scholarly journals Treatment of Acquired Hemophilia a with Rituximab and Emicizumab

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Evan C. Chen ◽  
William J. Gibson ◽  
Paula Temoczko ◽  
Nathan T. Connell ◽  
Robert Handin ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Case Series ◽  
High Dose ◽  
Recurrent Bleeding ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Private Company ◽  
Fviii Inhibitor ◽  
Fviii Activity

Background Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies that inhibit coagulation factor VIII (FVIII). The disorder is understudied given its rarity and there are no randomized prospective trials to guide therapy. In practice, treatment involves attaining hemostasis and eliminating the FVIII inhibitor, typically with high-dose steroids (1 mg/kg daily) and either cyclophosphamide or rituximab. However, current approaches carry risk of significant adverse events and delayed or inadequate responses. Emicizumab is a bispecific antibody that targets coagulation factors IXa and X to recapitulate the function of endogenous FVIII. We present a case series of patients with acquired hemophilia A who were successfully treated with a regimen consisting of rituximab and emicizumab. Methods We identified patients >18 years who were diagnosed with acquired hemophilia A and received treatment with rituximab and emicizumab at Brigham and Women's Hospital between 2019 and 2020. We performed a retrospective chart review. Data collected included the patients' clinical presentation, laboratory studies (including coagulation testing, FVIII activity, and FVIII inhibitor titer), and treatments received (including systemic therapies, recombinant factor VIIa [rFVIIa], red blood cell [RBC] transfusions, and vascular embolization). We recorded the time to normalization of the activated partial thromboplastin time (aPTT) and chromogenic FVIII activity following emicizumab and rituximab initiation, respectively. Activated prothrombin complex concentrate was avoided given the use of emicizumab. Results We identified 8 patients with acquired hemophilia A who received treatment with emicizumab and rituximab. The median patient age was 81 (range 47-93). All patients sought medical attention for extensive ecchymoses or bleeding and were found to have prolonged aPTT leading to FVIII inhibitor identification (Table 1). The median inhibitor titer was 18 Bethesda units (range 9.2-107.5). Patients concurrently received 4 weekly doses of rituximab 375mg/m2 and 4 weekly loading doses of emicizumab 3mg/kg. Patient (Pt) #1 continued emicizumab 3mg/kg every two weeks to complete three months of treatment. Pts #2, #3, and #8 received high-dose prednisone (1mg/kg) at the start of treatment for a range of 10-14 days. Pt #8 received 7 additional days of prednisone for an initial aPTT of 60.7 seconds before starting emicizumab and rituximab; she had no clinical response when treated with prednisone alone. Pts #2, #5, and #7 required vascular embolization. 7 patients (Pts #2 through #8) had aPTT retested within 1 week of starting emicizumab, and the aPTT for these patients normalized within 10 days of starting emicizumab (i.e. after only 1-2 doses; Figure 1). Except for Pt #5 who had recurrent hematuria from a persistent anatomic bladder defect that eventually required prostatic artery embolization, patients did not require rFVIIa or RBC transfusions for more than 7 days after starting emicizumab. Except for Pt #5 who required 28 doses of rFVIIa and 3 units of RBC transfusions after starting emicizumab, the median number of rFVIIa doses and RBC units given to the remaining 7 patients was zero (range 0-6 doses) and zero (range 0-4 units), respectively. Pts #2 and #3 had chromogenic FVIII levels obtained >30 days after starting rituximab with improvement in FVIII activity to 29% (day 71) and 86% (day 91), respectively. During a median follow-up of 102 days, no patients experienced recurrent bleeding. However, Pt #3 exhibited a slowly increasing aPTT that reached 46.3 seconds on day 233 of follow-up without symptoms; further diagnostic testing is pending. Conclusion Our case series demonstrates that the combination of rituximab and emicizumab can be an effective and safe regimen for the treatment of acquired hemophilia A. No thrombotic events or thrombotic microangiopathy occurred. Treatment with weekly emicizumab led to aPTT normalization after 1-2 doses and facilitated hemostasis, as reflected by a median usage of zero rFVIIA doses and zero RBC transfusions after starting emicizumab when excluding one patient with hematuria from an anatomic defect. This compares favorably to historical reports. While no patient has had recurrent bleeding, additional chromogenic FVIII activity testing for patients is needed to confirm long-term normalization of FVIII activity. Disclosures Gibson: Ampressa therapeutics: Current equity holder in private company; nference: Consultancy, Current equity holder in private company; ImmPACT-Bio: Consultancy; Boston Clinical Research Institute: Consultancy. Parnes:Bayer: Consultancy; I-Mab: Consultancy; Sunovion: Consultancy; UniQure: Consultancy; Sigilon: Consultancy; Shire/Takeda: Consultancy, Research Funding; Genentech: Research Funding; Geron: Current equity holder in publicly-traded company. OffLabel Disclosure: Emicizumab is used off-label in our case series for the treatment of acquired hemophilia A.

