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Semin Thromb Hemost 2014; 40(07): 803-811
DOI: 10.1055/s-0034-1390004
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Laboratory Diagnosis of Acquired Hemophilia A: Limitations, Consequences, and Challenges

Andreas Tiede
1   Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
,
Sonja Werwitzke
1   Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
,
Rüdiger E. Scharf
2   Department of Clinical and Experimental Hemostasis, Hemotherapy and Transfusion Medicine, Heinrich Heine University Medical Center, Düsseldorf, Germany
› Author Affiliations
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Publication History

Publication Date:
09 October 2014 (online)

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Abstract

Acquired hemophilia A (AHA) should be suspected in patients with a new onset of bleeding and an isolated prolongation of activated partial thromboplastin time. About 10% of patients do not bleed at the time of diagnosis, but are at risk of future bleeding, particularly during interventions or surgery. Diagnosis of AHA is confirmed by demonstrating markedly reduced factor VIII activity (FVIII:C) and neutralizing anti-FVIII antibodies, so-called inhibitors. Several limitations and pitfalls exist with the assays used to diagnose AHA. Interference can result from anticoagulants or lupus anticoagulant. The Bethesda assay used to measure inhibitor potency assumes a log–linear relationship between inhibitor concentration and effect on residual FVIII:C activity to allow exact quantification. However, this relationship is not present for the type 2 inhibitors typically seen in AHA. Therefore, this assay only provides a rough estimate of inhibitor potency. These limitations can explain, in part, why laboratory data, such as inhibitor potency, failed to predict bleeding or response to treatment in AHA. This article reviews the diagnostic approach to AHA, discusses assay-specific limitations and addresses some of the challenges for future research.

