Zeitschriftenartikel: „Viii ahau“

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Bazan-Socha, Stanisława, Joanna Zdziarska, Teresa Iwaniec, Jerzy Walocha, Jacek Musiał, Jerzy Dropiński und Renata Pacholczak. „Acquired Haemophilia A Associated with Subsequent Hepatocellular Carcinoma“. Hämostaseologie 39, Nr. 01 (15.08.2018): 095–99. http://dx.doi.org/10.1055/s-0038-1668570.

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AbstractAcquired haemophilia A (AHA) is a rare autoimmune disease caused by antibodies directed against clotting factor VIII. About half of cases are idiopathic, but AHA may also be secondary to autoimmune, dermatologic, or oncologic diseases. In approximately 10% of non-idiopathic cases, the disease occurs after or with the diagnosis of cancer as an extremely rare paraneoplastic syndrome. We describe the case of a 73-year-old male patient diagnosed with AHA and successfully treated with recombinant human activated factor VIIa and immunosuppression. Two and a half years later, however, the disease relapsed and a routine ultrasound revealed a liver tumour that was then diagnosed as hepatocellular carcinoma. We present this case to increase awareness that this life-threatening condition may develop years prior to the diagnosis of cancer.

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Rinaldi, Ikhwan, Findy Prasetyawaty, Siti Fazlines, Kevin Winston, Yusuf Aji Samudera Nurrobi, Jessica Leoni, Ilham Hidayat Restu Tulus Maha et al. „Diagnosis and Management of Acquired Hemophilia A: Case Reports and a Literature Review“. Case Reports in Medicine 2021 (14.09.2021): 1–9. http://dx.doi.org/10.1155/2021/5554664.

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Background. Acquired hemophilia A (AHA) is a potentially life-threatening autoimmune hemostatic disorder where autoantibodies that disrupt the functions of factor VIII (FVIII) are present in the circulation. The early diagnosis of AHA is difficult since the symptoms of AHA differ from those of congenital hemophilia A. Furthermore, the management of AHA is also more complex due to the presence of autoantibodies against FVIII (FVIII inhibitors). Here, we present three case reports and conduct a literature review of AHA with the aim to increase awareness and knowledge regarding the diagnosis and treatment of AHA. Case Presentations. We present three patients diagnosed with AHA in these case reports. The first patient was a young female, while the second and third patients were middle-aged and elderly males, respectively. All patients presented with a chief complaint of bruises without hemarthrosis and a history of bleeding. Laboratory examinations of the patients revealed isolated prolonged aPTT, normal PT, and the presence of autoantibodies against factor VIII, which are characteristics of AHA. Patients were then treated with corticosteroids to reduce the titer level of autoantibodies and received factor VIII transfusion to stop bleeding. Conclusion. AHA can be suspected in patients presenting with symptoms of bruises without hemarthrosis and without the history of bleeding. Isolated aPTT elevation with normal PT should raise high suspicion of AHA. The presence of FVIII inhibitors can help to confirm the diagnosis of AHA. Treatment consists of factor VIII transfusion and corticosteroid therapy. Bypassing agents are recommended as an alternative to FVIII transfusion.

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Kitamura, Tomohisa, Tsuyoshi Sato, Eiji Ikami, Yosuke Fukushima und Tetsuya Yoda. „A Case of a Patient Who Is Diagnosed with Mild Acquired Hemophilia A after Tooth Extraction Died of Acute Subdural Hematoma due to Head Injury“. Case Reports in Dentistry 2018 (09.12.2018): 1–3. http://dx.doi.org/10.1155/2018/7185263.

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Background. Acquired hemophilia A (AHA) is a rare disorder which results from the presence of autoantibodies against blood coagulation factor VIII. The initial diagnosis is based on the detection of an isolated prolongation of the activated partial thromboplastin time (aPTT) with negative personal and family history of bleeding disorder. Definitive diagnosis is the identification of reduced FVIII levels with evidence of FVIII neutralizing activity. Case report. We report a case of a 93-year-old female who was diagnosed as AHA after tooth extraction at her home clinic. Prolongation of aPTT and a reduction in factor VIII activity levels were observed with the presence of factor VIII inhibitor. AHA condition is mild. However, acute subdural hematoma of this patient occurred due to an unexpected accident in our hospital. Hematoma was gradually increased and the patient died 13 days after admission. Discussion. Although AHA is mild, intracranial bleeding is a life-threatening condition. We also should pay attention to the presence of AHA patients when we extract teeth.

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Scharf, R. E., C. Dobbelstein, S. Werwitzke und A. Tiede. „Management of acquired haemophilia A“. Hämostaseologie 35, Nr. 04 (2015): 311–18. http://dx.doi.org/10.5482/hamo-14-11-0064.

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SummaryAcquired haemophilia A (AHA) is caused by autoantibody inhibitors of coagulation factor VIII (FVIII : C). Recent onset of bleeds and isolated prolongation of the activated partial thromboplastin time (aPTT) are characteristic features of the disorder. Reduced FVIII : C activity and a detectable FVIII : C inhibitor in the Bethesda assay confirm the diagnosis. Patients should be referred to expert centres, whenever possible, and invasive procedures with a high risk of bleeding must be avoided, until haemostasis has been secured by adequate therapy.Bypassing agents capable of inducing sufficient thrombin formation in the presence of FVIII : C inhibitors are treatment of choice, including currently available recombinant factor VIIa (NovoSeven™) and activated prothrombin complex concentrate (FEIBA™). These agents represent first line therapy to control acute or severe bleeds. To eradicate inhibitors, immunosuppressive treatment (IST) is indicated in patients with AHA. Glucocorticoids, cytotoxic agents and rituximab are most widely used. However, an ideal IST regimen has not been established so far. Adverse events of IST, including infections as the foremost cause death, are frequent complications in AHA.

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Najafzadeh, Parisa, Chong Kim, Dandan Wang, Sierra Simmons und Huy Pham. „A Cost-Effectiveness Model for Different Treatments of Bleeding in Patients With Acquired Hemophilia“. American Journal of Clinical Pathology 152, Supplement_1 (11.09.2019): S152. http://dx.doi.org/10.1093/ajcp/aqz131.003.

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Abstract Objectives Acquired hemophilia A (AHA) is an autoimmune disorder with significant morbidity and mortality. Currently, bleeding AHA patients with high titer inhibitors can be treated with activated prothrombin complex concentrate (aPCC), recombinant factor VIIa (rFVIIa), or recombinant porcine-sequence factor VIII (rpFVIII). Given that these replacement therapies have inherent benefits and limitations, a cost-effectiveness analysis (CEA) was performed. Methods In high-titered AHA patients with bleeding treated with aPCC, rFVIIa, or rpFVIII, a Markov model was developed such that these patients were transitioned into four different health states: (1) continuous bleeding, (2) thrombosis, (3) stop bleeding, and (4) death, with states (2), (3), and (4) modeled as absorbing states during a 6-day period. Since the assessment for transition between stages (1) and (3) occurred at the beginning of the next day in the model, we assumed that the patient only required half of the medication dose on the day prior to the day the bleeding stopped. Model parameters, including probabilities, health utility index, and costs, were from the medical literature, except for the costs of aPCC, rFVIIa, and factor VIII assay, which were institutional data. Results During the 6-day period, aPCC is the least expensive option ($1,778) while rFVIIa is the most expensive ($13,925). The average quality-adjusted life days (QALDs) gained for aPCC is also slightly higher. Overall, aPCC prevailed over both rpFVIIIa and rFVIIa in deterministic and probabilistic analyses. When compared to aPCC, the incremental cost-effectiveness ratios (ICERs) for rpFVIII and rFVIIa are –$308,121/QALD and –$1,442,461/QALD, respectively. Sensitivity analyses confirmed the rmodel robustness across tested ranges of all input variables. Conclusion In high-titered AHA patients with bleeding, aPCC is the most cost-effective treatment option when compared to rpFVIII and rFVIIa. Thus, aPCC may be considered in these patients, if available, and provided there is no clinical contraindication.

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Fan, Zhiping, Qifa Liu und Jing Sun. „Acquired Haemophilia a after Allogeneic Stem Cell Transplant for Acute Myeloid Leukemia: Occurred during Cyclosporin a Used for Chronic Graft Versus Host Disease and Tolerance Induction with Rituximab“. Blood 124, Nr. 21 (06.12.2014): 5069. http://dx.doi.org/10.1182/blood.v124.21.5069.5069.

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Abstract Background: Acquired haemophilia A (AHA) is a potentially life-threatening bleeding disorder occurring in patients without a previous personal or family history of bleeding. Development of immune-mediated autoantibodies against coagulation factor VIII is associated with a wide range of clinical disorders including pregnancy, autoimmune disorders, malignancy, or with no apparent disease. AHAs occurring after autologous hematopoietic stem cell transplantation (auto-HSCT) HSCT for an autoimmune disease have been reported by the EBMT Autoimmune Disease Working Party, but AHA secondary to allogeneic (allo-) HSCT was rarely reported, except for a literature by Lozier JN, et al reported a AHA occurred after allo-HSCT for sickle cell disease. Here we reported a AHA secondary to allo-HSCT for acute myeloid leukemia (AML). Case report : A 54 years old female patient was diagnosed as having AML on March 7th 2011 in Nanfang Hospital, Guangzhou, China. She acquired complete remission after induction therapy with IA protocol, and then she received consolation therapy with IA and high dose cytarabine. As having HLA 10/10 loci matched sibling donor, she underwent allo-HSCT on July 4th 2011. The conditioning regimen consisted of fludarabine and busulfan, and standard short term methotrexate and cyclosporin A (CsA) was used to prevent acute graft versus host disease. She acquired hematopoietic reconstitution on day 11 after transplantation. She had no acute GVHD, but she acquired limited chronic GVHD 11 months after transplantation. CsA, prednisone and azathioprine was given to treat chronic GVHD. After chronic GVHD was gradually controlled, azathioprine and prednisone were stopped, CsA was tapered step by step. On October 5th 2013, she experienced onset of severe soft tissue haemorrhage (left upper arm, right gluteal and lower right leg) associated with a long aPTT and low FVIII activity (1.3%). Other pertinent coagulation studies were normal. The Bethesda assay showed a factor VIII inhibitor at 2.8 Bethesda units (BU)/ml, confirming a diagnosis of acquired AHA. Autoimmune and viral screens were negative. Considering of AHA happened during CsA used for chronic GVHD treatment, CsA was stopped, cyclophosphamide (CTX) and prednisone were given to treat AHA. The patients underwent 3 episodes of severe soft tissue haemorrhage during treatment, and factor VIII inhibitor increased to 1587.2 Bu/ml. Rituximab were started concomitant with prednisone treatment. After one dose of 375 mg/m2 and 4 doses of low dose Rituximab 100mg per week treatment, the inhibitor titre to human FVIII declined, and the patient had no signs of haemorrhage, Concomitantly, the patient’s FVIII activity rose to >100%, and remained normal after completion of 2 doses of rituximab and a complete taper of prednisone over the next 3 months. Conclusions : This is rarely AHA case emerged after allo-HSCT for AML. Prednisone and CTX were ineffective for this patient. Low dose Rituximab combined with prednisone may be a useful choice for the treatment of AHA occurring after allo-HSCT. Disclosures Liu: National Natural Science Foundation of China (81270647, 81300445, 81200388): Research Funding; National High Technology Research and Development Program of China (863 Program) (2011AA020105): Research Funding; National Public Health Grand Research Foundation (201202017): Research Funding; Natural Science Foundation of Guangdong Province (S2012010009299): Research Funding; the project of health collaborative innovation of Guangzhou city (201400000003-4, 201400000003-1): Research Funding; the Technology Plan of Guangdong Province of China (2012B031800403): Research Funding; the project of the Zhujiang Science & Technology Star of Guangzhou city (2013027): Research Funding.

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Gamage, Manori, Sadeepa Weerasinghe, Mohamed Nasoor, A. M. P. W. Karunarathne und Sashi Praba Abeyrathne. „Progressive Intramuscular Haematoma in a 12-Year-Old Boy: A Case of Acquired Haemophilia A“. Case Reports in Hematology 2018 (24.10.2018): 1–3. http://dx.doi.org/10.1155/2018/6208597.

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Acquired hemophilia A (AHA) is a rare bleeding disorder due to acquired antibodies against coagulation factor VIII (FVIII). It is rare in children less than 16 years old, and the incidence is 0.45/million/year. An otherwise healthy, 12-year-old boy was admitted to the ward with a history of swelling of the right and left forearms, for 1 day duration. He did not have any history of trauma or bleeding disorder. He had prolonged APPTT level with very high antibody titer against factor VIII. His gene expression for factor VIII was found to be normal. He was managed with FEIBA and recombinant FVII activated complexes and prednisolone 1 m/kg/day regime to control bleeding. AHA is associated with several underlying pathologies such as pregnancy, autoimmune diseases, malignancy, medications and infections; however, up to 50% of reported cases are idiopathic. In contrast to congenital haemophilia A, in which haemarthrosis is the hallmark clinical presentation, patients with AHA mainly bleed in to the skin, muscles, and soft tissues. High mortality rate of more than 20% is either to retroperitoneal or intracranial bleeds. Diagnosis is confirmed on isolated prolongation of activated partial thromboplastin time which does not normalize after addition of normal plasma, reducing the factor VIII levels with evidence of FVIII inhibitor activity. They have normal prothrombin time and platelet functions. Management of AHA involves two aspects, namely, eradication of antibodies and maintaining effective haemostasis during a bleeding episode.

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Ruck, Lela, Morey A. Blinder und William Berger. „Acquired Factor VIII Inhibitors: A Single Institution Retrospective, Observational Study“. Blood 128, Nr. 22 (02.12.2016): 4971. http://dx.doi.org/10.1182/blood.v128.22.4971.4971.