Overshoot of FVIII activity in patients with acquired hemophilia A who achieve complete remission

2020 ◽  
Vol 111 (4) ◽  
pp. 544-549
Author(s):  
Yoshiyuki Ogawa ◽  
Kunio Yanagisawa ◽  
Chiaki Naito ◽  
Hideki Uchiumi ◽  
Takuma Ishizaki ◽  
...  
Keyword(s):  
Complete Remission ◽  
Hemophilia A ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Fviii Activity

scholarly journals 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 ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1128-1128
Author(s):  
Carolyne Elbaz ◽  
Katerina Pavenski ◽  
Hina Chaudhry ◽  
Jerome M. Teitel ◽  
Michelle Sholzberg
Keyword(s):  
Factor Viii ◽  
Research Funding ◽  
Hemophilia A ◽  
De Novo ◽  
Factor Viia ◽  
Case Series ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
C2 Domains ◽  
Inhibitor Development

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

Circulating factor VIII immune complexes in patients with type 2 acquired hemophilia A and protection from activated protein C–mediated proteolysis

Blood ◽  
2001 ◽  
Vol 97 (3) ◽  
pp. 669-677 ◽  
Author(s):  
Keiji Nogami ◽  
Midori Shima ◽  
John C. Giddings ◽  
Kazuya Hosokawa ◽  
Masanori Nagata ◽  
...  
Keyword(s):  
Factor Viii ◽  
Light Chain ◽  
Immune Complexes ◽  
Protein C ◽  
Hemophilia A ◽  
Activated Protein C ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Fviii Activity

Abstract Factor VIII (FVIII) inhibitor antibodies are classified into 2 groups according to the kinetic pattern of FVIII inactivation. Type 2 antibodies are more commonly observed in patients with acquired hemophilia A and do not completely inhibit FVIII activity; in most cases, substantial levels of circulating FVIII are detected. Three type 2 autoantibodies from patients who had normal levels of FVIII antigen despite having low levels of FVIII activity were studied. The antibodies reacted exclusively with the light chain of FVIII but not with the C2 domain, and their epitopes were therefore ascribed to the regions in the A3-C1 domains. Heavy and light chains of FVIII were detected in plasma-derived immune complexes extracted by using protein G Sepharose. Direct binding assays using anhydro-activated protein C (anhydro-APC), a catalytically inactive derivative of activated protein C (APC) in which the active-site serine is converted to dehydroalanine, were used to examine the relation between immune complexes and APC. The intact FVIII, 80-kd light chain, and 72-kd light chain bound in a dose-dependent manner to anhydro-APC, with Kdvalues of 580, 540, and 310 nM, respectively, whereas no appreciable binding was detected for the heavy chain. The 3 autoantibodies blocked FVIII binding to anhydro-APC by approximately 80% and consequently inhibited APC-induced FVIII proteolytic inactivation. These antibodies also bound to a synthetic peptide, His2009-Val2018, which contains the APC binding site. The findings suggest that binding of type 2 autoantibodies, recognizing residues His2009 to Val2018, protects FVIII from APC-mediated proteolysis and might contribute to the presence of FVIII immune complexes in the circulation.

