Acquired Hemophilia A in Internal Medicine: A Case ReportBorro M, Tassara R, Paris L, Artom N, Brignone M, Rebella L, Tassara RTo the Editor,Acquired hemophilia A (AHA) is a rare bleeding disorder in patient with a previously normal hemostasis characterized by the presence of neutralizing autoantibodies, named inhibitors, whose target is the coagulation factor VIII (FVIII) (1). Typically, AHA incidence is associated with pregnancy and older age, e.g over 60 years old (2). Over 50% of patients with AHA have comorbidities, frequently autoimmune disorders, or malignancy (2, 3). Clinical manifestations may range from asymptomatic to life-threatening bleeding but, subcutaneous hematomas are present in 80% of patients and frequently the first sign of the disease (4). Moreover, especially in elderly with multiple chronic diseases, patient ongoing medications, i.e. antiplatelet agents and anticoagulants, may interfere with the clinical picture and delay the correct diagnosis (1). Laboratory investigations lead the diagnostic pathway of AHA and are characterized by prolonged activated partial thromboplastin time (APTT), confirmed with the APTT mixing study, various levels of reduced FVIII activity (usually ranging from <1% to 40%) and the presence of autoantibodies detected by the Bethesda assay or by enzyme-linked immunosorbent assay (5). The concomitant presence of a prolonged prothrombin time should be attributed to other causes, e.g. anticoagulants (1). In elderly patients, morbidity and mortality associated with AHA are extremely high and, unfortunately, because of the rarity of the condition and frequent severe clinical picture at presentation, comparative studies are lacking (1). Recent international recommendations suggest that both recombinant activated factor VII (eptacog alfa) and activated prothrombin complex concentrate and recombinant porcine factor VIII (susoctocog alfa), named bypassing agents, can be administered as first-line hemostatic treatment options (1). Because of its lower efficacy and the risk of fluid overload, heart failure and severe hyponatremia, especially in elderly patients, the use of human factor VIII concentrates associated with desmopressin is limited to those cases where therapy with bypassing agents is not available (1, 6). Here, we report a clinical case of AHA in an elderly patient presenting with diffuse subcutaneous hematomas and anemia, successfully treated with susoctocog-alfa.Case presentationA 79-year-old women was admitted to the hospital for lipothymia and presence of non-traumatic subcutaneous hematomas in the four limbs. Medical history showed ischemic heart disease with a six-month-earlier Non-ST-segment elevation myocardial infarction treated with percutaneous angioplasty and stenting, monoclonal gammopathy, hypertension and dislipidemia. Ongoing therapy was Nebivolol 5 mg, acetyl salicylic acid 75 mg, Perindopril 10 mg, Rosuvastatin 20 mg, and Furosemide 25 mg bid. Ticagrelor 90 mg was stopped ten days earlier in agreement with the cardiologic follow-up. Physical examination showed hypotension, multiple subcutaneous hematomas at various stage spread both to thighs, legs and arms. Laboratory tests showed worsening moderate-to-severe normocytic normochromic anemia, stage-I acute kidney injury, and prolonged activated partial thromboplastin time (aPTT) with normal prothrombin time (PT), 1,68 ratio and 78% respectively. Serum protein electrophoresis showed the known presence of a minor band in the gamma region (estimated 6%). No Bence Jones proteinuria was found. Patient was treated with multiple red blood cell concentrates and normal saline rehydration. Mixing test showed a persistent prolonged aPTT, thus suggesting the presence of factor inhibitors. Further investigation showed a reduced FVIII activity (2%) with normal activity of FIX, FXI and FXII. According to the International recommendations published in 2020 by Tiede et al. (1), acquired hemophilia A was diagnosed and confirmed with the positive finding of autoantibodies against FVIII detected by the Nijmegen modified Bethesda assay (38,4 N.B.U.). As recommended, methylprednisolone 1 mg/Kg and oral cyclophosphamide 2 mg/kg/day were started as soon as possible. Accordingly, the presence of porcine FVIII inhibitor was excluded. In order to limit the thromboembolic risk, especially related to the recent cardiac procedure, the rpFVIII Susoctocog alpha Obizur® was used as first-line therapy (loading dose: 100 U/kg; subsequent six doses: 50 U/Kg). FVIII levels were measured immediately before and after the first loading dose and resulted 5% and 82%, respectively. In few days, no other subcutaneous hematomas nor internal bleeding were noticed, and supportive transfusions were not needed anymore. A further dosage of autoantibodies against FVIII showed a significant reduction (3,4 N.B.U.). When hemoglobin levels and aPTT were persistently stable (12,6 g/dL and 1,06 ratio, respectively), the patient was discharged with indication to continue oral prednisone and cyclophosphamide for four weeks. At first laboratory follow-up visit FVIII and aPTT were 64% and 1,01 ratio, respectively. At first follow-up visit coagulation tests were normal, as well as hemoglobin levels. Patients continued therapy with cyclophosphamide 100 mg and tapered steroid therapy. At the end of eighth therapy cycle, given the complete stability of coagulation tests and hemoglobin levels, cyclophosphamide was completely discharged. Further follow-up visit showed stability of all parameters.DiscussionIn AHA patients, the bleeding is the first sign and the trigger for diagnosis in 89% of cases (2). Because of the high risk of bleeding and the significant bleed-related morbidity, irrespectively of the bleeding phenotype of the patient, immunosuppressive therapy (IST) should be started as soon as possible, simultaneously to the hemostatic treatment (7). From the first