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Abstract INTRODUCTION: Acquired hemophilia A (AHA) is a rare disorder caused by an autoantibody targeting factor VIII that causes severe, potentially, life-threatening bleeding. The worldwide incidence is estimated to be 1.5 cases/million with a mortality rate as high as 20-30%. Although occasionally associated with an underlying disorder such as an autoimmune disease or a malignancy, about one half of cases are idiopathic. Due to the rarity of the disease and the lack of prognostic indicators, there is little evidence to define optimal therapy. Effective therapy usually includes both controlling any bleeding with factor replacement or a bypassing agent and immunosuppression to reduce and eliminate the inhibitor. This study evaluates the various approaches to therapy of AHA. METHODS: Between 2000 and 2015, we identified 19 patients with AHA treated at Washington University Medical Center. All patients were treated at our institution and were identified using a search of the Division of Hematology medical records. Each patient's medical record was reviewed and the diagnosis of AHA was confirmed by low factor VIII activity and elevated factor VIII inhibitor. Our data was subsequently de-identified before any further analysis occurred. Laboratory testing was performed at Barnes-Jewish Hospital using standard assays. One patient was excluded as there was no documented testing confirming the diagnosis. Recovery was defined by either factor VIII activity ³50% or inhibitor level <1 BU, or both. RESULTS: Of the 18 eligible patients, 10 were male and 8 were female. The mean age at diagnosis was 70 years old (range 40-86). One patient was diagnosed with lymphoma within a year of diagnosis and one had concurrent rheumatoid arthritis. All of our patients presented with clinically significant bleeding, usually including subcutaneous bleeding. Only one patient died from complications directly related to AHA. The factor VIII activity was ²1% in 11 of 18 patients (range <1-27%) and the median inhibitor levels of 60.2 Bethesda Units (BU). Despite bleeding in all patients, 5/18 (28%) patients did not receive any blood factor treatment to control bleeding. Within our cohort, 10 patients (56%) received recombinant human factor VIIa. To date, doses were compiled in 5 patients and ranged from 8,200 µg-150,000 µg (mean 52,240 µg). Notably, the initial inhibitor level did not seem to correlate with the type of bleeding or the amount of product used. Sequential inhibitor levels were available for 13/18 patients (Figure). Among these patients, 7 achieved recovery within 6 months, with recovery occurring in 32-154 days. Despite 4 patients having persistently identified inhibitors (initial inhibitors ranging from 67-725 BU) for over 1 year and never achieving a recovery, their bleeding stabilized enough to be discharged without further factor product support. The initial inhibitor titer did not seem to correlate with time to recovery. Eighty-nine percent of patients (16/18) were treated with immunosuppressive therapy, all of whom received corticosteroids alone or in combination with other agents. One half of the treated patients received rituximab and all of these patients recovered. DISCUSSION: The rarity of AHA has severely limited the possibility of prospective trials evaluating different treatment approaches. Furthermore, the absence of prognostic markers impairs the ability to guide initial therapy including identifying patients needing blood factor support. In this study, all patients had bleeding at presentation, but 28% of patients did not receive any initial blood factor support and of the 22% of patients with a persistent inhibitor, sustained, long-term blood factor support was not utilized. Similarly, the role of immunosuppression is not well defined. In this study, patients with higher inhibitor titers tended to be treated with multiple immunosuppressive agents despite the lack of evidence that more aggressive treatments are more effective. Immunosuppressive treatment of patients with persistent inhibitors is undefined. It is unclear whether there are other factors that identify patients who are at higher risk of treatment failure or relapse. As new agents for blood factor support, such as recombinant porcine factor VIII are available, and as immunosuppressive therapy continues to evolve, further studies are warranted to address appropriate, cost-effective treatment approaches for AHA. Figure Figure. Disclosures Blinder: Janssen: Honoraria; CSL Behring: Honoraria; Novartis: Honoraria.

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Sihombing, Rasco Sandy, Henry Ratno Diono Silalahi, Hamzah Shatri, Lugyanti Sukrisman, Ikhwan Rinaldi, Findy Prasetyawati, Endy Novianto und Em Yunir. „Diagnosis dan Tata Laksana Acquired Hemophilia A (AHA) dengan Pemfigoid Bulosa“. Jurnal Penyakit Dalam Indonesia 3, Nr. 4 (27.01.2017): 218. http://dx.doi.org/10.7454/jpdi.v3i4.56.

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Acquired hemophilia A merupakan kondisi dimana faktor koagulasi VIII menjadi tidak aktif akibat pembentukan autoantibodi. Kondisi ini dikaitkan dengan kehamilan, keganasan, dan penyakit auitoimun dengan kelainan kulit. Pada kasus ini, seorang wanita berusia 66 tahun, datang dengan keluhan perdarahan paska tindakan yang disertai dengan lesi kulit. Pasien didiagnosis dengan acquired hemophilia A dengan ditemukannya inhibitor faktor VIII terkait dengan pemfigoid bulosa.Kata Kunci: Acquired hemophilia A, diagnosis, pemfigoid bulosa, tata laksana Diagnosis and Treatment of Acquired Hemophilia A (AHA) with Bullous PemphigoidAcquired hemophilia A is a condition in which coagulation factor VIII become inactive due to autoantibody formation. This condition is related to pregnancy, malignancy, and autoimmune disease with skin disorder. In this case report, a 66 years woman with a post procedural bleeding with skin disorder. Later on, patient diagnosed with acquired hemophilia A with a factor VIII inhibitors related to bullous pemphigoid. Keywords : Acquired hemophilia A, bullous pemphigoid, diagnosis, treatment

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Elbaz, Carolyne, Katerina Pavenski, Hina Chaudhry, Jerome M. Teitel und Michelle Sholzberg. „The Frequency and Effect of Baseline Cross-Reacting and De Novo Inhibitors to Recombinant Porcine FVIII in Patients with Congenital and Acquired Hemophilia a“. Blood 134, Supplement_1 (13.11.2019): 1128. http://dx.doi.org/10.1182/blood-2019-122260.

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Background Patients with severe congenital hemophilia A (CHA) have a 25-40% lifetime risk of alloantibody (inhibitor) development to FVIII. Patients with acquired hemophilia A (AHA) spontaneously develop neutralizing autoantibodies to factor VIII. In both cases, patients require pro-hemostatic therapy with bypassing agents: recombinant factor VIIa (rFVIIa), activated prothrombin complex concentrate (aPCC) and more recently recombinant porcine factor VIII (rpFVIII). Anti-human FVIII (hFVIII) inhibitors typically bind to the A2 and C2 domains of the FVIII molecule. RpFVIII is an effective pro-hemostatic treatment for AHA and CHA given the immunologic difference in the A2 and C2 domains of the rpFVIII while maintaining sufficient hFVIII homology to act as an effective cofactor to human FIX in the intrinsic tenase. However, some anti-hFVIII antibodies cross-react with rpFVIII and may interfere with its hemostatic function. Cross-reacting antibodies were reported in 35% of subjects in a phase II/III trial prior to initiation of rpFVIII. Moreover, de novo rpFVIII inhibitors may develop during or after the treatment with rpFVIII and may affect its hemostatic function. Here we describe the largest case series to date on baseline cross-reactivity of rpFVIII inhibitors and post-treatment de novo inhibitor development in patients with CHA and AHA to address the paucity of published literature in this area. Aim First, we describe the frequency of baseline cross-reacting rpFVIII inhibitors in patients with AHA and CHA (with inhibitors) at our institution. Second, we describe the effect of baseline rpFVIII antibodies on FVIII recovery after treatment with rpFVIII. We also describe the frequency and timing of de novo rpFVIII inhibitor development after exposure to rpFVIII. Methods Institutional research ethics board approval was obtained. Electronic charts of patients admitted to our institution with AHA or CHA who underwent testing for rpFVIII inhibitors were reviewed retrospectively. RpFVIII inhibitor assay is performed in the special coagulation laboratory using the Nijmegen modified Bethesda assay. The patient sample is initially heat-treated at 57 Results Twenty-seven patients (7 CHA, 20 AHA) underwent testing for porcine inhibitors since assay availability in 2016. 61% (5/7 CHA, 11/20 AHA) of patients had a detectable rpFVIII inhibitor prior to exposure to rpFVIII; median titer 1.6 BU/ml (range 0.6-192). Eight patients with AHA with baseline cross-reacting inhibitors received rpFVIII. Of those, three achieved an initial FVIII recovery beyond 100% (132%, 148% and 177%) after approximately 100U/kg of rpFVIII and all three had very low anti-rpFVIII Bethesda titers (0.70, 0.85 and 0.9 BU/ml). Five patients did not achieve a FVIII recovery above 50% (46%, 46%, 40%, 36% and 0%) despite approximately 100U/kg of rpFVIII. Most patients who received rpFVIII were tested weekly for the duration of their treatment or hospital stay. Upon discharge, patients who were seen in clinic for follow up were tested for anti-hFVIII and anti-rpFVIII. Two AHA patients without a baseline inhibitor who received rpFVIII treatment developed a de novo inhibitor after 20 days (1 BU/ml) and 133 days (12 BU/ml), respectively. One AHA patient had a rise in baseline anti-rpFVIII titer after exposure to rpFVIII. Conclusion In conclusion, we found that 61% of patients with AHA and CHA tested for rpFVIII inhibitors had a detectable baseline cross-reacting inhibitor which is higher than previously described. Of those patients with a baseline inhibitor treated with rpFVIII, only 37.5% of patients had an appropriate rise in FVIII. Finally, 13% of patients without baseline inhibitors developed a de novo inhibitor after exposure to rpFVIII, an incidence comparable to previously published findings. Disclosures Pavenski: Bioverativ: Research Funding; Alexion: Honoraria, Research Funding; Octapharma: Research Funding; Shire: Honoraria; Ablynx: Honoraria, Research Funding. Teitel:BioMarin: Consultancy; CSL Behring: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Shire: Consultancy; Pfizer: Consultancy, Research Funding; Bayer: Consultancy, Research Funding. Sholzberg:Takeda: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding. OffLabel Disclosure: Recombinant porcine factor VIII is used to treated patients with congenital hemophilia A with allo inhibitors

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Nishiya, Katsumi, Keiji Nogami, Kiyotaka Okada, Osamu Matsuo, Masahiro Takeyama, Kenichi Ogiwara, Ichiro Tanaka, Akira Yoshioka und Midori Shima. „Localization of Factor VIII Interactive Site within Plasmin/Plasminogen Which Is Responsible for Plasmin-Catalyzed Activation/Inactivation of Factor VIII.“ Blood 110, Nr. 11 (16.11.2007): 1759. http://dx.doi.org/10.1182/blood.v110.11.1759.1759.

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Abstract Plasmin (Plm), an active form of plasminogen (Plg), not only functions as a key enzyme in the fibrinolytic system, but also directly inactivates several coagulation factors. Especially, factor VIII is inactivated by Plm immediately after the activation by limited proteolytic cleavage at Lys36, Arg336, Arg372, and Arg740 in the heavy chain, and at Arg1689 and Arg1721 in the light chain (Nogami et al. J. Biol. Chem. 2007, 282, 5287). We recently have identified the plasmin-interactive sites on the A2 domain responsible for cleavages at Arg336 and Arg372, and on the light chain responsible for cleavage at Lys36 (Abst #1991/1709, BLOOD 102/108, 2005/2006). In the present study, we attempted to localize a factor VIII-interactive site on Plm (and Plg). Competitive binding assay using 6-aminohexanoic acid (6-AHA), a competitor of lysine-binding site (LBS) of Plm/Plg, showed that 6-AHA markedly inhibited (by >90%) the light chain binding to active-site modified Plm (anhydro-Plm), whilst inhibited weakly the A2 binding (by ∼30%). These results suggested that the light chain interaction with Plm was mainly dependent upon LBS, but the A2 interaction was independent. The addition of monoclonal antibody (mAb) against Plg kringle 5-catalytic domain (K5-CD) significantly inhibited Plm-catalyzed activation/inactivation of factor VIII or VIIIa with an ∼4-fold lower rate constant. On the other hand, anti-K1-3 and anti-K4 mAbs any little affected. SDS-PAGE analysis revealed that only anti-K5-CD mAb blocked Plm-catalyzed cleavages at Arg336 and Arg372 by ∼90% in dose-dependent manners (IC50: ∼20 nM). Surface plasmon resonance-based assays showed that the isolated K5-CD bound to factor VIII with an ∼50-fold higher affinity (Kd: 3 nM) compared to the K1-3 and K4, similar to the affinity obtained with anhydro-Plm (Kd: 4 nM). In particular, the K5-CD bound to the A2 domain with an ∼5-fold higher affinity (Kd: 42 nM) than those obtained with the K1-3 and K4. In contrast, both the K1-3 and K4 bound to the light chain predominantly (Kd: 43 and 87 nM, respectively), whilst the K5-CD failed to bind. Furthermore, the addition of a goat antibody against the CD (C-14; Santa Cruz Biotechnology) completely blocked the A2 and K5-CD interaction (by ∼95%). These findings suggest that the CD of Plm (and Plg) interacts with the factor VIII A2 domain through the LBS-independent mechanisms, whilst the K1-3 (and/or K4) interacts with the light chain through the LBS-dependent mechanisms. Furthermore, the CD and A2 interaction would regulate the activation/inactivation of factor VIII by proteolytic cleavages of Arg336 and Arg372.

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Celestino, Francesco, Cristian Verri, Francesco De Carlo und Savino Mauro Di Stasi. „Localised prostate cancer and hemophilia A (AHA): Case report and management of the disease“. Archivio Italiano di Urologia e Andrologia 86, Nr. 3 (30.09.2014): 227. http://dx.doi.org/10.4081/aiua.2014.3.227.

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Acquired Hemophilia A (AHA) is a rare bleeding diathesis characterized by the development of autoantibodies against factor VIII (FVIII). About half of the cases are idiopathic and the other half are associated with autoimmune diseases, postpartum problems, infections, inflammatory bowel disease, drugs, lymphoproliferative disorders or solid tumors . AHA is associated with malignancies in 7-15% of cases. We report a case of AHA in a 65 year old patient with prostatic carcinoma, who underwent retropubic radical prostatectomy (RP).

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Mauro, E., E. Garlatti Costa, A. Zanier, M. Maset, A. Ermacora, M. Ghersetti und P. Casarin. „Acquired Haemophilia A. Which is the best therapeutic choice in older adults? Single center study of 4 cases“. Reumatismo 71, Nr. 1 (01.04.2019): 37–41. http://dx.doi.org/10.4081/reumatismo.2019.1041.

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Acquired haemophilia A (AHA) is a rare bleeding disorder due to autoantibodies directed against coagulation factor VIII. The treatment is based on recombinant activated factor VII and activated prothrombin complex concentrate. However, mainly in older patients, severe thrombotic complications have been reported. Here we report the different therapeutic approaches in 4 cases of elderly patients with AHA and co-morbidities.

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Tiede, Andreas, Robert Klamroth, Rüdiger E. Scharf, Ralf U. Trappe, Katharina Holstein, Angela Huth-Kühne, Saskia Gottstein et al. „Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study“. Blood 125, Nr. 7 (12.02.2015): 1091–97. http://dx.doi.org/10.1182/blood-2014-07-587089.