Isolation and Characterization of an Antifactor VIII Antibody from a Patient with Acquired Hemophilia A and a Severe Hemorrhagic Syndrome.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4073-4073
Author(s):  
Michael A. Bukys ◽  
Paolo Simioni ◽  
Kerri Smith ◽  
Luca Spiezia ◽  
Michael Kalafatis
Keyword(s):  
Light Chain ◽  
Hemophilia A ◽  
Immunosuppressive Treatment ◽  
High Dose ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Upper Airways ◽  
Isolation And Characterization ◽  
Significant Prolongation ◽  
Total Immunoglobulin

Abstract Patients with hemophilia A usually develop inhibitory antibodies to factor VIII (fVIII) that are directed against epitopes in the A2 and C2 domains of the cofactor and result in increased morbidity and mortality because of an extended hemorrhagic syndrome. However, in some cases individuals spontaneously develop autoantibodies to fVIII resulting in acquired hemophilia A. While the etiology and mechanism of the disorder are still unknown, the study and determination of the properties of the autoantibodies is necessary to provide insights into their mechanism of generation. A 78-year-old woman was admitted to the Internal Medicine Department of the University-Hospital of Padua for severe anaemia and syncope. She developed an acute hemorrhagic syndrome characterized by the development of extended subcutaneous and mild intramuscular haematomas on both legs. The patient’s family history was negative for hemorrhagic manifestations. Total body computed tomography (CT) scan confirmed the presence of small intramuscular haematomas. Preliminary laboratory analyses revealed a significant prolongation of the aPTT (activated partial thromboplastin time) to 60 sec and a mild prolongation of the PT (prothrombin time) to 15 sec. Mixing experiments with normal plasma failed to correct the patient’s aPTT. Plasma fVIII levels were ~6%. Assay for fVIII inhibitor revealed a level of 6 Bethesda Units (BU). The patient was treated with high dose of steroids and recombinant fVIII (3,000 Units daily). Subsequently, she developed swelling to the neck in the sub maxillary region and symptoms consistent with an acute obstruction to the upper airways requiring oral-tracheal intubations and ventilation. These findings prompted the use of recombinant FVIIa to prevent progression of the hemorrhagic lesion. Three sessions of plasmapheresis were performed, which were followed by the administration of high dose immunoglobulin and the administration of immunosuppressive treatment. After 45 days, treatment was continued with steroids only. The patient recovered completely and no new bleeding episodes developed. The total immunoglobulin fraction was isolated from the patient’s plasma and found to induce a prolongation of the clotting time in an aPTT assay using purified reagents. The immunoglobulin fraction was also found to inhibit intrinsic tenase activity in an assay using purified reagents and a chromogenic substrate that detects factor X activation. In contrast, the total immunoglobulin fraction purified from normal pooled plasma didn’t prolong the aPTT nor inhibited intrinsic tenase activity. Immunoprecipitation experiments with the total immunoglobulins fraction purified from the patient’s plasma revealed that the antibody recognizes epitopes on the light chain of the cofactor. Immunobloting experiments performed with the same material demonstrated that the antibody recognizes fVIII heavy and light chains. Following activation by thrombin it was found that the antibody recognizes the Mr 73,000 light chain and the A2 domain of the cofactor. These data demonstrate that the immunoglobulin fraction isolated from the patient’s plasma has more than one epitope on the cofactor. Our findings provide the demonstration of a strong anti-fVIII acquired autoantibody with low titer which is not related to the presence of antiphospholipid antibodies and is responsible for a severe hemorrhagic syndrome.

scholarly journals Acquired hemophilia A developing cerebral infarction 36 days after the frequent administration of bypass hemostatic agents

