Evaluation of the Efficacy and Safety Immunosuppressive Therapy in Patients with Acquired Factor VIII and IX Inhibitor

Year 2023, Volume: 76 Issue: 1, 24 - 29, 25.05.2023

Derya Koyun , Güldane Cengiz Seval , Sinem Civriz , Muhit Özcan , Pervin Topçuoğlu

Abstract

Objectives: Acquired factor inhibitor is a rare disorder and can cause life-threatening bleeding. Consequently, we report the efficacy and safety of
our patients with acquired factor inhibitor treated with immunosuppressive drugs.

Materials and Methods: We retrospectively investigated acquired factor inhibitor patients who were followed and treated in our center between
November 2018 and March 2022.

Results: A total of seven patients, four of whom were male, with a median age of 65 (43-76) were included. Acquired factor inhibitor was
associated with malignancy (n=3), advanced age (n=2), postpartum period (n=1) and lupus anticoagulant (n=1). Median follow-up time was 9
months (range, 2-46). High inhibitor titres were detected in four patients [median: 7.06 BU/mL (range, 5.76-100)] and all of them were treated
with immunosuppressive drugs (metilprednisone in combination with cyclophosphamide, rituximab). The overall response rate was 100% (n=4) with 50% complete response and 50% partial response and one patient who developed the inhibitor in the postpartum period responded to single agent
rituximab. To achieve the hemostatic target, recombinant activated clotting factor VII (rFVIIa) and activated prothrombin complex concentrate
(aPCC) were used in two out of four patients with active bleeding. Hemostasis was achieved successfully. Three patients developed a low-titre factor inhibitor and immunosuppressive drugs were not started for inhibitor elimination. Coagulation assays disappeared when the underlying condition was self-limited.

Conclusion: Clinical presentation of factor inhibitors is highly variable and optimal treatment is not clearly established. Rituximab might be a
promising treatment for therapy-resistant factor inhibitor and bleeding control was achieved with rFVIIa and aPCC. Treatment plan of patients with
low-titre factor inhibitor should be provided considering the clinical situation and underlying disease.

Keywords

Factor Inhibitor , Immunosuppressive Theraphy , Hemostasis

Ethical Statement

-

Supporting Institution

-

Project Number

-

Thanks

-

Kazanılmış Faktör VIII ve IX İnhibitörü Olan Hastalarda İmmünosüpresif Tedavi Etkinlik ve Güvenilirliğinin Değerlendirilmesi

Abstract

Amaç: Mortalitesi yüksek kanamalara yol açabilen ve nadir gözlemlenen kazanılmış faktör inhibitörü olan hastalarda, immünosüpresif tedavi
etkinlik ve güvenilirlik sonuçlarının değerlendirilmesidir.

Gereç ve Yöntem: Kasım 2018-Mart 2022 tarihleri arasında merkezimizde kazanılmış faktör inhibitörü ile takip ve tedavi edilmiş hastalar çalışmaya
dahil edildi.

Bulgular: Çalışmaya ortanca yaşı 65 (aralık, 43-76) dördü erkek toplam yedi hasta dahil edildi. Faktör inhibitör gelişim nedenleri; postpartum dönem
(n=1), lupus antikoagülan (n=1), ileri yaş (n=2) ve malignite (n=3) olup, tüm hastalarda ortanca takip süresi 9 ay (aralık, 2-46 ay) idi. Dört hastada
tanıda yüksek titreli inhibitör vardı [ortanca: 7,06 BÜ/mL (aralık, 5,76-100)] ve tümü immünosüpresif tedavi (metilprednizolon ve siklofosfamid
kombinasyonu, rituximab) almıştı. Hastaların tamamı immünosüpresif tedaviye yanıt verirken (toplam yanıt oranı %100; tam yanıt %50, kısmi
yanıt %50), postpartum dönemde faktör inhibitörü gelişmiş bir hastada rituximab tedavisine yanıt alınmıştır. Hastaların ikisinde kanama sırasında
rekombinant aktive-faktör VII (rFVIIa) ve aktive protrombin kompleks konsantreleri (aPCC) hemostazı sağlamıştır. Düşük titrede faktör inhibitörü
saptanan üç hasta ise kanama olmadığından immünosüpresif tedavi almamış, hastalarda ihibitör gelişiminden sorumlu neden ortadan kalktığında
koagülasyon testleri düzelmiştir.