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Key Points This study is the first to assess prognostic factors in patients with AHA treated according to a uniform immunosuppressive regimen. Residual factor VIII activity and inhibitor concentration at baseline are potentially useful predictors of remission.

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Franchini, Massimo, und Pier Mannucci. „Acquired haemophilia A: A 2013 update“. Thrombosis and Haemostasis 110, Nr. 12 (2013): 1114–20. http://dx.doi.org/10.1160/th13-05-0363.

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SummaryAcquired haemophilia A (AHA) is a rare but often severe bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). AHA occurs more frequently in the elderly and in association with several conditions, such as the post-partum period, malignancies, autoimmune diseases or drug exposure; however, approximately 50% of reported cases are apparently idiopathic. Beside the elimination of the underlying disorder, the therapeutic approach to AHA should be directed toward the control of acute bleed and the eradication of FVIII autoantibody production. In this narrative review, we summarise the current knowledge on the epidemiology, diagnosis and clinical features of AHA, focusing in particular on advances in the management of this challenging bleeding disorder.

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Probowati, Wiwiek. „ACQUIRED HEMOPHILIA A IN DIABETIC WOMAN, Case Report“. Berkala Ilmiah Kedokteran Duta Wacana 3, Nr. 2 (20.10.2018): 107. http://dx.doi.org/10.21460/bikdw.v3i2.108.

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Background Acquired hemophilia is a rare condition in which autoantibodies, usually IgG class are produced against factor VIII or IX. Age distribution is bimodal. Although hemophilia is a hereditary disease, approximately 20-30% of patients have no family history of clotting disorders. Case report A 55-year-old lady with major complaints of gums bleeding, bruises on the both of leg and thighs that are varying colour (multiple spontaneus haematomas. No previous history of bleeding and no history of blood clotting disorders in the family. She has diabetes mellitus for 8 years was treated metformin three times a day, and )controlled level of blood glucose. Laboratory findings showed decreased haemoglobin (5,7 mg/dl) with prolonged aPTT 129 s(28 s control) but still got the normal PPT that is 17.2 s (14.4 s control) and normal INR 1,3, factor VIII activity got decrease with result of 1,5% (control 91,1%) but factor IX activity still normal 118,7% (control 108%). The Factor VIII inhibitor was 19.52 Bethesda Unit. After exclusion of other possible pathological condition and on the basis of lab criteria we diagnosed the case as acquired hemophilia A. Discussion The diagnosis of Acqured hemophlia A (AHA) shoud be considered in patient who present with bleeding and prolonged aPPT. The pattern of bleeding in AHA differs from that in congenital hemophilia A. Bleeding tends to occur in soft tissue, muscle, retroperitoneal space, iatrogenic bleeding is also common. The diagnosis is then confirmed by a Bethesda positive assay for F VIII inhibitor titre. Diagnostic test in AHA are clotting factor measurement (isolated low FVIII level) and quantification of the inhibitor titer (presence of inhibitor). Most often the cause is idiopathic in 50% of patient or it can be associated with autoimun disorders, hepatitis and diabetes. Chronic disease or diabetes mellitus makes misrecognition tends to self antigen.1,3 Conclusion A 55-years-old lady with diabetes got symptoms gum bleeding, multiple spontaneuos hematomes and very low in factor VIII activity and presence of factor VIII inhibitor. It is concluded that this patient is diagnosed of acquired hemophilia A. Keywords: Acquired Haemophilia A, activated partial thromboplastin time (APTT), Factor VIII. Multiple haematomes in acquired haemphilia References 1. Ma AD, Carrizosa D. Acquired Factor VIII Inhibitors: Pathophysiology and Treatment. American Society of Hematology. 2006. 2. Antonela Tufano, Antonio Copola, Anna Guida, Acquired Hemophilia in Elderly, Current Gerontology and Geriatric Research volume 2010 3. Giangrande P. Acquired Hemophilia. World Federation of Hemophilia. 2012. 4. Sakurai Y, Takeda T. Acquired Hemophilia A: A Frequently Overlooked Autoimmune Hemorrhagic Disorder. Journal of Immunology Research. 2014. 5. Srivastava A, et al. Guidelines for the Management of Hemophilia 2nd edition. World Federation of Hemophilia. 2012 6. Rotty LWA. Hemofilia A dan B dalam Buku Ajar Ilmu Penyakit Dalam. Interna Publishing. Jakarta. 2014. Laporan Kasus ACQUIRED HEMOPHILIA A PADA WANITA PENDERITA DIABETES Wiwiek Probowati1, Mardiah Suci Hardanti2 1 Bagian Penyakit Dalam, Rumah Sakit Bethesda, Yogyakarta 2 Bagian Haematologi Onkologi Medik, Bagian Penyakit Dalam Universitas Gadjah Mada, Rumah Sakit Umum Pusat Sardjito Yogyakarta Latar Belakang Acquired Hemofilia adalah kondisi sangat jarang di mana autoantibodi, IgG diproduksi terhadap faktor VIII atau IX. Distribusi usia adalah bimodal. Meskipun hemofilia adalah penyakit keturunan, sekitar 20-30% pasien tidak memiliki riwayat keluarga gangguan pembekuan. Laporan kasus Seorang wanita berusia 55 tahun dengan keluhan utama perdarahan gusi, memar di kedua kaki dan paha yang warnanya bervariasi (multiple spontaneus hematoma). Tidak ada riwayat perdarahan sebelumnya dan tidak ada riwayat gangguan pembekuan darah dalam keluarga. Ia menderita diabetes mellitus selama 8 tahun diterapi dengan metformin dan kadar glukosa darah terkontrol. Hasil laboratorium menunjukkan penurunan hemoglobin (5,7 mg / dl) dengan PT 129 (kontrol 28), PPT normal yaitu 17,2 s (kontrol 14,4 s) dan INR normal 1,3, aktivitas faktor VIII mengalami penurunan dengan hasil 1,5% (kontrol 91,1%) tetapi aktivitas faktor IX masih normal 118,7% (kontrol 108%). Inhibitor Faktor VIII adalah 19,52 Unit Bethesda. Berdasarkan kriteria laboratorium, diagnosis kasus ini adalah acquired hemofilia A. Diskusi Diagnosis Acqured hemophlia A (AHA) harus dipertimbangkan pada pasien yang datang dengan perdarahan dan pemanjangan PPT. Pola perdarahan pada AHA berbeda dari pada hemofilia kongenital A. Perdarahan cenderung terjadi pada jaringan lunak, otot, ruang retroperitoneal, perdarahan iatrogenik juga sering terjadi. Tes Bethesda positif untuk titer inhibitor F VIII. Tes diagnostik dalam AHA adalah dengan mengukur faktor pembekuan (tingkat FVIII rendah terisolasi) dan kuantifikasi titer inhibitor (inhibitor). Penyebab tersering pasien dikaitkan dengan gangguan autoimun, hepatitis dan diabetes. Penyakit kronis atau diabetes mellitus menimbulkan misrecognition terhadap antigen penderita.1,3 Kesimpulan Seorang wanita 55 tahun dengan diabetes mengalami gejala perdarahan gusi, hematom spontan di paha dan perut dengan aktivitas faktor VIII yang sangat rendah dan munculnya faktor VIII inhibitor. Pasien ini didiagnosis menderita Acquired hemofilia A. Kata kunci: Acquired Haemophilia A, activated partial thromboplastin time (APTT), Factor VIII. Hematom multipel pada acquired hemofilia Daftar Pustaka 1. Ma AD, Carrizosa D. Acquired Factor VIII Inhibitors: Pathophysiology and Treatment. American Society of Hematology. 2006. 2. Antonela Tufano, Antonio Copola, Anna Guida, Acquired Hemophilia in Elderly, Current Gerontology and Geriatric Research volume 2010 3. Giangrande P. Acquired Hemophilia. World Federation of Hemophilia. 2012. 4. Sakurai Y, Takeda T. Acquired Hemophilia A: A Frequently Overlooked Autoimmune Hemorrhagic Disorder. Journal of Immunology Research. 2014. 5. Srivastava A, et al. Guidelines for the Management of Hemophilia 2nd edition. World Federation of Hemophilia. 2012 6. Rotty LWA. Hemofilia A dan B dalam Buku Ajar Ilmu Penyakit Dalam. Interna Publishing. Jakarta. 2014.

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Khandelwal, Aditi, Syed Mahamad, Jerome M. Teitel und Michelle Sholzberg. „Surgery in Patients with Factor VIII Inhibitors: A Retrospective Case Series at the Largest Canadian Hemophilia Care Centre“. Blood 128, Nr. 22 (02.12.2016): 1418. http://dx.doi.org/10.1182/blood.v128.22.1418.1418.

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Abstract Introduction: Factor VIII (FVIII) inhibitors develop in a significant proportion of patients with severe congenital hemophilia A (CHA) and is also rarely acquired (AHA). These patients are at high risk of bleeding, particularly with surgical challenge. FVIII bypassing therapy and porcine factor VIII products have decreased the risk of bleeding complications and provided the opportunity for elective surgical intervention in this patient population. Factor VIII bypassing agents include activated Prothrombin Complex Concentrate (aPCC or FEIBA) and activated recombinant Factor VII (rFVIIa, Niastase). Porcine factor VIII products include plasma-derived Hyate C (historically) and currently, recombinant Obizur. To our knowledge, this is the largest Canadian review of perioperative management and outcomes in patients with factor VIII inhibitors. Methods: We conducted a retrospective review of CHA with FVIII inhibitors and AHA who underwent surgery at the largest Canadian Hemophilia Treatment Center (HTC) between January 1, 1998 - December 31, 2015. The primary objectives were to describe perioperative characteristics, hemostatic therapy use (including adjunctive), bleeding and thromboembolic outcomes. All included patients had to have an evidence of high responding inhibitor either previously or at the time of surgical intervention. Results: Twenty-two patients (10/22 with AHA) had surgical procedures at our institution between 1998 and 2015. All CHA were male, with the average age of 33 years (ranging 16 to 50 years) at first surgery at our center. Two out of 10 AHA were women. Mean age at first surgery for AHA patients was 59 years (ranging 24 to 85 years). A total of 21 major procedures and 26 minor procedures were performed (using World Hemophilia Federation definitions). The major procedures included 11 orthopedic procedures, nine abdominal surgeries and one breast surgery. Minor procedures included 11 oesophagogastroduodenoscopies (OGDs), three tracheostomies, two colonoscopies, two cystoscopies, two dental extractions, one nasopharyngoscopy, one bronchoscopy, one arthroscopy, one pacemaker insertion, one burr hole for subdural hemorrhage and one arteriovenous fistula creation. For each procedure, a hemophilia-focused hematologist tailored the hemostatic strategy. aPCC was used in six procedures and rFVIIa was used in 18 procedures. Two procedures required first rFVIIa then transition to aPCC; one procedure was managed with FVIII then rFVIIa and aPCC sequentially due to minor bleeding. One patient with subdural hematoma received high dose FVIII followed by porcine FVIII and aPCC in preparation for an urgent burr hole for hematoma evacuation. High dose FVIII alone was used in seven procedures, while a combination of FVIII and rFVIIa was used in three procedures and FVIII with aPCC in three procedures. Three patients, all of whom were AHA patients, experienced adverse perioperative outcomes. One patient had six urgent laparotomies for hepatojejunostomy complicated by abdominal compartment syndrome, recurrent hemorrhage, intra-abdominal abscess drainage and large ventral hernia mesh repair. Despite the severity of her illness, this patient made a full recovery and remains in complete remission. Another patient undergoing partial bowel resection for Crohn's disease had an intra-abdominal hemorrhage requiring repeat laparotomy. The third patient had esophageal cancer with recurrent bleeding from radiation gastritis. He underwent four OGDs and later died from metastatic disease. Conclusions: FVIII bypassing agents and porcine FVIII products have allowed for the safe performance of a variety of major and minor surgical procedures at our HTC in patients with FVIII inhibitors. Excessive perioperative bleeding despite hemostatic therapy that required repetitive surgical/endoscopic intervention occurred exclusively in AHA patients. Disclosures Sholzberg: Novonordisk: Honoraria; Shire (previously Baxter, Baxalta): Honoraria, Research Funding.

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Sakurai, Yoshihiko, und Tomohiro Takeda. „Acquired Hemophilia A: A Frequently Overlooked Autoimmune Hemorrhagic Disorder“. Journal of Immunology Research 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/320674.

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Acquired hemophilia A (AHA) is a rare hemorrhagic disease in which autoantibodies against coagulation factor VIII- (FVIII-) neutralizing antibodies (inhibitors) impair the intrinsic coagulation system. As the inhibitors developed in AHA are autoantibodies, the disease may have an autoimmune cause and is often associated with autoimmune disease. Although acute hemorrhage associated with AHA may be fatal and is costly to treat, AHA is often unrecognized or misdiagnosed. AHA should thus be considered in the differential diagnosis particularly in postpartum women and the elderly with bleeding tendency or prolonged activated partial thromboplastin time. Cross-mixing tests and measurement of FVIII-binding antibodies are useful to confirm AHA diagnosis. For treatment of acute hemorrhage, hemostatic therapy with bypassing agents should be provided. Unlike in congenital hemophilia A with inhibitors, in which immune tolerance induction therapy using repetitive infusions of high-dose FVIII concentrates is effective for inhibitor eradication, immune tolerance induction therapy has shown poor efficacy in treating AHA. Immunosuppressive treatment should thus be initiated to eradicate inhibitors as soon as the diagnosis of AHA is confirmed.

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Nguyen, S., P. Teh, J. Zhou, E. Y. Chang und A. von Drygalski. „Acquired Hemophilia A (FVIII Deficiency) Associated with Papillary Thyroid Cancer: Treatment with Recombinant Porcine FVIII“. Case Reports in Hematology 2019 (28.08.2019): 1–5. http://dx.doi.org/10.1155/2019/9026121.

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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.

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Binet, Quentin, Catherine Lambert, Laurine Sacré, Stéphane Eeckhoudt und Cedric Hermans. „Successful Management of Acquired Hemophilia A Associated with Bullous Pemphigoid: A Case Report and Review of the Literature“. Case Reports in Hematology 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/2057019.