Keywords

acquired hemophilia - factor VIII - inhibitor - autoantibody
 

  • References

  • 1 Collins PW. Therapeutic challenges in acquired factor VIII deficiency. Hematology (Am Soc Hematol Educ Program) 2012; 2012: 369-374
    PubMedGoogle Scholar
  • 2 Franchini M, Mannucci PM. Acquired haemophilia A: a 2013 update. Thromb Haemost 2013; 110 (6) 1114-1120
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Coppola A, Favaloro EJ, Tufano A, Di Minno MN, Cerbone AM, Franchini M. Acquired inhibitors of coagulation factors: part I-acquired hemophilia A. Semin Thromb Hemost 2012; 38 (5) 433-446
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Collins P, Baudo F, Huth-Kühne A , et al. Consensus recommendations for the diagnosis and treatment of acquired hemophilia A. BMC Res Notes 2010; 3: 161
    CrossrefPubMedGoogle Scholar
  • 5 Mulliez SM, Vantilborgh A, Devreese KM. Acquired hemophilia: a case report and review of the literature. Int J Lab Hematol 2014; 36 (3) 398-407
    CrossrefPubMedGoogle Scholar
  • 6 Sborov DW, Rodgers GM. How I manage patients with acquired haemophilia A. Br J Haematol 2013; 161 (2) 157-165
    CrossrefPubMedGoogle Scholar
  • 7 Knoebl P, Marco P, Baudo F , et al; EACH2 Registry Contributors. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost 2012; 10 (4) 622-631
    CrossrefPubMedGoogle Scholar
  • 8 Kershaw G, Jayakodi D, Dunkley S. Laboratory identification of factor inhibitors: the perspective of a large tertiary hemophilia center. Semin Thromb Hemost 2009; 35 (8) 760-768
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Kershaw G, Orellana D. Mixing tests: diagnostic aides in the investigation of prolonged prothrombin times and activated partial thromboplastin times. Semin Thromb Hemost 2013; 39 (3) 283-290
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Tiede A, Priesack J, Werwitzke S , et al. Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single-centre cohort study. J Thromb Haemost 2008; 6 (4) 569-576
    CrossrefPubMedGoogle Scholar
  • 11 Tiede A, Rand JH, Budde U, Ganser A, Federici AB. How I treat the acquired von Willebrand syndrome. Blood 2011; 117 (25) 6777-6785
    CrossrefPubMedGoogle Scholar
  • 12 Holstein K, Marx G, Lentz B, Bokemeyer C, Langer F. Successful eradication of a FVIII inhibitor in a 60-year-old patient with mild haemophilia A using single-agent prednisolone. Hamostaseologie 2012; 32 (Suppl. 01) S48-S51
    PubMedGoogle Scholar
  • 13 Peerlinck K, Jacquemin M. Mild haemophilia: a disease with many faces and many unexpected pitfalls. Haemophilia 2010; 16 (Suppl. 05) 100-106
    CrossrefPubMedGoogle Scholar
  • 14 Blanco AN, Cardozo MA, Candela M, Santarelli MT, Pérez Bianco R, Lazzari MA. Anti-factor VIII inhibitors and lupus anticoagulants in haemophilia A patients. Thromb Haemost 1997; 77 (4) 656-659
    PubMedGoogle Scholar
  • 15 Seethala S, Collins Jr NP, Comerci Jr G. An unusual etiology for elevation of activated partial thromboplastin time (aPTT) in SLE: acquired hemophilia and lupus anticoagulant. Case Rep Hematol 2013; 2013: 521785
    PubMedGoogle Scholar
  • 16 Taher A, Abiad R, Uthman I. Coexistence of lupus anticoagulant and acquired haemophilia in a patient with monoclonal gammopathy of unknown significance. Lupus 2003; 12 (11) 854-856
    CrossrefPubMedGoogle Scholar
  • 17 Lossing TS, Kasper CK, Feinstein DI. Detection of factor VIII inhibitors with the partial thromboplastin time. Blood 1977; 49 (5) 793-797
    CrossrefPubMedGoogle Scholar
  • 18 Ewing NP, Kasper CK. In vitro detection of mild inhibitors to factor VIII in hemophilia. Am J Clin Pathol 1982; 77 (6) 749-752
    PubMedGoogle Scholar
  • 19 Kasper CK. Measurement of factor VIII inhibitors. Prog Clin Biol Res 1984; 150: 87-98
    PubMedGoogle Scholar
  • 20 Cohen AJ, Kessler CM. Acquired inhibitors. Baillieres Clin Haematol 1996; 9 (2) 331-354
    CrossrefPubMedGoogle Scholar
  • 21 Huth-Kühne A, Baudo F, Collins P , et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica 2009; 94 (4) 566-575
    CrossrefPubMedGoogle Scholar
  • 22 Pengo V, Tripodi A, Reber G , et al; Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 2009; 7 (10) 1737-1740
    CrossrefPubMedGoogle Scholar
  • 23 Tripodi A, Mancuso ME, Chantarangkul V , et al. Lupus anticoagulants and their relationship with the inhibitors against coagulation factor VIII: considerations on the differentiation between the 2 circulating anticoagulants. Clin Chem 2005; 51 (10) 1883-1885
    CrossrefPubMedGoogle Scholar
  • 24 Blanco AN, Alcira Peirano A, Grosso SH, Gennari LC, Pérez Bianco R, Lazzari MA. A chromogenic substrate method for detecting and titrating anti-factor VIII antibodies in the presence of lupus anticoagulant. Haematologica 2002; 87 (3) 271-278
    PubMedGoogle Scholar
  • 25 Uggla B, Linder O, Schulman S. Acquired hemophilia masked by warfarin therapy: report on two cases. Blood Coagul Fibrinolysis 2003; 14 (8) 769-772
    CrossrefPubMedGoogle Scholar
  • 26 Gawryl MS, Hoyer LW. Inactivation of factor VIII coagulant activity by two different types of human antibodies. Blood 1982; 60 (5) 1103-1109
