Recombinant human activated FVII as prophylaxis in surgical treatment of cancer patient with acquired hemophilia A.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17006-e17006
Author(s):  
Giacinto La Verde ◽  
Antonella Ferrari ◽  
Vincenzo Ziparo ◽  
Virginia Naso ◽  
Maria Paola Bianchi ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Activity Level ◽  
Cytotoxic Agents ◽  
Bleeding Complications ◽  
Normal Range ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Fviii Inhibitor ◽  
Post Surgery ◽  
Inhibitor Titer

e17006 Background: Acquired hemophilia A is caused by the development of factor (F)VIII autoantibodies and results in more serious haemorrhagic symptoms than in congenital severe HA. About 50% of cases, not identified as idiopathic, are related to autoimmune diseases, viral infections, pregnancy and also neoplasms. To treat bleeds recombinant factor VIIa and activated prothrombin complex concentrate are equally efficacious while immunosuppression with steroids alone or combined with cytotoxic agents should be started as soon as the diagnosis is made. Methods: In February 2010 a woman of 58 years with acquired hemophilia A, previously treated in 1978 with cyclophosphamide and steroids without clinical benefits, was admitted to the Hematology Department of Sant’Andrea Hospital in Rome for a recent episode of spontaneous massive enterorrhagia. The diagnostic exams revealed a colorectal carcinoma (moderately differentiated G3) associated with papillary urothelial neoplasia with low malignant potential. A coagulation panel showed an aPTT ratio of 3.75 (normal range 0.8-1.2), INR 1.03 (normal range 0.9-1.2), fibrinogen 327 mg/dL (normal range 238-500), FVIII activity level of 3% (normal reference 50-150%) and FVIII inhibitor titer > 100 Bethesda Units. Results: The patient was treated with left hemicolectomy and removal of the bladder lesion associated with chemotherapy XELOX (oxaliplatin 130 mg/sm day 1 q21, capecitabine 1000 mg/sm orally day 1-14 q21). From day -1 to day +15 post surgery, the patient was treated with intravenous recombinant human activated FVII at standard dose (NovoSeven®, 90 mcg/kg every 4 hours). Our treatment avoided both intra and post-operative surgical bleeding complications, while not changing the titer of the inhibitor nor by normalizing the aPTT ratio. Actually the patient is in good clinical conditions with no further hemorrhagic episodes, although the FVIII inhibitor titer still remains high. Conclusions: We have described this case to emphasize that the presence of acquired hemophilia A in cancer patients, thanks to its specific prophylactic treatment, cannot be a limit in performing routine diagnostic and therapeutic procedures, especially surgical ones.

scholarly journals Diagnosis and Treatment of Acquired Hemophilia: One Single-Center Experience from PR. China

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4250-4250
Author(s):  
Rong-Fu Zhou ◽  
Yueyi Xu ◽  
Wenjin Gao
Keyword(s):  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Clinical Manifestations ◽  
Coagulation Factor ◽  
Factor Vii ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Coagulation Factor Vii ◽  
Prolonged Aptt ◽  
Inhibitor Titer

Abstract Objective: To deepen the understanding of the clinical manifestations of acquired hemophilia A for timely and correctly treatment. Methods: The clinical data of the acquired hemophilia A patients diagnosed in the hospital from Jan 2006 to Mar 2021 were retrospectively analyzed, and the relevant literature was reviewed. Results: 17 patients with acquired hemophilia A, male: female =10: 7, median age 61 years (19 to 78 years), were diagnosed and treated in the hospital with the median time from the onset to diagnosis 21 days (2 days to 6 months). Six patients had comorbidity, including hepatitis B carrying, chronic myelomonocytic leukemia, diabetes, hypertension and positive autoantibodies, pemphigoid and gastric cancer, respectively. Other 11 patients were healthy before the onset. All patients had large large ecchymosis of skin, and one case was combined with hematuria, and one case with retroperitoneal hematoma. All patients had APTT extension (45s-144.7s) and the prolonged APTT could not be corrected with normal mixed plasma with and without incubation at 37℃ for 2 hours. FVIII activity was 1% - 8.9% and inhibitor titer 2 - 128 Bu/ml. All patients with bleeding were with prothrombin complex/recombinant activated coagulation factor VII, some of them with pd-coagulation factor FVIII preparations. Inhibitors were removed with prednisone acetate (1 case) + chemotherapy (1 case), prednisone acetate / + CTX (11 cases) + chemotherapy (1 case), prednisone acetate/prednisolone + mabthera (2 cases) + CTX (1 case), respectively. The removal time of inhibitor was from 8 days to 4 years. During the treatment process, two patients developed lower extremity venous thrombosis, and one patient was complicated with lung infection. Conclusion: Patients with unexplained bleeding and prolonged APTT should be conducted normal mixed plasma correction test, coagulation factor activity and inhibitor titer examination. After correctly diagnosis, bypass agents /coagulation factor VIII preparations should be given timely for hemostasis, protocol based on glucocorticoid + CTX/mabthera to remove the inhibitor and symptomatic treatment for patients with primary comorbidity disease at the same time. Disclosures No relevant conflicts of interest to declare.

scholarly journals Acquired Hemophilia A (FVIII Deficiency) Associated with Papillary Thyroid Cancer: Treatment with Recombinant Porcine FVIII