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Background. Acquired hemophilia A (AHA) is a rare condition, due to the spontaneous formation of neutralizing antibodies against endogenous factor VIII. About half the cases are associated with pregnancy, postpartum, autoimmune diseases, malignancies, or adverse drug reactions. Symptoms include severe and unexpected bleeding that may prove life-threatening.Case Study. We report a case of AHA associated with bullous pemphigoid (BP), a chronic, autoimmune, subepidermal, blistering skin disease. To our knowledge, this is the 25th documented case of such an association. Following treatment for less than 3 months consisting of methylprednisolone at decreasing dose levels along with four courses of rituximab (monoclonal antibody directed against the CD20 protein), AHA was completely cured and BP well-controlled.Conclusions. This report illustrates a rare association of AHA and BP, supporting the possibility of eradicating the inhibitor with a well-conducted short-term treatment.

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Hansenne, Amandine, und Cedric Hermans. „Emicizumab in acquired haemophilia A: about two clinical cases and literature review“. Therapeutic Advances in Hematology 12 (Januar 2021): 204062072110381. http://dx.doi.org/10.1177/20406207211038193.

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Acquired haemophilia A (AHA) is a rare and severe haemorrhagic autoimmune disease caused by autoantibodies directed against factor VIII (FVIII). Treatment is based on two principles, including haemostatic control to compensate FVIII inhibition and eradication of inhibiting antibodies using immunosuppressive therapy. Rapid recognition and proper management are essential to avoid excess morbidity and mortality. Effective and safe treatments can be challenging, given that AHA patients are often elderly, with multiple comorbidities. Emicizumab, a bispecific antibody that mimics the action of FVIII, has proven effective in managing patients with congenital haemophilia, with or without inhibitors. Likewise, its mode of action suggests theoretical efficacy in AHA patients. We herein describe two AHA cases with comorbidities that were treated effectively using emicizumab combined with immunosuppressive therapy. We have also reviewed the current literature regarding the promising use of emicizumab in this indication.

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Takeyama, Masahiro, Keiji Nogami, Tomoko Matsumoto, Takehisa Kitazawa, Kunihiro Hattori und Midori Shima. „Anti-Factor IXa/Factor X Antibody (ACE910) Improves the Coagulation Function in Acquired Hemophilia A ex vivo“. Blood 126, Nr. 23 (03.12.2015): 3565. http://dx.doi.org/10.1182/blood.v126.23.3565.3565.

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Abstract <Introduction> Acquired hemophilia A (AHA) is a rare bleeding disorder in which autoantibodies (autoAbs) against coagulation factor (F)VIII impair the coagulation system. Anti-FVIII autoAbs developed in AHA are polyclonal and the majority of these autoAbs bind to the A2, A3, and/or C2 domains in FVIII. Different inhibitory actions of anti-FVIII autoAbs, depending on their epitopes, are well-known. We have recently developed a humanized anti-FIXa/X bispecific antibody, ACE910, which mimics the cofactor function of FVIIIa even in the presence of anti-FVIII alloantibodies. <Aim> In this study, we examined whether ACE910 improved the lower coagulation function in AHA patients using the comprehensive coagulation assays. <Methods> Two representative experiments were performed as follows; 1) In vitro effects of ACE910 on normal pooled plasmas (PNPs) mixed with various anti-FVIII monoclonal Abs (mAbs) as the reconstituted AHA-models. For this experiments, several anti-FVIII mAbs; VIII-9222 (epitope: anti-a1), VIII-2236 (anti-A2), VIII-3776 (anti-A3C1), ESH4 (anti-C2) were prepared. 2) Ex vivo effects of ACE910 on plasmas obtained from nine patients with AHA, whose regions of Abs were A1, A2 and light chain for four patients, A2 and light chain for three patients, A2 for one patient and light chain for one patient. The coagulation functions in obtained samples were evaluated using the comprehensive coagulation assays, clot waveform analysis (CWA) and thrombin generation assays (TGA). In CWA, the minimum value of the first derivative (min1) and the second derivative (min2) were calculated as an index of the maximum acceleration of the reaction and the maximum velocity of coagulation, respectively. In TGA, calibrated automated thrombin generation assays derived the standard parameters; peak thrombin, lagtime, and time to peak. Total thrombin generation at intervals from the beginning to peak level was quantified. These values (nmol/l) were divided by the sample times (min, time to peak - lagtime), and represented the mean velocity of thrombin generation until the reach to peak level, expressed as mean velocity to peak thrombin (MV-peak thrombin). We defined the attenuation of inhibitory effect (% of AIE) represented that ACE910 attenuated the parameters inhibited by mAbs in artificial AHA or by allo-Abs in AHA patients, respectively. Figure 1 represents the % of AIE on thrombin peak in TGA. <Results> PNPs were incubated with various anti-FVIII mAbs (100-500 mcg/ml) at 37 degrees Celsius for 2 hrs, and FVIII activities in these samples were decreased to 2.0-43%. These reactant mixtures were reacted with ACE910 (0-20 mcg/ml) for a further 2 hr-incubation. ACE910 improved the parameters of CWA (|min1|; 40-62%, and |min2|; 49-74% of AIE) and of TGA (thrombin peak; 46-72%, and MV-peak thrombin; 51-70% of AIE, respectively) in all PNPs with mAbs. These data indicated that ACE910 improved the coagulant activity in AHA patients. Therefore, we determined the efficacy of ACE910 for nine AHA patients ex vivo. FVIII activities and FVIII inhibitors were <1.0-7.5 % and 2.2-134 BU/ml, respectively. ACE910 improved the parameters for eight AHA patients in CWA (|min1|; 36-100 %, and |min2|; 52-100 % of AIE, respectively). For one AHA patient whose epitope was A2 and light chain, ACE910 showed the slight improvement in |min1| (12 % of AIE) and in |min2| (31 % of AIE). The reason was that the range of concentration of ACE910 was only from 0 to 5 mcg/dl. On the other hand, ACE910 improved the parameters for all AHA patients in TGA. ACE910 showed effect on thrombin peak (27-77 % of AIE). Furthermore, ACE910 improved MV-peak thrombin (17-73 % of AIE). Figure 2 shows representative TGA curve for the effect of ACE910 on one AHA patient whose allo-Ab was anti-light chain. <Conclusion> Our results indicated that ACE910 could improve the coagulant activities in AHA patients independent of the regions of antibodies and might be useful for the treatment of AHA patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Takeyama: Chugai Pharmaceutical Co., Ltd.: Research Funding. Nogami:Bayer, NovoNordisk, Baxalta, Chugai, Kaketsuken, Pfizer, Biogen: Honoraria; Chugai: Membership on an entity's Board of Directors or advisory committees; Bayer, Novo Nordisk, Baxalta. Biogen: Research Funding. Matsumoto:Chugai Pharmaceutical Co., Ltd: Research Funding. Kitazawa:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership, Patents & Royalties. Hattori:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership, Patents & Royalties. Shima:Chugai Pharmaceutical Co., Ltd. and F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Oba, Susumu, Mitsuhiko Nakahira, Yasunao Kogashiwa, Yasuhiro Ebihara und Masashi Sugasawa. „Acquired Hemophilia A Presenting as Massive Postoperative Bleeding in a Patient with Oral Squamous Cell Carcinoma“. Case Reports in Otolaryngology 2020 (04.09.2020): 1–5. http://dx.doi.org/10.1155/2020/8961785.

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Acquired hemophilia A (AHA) is an extremely rare and serious bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Approximately, 10% of patients with AHA have an underlying malignancy. We report on a 46-year-old man with AHA and advanced oral cancer who presented with massive bleeding after surgery. Preoperative blood coagulation tests showed no abnormalities. He underwent radical tumor resection followed by reconstruction using a free rectus abdominal musculocutaneous flap. Massive subcutaneous hemorrhage developed in his neck and abdomen on the first postoperative day. The hemorrhage remained uncontrolled, despite embolization of the responsible vessels. Subsequent laboratory data showed prolonged activated partial thromboplastin time and decreased FVIII levels. On the basis of his clinical course and the presence of the FVIII inhibitor, we speculated that the patient suffered from AHA. We administered recombinant activated factor VII and prednisolone, after which the spontaneous bleeding stopped and the subcutaneous hemorrhage resolved. A review of the literature identified only three previous documented cases of AHA associated with head and neck cancer. This case indicates that AHA should not be ruled out in patients with uncontrolled postoperative bleeding, while attempting to ensure bleeding control and preventing potentially catastrophic fatal consequences.

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Pauls, Mehrnoosh, Natalia Rydz, Nancy A. Nixon und Doreen Ezeife. „Paraneoplastic acquired haemophilia A in extensive-stage small cell lung cancer (ES-SCLC) in the era of immunotherapy“. BMJ Case Reports 14, Nr. 1 (Januar 2021): e236973. http://dx.doi.org/10.1136/bcr-2020-236973.

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Small cell lung cancer (SCLC) is a deadly and rapidly progressive disease that can present with various paraneoplastic syndromes on initial workup. Acquired factor VIII (FVIII) deficiency, also known as acquired haemophilia A (AHA), has been identified as a rare paraneoplastic syndrome in SCLC. Here, we present a 61-year-old woman with a massive gastrointestinal bleed and prolonged activated partial thromboplastin time (PTT) in the emergency department. She was diagnosed with rare paraneoplastic AHA secondary to extensive-stage SCLC (ES-SCLC). She was treated with high-dose steroids and factor bypassing agents, which led to the resolution of bleeding and undetectable FVIII inhibitor levels. She was subsequently treated for ES-SCLC with carboplatin, etoposide and atezolizumab. This case report highlights a rare clinical presentation of paraneoplastic AHA that necessitates prompt recognition in patients with SCLC with ongoing bleeding and elevated PTT.

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Wysokinska, Ewa M., Ramila Mehta, Diane Grill und Rajiv K. Pruthi. „Acquired Factor VIII Inhibitor: A Single Institution Experience With 62 Patients“. Blood 122, Nr. 21 (15.11.2013): 3610. http://dx.doi.org/10.1182/blood.v122.21.3610.3610.

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Abstract Background Acquired Factor VIII inhibitor or autoimmune hemophilia A (AHA), has an estimated incidence of up to 1.5 cases per million/year and may result in severe hemorrhagic complications and death. Approximately 50% of cases have an underlying condition such as malignancies, autoimmune disorders and post-partum state. AHA should be suspected in any patient presenting with unexplained bleeding and an inhibited aPTT. Management consists of maintaining hemostasis and elimination of the inhibitor, however management is not standardized. We present 62 cases of AHA managed at Mayo Clinic Rochester, over the course of 36 years. We also analyzed whether aPTT at presentation correlated with the strength of inhibition measured by Bethesda Titer. Methods After IRB approval, medical records of patients with AHA were reviewed and all clinical data collected. Cumulative incidence of death was estimated by Kaplan-Meier analysis. Spearman correlation was used to calculate relation of APTT to Bethesda titer. Results Between 1976 and 2012, we identified 62 patients (male: 35), with a median age at diagnosis of AHA 69 years (mean 64, range 20-86). Clinical presentation consisted of extensive ecchymoses (n=40, 64%) in majority of cases. 29/62 (47%) patients had at least 1 identifiable predisposing condition with 12/62 (19%) patients with an underlying malignancy and 16/62 (26%) with underlying autoimmune conditions. Median Bethesda titer was 29 (range 1 to 1178). Bethesda titer was not related to the number or duration of hospitalizations. Most (69%) patients had at least one hospitalization and 12 (19%) had more than one hospitalization for bleeding complication. Inpatient therapy for bleeding consisted most commonly of FEIBA in 21 pts (34%) and rFVIIa in 6 pts (10%). Prednisone was the most common immunosuppressant used in 54 (87%) patients while Rituximab was used in 11 (18%) patients. Of 32 patients with available follow up labs most (69%) achieved remission. There was no difference in remission rates between patients treated or not treated with Rituximab (p=0.1735). Conclusion Acquired Hemophilia A is a rare condition with very heterogenous presentation. It affects mostly older male patients who present with ecchymoses and elevated APTT. The degree of APTT prolongation at the time of diagnosis does not correlate with the strength of the Bethesda titer and should not guide choice of therapy in a patient presenting with an acute bleed. Rituximab use in the 11 patients treated at Mayo did not seem to influence remission rates or survival. Disclosures: No relevant conflicts of interest to declare.

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D'Arena, Giovanni, Elvira Grandone, Matteo Nicola Dario Di Minno, Pellegrino Musto und Giovanni Di Minno. „Acquired Hemophilia A successfully treated with rituximab“. Mediterranean Journal of Hematology and Infectious Diseases 7 (17.02.2015): e2015024. http://dx.doi.org/10.4084/mjhid.2015.024.

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Acquired hemophilia A (AHA) is a rare bleeding disorder due to the development of specific autoantibodies against factor VIII. The anti-CD20 monoclonal antibody Rituximab has been proven to be effective in obtaining a long-term suppression of inhibitors of AHA, besides other immunosuppressive standard treatments. Here we describe a case of idiopathic AHA in a 60-year old man successfully treated with rituximab. He showed a complete clinical response with a normalization of clotting parameters after 5 weekly courses of rituximab given at a dose of 375 mg/sqm. , but after stopping rituximab, an initial worsening of coagulation parameters induced the addition of 3 further courses. At present, the patient is in complete clinical and hematological remission after 200 days. This case confirms that Rituximab may be a safe and useful tool to treat AHA and, a prolonged administration can overcome the initial resistance. However, the precise position of this drug in the therapeutic strategy (first or second-line, alone or in combination with other drugs) remains to be established and warrants further investigation.

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Pasquino, Paola, Roberto Canaparo, Tiziana Capello, Barbara Deorsola, Laura Perazzolo, Claudio Marengo und Loredana Serpe. „Acquired Hemophilia a may be Associated with Ticagrelor Therapy in a 52-Year-Old Man after a Recent Percutaneous Transluminal Coronary Angioplasty“. Clinical Medicine Insights: Case Reports 9 (Januar 2016): CCRep.S39788. http://dx.doi.org/10.4137/ccrep.s39788.

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We present a case report of a 52-year-old man who was hospitalized for right leg pain due to a relevant hemorrhagic effusion. He was on dual antiplatelet therapy (DAPT): acetylsalicylic acid and ticagrelor, a reversible P2Y12 receptor antagonist. Signs, symptoms, and laboratory blood tests led to the diagnosis of acquired hemophilia A (AHA). Ticagrelor therapy-associated AHA was hypothesized due to the fact that, before adding this drug, all laboratory and clinical examinations were repeatedly normal. Prednisone and cyclophosphamide treatment was started without DAPT interruption due to the high risk of stent thrombosis. After 10 days, prolonged activated partial thromboplastin time dropped from 107 to 49 seconds, the patient's factor VIII (FVIII) levels gradually normalized over the following few weeks, and FVIII inhibitor titer was negative. Recently, some reports have established a link between the development of AHA and treatment with clopidogrel, an irreversible P2Y12 receptor antagonist. However, to the best of our knowledge, this is the first time that a link between AHA and ticagrelor has been reported.

