Advances in the understanding of acquired haemophilia A: implications for clinical practice. Br J Haematol 2010; 148: 183-194.
5 Baudo F. et al. Diagnosis and treatment of acquired haemophilia. Haemophilia 2010; 16: 102-106.
6 Coppola A. et al. Acquired inhibitors of coagulation factors: part I-acquired haemophilia A. Semin Thromb Haemost 2012; 38: 433-446.
7 Franchini M, Mannucci PM. Inhibitors of propagation of coagulation (factors VIII, IX and XI): a review of current therapeutic practice. Br J Clin Pharmacol 2011; 72: 553-562.
8 Collins P. et al. Acquired haemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors’ Organisation. Blood 2007; 109: 1870-1877.
9 Knoebl P. et al. Demographic and clinical data in acquired haemophilia A: results from the European acquired haemophilia (EACH2) registry. J Thromb Haemost 2012; 10: 622-631.
10 Huth-Kuhne A. et al. International recommendations on the diagnosis and treatment of patients with acquired haemophilia A. Haematologica 2009; 94: 566-575.
11 Collins P. et al. Consensus recommendations for the diagnosis and treatment of acquired haemophilia A. BMC Res Notes 2010; 3: 161.
12 Collins P. et al. A population based, unselected, consecutive cohort of patients with acquired haemophilia A. Br J Haematol 2004; 124: 86-90.
13 Franchini M. et al. Acquired haemophilia A: a concise review. Am J Hematol 2005; 80: 55-63.
14 Moraca RJ, Ragni MV. Acquired anti-FVIII inhibitors in children. Haemophilia 2002; 8: 28-32.
15 Franchini M. et al. Acquired haemophilia in pediatrics: a systematic review. Pediatr Blood Cancer 2010; 55: 606-611.
16 Tufano A. et al. Acquired haemophilia a in the elderly: case reports. Curr Gerontol Geriatr Res 2010; 2010: 927503.
17 Solymoss S. Postpartum acquired factor VIII inhibitors: results of a survey. Am J Haematol 1998; 59: 1-4.
18 Baudo F, de Cataldo F. Acquired factor VIII inhibitors in pregnancy: data from the Italian Haemophilia Registry relevant to clinical practice. Br J Obstetr Gynecol 2003; 110: 311-314.
19 Franchini M. Postpartum acquired factor VIII inhibitors. Am J Hematol 2006; 81: 768-773.
20 Tengborn L. et al. EACH2 registry contributors. Pregnancy-associated acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) registry. Br J Obstet Gynecol 2012; 119: 1529-1537.
21 Franchini M. et al. Laboratory, clinical and therapeutic aspects of acquired haemophilia A. Clin Chim Acta 2008; 395: 14-18.
22 Verbruggen B. et al. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73: 247-251.
23 Reding MT. Immunological aspects of inhibitor development. Haemophilia 2006; 12 (Suppl. 06) 30-35.
24 Reding MT. et al. Distribution of Th1- and Th2-induced anti-factor VIII IgG subclasses in congenital and acquired haemophilia patients. Thromb Haemost 2002; 88: 568-575.
25 Oldenburg J. et al. Genetic markers in acquired haemophilia. Haemophilia 2010; 16 (Suppl. 03) 41-45.
26 Toschi V, Baudo F. Diagnosis, laboratory aspects and management of acquired haemophilia A. Intern Emerg Med 2010; 5: 325-333.
27 Green D, Lechner K. A survey of 215 non-haemophilic patients with inhibitors to Factor VIII. Thromb Haemost 1981; 45: 200-203.
28 Bossi P. et al. Acquired haemophilia due to factor VIII inhibitors in 34 patients. Am J Med 1998; 105: 400-408.
29 Yee TT. et al. A survey of patients with acquired haemophilia in a haemophilia centre over a 28-year period. Clin Lab Haematol 2000; 22: 275-278.
30 Tay L. et al. Twelve years of experience of acquired haemophilia A: trials and tribulations in South Australia. Semin Thromb Haemost 2009; 35: 769-777.
31 Hauser I, Lechner K. Solid tumors and factor VIII antibodies. Thromb Haemost 1999; 82: 1005-1007.
32 Sallah S, Wan JY. Inhibitors against factor VIII in patients with cancer. Analysis of 41 patients. Cancer 2001; 91: 1067-1074.
33 Sallah S. et al. Acquired haemophilia in patients with hematologic malignancies. Arch Pathol Lab Med 2000; 124: 730-734.
34 Franchini M. et al. Acquired factor VIII inhibitors in oncohematology: a systematic review. Crit Rev Oncol Hematol 2008; 66: 194-199.
35 Coppola A. et al. Bleeding and thrombosis in multiple myeloma and related plasma cell disorders. Semin Thromb Haemost 2011; 37: 929-945.
