Treatment tactics for a patient with acquired hemophilia: continuous infusion of recombinant activated coagulation factor VII and the inhibitor eradication

Introduction. Acquired hemophilia is a rare autoimmune disease caused by an inhibitor to clotting factor VIII (FVIII). It complicates the course of many diseases, in particular autoimmune diseases, and in women is often associated with pregnancy.

Aim — to present a case of successful treatment of a patient with acquired hemophilia using long-term continuous infusion of rFVIIa and inhibitor eradication as a result of immunosuppressive therapy.

Main findings. A clinical observation of severe hemorrhagic syndrome in a patient with acquired hemophilia associated with pregnancy is presented. Uterine bleeding in the patient after spontaneous delivery, refractory to standard hemorrhagic syndrome treatment, required multiple surgical interventions. Laboratory tests showed prolongation of APTT, CT in the INTEM rotational thromboelastometry test, a decrease in plasma FVIII activity and presence of inhibitor to FVIII. Vacuum-assisted closure was applied to treat infected laparotomy wound. Therapy for acquired hemophilia consisted of hemostatic therapy and the inhibitor eradication. Hemostatic therapy included a continuous infusion of rFVIIa at a rate of 30 μg/kg/h with a gradual decrease up to 9.6 μg/kg/h, as well as its fractional administration before every surgery at a dosage of 80 μg/kg. The effectiveness of the therapy was assessed by the dynamics of CT in the INTEM test and the shortening of the APTT. The inhibitor eradication was achieved by prednisolone therapy, combined immunosuppression with rituximab and azathioprine, followed by its replacement with cyclophosphamide. As a result, the hemorrhage was stopped, reference plasma activity of FVIII and eradication of the inhibitor were reached.

1. Collins P., Macartney N., Davies R., et al. A population based, unselected, consecutive cohort of patients with acquired haemophilia A. Br J Haematol. 2004; 124(1): 86–90. DOI: 10.1046/j.1365-2141.2003.04731.x.

2. Delgado J., Jimenez-Yuste V., Hernandez-Navarro F., et al. Acquired haemophilia: Review and meta-analysis focused on therapy and prognostic factors. Br J Haematol. 2003; 121(1): 21–35. DOI: 10.1046/j.1365-2141.2003.04162.x.

3. Collins P.W., Hirsch S., Baglin T.P., et al. 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): 1870–7. DOI: 10.1182/blood-2006-06-029850.

4. Knoebl P., Marco P., Baudo F., et al. Demographic and clinical data in acquired hemophilia A: Results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost. 2012; 10(4): 622–31. DOI: 10.1111/j.1538-7836.2012.04654.x.

5. Ma A.D., Carrizosa D. Acquired factor VIII inhibitors: Pathophysiology and treatment. Hematology Am Soc Hematol Educ Program. 2006; 432–7. DOI: 10.1182/asheducation-2006.1.432.

6. Witmer C., Young G. Factor VIII inhibitors in hemophilia A: Rationale and latest evidence. Ther Adv Hematol. 2013; 4(1): 59–72. DOI: 10.1177/2040620712464509.

7. Oh J., Lim Y., Jang M.J., et al. Characterization of anti-factor VIII antibody in a patient with acquired hemophilia A. Blood Res. 2013; 48(1): 58–62. DOI: 10.5045/br.2013.48.1.58.

8. Kahle J., Orlowski A., Stichel D., et al. Frequency and epitope specificity of antifactor VIII C1 domain antibodies in acquired and congenital hemophilia A. Blood. 2017; 130(6): 808–16. DOI: 10.1182/blood-2016-11-751347.

9. Dolgov V.V., Svirin P.V. Laboratory diagnosis of hemostasis disorders. Moscow – Tver: Triada Publishing House; 2005. (In Russian).

10. Zozulya N.I., Kumskova M.A., Polyanskaya T.Yu., et al. Hemophilia. Clinical guidelines. National Hematological Society. 2018; 1–47. (In Russian).

11. Mazzucconi M.G., Baldacci E., Ferretti A., et al. Acquired haemophilia A: An intriguing disease. Mediterr J Hematol Infect Dis. 2020; 12(1): e2020045. DOI: 10.4084/MJHID.2020.045.

12. Franchini M., Lippi G. Acquired factor VIII inhibitors. Blood. 2008; 112(2): 250–5. DOI: 10.1182/blood-2008-03-143586.

13. Tiede A., Collins P., Knoebl P., et al. International recommendations on the diagnosis hemophilia and a treatment of acquired hemophilia A. Haematologica. 2020; 105(7): 1791–801. DOI: 10.3324/haematol.2019.230771.