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Szczepanik, Andrzej, Konrad Pielaciński, Anna Oses-Szczepanik und Piotr Paluszkiewicz. „Gastric ulcer bleeding in acquired hemophilia A patient and persistent inhibitor successfully treated with endoscopic methods of hemostasis“. Polish Journal of Surgery 93, Nr. 3 (26.04.2021): 1–5. http://dx.doi.org/10.5604/01.3001.0014.8451.

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ABSTRACT: Acquired hemophilia A (AHA) is extremely rare, life-threatening bleeding disorder caused by sudden development of autoantibodies against coagulation factor VIII. Invasive procedures in AHA patients with persistent inhibitor, resistant to eradication therapies, pose an extreme threat of life due to uncontrolled bleeding poorly respond to surgical methods of hemostasis and bypassing agents. We report a case of idiopathic AHA 71-year-old patient with persistent high-titer inhibitor (104 BU) resistant to immunosuppressive treatment and immune tolerance induction. The patient was admitted with severe bleeding gastric ulcer complicated by gastric mucosal lacerations (Mallory-Weiss tears). Repeated endoscopic treatment with injection therapy and argon plasma coagulation were applied resulting in bleeding arrest. As bypassing agent recombinant active factor VII (rFVIIa) was applied with an average dose of 91.26 µg/kg (administering cumulatively of 134 doses during 14 days) and the total dose of 855.82 mg. In conclusion, gastric ulcer bleeding in AHA patient with persistent inhibitor can be successfully arrested with the use of endoscopic hemostasis methods and proper doses of rFVIIa.

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Matsumoto, Tomoko, Kenichi Ogiwara, Midori Shima und Keiji Nogami. „A putative inhibitory mechanism in the tenase complex responsible for loss of coagulation function in acquired haemophilia A patients with anti-C2 autoantibodies“. Thrombosis and Haemostasis 107, Nr. 02 (2012): 288–301. http://dx.doi.org/10.1160/th11-05-0331.

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SummaryAcquired haemophilia A (AHA) is caused by the development of factor (F)VIII autoantibodies, demonstrating type 1 or type 2 inhibitory behaviour, and results in more serious haemorrhagic symptoms than in congenital severe HA. The reason(s) for this remains unknown, however. The global coagulation assays, thrombin generation tests and clot waveform analysis, demonstrated that coagulation parameters in patients with AHA-type 2 inhibitor were more significantly depressed than those in patients with moderate HA with similar FVIII activities. Thrombin and intrinsic FXa generation tests were significantly depressed in AHA-type 1 and AHA-type 2 compared to severe HA, and more defective in AHA-type 1 than in AHA-type 2. To investigate these inhibitory mechanism(s), anti-FVIII autoantibodies were purified from AHA plasmas. AHA-type 1 autoantibodies, containing an anti-C2 ESH4-epitope, blocked FVIII(a)-phospholipid binding, whilst AHA-type 2, containing an anti-C2 ESH8-epitope, inhibited thrombin-catalysed FVIII activation. The coagulation function in a reconstituted AHA-model containing exogenous ESH4 or ESH8 was more abnormal than in severe HA. The addition of anti-FIX antibody to FVIII-deficient plasma resulted in lower coagulation function than its absence. These results support the concept that global coagulation might be more suppressed in AHA than in severe HA due to the inhibition of FIXa-dependent FX activation by steric hindrance in the presence of FVIII-anti-C2 autoantibodies. Additionally, AHA-type 1 inhibitors prevented FVIIIa-phospholipid binding, essential for the tenase complex, whilst AHA-type 2 antibodies decreased FXa generation by inhibiting thrombin-catalysed FVIII activation. These two distinct mechanisms might, in part, contribute to and exacerbate the serious haemorrhagic symptoms in AHA.Presented in abstract form at the 52nd annual meeting of the American Society of Hematology, Orlando, Florida, USA, December 6, 2010.

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Cameron, Hunter, und Juliana Perez Botero. „Recognition of the unique bleeding pattern and laboratory findings in acquired haemophilia A facilitates prompt treatment of a life-threatening disorder“. BMJ Case Reports 14, Nr. 8 (August 2021): e244238. http://dx.doi.org/10.1136/bcr-2021-244238.

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Acquired haemophilia A (AHA) is an uncommon but severe acquired bleeding disorder caused by the development of antibodies against clotting factor VIII, impairing secondary haemostasis. It is more common in older individuals and characteristically presents with spontaneous soft tissue bleeding that can rapidly become life-threatening. Definitive treatment requires immunosuppression to eradicate anti-FVIII antibodies, while providing haemostatic support to manage bleeding. Transfusions of fresh frozen plasma or cryoprecipitate, typically used to treat severe bleeding, are ineffective in patients with AHA. Instead, highly specialised clotting factor concentrates are required. While the appearance and extent of the soft tissue bleeding and the markedly prolonged activated partial thromboplastin time are characteristic, lack of familiarity with this disease process can lead to significant treatment delays. We report the clinical course and management of a 65-year-old woman who presented with severe anaemia of unclear aetiology with unrecognised soft tissue bleeding who was subsequently diagnosed with AHA.

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Houston, Brett L., Christine M. Cserti-Gazdewich, Richard Ward, Jean St. Louis, Georges E. Rivard, Jerome M. Teitel und Michelle Sholzberg. „An Unusual Case of Acquired Hemophilia a and Factor XIII Consumption“. Blood 126, Nr. 23 (03.12.2015): 4701. http://dx.doi.org/10.1182/blood.v126.23.4701.4701.

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Abstract BACKGROUND: Acquired hemophilia A (AHA) results from auto-antibodies that neutralize factor VIII (FVIII) coagulant function. AHA is rare, usually occurring late in life, and occasionally post-partum. It is most often idiopathic, but can be associated with malignancy, autoimmunity, or drugs. In contrast to congenital hemophilia, AHA generally manifests as mucocutaneous bleeding, with poor correlation to antibody titer or residual FVIII activity. Management goals are the achievement of hemostasis and antibody eradication. Here we describe an unusual case of AHA and concomitant factor XIII consumption in a young nulliparous woman. CASE REPORT: A 24-year-old woman with a symptomatic congenital choledochal cyst underwent a Roux-en-Y bypass, bile duct resection and cholecystectomy. Abdominal sepsis ensued from extended spectrum beta-lactamase Klebsiella, with ertapenem initiation on post-operative day (POD) 5. On POD6 she developed severe intra-abdominal bleeding associated with prolongation of the activated partial thromboplastin time (aPTT) from 35 seconds (pre-operative) to 40 seconds (reference interval 28-35 seconds). On POD10, FVIII activity and FVIII inhibitor titer, using the modified Nijmegen Bethesda assay, were measured at 0.08 U/ml and 4.5 BU/ml, respectively. In addition to supportive transfusion therapy, the patient received a sequence of desmopressin (0.3 mcg/kg IV), recombinant FVIII (50 U/kg), and activated prothrombin complex concentrate (aPCC) (50-75 U/kg IV q8h) with tranexamic acid (10-20 mg/kg IV q8h) from POD13-20. Prednisone was concomitantly initiated (1.5 mg/kg/day) (Figure 1). Bleeding persisted despite reduction in clotting time on rotational thromboelastometry post-aPCC. As neither intensified aPCC nor recombinant factor VIIa (rFVIIa) (80 mcg/kg IV q2h) provided substantial benefit, recombinant porcine factor VIII (rpFVIII) was administered from POD20-28 (100 U/kg IV qd). RpFVIII resulted in hemostatic improvement until anti-porcine FVIII antibodies developed on POD27. On POD28, she was transferred to the local hemophilia treatment center where complete factor analysis identified concurrent FXIII deficiency [0.08 U/ml] using a latex immunoassay. FXIII inhibitor analysis using a chromogenic assay was negative. The peak FVIII inhibitor titer and nadir FVIII activity were 74 BU/ml and <0.01 U/ml, respectively. APCC was resumed [POD28-37] and plasma derived factor XIII (pdFXIII) was given every 4 days to maintain FXIII >0.20 U/ml. The patient was also treated with rituximab [POD28,36,43,50]. On POD37, massive intra-abdominal bleeding prompted sequential aPCC, rFVIIa and pd von Willebrand factor (VWF):FVIII concentrate. Once the FVIII inhibitor titer began to wane, bypassing therapy was discontinued and she was managed solely with pdVWF:FVIII. On POD47 all FVIII-related support was discontinued, as the FVIII inhibitor was undetectable and endogenous FVIII normalized. Her FXIII consumption and requirement for FXIII replacement, however, persisted. DISCUSSION: The unusual features of this case of AHA include the patient's young age, the possible triggers for the FVIII inhibitor (extensive abdominal surgery, sepsis, and/or carbapenem use), and concomitant FXIII deficiency. We hypothesize that FXIII deficiency was secondary to consumption from the massive abdominal wound given its persistence despite normalization of hepatic function. Repeated life-threatening bleeding required trials of multiple hemostatic agents. Persistent and prolonged bleeding despite ongoing FVIII replacement should trigger investigation for a concomitant hemostatic deficiency. AHA is a rare condition, and treatment requires intensive monitoring, clinical experience and specialized laboratory support. Current guidelines are largely derived from expert opinion, and contemporary case descriptions for rare disorders are essential to advance options in best care. Figure 1. Case summary outlining clinical course, factor activity levels, and management strategies Figure 1. Case summary outlining clinical course, factor activity levels, and management strategies Disclosures St. Louis: Baxter/Baxalta: Consultancy. Sholzberg:CSL Behring: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding; Amgen: Honoraria.

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Takeyama, Masahiro, Keiji Nogami, Tomoko Matsumoto und Midori Shima. „Factor VIII A2 Domain Contains a Binding Site for Factor X“. Blood 124, Nr. 21 (06.12.2014): 4226. http://dx.doi.org/10.1182/blood.v124.21.4226.4226.

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Abstract Acquired hemophilia A (AHA) is a rare hemorrhagic disease in which autoantibodies against coagulation factor (F) VIII impair the coagulation system. The inhibitors developed in AHA are polyclonal autoantibodies and the majority of FVIII inhibitors bind to the A2, A3, or C2 domains. Depending on the location of the epitope, different mechanisms of action for the anti-FVIII antibodies have been reported. Anti-A3 antibodies neutralize the procoagulant activity of FVIII by preventing its interaction with FIXa. Anti-C2 antibodies inhibit the binding of FVIII to phospholipid membrane and/or von Willebrand factor, whereas A2 and A3 inhibitors block the binding of FVIII to FIXa and FX, respectively, and obstruct the formation of the Xase complex. We have a case of AHA whose inhibitor recognizes only A2 domain and attempted several approaches to determine the mechanism of neutralizing FVIII. Thrombin and plasmin generation assay using patient’s plasma showed that the thrombin and plasmin generation in this AHA patient were decreased compared with that in congenital severe hemophilia A patient. Furthermore, FX generation (Coatest) in this AHA was also decreased compared with that in congenital severe hemophilia A patient (p<0.05). These results indicated that this inhibitor impaired the generation of Xase complex and might cause the severe bleeding disorder in this patient. The IgG subclass of inhibitor in our case was IgG1 and IgG4. Western blotting analysis using FVIIIa revealed that the inhibitor IgG recognized only A2 domain. Furthermore, western blotting analysis using FVIII A2 fragment, digested by activated protein C, showed that the inhibitor IgG bound to FVIII A2N (residue 372-562) fragment. It is known that FVIII A2 domain contains FIXa and thrombin binding sites. Western blotting analysis revealed that the inhibitor IgG inhibited Arg336 cleavage in FVIIIa by FIXa and Arg372 cleavage in FVIII by thrombin. However, the FXa-catalyzed cleavage at Arg372 in FVIII was inhibited by this inhibitor IgG. ELISA-based assay showed that the inhibitor IgG inhibited FX binding to FVIII A2. These results suggest that FX(a) binds to FVIII A2 domain. Therefore, to determine the direct binding of FX and FVIII A2 domain, ELISA-based assay was employed to assess this interaction. ELISA-based assay showed that FVIII A2 fragment bound FX in a dose-dependent manner with moderate affinity (Kd = 338 nM). FX inhibited FVIII A2 fragment binding to immobilized FX up to 70% with an inhibition constant (Ki = 254 nM) similar to the affinity constant. It is known that the residue 484-509 in the A2 domain interacts with FIXa. We hypothesized that FX binding site in the A2 domain might be in the opposite side of FIXa binding site in the A2 domain. According to the 3-D model of FVIII molecule, we prepared synthetic peptides corresponding to FVIII A2 residues 400-409, 409-419, and 420-429. To determine the specificity of these sequences for FX interaction, we examined the effects of these peptides on FVIII A2 binding to FX using ELISA-based assay. The 400-409 peptide inhibited the A2 and FX interaction up to 70%. In contrast, the 410-419 and the 420-429 peptides inhibited the interaction up to 30%. Covalent cross-linking was observed between the 400-409 peptide and FX following reaction with EDC using SDS-PAGE. These results indicate that FVIII A2 domain contains the binding site for FX(a), and the 400-409 region in the FVIII A2 domain contributes to a unique FX(a)-interactive site. Disclosures No relevant conflicts of interest to declare.

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Araki, Takeshi, Shinya Ohata, Kohei Okamoto, Kazuhide Morimoto, Mana Hiraishi, Shinichiro Yamada, Ishikazu Mizuno und Takeshi Sugimoto. „A Case of Acquired Haemophilia A in a Patient with Chronic Myelomonocytic Leukaemia“. Case Reports in Hematology 2019 (27.02.2019): 1–7. http://dx.doi.org/10.1155/2019/8612031.

