Inhibitors in Coagulation

  • Prashant SharmaEmail author


Inhibitors in coagulation are acquired antibodies that act by either neutralizing or inhibiting the activity of specific clotting factors or, alternatively, enhancing their degradation and clearance [1]. Clinically, these occur in two pathogenetically distinct scenarios. The first is when these antibodies occur idiopathically, or in association with other disorders like malignancies, pregnancy, drug exposures, or systemic autoimmune disorders. Such autoantibodies (“auto” since they are directed against the affected individual’s own antigens) usually result in a bleeding diathesis as their most common clinical manifestation. Antiphospholipid antibodies (APLA) are a special subset of this group, since their unique properties cause thromboses more often than abnormal bleeding [2].


Acquired hemophilia Antiphosphoplipid antibodies Bleeding Coagulation Hemostatic disorders Inhibitors Thrombosis 


  1. 1.
    Hurwitz A, Massone R, Lopez BL. Acquired bleeding disorders. Hematol Oncol Clin North Am. 2017;31(6):1123–45.CrossRefGoogle Scholar
  2. 2.
    Giangrande P. Acquired hemophilia. Monograph published by the World Federation of Hemophilia (WFH) 2005, revised 2012. No. 38; Nov 2012. Accessed 31 Jul 2018.
  3. 3.
    Ljung RCR. How I manage patients with inherited haemophilia A and B and factor inhibitors. Br J Haematol. 2018;180(4):501–10.CrossRefGoogle Scholar
  4. 4.
    Bain BJ, Bates I, Laffan MA, Lewis SM. Dacie and lewis’ practical haematology. 12/e; 2017.Google Scholar
  5. 5.
    Collins P, Baudo F, Huth-Kühne A, Ingerslev J, Kessler CM, Castellano ME, Shima M, St-Louis J, Lévesque H. Consensus recommendations for the diagnosis and treatment of acquired hemophilia A. BMC Res Notes. 2010;3:161.CrossRefGoogle Scholar
  6. 6.
    Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, Tiede A, Kessler CM. Acquired hemophilia A: updated review of evidence and treatment guidance. Am J Hematol. 2017;92(7):695–705.CrossRefGoogle Scholar
  7. 7.
    Mahendra A, Padiolleau-Lefevre S, Kaveri SV, Lacroix-Desmazes S. Do proteolytic antibodies complete the panoply of the autoimmune response in acquired haemophilia A? Br J Haematol. 2012;156(1):3–12.CrossRefGoogle Scholar
  8. 8.
    Ling M, Duncan EM, Rodgers SE, Somogyi AA, Crabb GA, Street AM, Lloyd JV. 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):861–7.CrossRefGoogle Scholar
  9. 9.
    Franchini M, Castaman G, Coppola A, Santoro C, Zanon E, Di Minno G, Morfini M, Santagostino E, Rocino A, AICE Working Group. Acquired inhibitors of clotting factors: AICE recommendations for diagnosis and management. Blood Transfus. 2015;13(3):498–513.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Depreter B, Devreese KM. Differences in lupus anticoagulant final conclusion through clotting time or Rosner index for mixing test interpretation. Clin Chem Lab Med. 2016;54(9):1511–6.PubMedGoogle Scholar
  11. 11.
    Keeling D, Mackie I, Moore GW, Greer IA, Greaves M, British Committee for Standards in Haematology. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol. 2012;157(1):47–58.CrossRefGoogle Scholar
  12. 12.
    Danowski A, Rego J, Kakehasi AM, Funke A, Carvalho JF, Lima IV, Souza AW, Levy RA, Comissão de Vasculopatias da Sociedade Brasileira de Reumatologia. Guidelines for the treatment of antiphospholipid syndrome. Rev Bras Reumatol. 2013;53(2):184–92.CrossRefGoogle Scholar
  13. 13.
    Groot N, de Graeff N, Avcin T, Bader-Meunier B, Dolezalova P, Feldman B, Kenet G, Koné-Paut I, Lahdenne P, Marks SD, McCann L, Pilkington CA, Ravelli A, van Royen-Kerkhof A, Uziel Y, Vastert SJ, Wulffraat NM, Ozen S, Brogan P, Kamphuis S, Beresford MW. European evidence-based recommendations for diagnosis and treatment of paediatric antiphospholipid syndrome: the SHARE initiative. Ann Rheum Dis. 2017;76(10):1637–41.CrossRefGoogle Scholar