36 Meiklejohn DJ, Watson HG. Acquired haemophilia in association with organ-specific autoimmune disease. Haemophilia 2001; 7: 523-525.
37 Trotta F. et al. Long-lasting remission and successful treatment of acquired factor VIII inhibitors using cyclophosfamide in a patient with systemic lupus erythematosus. Rheumatology 1999; 38: 1007-1009.
38 Soriano RM. et al. Acquired haemophilia and rheumatoid arthritis. Br J Rheumatol 1987; 26: 381-383.
39 Vignes S. et al. Acquired haemophilia: a rare complication of Sjögren’s syndrome. Clin Exp Rheumatol 1996; 14: 559-560.
40 Sievert R. et al. Graves’ disease and autoimmune factor VIII deficiency. Thyroid 1996; 6: 245-247.
41 Sallah S, Wan JY. Inhibitors against factor VIII associated with the use of interferon-alpha and fludarabine. Thromb Haemost 2001; 86: 1119-1121.
42 Regina S. et al. Acquired inhibitor to factor VIII in a patient with Hodgkin’s disease following treatment with interferon-alpha. Haemophilia 2001; 7: 526-527.
43 Mauser-Bunschoten EP. et al. Formation of antibodies to factor VIII in patients with haemophilia A who are treated with interferon for chronic hepatitis C. Ann Intern Med 1996; 125: 297-299.
44 Tiplady CW. et al. Acquired haemophilia complicating the remission of a patient with high grade non-Hodgkin’s lymphoma treated by fludarabine. Clin Lab Haem 2000; 22: 163-165.
45 Franchini M. et al. Drug-induced anti-factor VIII antibodies: a systematic review. Med Sci Monit 2007; 13: RA55-61.
46 Dentale N. et al. Acquisition of factor VIII inhibitor after acute hepatitis C virus infection. Blood 1997; 90: 3233-3234.
47 Hauser I. et al. Post-partum factor VIII inhibitors: a review of the literature with special reference to the value of steroid and immunosuppressive treatment. Thromb Haemost 1995; 73: 1-5.
48 Michiels JJ. Acquired haemophilia A in women post-partum: clinical manifestations, diagnosis and treatment. Clin Appl Thromb Haemost 2000; 6: 82-86.
49 Santoro RC, Prejanò S. Postpartum-acquired haemophilia A: a description of three cases and literature review. Blood Coagul Fibrinolysis 2009; 20: 461-465.
50 Ries M. et al. Severe intracranial haemorrhage in a newborn infant with trans-placental transfer of an acquired factor VIII:C inhibitor. J Pediatr 1995; 127: 649-650.
51 Lottenberg R. et al. Acquired haemophilia: a natural history study of 16 patients with factor VIII inhibitor receiving little or no therapy. Arch Intern Med 1987; 147: 1077-1081.
52 Hay CR. et al. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the UK Haemophilia Centre Doctors Organisation (UKHCDO). Br J Haematol 2006; 133: 591-605.
53 Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood 2008; 112: 250-255.
54 Collins PW. Management of acquired haemophilia A. J Thromb Haemost 2011; 9 (Suppl. 01) 226-235.
55 Collins PW. Therapeutic challenges in acquired factor VIII deficiency. Hematology Am Soc Hematol Educ Program 2012; 2012: 369-374.
56 Baudo F. et al. Treatment of acquired factor VIII inhibitor with recombinant activated factor VII: data from the Italian Registry of acquired haemophilia. Haematologica 2004; 89: 759-761.
57 Franchini M. et al. Clinical efficacy of recombinant activated factor VII (rFVIIa) in a patient with acquired haemophilia A with high inhibitor titre. Haematologica 2001; 86: 12.
58 Sallah S. Treatment of acquired haemophilia with factor eight inhibitor bypassing activity. Haemophilia 2004; 10: 169-173.
59 Hay CRM. et al. The treatment of bleeding in acquired haemophilia with recombinant factor VIIa: a multicenter study. Thromb Haemost 1997; 78: 3-7.
60 Sumner MJ. et al. Treatment of acquired haemophilia with recombinant activated FVII: a critical appraisal. Haemophilia 2007; 13: 451-461.
61 Franchini M, Lippi G. Recombinant activated factor VII: Mechanisms of action and current indications. Semin Thromb Haemost 2010; 36: 485-492.
62 Baudo F. et al. EACH2 registry contributors. Management of bleeding in acquired haemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood 2012; 120: 39-46.
63 Aledort LM. Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity. J Thromb Haemost 2004; 2: 1700-1708.
64 Aledort LM. Factor VIII inhibitor bypassing activity (FEIBA) – addressing safety issues. Haemophilia 2008; 14: 39-43.
65 Ehrlich JH. et al. Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events. Haemophilia 2001; 8: 83-90.
66 Mudad R, Kane WH. DDAVP in acquired haemophilia A: case report and review of the literature. Am J Hematol 1993; 43: 295-299.