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A 67-year-old male, with a known diagnosis of myelodysplastic syndromes with multilineage dysplasia (MDS-MLD) was admitted to our hospital with a primary complaint of subcutaneous bleeding in his left thigh. Laboratory data showed anaemia and prolongation of activated partial thromboplastin time (85.8 s, normal range 24–39 s) without thrombocytopenia. Coagulation factor VIII (FVIII) activity was less than 1% (normal range 60–150%), and a FVIII inhibitor was identified and quantified at 166 BU/mL to indicate a diagnosis of acquired haemophilia A (AHA). A recent, but sustained circulating monocytosis (>1 × 109/L) was observed, which combined with elevated numbers of neutrophil and monocytic cells in the marrow, suggested evolution of MDS-MLD to chronic myelomonocytic leukaemia (CMML), coinciding with AHA. Further analysis revealed a karyotype of 46, XY, i(14) (q10), which was the same abnormality previously identified in the patient. To treat bleeding caused by AHA, steroid and activated prothrombin complex concentrate were administered. Azacitidine (AZA) was used to treat CMML. During the clinical course, bleeding partially improved; however, subsequent acute myocardial infarction occurred on day 87. Worsening bone marrow failure was observed 4 months after the original admission, despite administration of AZA therapy, and the patient died due to bleeding from AHA. This case suggests that the evolution of MDS to CMML status can be associated with AHA conferring a bleeding tendency.

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Tiede, Andreas, Christoph J. Hofbauer, Sonja Werwitzke, Paul Knöbl, Saskia Gottstein, Rüdiger E. Scharf, Jürgen Heinz et al. „Anti–factor VIII IgA as a potential marker of poor prognosis in acquired hemophilia A: results from the GTH-AH 01/2010 study“. Blood 127, Nr. 19 (12.05.2016): 2289–97. http://dx.doi.org/10.1182/blood-2015-09-672774.

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Key Points This study is the first to assess the prognostic value of FVIII-specific antibody data in patients with AHA. Anti-FVIII IgA, but not immunoglobulin G, autoantibodies at baseline are potential predictors of recurrence and poor outcome of AHA.

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Collins, Peter, Francesco Baudo, Paul Knoebl, Hervé Lévesque, László Nemes, Fabio Pellegrini, Pascual Marco, Lilian Tengborn und Angela Huth-Kühne. „Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2)“. Blood 120, Nr. 1 (05.07.2012): 47–55. http://dx.doi.org/10.1182/blood-2012-02-409185.

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Abstract Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

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Jalowiec, Katarzyna Aleksandra, Martin Andres, Behrouz Mansouri Taleghani, Anne Angelillo-Scherrer, Alicia Rovo und Johanna A. Kremer Hovinga. „Acquired Hemophilia and Plasma Cell Neoplasms, a Rare Association“. Blood 134, Supplement_1 (13.11.2019): 4930. http://dx.doi.org/10.1182/blood-2019-128048.

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Acquired hemophilia A (AHA) is a rare autoimmune disease caused by circulating autoantibodies inhibiting coagulation factor VIII (FVIII), leading to a clinically significant bleeding diathesis. While in half of AHA cases, no underlying cause is identified, in the other half an association with autoimmune diseases, cancer, the use of certain drugs, pregnancy or the post-partum period is found. We present a case with severe bleeding in which AHA was diagnosed and subsequently a smoldering myeloma was found as underlying disease (case 16, Table 1). We conducted a systematic review of the literature in PubMed looking for the association of AHA and plasma cell neoplasm (PCN) (key words used: hemophilia, inhibitor, factor VIII, myeloma, plasma cell disorder or neoplasms, smoldering myeloma, MGUS, monoclonal gammopathy, paraprotein) and identified 15 additional cases. Description of the cases, sequence of occurrence of both diseases, their treatment, evolution and outcome are here analyzed (Table 1). We found that patients having AHA and PCN were more often males (9/16, 56%), had a median age of 61.5 (range 43-87) years at AHA diagnosis. The most common pattern of bleeding was a soft tissue bleeding. In two cases, AHA was diagnosed after excessive post-operative bleeding, in one patient following a life threatening pericardial bleeding and a hemarthrosis. AHA with active bleeding was the presenting sign in 6 cases (38%) (Table 1, cases 4, 5, 6, 10, 13, 16), in search for an underlying diseases, a PCN was diagnosed subsequently. In the other 10 cases, AHA was diagnosed after PCN. In 3 of them, the occurrence of AHA was interpreted to be secondary to multiple myeloma treatment; the implicated drugs were interferon alpha in one and lenalidomide in two cases. Information about the type of monoclonal gammopathy was available in 11 cases; no particular type of paraprotein or clonal light-chain was discernable. Factor concentrates were used in 12 cases to treat relevant bleedings. Further treatment of AHA consisted of immunosuppression with steroids (N=4), steroids in combination with cyclophosphamide (N=5), or cyclophosphamide alone (N=1). Rituximab was used in 3 cases. Plasma exchange to remove FVIII antibodies was performed in 2 cases, and immunoadsorption was done in our patient. Different therapy regimens were used to treat the underlying PCN over the years (Table 1). At the time of reporting 13 patients were alive, while 2 of 3 patients who died, died of bleeding complications. Information on outcome of AHA and/or PCN was available for 9 of 13 survivors: 6 had normal coagulation tests, while FVIII activity was mildly reduced in two. PCN was in complete and partial remission in 7 and 2 cases, respectively (table 1). Management of AHA is based on four pillars: avoidance of procedures that may have induced bleedings, control of bleeding, inhibitor eradication and treatment of the underlying disease. Our case, together with those described in the literature, emphasizes the possibility of PCN as an underlying cause of AHA. Accordingly, diagnostics including protein-electrophoresis, immune-fixation and free light chains should be considered in patients with AHA. In our experience, early intervention with immunoadsorption can be lifesaving in cases with high FVIII inhibitor titers. The occurrence of excessive unexplained bleeding in PCN should raise the suspicion of secondary AHA and trigger the investigation of coagulations tests. Whether PCN treatment alone can control AHA in these cases remains open, 11/16 (69%) of the reported cases received treatment for both diseases. Disclosures Jalowiec: Amgen: Other: Travel grant; Pfizer: Other: Travel grant; Novartis: Other: Travel grant. Andres:AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel support ; Gilead: Other: Travel support ; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Travel support ; Mundipharma: Other: Travel support ; AbbVie: Other: Travel support; Celgene: Other: Travel support . Kremer Hovinga:CSL-Behring: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Ablynx/Sanofi: Consultancy, Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Roche: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology); Shire: Consultancy, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology), Research Funding; Siemens: Honoraria, Other: Honoraria go to employer (Insel Gruppe AG, Department of Hematology).

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Girelli, Francesco, Chiara Biasoli, Bruna Bassi, Franco Bagioni, Gabriele Bondi, Claudio Camporesi, Lucia Gardelli, Vincenzo Mazzeo und Maurizio Nizzoli. „Efficacy of Corticosteroids Alone in the Eradication of Factor VIII Inhibitor in an Old Female with Idiopathic Acquired Haemophilia A: Description of a Case“. Case Reports in Rheumatology 2012 (2012): 1–3. http://dx.doi.org/10.1155/2012/310730.

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Acquired haemophilia A (AHA) is a rare and serious disorder mainly affecting elderly patients. It is caused by the production of autoantibodies directed against coagulation factors; patients present with spontaneous bleeding, potentially fatal, in the absence of familial or personal history. Autoimmune disorders, infections, solid and hematologic tumors, and drugs are predisposing factors, but up to 50 percent of cases remain unexplained. The diagnosis of AHA is confirmed by specific laboratory tests; and the therapy is a clinical challenge, due to the fact that older patients are often affected by comorbidities. By passing agents may be used when persistent bleeding or haemodynamic instability is observed; corticosteroids, alone or with immunosuppressive therapy, are necessary to inhibit the production of the autoantibodies. We describe a case in which steroids in monotherapy successfully, safely, and persistently inhibited the production of anti-Factor VIII antibodies, in an old patient admitted after rheumatologic consult.

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Tufano, Antonella, Antonio Coppola, Anna Guida, Ernesto Cimino, Angela Maria De Gregorio, Anna Maria Cerbone und Giovanni Di Minno. „Acquired Haemophilia A in the Elderly: Case Reports“. Current Gerontology and Geriatrics Research 2010 (2010): 1–5. http://dx.doi.org/10.1155/2010/927503.

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Acquired hemophilia A (AHA) is a very rare disease, caused by the development of autoantibodies, directed against circulating factor VIII of coagulation. Age distribution is bimodal, with a first peak occurring among young women in the postpartum period, and a second major peak of incidence among elderly patients in whom it is frequently associated with malignancy and drugs. This disease often represents a life-threatening bleeding condition, especially in the elderly, thus requiring a prompt therapeutic intervention, including control of acute bleeding and eradication of the inhibitor by immunosuppressive therapy. The diagnosis of AHA should be considered in any elderly patient who presents with bleeding and prolonged activated Partial Thromboplastin Time. Moreover, the coexistence of a series of underlying diseases associated with AHA should be always searched for. An early recognition and an adequate treatment of this coagulation disorder and of the possible associated diseases play a significant role for a favourable outcome, but concomitant morbidities in the elderly may limit aggressive therapy and may complicate the clinical scenario. We report 3 consecutive elderly patients successfully treated with recombinant activated factor VII and standard immunosuppressive regimens, with remission of the disease.

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Kahle, Joerg, Aleksander Orlowski, Anja Schmidt, Kerstin Brettschneider, Thomas Klingebiel, John F. Healey, Ernest T. Parker et al. „Frequency and Epitope Specificity of Anti-Factor VIII C1 Domain Antibodies in Acquired and Hereditary Hemophilia Inhibitor Patient Plasma“. Blood 126, Nr. 23 (03.12.2015): 3491. http://dx.doi.org/10.1182/blood.v126.23.3491.3491.

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Abstract Acquired hemophilia A (AHA) is a rare autoimmune disease caused by development of inhibitory anti-factor VIII (fVIII) antibodies (also called inhibitors) resulting in severe hemorrhages. In addition, inhibitor development is the most serious complication of today's replacement therapy in patients with hereditary X-linked hemophilia A (HA) disorder. Earlier studies showed that antibodies in AHA and HA inhibitor plasmas are both primarily directed to the A2 and C2 domains suggesting that these two domains are the predominant immunogenic fVIII regions (Fulcher et al, 1987; Prescott et al, 1997; Lollar, 2004). However, the C1 domain also makes a major contribution to the humoral anti-fVIII immune response in hemophilic mice (Healey et al, 2007), which motivated us to analyze the frequency and epitope specificity of anti-C1 antibodies in AHA and HA inhibitor patient plasma. The frequency of domain-specific antibodies were studied by antibody binding to human A2, C1 and C2 domains presented as (i) single human domain (SHD) human/porcine hybrid fVIII and (ii) HSA-fusion proteins. While similar frequencies of A2- and C2-specific antibodies were observed for both applied mapping strategies the use of isolated C1 domain resulted in much higher detection level of anti-C1 antibodies compared to the use of the human C1 domain human/porcine hybrid fVIII protein. As homologue-scanning mutagenesis relies on differences among human and porcine sequences these results suggest the presence of a large number of cross-reactive anti-C1 antibodies binding to species-conserved epitopes. Overall, anti-C1 antibodies were detected in 90 of 115 (78%) AHA and 36 of 63 (57%) HA inhibitor patients. Two well-characterized monoclonal C1 inhibitors, human LE2E9 (Jacquemin et al, 2000) and murine MAb 2A9 (ASH 2014 poster, Batsuli et al) were used for indirect epitope mapping of anti-C1 antibodies in AHA patients by competition binding studies. Our results for AHA patients with non-crossreactive anti-C1 antibodies only (n=11) show that antibody binding to human C1 domain human/porcine hybrid fVIII (HP53) protein was completely blocked in the presence of MAb 2A9. In contrast, antibody binding to the isolated C1 domain was only partially reduced in the presence of MAb 2A9 for a selected number of (high responding) AHA patients (n=10) suggesting the presence of a second population of crossreactive anti-C1 antibodies that exclusively bind to conserved amino acid residues. Competition binding to native and denatured fVIII and HP53 proteins revealed that MAb 2A9 and LE2E9 bind mutually exclusive to a conformational C1 epitope involving amino acid residues that are not conserved between humans and pigs. Consequently, essential binding residues were identified for both C1 inhibitors via the use of HP53 variants, in which surface exposed non-conserved amino acid residues on the human C1 domain were substituted for porcine residues. The results of this mutational analysis showed that despite their competitive binding different amino acid residues are essential for binding of MAb 2A9 and LE2E9. These findings are in agreement with the different specific inhibitory activities of the two C1 inhibitors (97 BU/mg vs 10000 BU/mg). Finally, HSA-C1 point mutants were used to directly map essential epitope residues of anti-C1 antibodies in AHA and HA inhibitor patient plasma. Our study demonstrates that a large number of AHA and HA inhibitor patients (126 of 178; 71%) have anti-C1 antibodies that comprise at least two different populations, crossreactive and non-crossreactive to porcine fVIII. Therefore, in addition to the A2 and C2 domains, the C1 domain seems to significantly contribute to the immune response to fVIII in these patients. As recent data point toward a functional role of the fVIII C1 domain for membrane-, fX-, and von Willebrand factor-binding (Lü et al, 2011) the clinical relevance of anti-C1 antibodies should be analyzed in further studies. Disclosures Tiede: Leo Pharma: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Research Funding; Coachrom: Research Funding; SOBI: Consultancy, Honoraria; Biogen Idec: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Octapharma: Other: Investigator, Speakers Bureau; Biotest: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Investigator, Research Funding; Baxter: Consultancy, Honoraria, Research Funding. Königs:Bayer: Research Funding, Speakers Bureau; Biotest: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Sobi: Consultancy; CSL Behring: Research Funding, Speakers Bureau; Intersero: Research Funding; NovoNordisk: Speakers Bureau.

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Tiede, Andreas, Sonja Werwitzke, Ulrich Geisen, Ulrike Nowak-Göttl, Hermann Eichler, Bernhard Stephan, Ute Scholz et al. „Diagnostic and Prognostic Value of Factor VIII Binding Antibodies in Acquired Hemophilia A: Data from the GTH-AH 01/2010 Study“. Blood 126, Nr. 23 (03.12.2015): 3515. http://dx.doi.org/10.1182/blood.v126.23.3515.3515.

