An Unusual Association Between Acquired Hemophilia A and Type 2 Autoimmune Pancreatitis.

A United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) guideline approved by the British Committee for Standards in Haematology Peter W Collins, Elizabeth Chalmers, Daniel Hart, Ian Jennings, Ri Liesner, Savita Rangarajan, Kate Talks, Michael Williams and Charles R. M. Hay School of Medicine, Cardiff University, University Hospital of Wales, Cardiff, Royal Hospital for Sick Children, Glasgow, Royal London Hospital, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK NEQAS Blood Coagulation, Sheffield, Great Ormond Street NHS Trust, London, Hampshire Hospital NHS Foundation Trust, Basingstoke & North Hampshire Hospital, Basingstoke, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, and Manchester University Dept of Haematology, Manchester Royal Infirmary, Manchester, UK

Recombinant Porcine Factor VIII, Obi-1, Successfully Controlled Gastrointestinal Bleeding in a Patient with Acquired Hemophilia A

Introduction: Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by factor VIII (FVIII) autoantibodies that interfere with FVIII coagulant function, predisposing affected patient to an often severe bleeding diathesis. The management of AHA is primarily directed toward the eradication of the autoantibody using immunosuppressive agents (i.e., steroids alone or in association with cyclophosphamide). Hemostatic treatment to control severe bleeding is based on the use of bypassing agents (i.e., activated prothrombin complex concentrate and recombinant activated factor VII).Areas covered: After an overview of the main clinical, diagnostic and therapeutic aspects of AHA, this review focuses on the investigational agents aimed at improving the control of bleeding in AHA patients, which represents the most important challenge among physicians in this clinical setting.Expert opinion: Among the promising new hemostatic drugs, recombinant porcine FVIII has been evaluated and recently approved for AHA treatment in the USA by FDA and provides an additional option for successfully controlling severe bleeding episodes in patients with FVIII autoantibodies.

Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by autoantibodies against Factor VIII (FVIII). It has a high mortality due to bleeding complications. FVIIa-based bypassing agents are the first line of treatment but not always effective. Recombinant porcine (rp) FVIII (Obizur®) was recently approved for rescue treatment but with little evidence-based information regarding efficacy. We report a case of papillary thyroid cancer associated with AHA malignancy that responded to a single dose of rpFVIII after failure to achieve hemostasis with FVIIa-based bypassing products.

Recombinant porcine FVIII for bleed treatment in acquired hemophilia A: findings from a single-center, 18-patient cohort.

Treatment of Acquired Hemophilia A (AHA) with Rituximab (R): Clinical Outcomes and Cost of Hemostatic Agents

Emicizumab, a monoclonal bispecific antibody that mimics the function of activated factor VIII (FVIII), is currently licensed for prophylactic use in patients with congenital hemophilia A with and without inhibitors. Acquired hemophilia A (AHA) is a very rare bleeding disorder caused by the development of autoantibodies that inhibit FVIII activity in plasma; males and females are equally affected. Therapeutic options for patients with AHA currently include eradication of the inhibitor with immunosuppressive treatments and management of acute bleeding with bypassing agents or recombinant porcine FVIII. More recently, several reports described the off-label use of emicizumab in patients with AHA and a phase III study is ongoing in Japan. The aims of this review are to describe the 73 reported cases, and to highlight the advantages and disadvantages of this novel approach to the prevention and treatment of bleeding in AHA.

Acquired hemophilia A (AHA), a rare bleeding disorder caused by neutralizing autoantibodies against coagulation factor VIII (FVIII), occurs in both men and women without a previous history of bleeding. Patients typically present with an isolated prolonged activated partial thromboplastin time due to FVIII deficiency. Neutralizing antibodies (inhibitors) are detected using the Nijmegen-modified Bethesda assay. Approximately 10% of patients do not present with bleeding and, therefore, a prolonged activated partial thromboplastin time should never be ignored prior to invasive procedures. Control of acute bleeding and prevention of injuries that may provoke bleeding are top priorities in patients with AHA. We recommend treatment with bypassing agents, including recombinant activated factor VII, activated prothrombin complex concentrate, or recombinant porcine FVIII in bleeding patients. Autoantibody eradication can be achieved with immunosuppressive therapy, including corticosteroids, cyclophosphamide and rituximab, or combinations thereof. The median time to remission is 5 weeks, with considerable interindividual variation. FVIII activity at presentation, inhibitor titer and autoantibody isotype are prognostic markers for remission and survival. Comparative clinical studies to support treatment recommendations for AHA do not exist; therefore, we provide practical consensus guidance based on recent registry findings and the authors’ clinical experience in treating patients with AHA.