2018 ◽  
Vol 10 (2) ◽  
Author(s):  
Makoto Saito ◽  
Hajime Senjo ◽  
Minoru Kanaya ◽  
Koh Izumiyama ◽  
Akio Mori ◽  
...  
Keyword(s):  
Cerebral Infarction ◽  
Factor Viii ◽  
Hemophilia A ◽  
Activity Level ◽  
High Dose ◽  
Factor Viii Inhibitor ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Hemostatic Agents ◽  
Frequent Administration

A 74-years-old male who was a smoker and received treatment for hypertension, dyslipidemia, peripheral arterial disease and idiopathic interstitial pneumonia complained of subcutaneous hemorrhage of the right lower thigh. Marked anemia (hemoglobin 5.5 g/dL) and prolonged activated partial thromboplastin time (≥130 seconds) were noted. The factor VIII activity level was reduced to 1.2 %, and the factor VIII inhibitor titer was 285.3 BU/mL, a diagnosis of acquired hemophilia A (AHA) was made. Then, hematomas of 5 intra-muscles were recurred. Hemostasis became difficult despite frequent and high-dose administration of recombinant human coagulation factor VIIa (total: 18 days, 305 mg). Hemostasis was achieved by switching to activated prothrombin complex concentrate (for 3 days, 18,000 units), however, cerebral infarction occurred after 36 days. After the frequent administration of bypass hemostatic agents on elderly AHA patients with several risk factors for ischemic stroke, the risk of subsequent thrombotic events may persist for 1 month.

scholarly journals Acquired Hemophilia A: A Frequently Overlooked Autoimmune Hemorrhagic Disorder

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Yoshihiko Sakurai ◽  
Tomohiro Takeda
Keyword(s):  
Induction Therapy ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
High Dose ◽  
Bleeding Tendency ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Acute Hemorrhage ◽  
Immune Tolerance Induction

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.

scholarly journals Acquired Hemophilia: A Ten Year Population-Based Review of Incidence Rate, Patient Demographics, and Treatment Outcomes in Manitoba, Canada

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3783-3783 ◽  
Author(s):  
Brittany Perija ◽  
Donald S Houston ◽  
Rami Kotb ◽  
Sara J. Israels ◽  
Emily K. Rimmer ◽  
...  
Keyword(s):  
Adverse Events ◽  
Hospital Admission ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Population Based ◽  
First Line ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Fviii Inhibitor ◽  
Hemostatic Therapy