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Abstract Background: Acquired hemophilia A (AHA) is a severe bleeding disorder that requires fast and accurate diagnosis as it occurs often unexpectedly in previously healthy men and women of every age. The Nijmegen-modified Bethesda assay (NBA) is the diagnostic gold standard detecting neutralizing anti-FVIII autoantibodies, but is not widely available, not ideal to quantify the complex type 2 inhibitors seen in AHA, and suffers from high inter-laboratory variability. Objectives: To assess the diagnostic and prognostic value of FVIII binding antibodies as detected by a commercial ELISA (Hyphen Biomed/Coachrom) compared with the NBA. Methods: Samples and clinical data were available from 102 patients with AHA enrolled in the prospective GTH-AH 01/2010 study. Controls were matched for gender and age. Diagnostic cut-offs were determined by receiver-operator curve (ROC) analysis on training and validation sets, assigned by 1:1 randomization, and by classification and regression tree (CRT) analysis. Prognostic value was assessed by Cox regression analysis of time to partial remission. Results: Anti-FVIII IgG above the 99th percentile (>15 AU/ml) revealed high sensitivity (1.0, 95% confidence interval [CI] 0.92-1.0) and specificity (1.0, CI 0.92-1.0) to diagnose AHA. The likelihood of achieving remission was strongly related to antibody concentration (anti-FVIII IgG <100 AU/ml: 1.0; 100-<1000 AU/ml: 0.40; ≥1000 AU/ml: 0.21). This association was stronger than that between NBA inhibitor titer and likelihood of remission. Conclusion: Although the NBA is the gold standard for demonstrating neutralizing antibodies in AHA, the detection of FVIII-binding antibodies by anti-FVIII IgG ELISA is similarly sensitive and specific to diagnose AHA. In addition, anti-FVIII IgG provides important prognostic information. Disclosures Tiede: CSL Behring: Consultancy, Honoraria, Research Funding; Baxter: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Investigator, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; Leo Pharma: Consultancy, Honoraria; SOBI: Consultancy, Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy, Honoraria; Coachrom: Research Funding; Octapharma: Other: Investigator, Speakers Bureau. Geisen:Roche Diagnostics International AG, Switzerland: Research Funding; Baxalta: Honoraria; Bayer: Research Funding; Novo Nordisk: Consultancy, Honoraria. Nowak-Göttl:Bayer: Consultancy; LFB: Consultancy; Octapharma: Consultancy. Eichler:CSL Behring: Consultancy, Research Funding; Biotest: Consultancy, Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Consultancy, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Klamroth:Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau; Biogen and SOBI: Honoraria, Speakers Bureau. Huth-Kühne:Biotest: Consultancy; Baxalta: Consultancy; CSL: Consultancy; Bayer: Consultancy.

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Fosbury, Emma, Anja Drebes, Anne Riddell und Pratima Chowdary. „Review of recombinant anti-haemophilic porcine sequence factor VIII in adults with acquired haemophilia A“. Therapeutic Advances in Hematology 8, Nr. 9 (03.08.2017): 263–72. http://dx.doi.org/10.1177/2040620717720861.

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Acquired haemophilia A (AHA) is a rare, serious bleeding disorder most often encountered in elderly patients. The mainstay of haemostatic management is with bypassing agents (BPAs) including recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrates (aPCCs). Their major limitation is incomplete efficacy, potential risk for thrombosis and the lack of routine laboratory assays for monitoring treatment response. Plasma-derived porcine FVIII (pd-pFVIII, Hyate C®), first used in the 1950s for the management of congenital haemophilia, has sufficient sequence homology to be haemostatic in humans, but the lack of complete homology facilitates efficacy even in the presence of human allo- and autoantibodies against human FVIII (hFVIII). In a small phase II/III study, recombinant porcine FVIII (rpFVIII, Obizur®, OBI-1, susoctocog alfa) was shown to be safe and effective for the management of bleeding episodes in patients with AHA with anti-porcine FVIII (anti-pFVIII) antibody levels of 20 BU/ml or less. Treatment outcome was judged on clinical response and FVIII levels after an initial fixed dose of 200 IU/kg. The rise in FVIII levels showed considerable inter-individual variability and was significantly influenced by the presence of anti-pFVIII antibodies. Based on the baseline levels of anti-pFVIII antibodies and response to treatment, three potential patient groups were identifiable. In the first group, the absence of cross-reacting antibodies was associated with supra-therapeutic FVIII levels, fewer infusions and lower rpFVIII utilization per treatment episode. The second group had patients with low levels of cross-reacting anti-pFVIII antibodies (0.8–5 BU/ml) with near-normal response to rpFVIII. The last group had higher titres of anti-pFVIII antibody (10–30 BU/ml) associated with lower FVIII levels, more infusions and higher consumption of rpFVIII. We propose a new treatment algorithm for the haemostatic management of AHA that includes the potential first-line clinical use of rpFVIII that takes into account availability of anti-pFVIII antibody results, titre of anti-pFVIII antibodies and severity of bleeding episode.

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Ellsworth, Patrick, Sheh-Li Chen, Raj S. Kasthuri, Nigel S. Key, Micah J. Mooberry und Alice D. Ma. „Recombinant porcine FVIII for bleed treatment in acquired hemophilia A: findings from a single-center, 18-patient cohort“. Blood Advances 4, Nr. 24 (17.12.2020): 6240–49. http://dx.doi.org/10.1182/bloodadvances.2020002977.

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Abstract Acquired hemophilia A (AHA) is a rare bleeding disorder in which acquired autoantibodies to endogenous factor VIII (FVIII) decrease FVIII activity and lead to a bleeding phenotype. A substantial majority of individuals who develop AHA present with severe bleeding. Effective treatment requires both immunosuppressive therapy and prompt hemostatic treatment. Bleeding is commonly treated with bypassing agents (BPAs) such as recombinant activated FVII (rFVIIa) or activated prothrombin complex concentrates Disadvantages to BPAs include the inability to monitor response with standard laboratory assays, inconsistent hemostatic efficacy, and thrombosis. Recombinant porcine FVIII (rpFVIII: Obizur, Baxter, Deerfield, IL) was approved by the US Food and Drug Administration (FDA) for bleed treatment in AHA in 2014, and has the advantage of laboratory monitoring of FVIII activity levels and known hemostatic efficacy in the presence of anti-human FVIII inhibitors and after failure of BPAs. Using an algorithm-based approach, rpFVIII has been used to successfully treat 18 patients with AHA at our center with substantially lower doses than the current FDA-recommended dosing. Additionally, data from our cohort show that the preexposure anti-porcine Bethesda titer does not reliably predict the clinical response to rpFVIII treatment and is not correlated with the anti-human Bethesda titer. We also present data showing lower total rpFVIII use for initial bleed resolution when rpVIII is used upfront, as compared with use as rescue therapy. We validated our dosing algorithm, which uses much lower than FDA-recommended doses with 14 more patients than in our previously reported patient series.

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Riaz, Muhammad Kashif, Saulius Girnius und Joseph Edward Palascak. „Recombinant Porcine Factor VIII, Obi-1, Successfully Controlled Gastrointestinal Bleeding in a Patient with Acquired Hemophilia A“. Blood 126, Nr. 23 (03.12.2015): 4676. http://dx.doi.org/10.1182/blood.v126.23.4676.4676.

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Abstract Introduction: Acquired hemophilia A (AHA) is a rare, life-threatening bleeding diathesis categorized by low levels of Factor VIII (FVIII) due to an acquired auto-antibody against FVIII. Treatment for AHA requires both control of the bleeding and eradication of the inhibitor. Recombinant activated factor VII (rFVIIa) maybe used to control the bleeding, but with only mixed results in controlling gastrointestinal bleeding (GIB). rFVIIa is associated with thrombosis risk and lack of ability to monitor. The recombinant porcine FVIII (rpFVIII), OBI-1, recently obtained regulatory approval based on the results of Phase 2/3 trial, but the patients in this cohort did not have GIBs. Here we present a patient with AHA admitted with a GIB and successfully treated with OBI-1. Case: A 69 year old African American female with T1N0M0 infiltrative ductal carcinoma of the left breast and Stage IVA Squamous cell carcinoma of the cervix, treated in 1997 and 2007 respectively, presented to the emergency department with two days of painless bright red blood per rectum. She was orthostatic (supine: HR 79, BP 112/77 and standing: HR 111, BP 100/72) with hemoglobin (Hb) of 5.7gms/dl. An EGD demonstrated a bleeding vessel and multiple arteriovenous malformations (AVM) in the gastric body that were secured with clipping. Over the next 5 days EGD was repeated twice and multiple endoclips were placed in an attempt to achieve hemostasis. She subsequently underwent angiography to identify a target vessel for embolization, but one could not be found. On hospital day 11, hematology was consulted for a prolonged aPTT (113.8 seconds) and inadequate correction with mixing studies (63.7 seconds). FVIII level was <1% with factor VIII inhibitor titer of 245 Bethesda Units/ml (BU). Prior to starting OBI-1, she received 9 units of packed red blood cells and 2 units of fresh frozen plasma. OBI-1 was started at 200u/kg q4h for first 2 days and then decreased to q8h, with cessation of bleeding within 24 hours. Upon completion of the bolus of OBI-1, her FVIII level was 14%, then 38% at 8 hours, 48% at 16 hours and 62% at 24 hours. Rituximab (375mg/m2 weekly) and corticosteroids (prednisone 1mg/kg daily x7 days) were given in an attempt to eliminate the inhibitor. She remained stable for 6 days but subsequently developed abdominal pain. A CT of the abdomen revealed free air prompting emergent surgical intervention. She had internal hernia in the pelvis, ischemic small bowel and perforated jejunum requiring extensive resection. During this time she remained on rpFVIII (200u/kg q8h) with FVIII pre-infusion levels ranging from 2% - 14% and post-infusion levels from 80% to 217% and had only 25ml estimated blood loss during surgery. Unfortunately, 1 day after surgery she developed multi-organ failure and expired on hospital day 19. Discussion: OBI-1 is a glycosylated, B-domain deleted recombinant porcine factor VIII that retains the ability to interact with Factor IXa and activate Factor X, but it is less inhibited by auto-antibodies to human FVIII. For FVIII inhibitor titers >5 BU, an inhibitor bypassing agent is usually necessary because human FVIII products are not able to overcome the inhibitor. Given the high FVIII inhibitor titers in this patient, administration of rFVIIa or OBI-1 was necessary. Our own institutional experience of treating GIBs in patients with AHA had poor outcomes. The efficacy of rFVIIa in treating GIB is inconclusive, with response rate ranging from 53% to 71%. However, rFVIIa is associated with a risk of thrombosis approaching 9.4%, especially in older patients and those with vasculopathy, a common demographic in AHA. Unlike rFVIIa, OBI-1 allows close monitoring of FVIII and in the aforementioned Phase 2/3 trial, there were no thrombotic complications or serious adverse events. We were successful in controlling the bleeding within 24 hours with OBI-1 and were able to achieve therapeutic levels of FVIII despite high Bethesda titers. Unfortunately, our patient died from an ischemic bowel and perforated jejunum that was likely related to hernia or repeated instrumentation in an attempt to stop the bleeding prior to the diagnosis of AHA. Conclusion: OBI-1 appears to effectively and rapidly overcome a high titer FVIII inhibitor and control bleeding in a patient with AHA and GIB. While this is a promising therapy, additional study is necessary to determine safety, efficacy, and cost-effectiveness. Disclosures No relevant conflicts of interest to declare.

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Ricca, Irene, Marisa Coggiola, Silvia Destefanis und Claudio Pascale. „A case of serious bleeding“. Clinical Management Issues 5, Nr. 2S (13.10.2015): 15–19. http://dx.doi.org/10.7175/cmi.v5i2s.1106.

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Acquired haemophilia A (AHA) is a rare disorder with a high mortality rate. It occurs due to autoantibodies against coagulation factor VIII (FVIII) which neutralise its procoagulant function resulting in severe bleeding. This disease may be associated with autoimmune diseases, malignancies, infections or medications and occurs most commonly in the elderly. Diagnosis is based on the isolated prolongation of aPTT which does not normalise after the addition of normal plasma along with reduced FVIII levels. Treatment involves eradication of antibodies and maintaining effective haemostasis during bleeding. We report a case of a 76-year-old patient with a history of haemorrhage with severe anaemia. The article describes difficulties and complexities of clinical and therapeutic management of the patient.

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Louis, Jean St, Rebecca Kruse-Jarres, Anne Greist, Amy D. Shapiro, Hedy Smith, Anja B. Drebes, Jay N. Lozier und Edward D. Gomperts. „Recombinant B-Domain Deleted Porcine Factor VIII (OBI-1) Safety and Efficacy in the Treatment of Acquired Hemophilia A: Interim Results.“ Blood 120, Nr. 21 (16.11.2012): 2224. http://dx.doi.org/10.1182/blood.v120.21.2224.2224.

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Abstract Abstract 2224 Introduction OBI-1 is an investigational B-domain deleted recombinant porcine factor VIII (FVIII) with low cross-reactivity to anti-human FVIII antibodies. Acquired hemophilia A (AHA) is caused by autoantibodies (inhibitors) against human FVIII. Patients are predominantly elderly and have co-morbidities. Current pharmacologic treatment of bleeds is guided by clinical assessment alone as there is no laboratory surrogate for efficacy. Importantly, OBI-1 efficacy can be monitored by FVIII levels in addition to clinical assessment. Methods Accur8 Auto-antibody trial (NCT01178294) is a prospective, open label, Phase 2/3 study. The primary objective is to evaluate efficacy of OBI-1 treatment for serious (life- or limb-threatening) bleeds in patients ≥18 years with AHA. FVIII levels are obtained before and within 10–20 min following initial OBI-1 dose (200U/kg) and at 2–3 h. Additional OBI-1 doses (≤400U/kg every 2–3 h) are administered to achieve target FVIII levels. The primary efficacy outcome is the control of bleeding 24 h after starting OBI-1. Results As of July, 2012, fifteen patients with severe bleeds were entered into the trial along with one individual treated under compassionate use and all had successful control of hemorrhage at 24 h and subsequent resolution of the bleed. Therapeutic FVIII activity levels were achieved and maintained with intermittent OBI-1 administration based on FVIII levels. Six serious adverse events were reported including four deaths after treatment was discontinued, all being unrelated to OBI-1 as determined by the investigators. Antibodies to OBI-1 developed in two subjects indicated with an * in the table below. However, both responded toOBI-1. Conclusions These interim results provide support for the safety and efficacy of OBI-1 in the treatment of serious bleeding episodes in AHA. Additional confirming data could establish OBI-1 as a useful treatment option for AHA. Disclosures: St. Louis: Inspiration Biopharmaceuticals Inc: Research Funding. Kruse-Jarres:Inspiration Biopharmaceiticals Inc: Research Funding. Greist:Inspiration Biopharmaceuticals Inc: Research Funding. Shapiro:Inspiration Biopharmaceuticals Inc: Research Funding. Smith:Inspiration Biopharmaceuticals Inc: Research Funding. Drebes:Inspiration Biopharmaceuticals Inc: Research Funding. Gomperts:Inspiration Biopharmaceuticals Inc: Consultancy.