Experience with Continuous Infusion of Recombinant Porcine FVIII in Patients with Acquired Hemophilia a

Background: Emicizumab is a humanized bispecific monoclonal antibody that mimics activated factor VIII (FVIII) and is currently approved as prophylaxis for patients with congenital severe and moderate hemophilia A, with or without inhibitors. Acquired hemophilia A (AHA) is a very rare bleeding disorder caused by the development of autoantibodies against FVIII, leading to severe and spontaneous bleeding, either cutaneous or intramuscular. AHA is often secondary to conditions such as cancer, autoimmune diseases, or infections. Standard therapy involves immunosuppressive treatment aimed at eradicating the inhibitor, which can be complicated by infections especially in older frail patients, and agents to manage acute bleeding; these include recombinant activated factor VII (rFVIIa), activated prothrombin complex concentrate (aPCC), and recombinant porcine FVIII concentrate (rpFVIII). Recent case reports and case series have shown clinical improvement in AHA patients treated off-label with emicizumab, indicating a promising new therapeutic option. In Italy, its use is permitted under AIFA’s law 648/1996. Case Report: The first case (Figure 1A) involves a female patient born in 1952, diagnosed with AHA in 1978. Over the first three decades following diagnosis, she was treated with corticosteroids and cyclophosphamide, without inhibitor eradication, and for acute bleeding episodes she received rFVIIa and porcine FVIII. In 2014, she was referred to our department. At that time, FVIII level was 0.3% with an inhibitor titer of 83 BU. Treatment with rituximab was started, leading to partial disease control (FVIII ~ 5%; inhibitor ≤10 BU), maintaining disease stability for years with only occasional gingival or post-dental bleedings. In March 2024, however, she experienced a severe bleeding after a breast fine-needle biopsy. Despite aPCC treatment, bleeding persisted (FVIII 5.8%; inhibitor 3.55 BU). Due to the inadequate bleeding control, emicizumab was started in May 2024 at 3 mg/kg weekly, then every two weeks. After one year, no further bleeding episodes occurred. During this period she underwent 2 dental extractions managed with only 2 doses of rFVIIa with an optimal outcome. The second case (Figure 1B) involves a 60-year-old female diagnosed with AHA in 2023 after bleeding from a chronic lower limb ulcer. She started corticosteroid therapy, followed shortly by systemic antibiotic treatment due to ulcer infection. She achieved a FVIII level of 40% with an inhibitor titer of 1.72 BU. During steroid tapering, she had frequent episodes of epistaxis, treated with rFVIIa. In September 2024, after steroid discontinuation, she developed severe anemia (Hb 5.4 g/dL) due to spontaneous intramuscular bleeding, which was treated with aPCC (FVIII 10.5%, inhibitor 8.9 BU). Steroids were reintroduced, and emicizumab was started at 3 mg/kg weekly, with the aim of either controlling bleeding or discontinuing steroid therapy to promote ulcer healing. After 4 doses, it was stopped because FVIII level rose to 152%, with complete inhibitor disappearance. Steroids were discontinued in January 2025, and to date, the patient has not experienced any further bleeding episodes. Conclusions: These cases suggest that emicizumab is effective in AHA patients, and it can be very useful to manage difficult situations in fragile patients or in those rare cases who have not eradicate the inhibitor.