    PubMedGoogle Scholar
  • 27 Ling M, Duncan EM, Rodgers SE , et al. Classification of the kinetics of factor VIII inhibitors in haemophilia A: plasma dilution studies are more discriminatory than time-course studies. Br J Haematol 2001; 114 (4) 861-867
    CrossrefPubMedGoogle Scholar
  • 28 Gharagozlou S, Sharifian RA, Khoshnoodi J , et al. Epitope specificity of anti-factor VIII antibodies from inhibitor positive acquired and congenital haemophilia A patients using synthetic peptides spanning A and C domains. Thromb Haemost 2009; 101 (5) 834-839
    PubMedGoogle Scholar
  • 29 Lewis KB, Hughes RJ, Epstein MS , et al; PATH (Personalized Alternative Therapies for Haemophilia) Study Investigators. Phenotypes of allo- and autoimmune antibody responses to FVIII characterized by surface plasmon resonance. PLoS ONE 2013; 8 (5) e61120
    CrossrefPubMedGoogle Scholar
  • 30 Whelan SF, Hofbauer CJ, Horling FM , et al. Distinct characteristics of antibody responses against factor VIII in healthy individuals and in different cohorts of hemophilia A patients. Blood 2013; 121 (6) 1039-1048
    CrossrefPubMedGoogle Scholar
  • 31 Favaloro EJ, Verbruggen B, Miller CH. Laboratory testing for factor inhibitors. Haemophilia 2014; 20 (Suppl. 04) 94-98
    CrossrefPubMedGoogle Scholar
  • 32 Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, Mauser-Bunschoten E. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73 (2) 247-251
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Verbruggen B. Diagnosis and quantification of factor VIII inhibitors. Haemophilia 2010; 16 (102) 20-24
    PubMedGoogle Scholar
  • 34 Meijer P, Verbruggen B. The between-laboratory variation of factor VIII inhibitor testing: the experience of the external quality assessment program of the ECAT foundation. Semin Thromb Hemost 2009; 35 (8) 786-793
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Favaloro EJ, Bonar R, Kershaw G, Mohammed S, Duncan E, Marsden K ; RCPA Haematology QAP Haemostasis Committee. Laboratory identification of factor VIII inhibitors in the real world: the experience from Australasia. Haemophilia 2010; 16 (4) 662-670
    PubMedGoogle Scholar
  • 36 Verbruggen B, Giles A, Samis J, Verbeek K, Mensink E, Novákovà I. The type of factor VIII deficient plasma used influences the performance of the Nijmegen modification of the Bethesda assay for factor VIII inhibitors. Thromb Haemost 2001; 86 (6) 1435-1439
    PubMedGoogle Scholar
  • 37 Batty P, Platton S, Bowles L, Pasi KJ, Hart DP. Pre-analytical heat treatment and a FVIII ELISA improve factor VIII antibody detection in acquired haemophilia A. Br J Haematol 2014; 166 (6) 953-956
    CrossrefPubMedGoogle Scholar
  • 38 White II GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J ; Factor VIII and Factor IX Subcommittee. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 2001; 85 (3) 560
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Sørensen B, Dargaud Y, Kenet G , et al. On-demand treatment of bleeds in haemophilia patients with inhibitors: strategies for securing and maintaining predictable efficacy with recombinant activated factor VII. Haemophilia 2012; 18 (2) 255-262
    CrossrefPubMedGoogle Scholar
  • 40 Haya S, Moret A, Cid AR , et al. Inhibitors in haemophilia A: current management and open issues. Haemophilia 2007; 13 (Suppl. 05) 52-60
    CrossrefPubMedGoogle Scholar
  • 41 Baudo F, Collins P, Huth-Kühne A , et al; EACH2 registry contributors. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood 2012; 120 (1) 39-46
    CrossrefPubMedGoogle Scholar
  • 42 Delgado J, Jimenez-Yuste V, Hernandez-Navarro F, Villar A. Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors. Br J Haematol 2003; 121 (1) 21-35
    CrossrefPubMedGoogle Scholar
  • 43 Collins P, Macartney N, Davies R, Lees S, Giddings J, Majer R. A population based, unselected, consecutive cohort of patients with acquired haemophilia A. Br J Haematol 2004; 124 (1) 86-90
    CrossrefPubMedGoogle Scholar
  • 44 Collins PW, Hirsch S, Baglin TP , et al; UK Haemophilia Centre Doctors' Organisation. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood 2007; 109 (5) 1870-1877
    CrossrefPubMedGoogle Scholar
  • 45 Collins P, Baudo F, Knoebl P , et al; EACH2 registry collaborators. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). Blood 2012; 120 (1) 47-55
    CrossrefPubMedGoogle Scholar
  • 46 Borg JY, Guillet B, Le Cam-Duchez V, Goudemand J, Lévesque H ; SACHA Study Group. Outcome of acquired haemophilia in France: the prospective SACHA (Surveillance des Auto antiCorps au cours de l'Hémophilie Acquise) registry. Haemophilia 2013; 19 (4) 564-570
    CrossrefPubMedGoogle Scholar
  • 47 Tiede A, Huth-Kühne A, Oldenburg J , et al. Immunosuppressive treatment for acquired haemophilia: current practice and future directions in Germany, Austria and Switzerland. Ann Hematol 2009; 88 (4) 365-370
    CrossrefPubMedGoogle Scholar
  • 48 Tiede A, Blumtritt JM, Klamroth R , et al. Prognostic parameters for survival and remission from acquired hemophilia: results from the GTH-AH 01/2010 Study. Blood 2013; 122 (21) 205
    PubMedGoogle Scholar