Auswahl der wissenschaftlichen Literatur zum Thema „Viii ahau“

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.

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.

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.

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.

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.

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.

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.

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.

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

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

This chapter reviews the book Zionism without Zion: The Jewish Territorial Organization and Its Conflict with the Zionist Organization (2016), by Gur Alroey. In Zionism without Zion, Alroey examines the movement that became Zionism’s fiercest rival—Territorialism—and how it ultimately lost the ideological contest concerning the location of the future Jewish state. Zionism and Territorialism shared the same precursors, and their proponents held a similar worldview with regard to the urgency of providing a refuge for Jews. In contrast, there were those who called for integration of the Jews into the various countries in which they already lived. This group was divided into two, one of which included Communists and Bundists. There was also a “cultural” stream in the Zionist Organization, which was led by Ahad Ha’am. According to Alroey, Ahad Ha’am sought to resolve the problem of Jewish religion in Palestine.

Factor XI (plasma thromboplastin antecedent) is a plasma glycoprotein that participates in the contact activation of blood coagulation. In the present study, the organization of the gene for human factor XI has been elucidated. The gene for human factor XI has been isolated from two independent human genomic λ phage libraries using a full length cDNA for human factor XI as a hybridization probe. Four overlapping recombinant λ phage containing the human factor XI gene have been isolated and characterized. Restriction mapping, Southern blotting and hybridization studies indicate that the entire gene for human factor XI is 25 kilobases in length. Overlapping regions of the gene have been subcloned and the DNA sequence of selective regions has been determined. These results show that the gene for factor XI is composed of 15 exons and 14 introns. Exon I codes for the 5′ noncoding sequences and exon II codes for the signal peptide of 18 amino acid residues. The four tandem repeats that constitute the heavy chain of factor XIa are each encoded by two consecutive exons (exons III and IV, V and VI, VII and VIII, IX and X). The location of the introns and the junction type among these four tandem repeats are strictly conserved. Exon XI, XII, XIII, XIV and XV code for the light chain of factor XIa that contains the serine protease part of the molecule. The location of the introns and the junction types in this region of the gene are identical to those in the corresponding regions of the genes for human tissue plasminogen activator and porcine urokinase. These results show that gene duplication and exon shuffling play a significant role in the evolution of the human factor XI gene. (Supported in part by NIH Grant HL 16919 and AHA Grant 82-221.)