Abstract Introduction: Acquired hemophilia A (AHA) is a rare disease characterized by inhibitory autoantibodies to coagulation factor VIII (FVIII). Although this entity is well described clinically, there are few population-based data available to allow accurate estimates of incidence or outcomes. The reported incidence is approximately 1.48/million/year.Up to 50% of cases of AHA may be associated with a variety of clinical conditions. Treatment typically involves immunosuppression to eradicate the FVIII inhibitor, as well as hemostatic therapy to control bleeding. Methods: We identified all unique cases of AHA in Manitoba, Canada between April 2006 and November 2015 from the records of the provincial reference hemostasis laboratory at the Health Sciences Center in Winnipeg. Since 2006, this laboratory has provided testing for the province's entire population. AHA was defined by a positive Bethesda inhibitor assay titre (> 0.5 B.U); patients with congenital hemophilia were excluded. The diagnosis was confirmed through chart review of medical records from CancerCare Manitoba (the sole provider of tertiary out-patient hematology care in Manitoba, and site of the Manitoba Bleeding Disorders Program), as well as from hospital admission records. We used a piloted case report form to gather patient and clinical demographics such as age, sex, and comorbidities; coagulation factor and inhibitor levels, pharmacotherapeutic treatments, blood product administration, adverse events, clinical outcomes, and survival. Results: 23 new cases of AHA were identified between 1 April 2006 and 1 November 2015, corresponding to an incidence rate for the Manitoba population of 1.98 cases per million per year. The median age at diagnosis was 75 years (range 49 to 88 years). The male to female ratio was 0.92:1. 22% (n=5) of patients had an underlying condition associated with AHA: 4 had autoimmune disease, 1had an active malignancy. Most patients initially presented to an emergency department (78%, n=18), with 70% of patients (n=16) requiring hospital admission. All patients had bleeding symptoms at the time of diagnosis. 57% (n=13) had a major bleed at the time of diagnosis, defined as a decrease in hemoglobin of ≥ 20 g/L from baseline or requiring transfusion of at least two units of red blood cells in 24 hours. Combined cyclophosphamide and prednisone was the most common immunosuppressive regimen used to eradicate the FVIII inhibitor (n = 18); two of these patients also received IVIG as part of their first line therapy. One patient was treated with prednisone alone due to concurrent esophageal adenocarcinoma, and plans for future chemotherapy. Three patients were not treated due to palliation, death prior to treatment initiation, and active tuberculosis. Data regarding immunosuppressive treatment is unknown in one patient. Activated recombinant factor VII was the most common first line hemostatic agent used (43%, n = 10). 13% of patients (n=3) were treated initially with tranexamic acid because AHA had not yet been recognized as the cause of bleeding. Adverse reactions to treatment occurred in almost all patients; the most common being mood disturbance and leukopenia. The median time to remission (Bethesda titre <0.5 B.U and/or normal FVIII level) was 62 days (range 16-166 days). The median survival after diagnosis was less than 5 years. The cause of death was not available for the majority patients, but at least one patient died as a result of bleeding. Disease relapse was rare, occurring in only 2 patients. Conclusions: The incidence of AHA identified in Manitoba, Canada is 1.98/million/year, slightly higher than previous estimates. Only 21% of patients had an associated comorbidity, which is lower than previous estimates, and may reflect a bias in non-population based series. Major bleeding requiring multiple transfusions is common, as is the need for hemostatic therapy and hospitalization. Adverse events related to treatment are common. There is high mortality seen in patients with AHA. Patients who die early are likely to be undercounted in non-population based series. Disclosures No relevant conflicts of interest to declare.

Rituximab in the Treatment of Acquired Hemophilia a (AHA): A Novel Eradicating Therapy?

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4533-4533 ◽  
Author(s):  
Karla O. Mota ◽  
Silvia Nakanishi Bastos
Keyword(s):  
B Cell ◽  
Soft Tissues ◽  
Hemophilia A ◽  
Clinical Findings ◽  
High Rate ◽  
Severe Bleeding ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Fviii Inhibitor