Targeting early immunologic decline in acquired hemophilia A: A case for prophylactic rituximab

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder resulting from the development of inhibitory autoantibodies against the circulating factor VIII (FVIII:C). It occurs in patients without a family or personal history of bleeding.1 AHA incidence is approximately 1.5 cases/million/year2 and is idiopathic in about 50% of cases AHA.3 AHA is biologically characterized by an isolated deficiency of coagulation factor VIII (FVIII:C) secondary to autoantibodies targeting specific epitopes that cause neutralization and/or accelerated clearance of FVIII from the plasma (auto-FVIII Abs).4 More often, diagnosis is triggered by a bleeding event3 and confirmed by laboratory data: a decreased level of FVIII:C, usually lower than 30% and the presence of anti-FVIII antibodies with a titer >0.6 Bethesda Unit/mL.5 In case of severe bleeding event, an hemostatic treatment with bypassing agents, including recombinant Factor VIIa (rFVIIa) or activated prothrombin complex concentrates (aPCCs), is recommended.6, 7 More recently, the recommendations for hemostatic treatment in AHA included a "new" treatment, susoctocog alfa (Obizur®): a recombinant porcine FVIII (rpFVIII).5 This recombinant and highly purified protein has comparable biochemical and hemostatic properties to plasma-derived porcine factor VIII, but much lower risks of infection and toxicity. This recombinant anti-hemophilic factor porcine sequence (rpFVIII) is a B-domain deleted FVIII produced in baby hamster kidney (BHK) cells. Susoctocog alfa was approved for treatment of bleeding episodes in AHA in October 2014 in the United States and in November 2015 in Europe. Nevertheless, as recommended in the summary of product characteristics (SmPC), prior to any treatment with rpFVIII, it is necessary to test the cross-reactivity of auto-FVIII Abs with rpFVIII. A close monitoring of rpFVIII activity during treatment is also recommended.5 However, some questions remain concerning this laboratory assessment. The method used for the titration of anti-porcine FVIII inhibitors is comparable to that conventionally used in our laboratories. However, SmPC notifies that the patient's plasma must be incubated with plasma titrated for porcine factor-VIII instead of the normal human plasma usually used. In addition, the reference/control should be obtained by diluting rpFVIII in plasma deficient in factor VIII and not in imidazole buffer, as usually carried out.8 The aim objective of this study is first to validate in a field study the modified Nijmegen method used in our laboratories for the anti-rpFVIII titration. Ten French laboratories participated to this study and each used its local own automated, aPTT reagent and FVIII deficient plasma to perform the FVIII one-stage assay (OSA). We first compared the stability of rpFVIII after 2 h-incubation at 37°C in buffered FVIII-deficient plasma (FVIII-DP) or in imidazole buffer (IB). Recombinant pFVIII was supplied by Takeda and was first reconstituted with 1 mL of distilled water, then diluted (1/11) in buffered factor VIII-DP containing von Willebrand factor (Siemens) to obtain a concentration close to 100 IU/dL. Two different volume-to-volume mixtures were then prepared: Mixture 1: rpFVIII at 100 IU/dL + FVIII-DP and Mixture 2: rpFVIII at 100 IU/dL + IB. Factor VIII activity was measured, with a FVIII assay calibrated with NIBSC calibrator, immediately and after 2 h incubation at 37°C. Procedure was repeated in each participant laboratory three times (i.e., on three different days) resulting in three assay runs. After 2 h incubation, a decrease in rpFVIII activity was observed in each mixture and the mean differences ± standard deviation (SD) were minus 1.9 ± 3.4 IU/dL and minus 1.8 ± 2.9 IU/dL when standard rpFVIII was diluted in FVIII-deficient plasma or Imidazole buffer, respectively (Figure 1) without statistical difference between these variations (t-test: p = 0.938). We then applied the modified Nijmegen method to assess the cross-reactivity of plasma from patients with congenital hemophilia A with inhibitors (PWA) or AHA. In this step, each sample was systematically tested in two different centers (paired-centers described in Table 1). Thirty eight samples from 26 patients with AHA and 12 samples from 7 patients with hemophilia A (PWA) with circulating anti-FVIII antibodies were tested. In each laboratory, plasma samples dilutions were performed with IB instead of FVIII-DP. To evaluate the inter-laboratory variations, a set of 10 samples were systematically sent to two different laboratories. In addition, a control sample (weak human FVIII inhibitor plasma control, Cryopep, Montpellier, France) was tested in each run. Anti-rpFVIII titration was performed in each center using the following method: prior to testing, plasma samples were incubated for 30 min at 58°C as recommended by Verbruggen et al.9 and