Sonuç: Kazanılmış yüksek titreli faktör inhibitörü olan hastalarda bilinen tedavi seçeneklerinin birbirine üstünlüğü kanıtlanmamıştır. Dirençli faktör
inhibitör tedavisinde rituximab alternatif bir seçenek olabilir ve hastalarda hemostazı sağlamada rFVIIa ve aPCC kullanımı etkindir. Düşük titrede
faktör inhibitörü olan hastaların tedavisinde ise klinik durum ve altta yatan hastalık göz önünde bulundurularak tedavi planı yapılmalıdır.

Keywords

Faktör İnhibitör , İmmünosüpresif Tedavi , Hemostaz

Ethical Statement

Çalışmamız, Ankara Üniversitesi Tıp Fakültesi, İnsan Araştırmaları Etik Kurulu tarafından onaylandı (tarih: 10.12.2021, karar no: İ11-696-21).

Supporting Institution

-

Project Number

-

Thanks

-

References

• 1. Franchini M, Gandini G, Di Paolantonio T, et al. Acquired hemophilia A: a concise review. Am J Hematol. 2005;80:55-63.
• 2. 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;10:622-631.
• 3. Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood. 2008;112:250-255.
• 4. Sallah S, Wan JY. Inhibitors against factor VIII in patients with cancer. Analysis of 41 patients. Cancer. 2001;91:1067-1074.
• 5. Napolitano M, Siragusa S, Mancuso S, et al. Acquired haemophilia in cancer: A systematic and critical literature review. Haemophilia. 2018;24:43-56.
• 6. Saito M, Ogasawara R, Izumiyama K, et al. Acquired hemophilia A in solid cancer: Two case reports and review of the literature. World J Clin Cases. 2018;6:781-785.
• 7. 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;121:21-35.
• 8. Kruse-Jarres R, Kempton CL, Baudo F, et al. Acquired hemophilia A: Updated review of evidence and treatment guidance. Am J Hematol. 2017;92:695-705.
• 9. Huth-Kühne A, Baudo F, Collins P, et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica. 2009;94:566-575.
• 10. Peyvandi F, Ettingshausen CE, Goudemand J, Jiménez-Yuste V, Santagostino E, Makris M. New findings on inhibitor development: from registries to clinical studies. Haemophilia. 2017;23:4-13.
• 11. Zeitler H, Ulrich-Merzenich G, Hess L, et al. Treatment of acquired hemophilia by the Bonn-Malmo Protocol: documentation of an in vivo immunomodulating concept. Blood. 2005;105:2287-2293.
• 12. Spero JA, Lewis JH, Hasiba U. Corticosteroid therapy for acquired F VIII:C inhibitors. Br J Haematol. 1981;48:635-642.
• 13. Lottenberg R, Kentro TB, Kitchens CS. Acquired hemophilia. A natural history study of 16 patients with factor VIII inhibitors receiving little or no therapy. Arch Intern Med. 1987;147:1077-1081.
• 14. Lian EC, Larcada AF, Chiu AY. Combination immunosuppressive therapy after factor VIII infusion for acquired factor VIII inhibitor. Ann Intern Med. 1989;110:774-778.
• 15. Shaffer LG, Phillips MD. Successful treatment of acquired hemophilia with oral immunosuppressive therapy. Ann Intern Med. 1997;127:206-209.
• 16. Franchini M. Rituximab in the treatment of adult acquired hemophilia A: asystematic review. Crit Rev Oncol Hematol. 2007;63:47-52.
• 17. Sperr WR, Lechner K, Pabinger I. Rituximab for the treatment of acquired antibodies to factor VIII. Haematologica. 2007;92:66-71.
• 18. Collins P, Baudo F, Knoebl P, et al. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). Blood. 2012;120:47-55.
• 19. Zeitler H, Ulrich-Merzenich G, Goldmann G, 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.
• 20. Jones DW, Gallimore MJ, MacKie IJ, et al. Reduced factor XII levels in patients with the antiphospholipid syndrome are associated with antibodies to factor XII. Br J Haematol. 2000;110:721-726.