Abstract Background: Acquired inhibitors against factor VIII (FVIII), also termed Acquired Hemophilia A (AHA), occur rarely in the nonhemophilic population. Its incidence is approximately 1 to 4 per million/year. The incidence of AHA increases with age and a major peak is seeing in patients aged 68 to 80 years. These autoantibodies are associated with high rate of morbidity (90% of severe bleeding in affected patients) and mortality (8–22% of the cases). The diagnosis of AHA is based on the demonstration of an isolated prolongation of the activated partial thromboplastin time (APTT), not corrected by incubating the patient’s plasma with equal volumes of normal plasma (mixing study), associated with FVIII reduced levels and formal evidence of a FVIII inhibitor in a patient with no previous personal or family history of bleeding. In approximately half of affected patients there is no identification of relevant concomitant diseases. The bleeding pattern in AHA is characterized by hemorrhages into the skin, muscles or soft tissues, and mucous membranes. Rituximab (Mabthera®; Roche; Switzerland) is a chimeric monoclonal antibody against the pan B-cell antigen CD20 that induces a rapid in vivo depletion of normal B lymphocytes. Primarily developed to treat B-cell non Hodgkin Lymphomas, more recently, Rituximab has demonstrated effectiveness in a number of autoantibody-mediated diseases including AHA. Case Report: We treated a 69-year-old diabetic and hypertensive patient with AHA. In March 2007, the diagnosis was made by a prolonged APTT (ratio 2.74 sec), not corrected by the mixing study, and FVIII inhibitor 320 Bethesda units. The patient had no evidence of malignancy, autoimmune disease or use of drugs. His bleeding manifestations were large ecchymosis of upper and lower extremities for almost a year, and at admission to the hospital, a hematoma of left calf and gengival bleeding. First line therapy consisted of steroids and cyclophosphamide (CFM). The steroids had to be withdraw after one week of use, because of very difficult glycemic control. The CFM were use in the dose of 50mg/day adding an total accumulative dose of 3g. This protocol were used considering the incapacity of the patient to tolerate higher dose of CFM due to leukopenia. After treatment, the patient was evaluated and neither normalization of APTT nor improvement of clinical findings happened. Therefore, considering all the above, it was decided to use Rituximab 375mg/m2, weekly, for four weeks. In June 2007, the patient received and tolereted very well all the infusions. In August 2007, he had no bleeding symptoms and his APTT was normal. At his laterest visit to the clinic in July 2008, an year after finishing his treatment, he was still very well and his bleeding tests were normal. Conclusion: Rituximab should be considered a treatment option for AHA.

Anti-FVIII Autoantibodies Share Similar Characteristics In Acquired Hemophilia A Patients With and Without An Associated Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1110-1110
Author(s):  
Joerg Kahle ◽  
Christoph Königs ◽  
Anja Naumann ◽  
Thomas Klingebiel ◽  
John F Healey ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Underlying Disease ◽  
Severe Bleeding ◽  
Bleeding Tendency ◽  
C2 Domain ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Fviii Inhibitor

Abstract Introduction Acquired hemophilia A (AHA) is an autoimmune disease caused by the development of inhibitory autoantibodies against factor VIII (FVIII) resulting in severe hemorrhages. Associated pathologies, such as autoimmune disease, malignancy and pregnancy are observed in approximately 50% of patients. Aim To elucidate the relationship between an underlying disease, the bleeding tendency and patients immunological profile the characteristics of anti-FVIII autoantibodies in AHA patients with (n=6) and without an underlying disease (n=9) were determined. Patients and Methods The median age of this cohort (n=15) was 71 years with two-thirds older than 70 years. Treatment parameters were analysed and patients were classified according to there bleeding tendency into a mild, moderate and severe phenotype. FVIII domain specificity of anti-FVIII autoantibodies was analysed in ELISA by binding to (i) FVIII fragments (heavy (HC) and light chain (LC), A2 and C2 domain) and (ii) single human domain hybrid human/porcine FVIII proteins. The amount of FVIII-specific IgGs was measured by ELISA and their relative contribution to the total amount of anti-FVIII IgG was calculated from standard curves for FVIII-specific IgG1, IgG2, IgG3, and IgG4. Results All but one patient were treated with bypassing agents including activated FVII, activated prothrombin complex concentrate or porcine FVIII. All patients received immunosuppressive treatments. 14/15 achieved initial complete remission with 6 patients experiencing another episode of inhibitors. Characteristics of anti-FVIII autoantibodies in AHA patients with or without an underlying disease were similar: FVIII-specific autoantibodies targeted primarily the FVIII LC with a dominance of epitopes located C2 domain compared to the C1 domain. FVIII-specific antibodies belonged to the subclasses IgG1, IgG2, and IgG4. The individual IgG subclass levels did not correlate with the total amount of anti-FVIII antibodies or inhibitory anti-FVIII antibodies in Bethesda units. IgG1 and 2 vs IgG4 levels did not correlate with bleeding tendency. Patients with a mild bleeding phenotype only recognized the C2 domain, whereas other patients had antibodies against C2 and or other domains. Although lower levels of FVIII activity (FVIII:C) were observed in disease-associated AHA patients with a median FVIII:C of 0.5% (range, 0-6%) compared to 1.5% (range, 0-10%) in idiopathic AHA patients, this difference was not statistically significant. FVIII:C levels and FVIII inhibitor titers at clinical presentation did not correlate to the severity of bleeds: the median FVIII:C level in patients who had strong bleeds was 0.5% (range, 0-10%), moderate bleeds 3.6% (range, 0-6%), and mild bleeds 1.2% (range, 1-6%). The FVIII inhibitor titer at presentation was similar in patients who had mild, moderate and severe bleeding tendency with a median of 35 BU/mL (range, 29-55 BU/mL), 49.5 BU/mL (range, 9-156 BU/mL), and 17.3 BU/mL (range, 2.2-614 BU/mL), respectively. Conclusion The presented data challenges the view from other small cohorts that differential immunological profiles exist between disease-associated and idiopathic AHA patients. Data on the influence of epitopes and IgG subclasses on outcome in AHA patients remains conflicting and needs further study. Disclosures: No relevant conflicts of interest to declare.