67 Franchini M, Lippi G. The use of desmopressin in acquired haemophilia A: a systematic review. Blood Transfus 2011; 9: 377-382.
68 Morrison AE. et al. Use of porcine factor VIII in the treatment of patients with acquired haemophilia. Blood 1993; 81: 1513-1520.
69 Toschi V. OBI-1, porcine recombinant Factor VIII for the potential treatment of patients with congenital haemophilia A and alloantibodies against human Factor VIII. Curr Opin Mol Ther 2010; 12: 617-625.
70 ClinicalTrials.gov Study of Modified Recombinant Factor VIII (OBI-1) in Subjects With Acquired Haemophilia A. Available at: Recdombinant http://clinicaltrials.gov/ct2/show/NCT01178294?term=acquired+haemophilia+obi-1&rank=1 Last accessed: April 24, 2013.
71 Negrier C. et al. Successful treatment of acquired factor VIII antibody by extra-corporeal immunoadsorption. Acta Haematol 1991; 85: 107-110.
72 Jansen M. et al. Treatment of coagulation inhibitors with extracorporeal immunoadsorption (Ig-Therasorb). Br J Haematol 2001; 112: 91-97.
73 Franchini M. et al. Extracorporeal immunoadsorption for the treatment of coagulation inhibitors. Semin Thromb Haemost 2009; 35: 76-80.
74 Spero JA. et al. Corticosteroid therapy for acquired FVIII:C inhibitors. Br J Haematol 1981; 48: 635-642.
75 Lian EC. et al. Combination immunosuppressive therapy after factor VIII infusion for acquired factor VIII inhibitor. Ann Intern Med 1989; 110: 774-778.
76 Shaffer LG, Phillips MD. Successful treatment of acquired haemophilia with oral immunosuppressive therapy. Ann Intern Med 1997; 127: 206-209.
77 Green D. et al. A prospective, randomized trial of prednisone and cyclophosphamide in the treatment of patients with factor VIII autoantibodies. Thromb Haemost 1993; 70: 753-757.
78 Bitting RL. et al. The prognosis and treatment of acquired haemophilia: a systematic review and meta-analysis. Blood Coagul Fibrinolysis 2009; 20: 517-523.
79 Collins PW. et al. Immunosuppression for acquired haemophilia A: results of the European Acquired Haemophilia (EACH) registry. Blood 2012; 120: 47-55.
80 Schulman S. et al. Cyclosporine therapy for acquired factor VIII inhibitor in a patient with systemic lupus erythematosus. Thromb Haemost 1996; 76: 344-346.
81 Petrovic M. et al. Cyclosporine treatment of acquired haemophilia due to factor VIII antibodies. Haematologica 2000; 85: 895-896.
82 Pardos-Gea J. et al. Acquired haemophilia A: successful treatment with immunosuppression, methylprednisolone pulses and oral cyclosporin. Thromb Haemost 2006; 95: 735-737.
83 Stasi R. et al. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura. Blood 2001; 98: 952-957.
84 Wiestner A. et al. Rituximab in the treatment of acquired factor VIII inhibitor. Blood 2002; 100: 3426-3428.
85 Onitilo A. et al. Rituximab in the treatment of acquired factor VIII inhibitors. Thromb Haemost 2006; 96: 84-87.
86 Field JJ. et al. Rituximab for the treatment of patients with very high-titre acquired factor VIII inhibitors refractory to conventional chemotherapy. Haemophilia 2007; 13: 46-50.
87 Franchini M. Rituximab in the treatment of adult acquired haemophilia A: a systematic review. Crit Rev Oncol Hematol 2007; 63: 47-52.
88 Sperr WR. et al. Rituximab for the treatment of acquired antibodies to factor VIII. Haematologica. 2007; 92: 66-72.
89 Aggarwal A. et al. Rituximab for autoimmune haemophilia: a proposed treatment algorithm. Haemophilia 2005; 11: 13-19.
90 Coppola A. et al. Optimising management of immune tolerance induction in patients with severe haemophilia A and inhibitors: towards evidence-based approaches. Br J Haematol 2010; 150: 515-528.
91 Green D. Suppression of an antibody to factor VIII by a combination of factor VIII and cyclophosphamide. Blood 1971; 37: 381-387.
92 Nemes L, Pitlik E. New protocol for immune tolerance induction in acquired haemophilia. Haematologica 2000; 85: 64-68.
93 Zeitler H. et al. Treatment of acquired haemophilia by the Bonn-Malmo Protocol: documentation of an in vivo immunomodulating concept. Blood 2005; 105: 2287-2293.
94 Zeitler H. et al. The relevance of the bleeding severity in the treatment of acquired haemophilia–an update of a single-centre experience with 67 patients. Haemophilia 2010; 16: 95-101.