  14. 14.
    Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295.CrossRefGoogle Scholar
  15. 15.
    Pengo V, Tripodi A, Reber G, Rand JH, Ortel TL, Galli M, De Groot PG, 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. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2009;7(10):1737–40.CrossRefGoogle Scholar
  16. 16.
    Ortel TL. Antiphospholipid syndrome: laboratory testing and diagnostic strategies. Am J Hematol. 2012;87(Suppl 1):S75–81.CrossRefGoogle Scholar
  17. 17.
    Miller CH. Laboratory testing for factor VIII and IX inhibitors in haemophilia: a review. Haemophilia. 2018;24(2):186–97.CrossRefGoogle Scholar
  18. 18.
    Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A, Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1–47.CrossRefGoogle Scholar
  19. 19.
    Brown SA, Barnes C, Curtin J, Dunkley S, Ockelford P, Phillips J, Rowell J, Smith M, Tran H, Hematology Working Group. How we use recombinant activated Factor VII in patients with haemophilia A or B complicated by inhibitors. Working group of hematology experts from Australia and New Zealand, Melbourne, April 2011. Intern Med J. 2012;42(11):1243–50.CrossRefGoogle Scholar
  20. 20.
    Gringeri A, Mannucci PM, Italian Association of Haemophilia Centres. Italian guidelines for the diagnosis and treatment of patients with haemophilia and inhibitors. Haemophilia. 2005;11(6):611–9.CrossRefGoogle Scholar
  21. 21.
    Lai J, Hough C, Tarrant J, Lillicrap D. Biological considerations of plasma-derived and recombinant factor VIII immunogenicity. Blood. 2017;129(24):3147–54.CrossRefGoogle Scholar
  22. 22.
    Clere AS, Diaz I, Lebreton A, Lavigne-Lissalde G, Schved JF, Biron-Andreani C. Are low-density lipoprotein receptor-related protein 1 or non-neutralizing antibodies predictors of FVIII in vivo recovery in haemophilia A patients? Haemophilia. 2014;20(6):e406–8.CrossRefGoogle Scholar
  23. 23.
    Santagostino E, Young G, Carcao M, Mannucci PM, Halimeh S, Austin S. A contemporary look at FVIII inhibitor development: still a great influence on the evolution of hemophilia therapies. Expert Rev Hematol. 2018;11(2):87–97.CrossRefGoogle Scholar
  24. 24.
    Rosendaal FR, Palla R, Garagiola I, Mannucci PM, Peyvandi F, SIPPET Study Group. Genetic risk stratification to reduce inhibitor development in the early treatment of hemophilia A: a SIPPET analysis. Blood. 2017;130(15):1757–9.CrossRefGoogle Scholar
  25. 25.
    Lai JD, Lillicrap D. Factor VIII inhibitors: advances in basic and translational science. Int J Lab Hematol. 2017;39(Suppl 1):6–13.CrossRefGoogle Scholar
  26. 26.
    ter Avest PC, Fischer K, Mancuso ME, Santagostino E, Yuste VJ, van den Berg HM, van der Bom JG, CANAL Study Group. Risk stratification for inhibitor development at first treatment for severe hemophilia A: a tool for clinical practice. J Thromb Haemost. 2008;6(12):2048–54.CrossRefGoogle Scholar
  27. 27.
    Marcucci M, Mancuso ME, Santagostino E, Kenet G, Elalfy M, Holzhauer S, Bidlingmaier C, Escuriola Ettingshausen C, Iorio A, Nowak-Göttl U. Type and intensity of FVIII exposure on inhibitor development in PUPs with haemophilia A. A patient-level meta-analysis. Thromb Haemost. 2015;113(5):958–67.CrossRefGoogle Scholar
  28. 28.
    Coppola A, Santoro C, Tagliaferri A, Franchini M, DI Minno G. Understanding inhibitor development in haemophilia A: towards clinical prediction and prevention strategies. Haemophilia. 2010;16(Suppl 1):13–9.CrossRefGoogle Scholar
  29. 29.
    Ragni MV. Novel alternate hemostatic agents for patients with inhibitors: beyond bypass therapy. Hematology Am Soc Hematol Educ Program. 2017;2017(1):605–9.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Hematology DepartmentPostgraduate Institute of Medical Education and Research, Level 5, Research Block A, Sector 12ChandigarhIndia

Personalised recommendations