centrifuged for 10–15 min at 2500 g. Recombinant pFVIII (substrate) was reconstituted with 1 mL of distilled water and diluted 1:11 in FVIII-deficient plasma containing VWF to obtain an activity close to 100 IU/dL. For anti-rpFVIII titration, each laboratory used its own aPTT reagent and calibration curves. Several dilutions of the samples with IB were systematically performed (1:1, 1:2, 1:5, 1:10, 1:20, and 1:30). Results of rpFVIII antibodies titration of the 50 plasmas selected are shown in Table 1, and the median results obtained in the two different laboratories are shown in Figure 2 according to the population studied. We did not observed cross-reactivity to rpFVIII with the FVIII inhibitor control plasma (data none show). In 25/50 plasma samples tested, no cross-reactivity against rpFVIII was detected in either laboratory. The mean anti-hFVIII titer of these 25 samples was 14.9 BU/mL [range: 0.7–112 BU/mL]. In contrast, cross-reactivity with rpFVIII was detected by both laboratories in 19/50 samples with a mean titer of 8.5 BU/mL [range: 1.0–93.3 BU/mL]. The mean anti-hFVIII titer of these 19 samples was 37.6 BU/mL [range: 1–320 BU/mL]. Among these 19 samples, 10 came from AHA patients and 9 came from PWA with inhibitors. Cross-reactivity was clearly detected in 26% (10/38) of samples from AHA patients versus 75% (9/12) of samples from PWA with inhibitors. However, several samples from one patient were tested, and if we analyze the frequency of cross-reactivity according to patients, it was detected in 7/26 (27%) patients with AHA versus 4/7 (57%) PWA with inhibitors. Discrepancies between laboratories were reported in six samples (CO04, TOP1, NA12, RO08, LI01, and LI03) with a mean anti-rpFVIII titer equal to 0.9 BU/mL [range 0.6–1.36 BU/mL]. Among these, five were from AHA patients with probably a type 2 kinetic, which is more frequent in AHA.6 In addition, due to the multiplicity of reagents/methods used to measure residual FVIII, the concordance of results between laboratories can be relatively poor. Cross-reactivity was therefore considered positive in 16 of the 38 AHA samples (42%) but a cross-reactivity against rpFVIII above 20 BU/mL was detected in only one sample from a PWA with a titer of anti-hFVIII inhibitor at 57 BU/mL. In conclusion, our field study demonstrated the feasibility of using imidazole buffer to detect anti-rpFVIII antibodies, and confirmed the absence of impact of aPTT reagent and calibration curves on the method.10 The United Kingdom Haemophilia Centre Doctor's organisation guidelines11 recommended to use "a locally verified one-stage APTT-based assays calibrated against plasma standards to monitor rpFVIII" and a modified Bethesda assay using rpFVIII as the substrate without precision about the use of FVIII deficient plasma or imidazole buffer. A specific calibration curve using rpFVIII has been recommended by Novembrino to determine recovery as well as FVIII-DP containing VWF both for diluting standard rpFVIII and for performing OSA.12 Our study confirmed a frequency of cross-reactivity with rpFVIII close to 40% in AHAs. However, high cross-reactivity, above 20 BU/mL, contraindicating treatment, is rare and has not been observed in our AHA population. All authors contributed to perform analysis of this study. V. Le Cam Duchez, C. Ternisien, and C. Pouplard contributed to the design of study and wrote the manuscript. All authors read and approved the final manuscript. This work was supported by Takeda. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Acquired Hemophilia A (AHA) is a rare autoimmune disorder characterized by the onset of a sudden and unexpected bleeding episode in a patient with no personal or family history of bleeding diathesis, and with a typical laboratory feature, i.e., a prolonged activated partial thromboplastin time that is not otherwise explained. This bleeding disorder is caused by autoantibodies directed against the coagulation factor VIII (FVIII). AHA is idiopathic in 50% of cases and is secondary to well-defined diseases in the remaining 50%. AHA affects elderly patients although it has also been observed in the post-partum period. Bleeding manifestations are heterogeneous, ranging from mild to life-threatening bleeds involving limbs and organs. Severe bleeding with a significant decrease in hemoglobin levels must be promptly and adequately treated in order to avoid a worsening of the hemorrhages and their complications. According to international recommendations, the bypass agents (i.e., activated prothrombin complex concentrate and activated recombinant factor VII) and the replacement therapy with recombinant porcine FVIII are considered as the first-line therapy for bleeding control, due to their proven clinical efficacy. Plasma-derived or recombinant FVIII concentrates could be used as second-line treatments. Emicizumab may represent a valid and interesting therapeutic option for prophylaxis of bleeding recurrences.