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Yamaguchi, Tomoya, Naoko Kudo, Susumu Endo, Takeo Usui und Shinsaku Imashuku. „Management of Acquired Hemophilia A in Elderly Patients“. Case Reports in Hematology 2018 (13.11.2018): 1–5. http://dx.doi.org/10.1155/2018/6757345.

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This report describes six elderly patients with acquired hemophilia A (AHA), including four individuals aged ≥90 years. Bleeding symptoms were subcutaneous or intramuscular hemorrhage (n=4), hematuria (n=1), and hemorrhagic shock after tooth extraction (n=1). Factor VIII (FVIII) activity ranged from <1.0% to 3.0%, and anti-FVIII inhibitor titers ranged from 8.8 to 240 BU/mL. Treatment was administered at the discretion of the responsible physician. Hemostatic agents applied in the six patients comprised rFVIIa (NovoSeven®) (n=4), APCC (Feiba®) (n=2), and fresh frozen plasma/plasma exchange (n=1). Agents employed for inhibitor eradication comprised prednisolone only (n=3), prednisolone with cyclophosphamide (n=1), prednisolone with cyclosporine (n=1), and prednisolone with rituximab (n=1). In five patients, management was successful, with complete response. Treatment failed in the patient with the highest inhibitor level (240 BU/mL) in whom treatment with APCC (Feiba®; 100 U/kg/dose, three doses) and prednisolone (0.5 mg/kg/day) was followed by several episodes of relapse. The present data demonstrate that AHA severity shows wide variation in elderly subjects, indicating the necessity of individualized management.

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Oladapo, Abiola, Joshua Epstein, Aaron Novack und Heinrich D. Farin. „The Benefit of FVIII Measurement: Tailored Treatment with Obi-1, a Recombinant Porcine Sequence Factor VIII, in Subjects with Acquired Hemophilia a“. Blood 124, Nr. 21 (06.12.2014): 3509. http://dx.doi.org/10.1182/blood.v124.21.3509.3509.

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Abstract Introduction: A significant unmet need in the management of acquired hemophilia A (AHA) is a replacement therapy that can be used without consideration of anti-human FVIII titer and allows for the ability to measure FVIII levels. The ability to measure FVIII levels during treatment: (1) identifies treatment response and leads to the ability to individually tailor treatment; (2) reduces treatment safety concerns; and (3) optimizes the utilization of therapy during treatment to minimize cost impact. OBI-1 is a recombinant porcine sequence FVIII developed to meet this need. Objective: To determine the impact of FVIII monitoring on OBI-1’s utilization during the treatment phase in the OBI-1 Phase 2/3 trial in AHA. Methods: A post-hoc analysis of the utilization data from the prospective, open label, Phase 2/3 study of OBI-1 in AHA was conducted. Subjects were administered an initial dose of 200U/kg of OBI-1 and subsequent doses were based on subject’s post-infusion FVIII activity levels and clinical assessments. The impact of FVIII monitoring on OBI-1’s utilization was evaluated by comparing: (A) the initial administered dose to the subsequent doses infused in the treatment period; and (B) the initial total administered dose within the first 24 hours of treatment to the doses infused in the subsequent 24-hour period(s) in the treatment period. The magnitude and the statistical significance of the dose adjustment were determined using non-parametric statistics (signed rank test). Results: Of the 29 subjects enrolled in the study, 65.5% (n=19) were males and median (range) age was 70 (42-90) years. Twenty-eight of the enrolled subjects had AHA while presence of anti-human FVIII titer could not be confirmed in the twenty-ninth subject. Of the subjects with AHA, 27 had a serious bleeding episode while one was enrolled for hemostatic cover for a planned surgery. Two subjects (7.1%) successfully responded requiring only the initial administered dose (100U/kg; 200U/kg). Two additional subjects were successfully treated within the first 24 hours. After the initial dose, subsequent doses indicated a median (IQR) dose reduction of 41.2% (50%) [n=26, p<0.01]. After the first 24-hour period, subsequent 24-hour periods showed a median (IQR) dose reduction of 65.4% (32.5%) [n=24, p<0.0001]. Conclusion: Study data indicate a significant reduction in the treatment dose after the initial dose or subsequent daily dosing after the first 24 hours. The ability to measure and monitor FVIII activity levels allow for the tailoring of OBI-1’s treatment dose and regimen. This measurability likely has a significant impact on dosing decisions to control the bleed. Disclosures Oladapo: Baxter Healthcare Corporation: Employment. Epstein:Baxter Healthcare Corporation: Employment. Novack:Baxter Healthcare: Employment. Farin:Baxter Healthcare: Employment.

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Ogawa, Yoshiyuki, Kunio Yanagisawa, Hiroaki Shimizu, Takuma Ishizaki, Akitada Ichinose und Hiroshi Handa. „Overshoot of FVIII Activity in Patients with Acquired Hemophilia“. Blood 132, Supplement 1 (29.11.2018): 2497. http://dx.doi.org/10.1182/blood-2018-99-112126.

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Abstract Background: Acquired hemophilia A (AHA) is a rare, life-threatening bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII) [J Thromb Haemost. 2011;9:226-235]. The disease is characterized by spontaneous hemorrhage or prolonged bleeding after surgery, trauma, or other invasive procedures in patients with neither family nor personal histories of hemorrhagic diathesis [BMC Res Notes. 2010;3:161]. The main goal of AHA therapy is arrest of bleeding by eliminating FVIII inhibitors. Once AHA is diagnosed, the patient should be placed on immunosuppressive therapy comprising corticosteroids either alone or in combination with effective cytotoxic agents such as cyclophosphamide, cyclosporine, azathioprine or, more recently, rituximab. Through these therapeutic interventions, 70-80% of patients with AHA reportedly achieve complete remission (CR) [Blood. 2007;109:1870-1877]. Overshoot of FVIII activity after achieving CR has been known anecdotally in some AHA patients, but the details remain unclear. Patients and methods: CR was defined when the following criteria were met: resolution of hemorrhagic signs; FVIII activity >60 IU/dl; and negative results for FVIII inhibitor. We treated a total of 20 patients with AHA between January 2009 and December 2017 at Gunma University Hospital (GUH). Data from the 15 AHA patients (median age, 74 years; range, 30-87 years; 10 males) who achieved CR under immunosuppressive therapy were retrospectively analyzed. Overshoot of FVIII activity was defined as a level ³150 IU/dl. All patients provided written informed consent for review of their medical records. The institutional review board at GUH approved the study protocol. Results: Baseline AHA-related parameters are shown below. All 15 patients showed a prolonged APTT (median, 77.0 s; range, 63.4-124.7 s). FVIII activity had decreased to <10 IU/dl in all patients (median, 2.3 IU/dl; range, <1.0-8.0 IU/dl), and two patients were very deficient in FVIII (<1.0 IU/dl). Median titer of FVIII inhibitor was 13.0 BU/mL (range, 2.0-234 BU/ml). Eleven patients required therapy with bypassing agents. Hemostatic therapy was generally effective and no deaths due to bleeding events were encountered. All 15 patients achieved CR by immunosuppressive therapy primarily due to steroids, within a median of 39 days (range, 19-173 days). Overshoot was observed in 10 patients (66.7%), with maximum FVIII activity >200 IU/dl in 5 patients. Median duration from CR to overshoot was 17 days (range, 0-154 days). Venous thromboembolism as a severe complication caused by overshoot was observed in one patient, with a giant hematoma compressing the left iliac vein. Discussion and Conclusion: We have provided, here, the first report on the frequency of FVIII overshoot after CR in AHA patients, revealing a higher than expected frequency. Most AHA patients are elderly, relatively inactive and receiving steroid therapy, and so are a prime group for developing thromboembolism. Some patients have been reported to develop thrombosis during AHA treatment [Haemophilia. 2007;13:451-461]. In addition, high FVIII activity (>150 IU/dl) has been reported as a risk factor for venous thromboembolism [Lancet. 1995;345:152-155]. Overshoot of FVIII activity after CR may risk thromboembolism when combined with other thrombotic triggers. Disclosures Handa: Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau.

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Dobbelstein, Christiane, Georgios Leandros Moschovakis und Andreas Tiede. „Reduced-intensity, risk factor–stratified immunosuppression for acquired hemophilia A: single-center observational study“. Annals of Hematology 99, Nr. 9 (03.07.2020): 2105–12. http://dx.doi.org/10.1007/s00277-020-04150-y.

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Abstract Immunosuppressive therapy (IST) is administered to patients with acquired hemophilia A (AHA) to eradicate autoantibodies against coagulation factor VIII (FVIII). Data from registries previously demonstrated that IST is often complicated by adverse events, in particular infections. This pilot study was set out to assess the feasibility of reduced-intensity, risk factor–stratified IST. We followed a single-center consecutive cohort of twenty-five patients with AHA receiving IST according to a new institutional treatment standard. Based on results from a previous study, GTH-AH 01/2020, patients were stratified into “poor risk” (FVIII < 1 IU/dl or inhibitor ≥ 20 Bethesda units (BU)/ml) or “good risk” (FVIII ≥ 1 IU/dl and inhibitor < 20 BU/ml). Outcomes were compared between the current cohort and the GTH registry as a historic control (n = 102). Baseline characteristics of the cohort were not different from the historic control. Partial remission, defined as FVIII recovered to > 50 IU/dl, was achieved by 68% of patients after a median time of 112 days, which was lower and significantly later than in the historic control (hazard ratio: 1.8, 95% confidence interval 1.2–2.8). Complete remission, overall survival, and frequency of fatal infections were not different. Grade 3 and 4 infections were more frequent. The impact of risk factors that was observed in the historic cohort was no longer apparent, as partial and complete remission and overall survival were similar in “good risk” and “poor risk” patients. In conclusion, reduced-intensity, risk factor–stratified IST is feasible in AHA but did not decrease the risk of infections and mortality in this cohort.

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Ellsworth, Patrick, Sheh-Li Chen, Yasmina L. Abajas, Stephan Moll, Nigel S. Key und Alice D. Ma. „Recombinant Porcine Factor VIII Use in Bleed Treatment in Non-Severe Hemophilia a Inhibitor Patients: Dosing Strategies and Efficacy“. Blood 132, Supplement 1 (29.11.2018): 1202. http://dx.doi.org/10.1182/blood-2018-99-119196.

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Abstract Introduction and Rationale: The development of alloantibodies to factor VIII remains a challenging and significant complication in the treatment of patients with congenital hemophilia A (HA). Inhibitor development is more common in severe HA than in non-severe HA (NSHA). Incidence of inhibitors in NSHA is approximately 3-13%, and even with attempted immune tolerance induction and immunosuppression, inhibitors have been reported to persist long-term in about 40% of NSHA patients (Hay 1998). Inhibitors in patients with NSHA can have variable kinetics, causing clinical characteristics similar to patients with acquired hemophilia A (AHA), with observable type 2 kinetics and inhibition of exogenous and endogenous FVIII activity (d'Oiron et al. 2006). Optimal treatment regimens have yet to be established for these patients, in terms of inhibitor eradication and choice of agent for control of bleeding episodes, with known thrombotic side effects when using bypassing agents, including in pediatric patients (d'Oiron et al. 2006). It has been observed as well that the efficacy of bypassing agents, such as activated prothrombin complex concentrates (aPCC) and recombinant activated factor VII (rFVIII), is diminished in the presence of an inhibitor (Rocino et al. 2017). Challenge with aPCC or rFVIII can also induce inhibitor recurrence in patients who have had previous resolution (Giuffrida et al. 2008). Recombinant porcine FVIII (rpFVIII) is an alternative therapy, which by virtue of its incomplete homology in the A2 and C2 domains of the FVIII molecule, has decreased reactivity with anti-human FVIII (hFVIII) inhibitors (Mulliez et al. 2014). rpFVIII has demonstrated efficacy in patients with severe HA with inhibitors, as well as in acquired HA (AHA) (Kempton et al. 2012; Kruse-Jarres et al. 2015). However, experience is limited for use in patients with NSHA and inhibitors. We report successful bleed treatment with rpFVIII of 3 adult patients and 1 child with NSHA who developed inhibitors at the University of North Carolina, with excellent hemostatic efficacy and no adverse treatment-related effects. Methods: We analyzed clinical, pharmacy, and laboratory data from 4 patients with NSHA who developed inhibitors treated with rpFVIII after failure of or contraindication to bypassing agents at the University of North Carolina. Investigational review board approval was obtained for our data collection and analysis. Results: Average baseline FVIII activity was 9.5%, with 3 of our 4 patients having a FVIII activity of <1 after inhibitor development. Mean anti-human FVIII inhibitor titer (hBIA) was 83 BU, ranging from 0.8 to 306 BU. Mean cumulative dose of rpFVIII used in the first 24 hours was 735 U/kg, but only 163 U/kg in our adult patients. Mean number of infusions used in the first 24 hours was 2.3 in our adult patients, and the pediatric patient required 18 infusions in the first 24 hours. Mean peak FVIII recovery was 153%. Hemostasis was achieved in all 4 patients with no treatment-related adverse effects, despite 3 of 4 patients developing a detectable anti-porcine FVIII inhibitor titer (pBIA). Conclusions: rpFVIII appears to be a safe and effective therapy in patients with NSHA who develop inhibitors. Our patients treated with immunosuppression in addition to rpFVIII, similar to how we treat patients with AHA. Of note, we achieved effective hemostasis in our 3 adult patients at much lower than FDA-recommended doses for AHA by using our previously established dosing algorithm for rp FVIII (Martin et al. 2016; Fig 1). Our pediatric patient required much more rpFVIII for effective hemostasis. This patient also had a much higher hBIA, and was being treated after the failure of multiple bypassing agents. However, once it seemed inhibitor binding sites were saturated after frequent higher rpFVIII doses, FVIII recovery was achieved, with concomitant decrease in doses required. FVIII activity was an effective means of monitoring efficacy of rpFVIII use, as in severe HA and AHA. One adult patient in particular had a very good clinical response to rpFVIII, requiring only 1 dose in the first 24 hours, with doses as low as 19 U/kg given daily required for bleeding control. Disclosures Abajas: CSL Limited: Honoraria; Bayer: Honoraria. Moll:Stago Diagnostics: Consultancy. Ma:CSL: Consultancy; Novo Nordisk: Consultancy; Shire: Honoraria, Research Funding; CVS: Honoraria.

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