14. Esteves Pereira M., Bocksrucker C., Kremer Hovinga J.A., et al. Immunoadsorption for the treatment of acquired hemophilia: New observational data, systematic review, and meta-analysis. Transfus Med Rev. 2021; 35(2): 125–34. DOI: 10.1016/j.tmrv.2021.01.001.

15. Novo Nordisk. NovoSeven Prescribing Information (FDA Approved). 2014; 1–31.

16. Christensen A., Jensen J.T., Nøhr A.M., Cooper D.L. Room-temperature-stable recombinant activated coagulation factor VII recombinant: Chemical and microbiologic stability over 24 hours during continuous in vitro infusion. Clin Ther. 2011; 33(12): 1997–2001. DOI: 10.1016/j.clinthera.2011.10.023.

17. Gupta D., Chatterjee T., Sharma A., et al. Rare case of acquired haemophilia and lupus anticoagulant. Indian J Hematol Blood Transfus. 2014; 30(3): 197–200. DOI: 10.1007/s12288-012-0204-5.

18. Bossi P., Cabane J., Ninet J., et al. Acquired hemophilia due to factor VIII inhibitors in 34 patients. Am J Med. 1998; 105(5): 400–8. DOI: 10.1016/s0002-9343(98)00289-7.

19. Michiels J.J. Acquired hemophilia A in women postpartum: Clinical manifestations, diagnosis, and treatment. Clin App Thromb Hemost. 2000; 6(2): 82–6. DOI: 10.1177/107602960000600206.

20. Baudo F., De Cataldo F., Bari S.M., et al. Acquired factor VIII inhibitors in pregnancy: Data from the Italian Haemophilia Register relevant to clinical practice. BJOG. 2003; 110(3): 311–4. DOI: 10.1016/s1470-0328(03)01935-9.

21. Voke J., Letsky E. Pregnancy and antibody to factor VIII. J Clin Pathol. 1977; 30(10): 928–32. DOI: 10.1136/jcp.30.10.928.

22. Cao X.Y., Li M.T., Zhang X., et al. Characteristics of acquired inhibitors to factor VIII and von Willebrand factor secondary to systemic lupus erythematosus. J Clin Rheumatol. 2021; 27(5): 201–5. DOI: 10.1097/RHU.0000000000001284.

23. Kozek-Langenecker S.A., Ahmed A.B., Afshari A., et al. Management of severe perioperative bleeding. Guidelines from the European Society of Anaesthesiology. Russian journal of hematology and transfusiology. 2021; 66(1): 88–160. (In Russian).

24. Mauser-Bunschoten E.P., De Goede-Bolder A., Wielenga J.J., et al. Continuous infusion of recombinant factor VIIa in patients with haemophilia and inhibitors: Experience in the Netherlands and Belgium. Neth J Med. 1998; 53(6): 249–55. DOI: 10.1016/S0300-2977(98)00111-9.

25. Rajpurkar M., Cooper D.L. Continuous infusion of recombinant activated factor VII: A review of data in congenital hemophilia with inhibitors and congenital factor VII deficiency. J Blood Med. 2018; 9: 227–39. DOI: 10.2147/JBM.S184040.

26. Galstyan G.M., Polevodova O.A., Terekhova I.V., et al. The use of thromboelastography, thrombin generation test and clotting tests to evaluate the efficacy of hemostatic therapy with recombinant activated factor VII in hemophilia patients with inhibitor. Rossiyskiy Journal Detskoy Gematologii I Onkologii. 2017; 4(4): 33–8. DOI: 10.17650/2311-1267-2017-4-4-33-38. (In Russian).

27. Spero J.A., Lewis J.H., Hasiba U. Corticosteroid therapy for acquired F VIII:C inhibitors. Br J Haematol. 1981; 48(4): 635–42. DOI: 10.1111/j.1365-2141.1981.00635.x.

28. Green D., Lechner K. A survey of 215 non-hemophilic patients with inhibitors to Factor VIII. Thromb Haemost. 1981; 45(3): 200–3.

29. Collins P., Baudo F., Knoebl P., et al. Immunosuppression for acquired hemophilia A: Results from the European Acquired Haemophilia Registry (EACH2). Blood. 2012; 120(1): 47–55. DOI: 10.1182/blood-2012-02-409185.

30. Remmington T., Smith S. Rituximab for eradicating inhibitors in people with acquired haemophilia A. Cochrane Database Syst Rev. 2021; 8(8): CD011907. DOI: 10.1002/14651858.CD011907.pub3.