Acquired Hemophilia A. Experience Of a Single Center

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4781-4781 ◽  
Author(s):  
Mauricio A Alzate ◽  
Susana S Meschengieser ◽  
Alicia Blanco ◽  
Silvia Grosso ◽  
María A Lazzari ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Initial Symptoms ◽  
Bleeding Episodes ◽  
The Mean ◽  
Inhibitor Titer

Introduction Acquired hemophilia A is a rare and serious autoimmune disease. Morbidity and mortality are associated with advanced age, comorbidities, toxicity of treatment and bleeding severity. Treatment goals are control of the bleeding and eradication of the inhibitor, while treating the underlying condition if it is present. Objective To describe the baseline characteristics of acquired hemophilia A patients and to assess the response to treatment. Patients and Methods Between November 1991 and April 2013, 27 patients were diagnosed with acquired hemophilia A (mean age 59, range 21-86; 18 women - 66%) in the Departamento de Hemostasia y Trombosis. Five patients were lost from follow-up. APTT mixing studies with normal plasma (1:1) and time-temperature dependent effect on the APTT were performed for a-FVIII diagnosis. Whenever possible, inhibitor activity was titrated by Bethesda method at diagnosis (BU/mL). Medical records were reviewed to evaluate the initial symptoms, underlying diseases, treatments and outcome. Results The mean follow-up was 86 weeks (range 1-640). Underlying etiologies included: idiopathic 70.4%, postpartum 14.8%, malignancy 11.1%, autoimmune disease 3.7%. All patients had bleeding at diagnosis. The most frequent sites of bleeding were: muscular 32%, soft tissue 18%, urinary tract 9%, gastrointestinal tract 6%; being from multiple sites in 9%. At diagnosis, the mean value for FVIII was 6% (range 1-40), and inhibitor titer 220 BU/mL (range 2.2-1173). Initial therapeutic scheme included glucocorticoids in 97% of the patients, 13 in monotherapy (mean age 53 years ± 19), 13 with cyclophosphamide (63 years ± 18) (p= ns), and human immunoglobulin in 1 patient. This last patient died after 1 week of diagnosis due to uncontrolled gastrointestinal bleeding (previous to the era of rVIIa). As a second-line therapy, rituximab was used in 3 patients. Sixty-three (63%) patients achieved complete response (CR) (inhibitor titer < 0.6 BU/mL without bleeding episodes), and 23% achieved partial response (PR) (reduction in inhibitor titer > 50% without bleeding episodes), without differences between monotherapy or combined. Overall, women responded more frequently than men (93.3% vs. 71.4%, p= ns). All patients that received rituximab achieved CR. Conclusions In this study, the overall response rate was higher than 80%. In most cases, the disease has a prolonged course like other autoimmune diseases, with remissions and relapses. Disclosures: No relevant conflicts of interest to declare.

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