Acquired hemophilia A associated with amlodipine use in a hypertensive patient: A case report

Introduction: Acquired hemophilia A (AHA) is a rare bleeding disorder with an estimated incidence of 1-2/million/year. It is caused by production of auto-antibodies which inhibit the coagulant activity of factor VIII. It can be idiopathic or associated with postpartum status, autoimmune disorders, infection and malignancy. We present a case of intractable GI bleeding due to AHA as a paraneoplastic manifestation in a patient with rectal cancer. Case report: An 87 year old male presented with new onset lower GI bleed and easy bruising. A colonoscopy with biopsies diagnosed rectal adenocarcinoma. CT angiogram was then performed due to persistent bleeding and showed extravasation of contrast at the rectal mass. Prolonged activated thromboplastin time (aPTT) of 76 sec was noted, with normal platelets and INR. Further work-up revealed a positive mixing study, severe Factor VIII activity deficiency, and a positive Factor VIII inhibitor. The diagnosis of Acquired Hemophilia A was established. Efforts were made to control the bleeding with recombinant activated factor VII, Factor VIII Inhibitor Bypassing Agent, and Methylprednisolone. The rectum also underwent packing, followed by radiation. Ultimately, due to continued rectal bleeding, he underwent lower anterior resection with end-colostomy. Following surgery, he had surgical wound bleeding requiring multiple abdominal washouts and packing. Hospital course was further complicated by multi-organ failure and family decided to withdraw care.Figure: Angiography shows the gastroduodenal artery before (Fig 1a) and after (Fig 1b) angioembolization.Figure: CT imaging done the day after angioembolization of the gastroduodenal artery showed hypodense non-enhancing areas in the head and uncinate process of pancreas with acute necrotic collections consistent with acute pancreatitis (Fig 2a). The common bile duct (CBD) was not dilated (Fig 2b), however interval CT imaging 3 months later showed significant CBD dilatation (Fig 2c).Figure: EUS (Fig 3a) noted a dilated CBD and distal CBD stricture with no accompanying biliary wall thickening or mass. Contrast hold-up was noted at the distal CBD during ERCP (Fig 3b). Subsequent attempts to cross the CBD stricture during attempted internalization of the percutaneous transhepatic biliary drain were unsuccessful (Fig 3c).Discussion: Acquired hemophilia A is a rare disease that may cause life-threatening GI bleeding. A paraneoplastic phenomenon is reported in approximately 10% of AHA cases. The most common solid cancer associated with AHA is prostate cancer with rare reports of rectal cancer. Time to diagnosis is critical due to the difficulties in treating this disease and its high mortality. Diagnosis is made in a patient with prolonged aPTT not corrected with mixing study and demonstrating: 1) reduced FVIII level and 2) detectable FVIII inhibitor. Treatment includes hemostasis and suppression of inhibitor production. Hemostasis should be attempted with a bypassing agent such as recombinant activated factor VII (rFVIIa) or Factor VIII Inhibitor Bypassing Agent (FEIBA). Immunosuppression options include use of corticosteroids alone or corticosteroids combined with cyclophosphamide. Rituximab has been also been found to be successful as a second line treatment option.Figure: CT angiogram showing luminal extravasation of contrast.Table: Table. Lab Results