guidelines, back in 2009 (6), to the most recent one in 2020 (1) IST has changed significantly: updated recommendations suggest the use of corticosteroids alone for 3-4 weeks in those patients with FVIII ≥1% and inhibitor ≤20 BU and the use of a 3-4 week combination therapy (corticosteroid and cytotoxic agent or rituximab) when FVIII <1% or inhibitor titer >20 BU (2). In contrast with congenital hemophilia, because of the high risk of bleeding and the lack of protection from new bleeding until FVIII is over 50%, the hemostatic treatment should be started simultaneously to IST. The choice of the most appropriate hemostatic treatment is usually based on availability of agents, the anti-porcine titer, costs, monitoring requirements, personal experience, and the risk of thrombotic events and safety profile (1, 8). Treatment with both recombinant activated factor VII, activated prothrombin complex concentrate and recombinant porcine factor VIII is associated with a certain risk of arterial and/or venous thrombotic events, especially in elderly patients with risk factors (e.g. cardiovascular disease), recent thromboembolic events and immobility due to the present bleeding (1). The administration of recombinant porcine factor VIII both at an initial dose of 200 U/kg with subsequent doses assigned by clinical response and FVIII activity (9) and at a reduced dosage (100 U/Kg of loading dose and subsequent doses at 50 U/Kg) has proven to maintain excellent hemostatic efficacy with a possibly lower risk of thromboembolic events in small case series (10-13) and in the pivotal phase II/III trial (10, 14) if compared with other bypassing agents. Specifically, recombinant factor VIIa (eptacog alfa activated) showed a thromboembolic risk of 0-5% and 2,9% in a systematic review (15) and in the EACH2 registry (16), respectively; the thromboembolic risk related to the administration of activated prothrombin complex concentrate was found 4,8% in the EACH2 registry (16). In our case report, loading dose and subsequent doses were administered at a lower dosage showing efficacy in hemostasis without thromboembolic events, despite patient age, comorbidity, and recent myocardial infarction treated with stenting. Moreover, as described in the international recommendations, the efficacy and safety of Susoctocog alfa can be monitored by measuring the FVIII activity using readily available standard FVIII assays, thus guiding the adequate dosing (1).In conclusion, although it is a rare condition, clinicians should be aware of AHA as a potential cause of bleeding in patient admitted to the hospital for hemorrhage and hematomas, especially in elderly patients with comorbidities and often ongoing with anti-platelets and/or anticoagulant treatment that may mime and mask the characteristics of the disease. Moreover, the choice of the most adequate hemostatic approach is challenging: clinicians should correctly balance the bleeding risk and the thromboembolic risk in the context of the clinical situation of the patient.Reference list1. Tiede A, Collins P, Knoebl P, Teitel J, Kessler C, Shima M, et al. International recommendations on the diagnosis and treatment of acquired hemophilia A. Haematologica. 2020;105(7):1791-801.2. Knoebl P, Marco P, Baudo F, Collins P, Huth-Kuhne A, Nemes L, et al. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). J Thromb Haemost. 2012;10(4):622-31.3. Napolitano M, Siragusa S, Mancuso S, Kessler CM. Acquired haemophilia in cancer: A systematic and critical literature review. Haemophilia. 2018;24(1):43-56.4. Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, et al. Acquired hemophilia A: Updated review of evidence and treatment guidance. Am J Hematol. 2017;92(7):695-705.5. Tiede A, Klamroth R, Scharf RE, Trappe RU, Holstein K, Huth-Kuhne A, et al. Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study. Blood. 2015;125(7):1091-7.6. Huth-Kuhne A, Baudo F, Collins P, Ingerslev J, Kessler CM, Levesque H, et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica. 2009;94(4):566-75.7. Holstein K, Liu X, Smith A, Knobl P, Klamroth R, Geisen U, et al. Bleeding and response to hemostatic therapy in acquired hemophilia A: results from the GTH-AH 01/2010 study. Blood. 2020;136(3):279-87.8. Tiede A. Critical Bleeding in Acquired Hemophilia A: Bypassing Agents or Recombinant Porcine Factor VIII? Hamostaseologie. 2020.9. Kruse-Jarres R, St-Louis J, Greist A, Shapiro A, Smith H, Chowdary P, et al. Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A. Haemophilia. 2015;21(2):162-70.10. Tarantino MD, Cuker A, Hardesty B, Roberts JC, Sholzberg M. Recombinant porcine sequence factor VIII (rpFVIII) for acquired haemophilia A: practical clinical experience of its use in seven patients. Haemophilia. 2017;23(1):25-32.11. Martin K, Kasthuri R, Mooberry MJ, Chen SL, Key NS, Ma AD. Lower doses of recombinant porcine factor VIII maintain excellent haemostatic efficacy. Haemophilia. 2016;22(6):e549-e51.12. Stemberger M, Mohnle P, Tschop J, Ney L, Spannagl M, Reincke M. Successful bleeding control with recombinant porcine factor VIII in reduced loading doses in two patients with acquired haemophilia A and failure of bypassing agent therapy. Haemophilia. 2016;22(5):e472-4.13. Zanon E, Pasca S, Borchiellini A, Lodigiani C, Molinari AC, Ambaglio C, et al. Susoctocog-alfa (Obizur((R))) in the treatment of nine elderly patients with acquired haemophilia A: an Italian multicentre real world experience. Blood Transfus. 2020;18(4):312-21.14. Burness CB, Scott LJ. Susoctocog Alfa: A Review in Acquired Haemophilia A. Drugs. 2016;76(7):815-21.15. Tiede A, Worster A. Lessons from a systematic literature review of the effectiveness of recombinant factor VIIa in acquired haemophilia. Ann Hematol. 2018;97(10):1889-901.16. Baudo F, Collins P, Huth-Kuhne A, Levesque H, Marco P, Nemes L, et al. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. Blood. 2012;120(1):39-46.