2019 ◽  
Vol 2019 ◽  
pp. 1-5
Author(s):  
S. Nguyen ◽  
P. Teh ◽  
J. Zhou ◽  
E. Y. Chang ◽  
A. von Drygalski
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Hemophilia A ◽  
Autoimmune Disorder ◽  
Bleeding Complications ◽  
Papillary Thyroid ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Rescue Treatment ◽  
Bypassing Agents

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.

scholarly journals Aortic root repair in a patient with acquired hemophilia A: case report

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Emre Gok ◽  
Mehmet H. Akay ◽  
Ismael Salas de Armas ◽  
Kimberly Klein ◽  
Hlaing Tint ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Factor Viii ◽  
Perioperative Management ◽  
Hemophilia A ◽  
Open Heart Surgery ◽  
Bleeding Complications ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Severe Aortic Regurgitation ◽  
Root Repair

Abstract Background Patients with acquired hemophilia A (AHA) who require open heart surgery have a life-threatening risk of hemorrhage. Limited data exist to guide perioperative management of these patients. Case presentation A 53-year-old female with rheumatoid arthritis, concomitant aortic valve endocarditis, and severe aortic regurgitation presented to our hospital. Bleeding and abnormal coagulation tests were noted during the initial workup, and she was diagnosed with AHA. The perioperative management plan included the use of pharmaceuticals, porcine recombinant factor VIII, and blood products. Extensive preoperative coagulation data were obtained, and factor VIII levels were continuously monitored to mitigate bleeding complications. The aortic valve replacement and root repair were uneventful. Conclusion Cardiac surgery in patients with AHA is possible as long as complex perioperative hemostatic and hematology management is used.

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.

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 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.

Prognostic Parameters For Remission Of and Survival In Acquired Hemophilia A: Results Of The GTH-AH 01/2010 Multicenter Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 205-205 ◽  
Author(s):  
Andreas Tiede ◽  
Jan-Malte Blumtritt ◽  
Robert Klamroth ◽  
Saskia Gottstein ◽  
Katharina Holstein ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Performance Status ◽  
Immunosuppressive Treatment ◽  
Treatment Protocol ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Advisory Committees ◽  
Inhibitor Titer

Abstract Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by neutralizing autoantibodies against coagulation factor VIII (FVIII:C). Immunosuppressive treatment may result in remission of disease over a period of days to months. Until remission, patients are at high risk of bleeding and complications from immunosuppression. Prognostic parameters to predict remission and the time needed to achieve remission could be helpful to guide treatment intensity, but have not been established so far. GTH-AH01/2010 was a prospective multicenter cohort study using a standardized immunosuppressive treatment protocol. The primary study endpoint was time to achieve partial remission (PR, defined as FVIII:C activity >50 IU/dl after cessation of any hemotherapy for >24h, and no active bleeding). Secondary endpoints were time to achieve complete remission (CR, defined as PR plus negative FVIII:C inhibitor, steroid tapered to <15 mg/d prednisolone, and cessation of any other immunosuppressive treatment), and overall survival (OS). Enrolment was strictly prospective and only allowed within 7 days of starting immunosuppression. Outcome data were recorded in all patients enrolled. The treatment protocol consisted of prednisolone (100 mg/d from day 1 to the day of PR, then tapered down to <15 mg/d over 5 weeks), oral cyclophosphamide (150 mg/d, from day 21-42, unless PR was achieved), and rituximab (375 mg/m2 weekly for 4 weeks starting on day 43, unless PR was achieved). If AHA was first diagnosed in patients previously on prednisolone >15 mg/d, or equivalent, they received prednisolone (100 mg/d) and rituximab from day 1. If cyclophosphamide was contraindicated, patients received prednisolone (100 mg/d) and rituximab from day 21. One hundred twenty-four patients from 21 treatment centers in Germany and Austria were enrolled between April 2010 and April 2013 (36 months). The patients from two centers not compliant with the treatment protocol were excluded (N=18), as were patients in whom AHA was not confirmed (N=2) or follow-up was too short at the time of this analysis (N=7). The remaining 97 patients from 17 centers were followed for a median of 256 days (interquartile range [IQR] 84-561). Median age was 74 years (IQR 64-82). AHA was associated with other autoimmune disorders (19%), malignancy (12%), pregnancy or puerperium (5%), but was most often idiopathic (66%). The median FVIII:C activity at baseline was 1 IU/dl (IQR <1-3), and the median inhibitor titer was 20 BU/ml (IQR 7.7-78). PR and CR were achieved after a median time of 35 and 102 days, respectively. Patients achieving PR prior to day 21 (N=22) compared with patients not achieving PR within 21 days (N=75) had a higher baseline FVIII:C activity (median 3 vs. <1 IU/dl, p<0.01) and a lower FVIII:C inhibitor (median 12 vs. 29 BU/ml, p<0.05). Multivariate analysis with adjustment for age, sex, underlying disorder, and WHO performance status on admission demonstrated that baseline FVIII:C activity (<1 IU/dl vs. >=1 IU/dl) had a strong impact on the time to achieve PR (HR 2.76 [95% confidence interval 1.73-4.42], p<0.001) and CR (HR 2.36 [1.34-4.14], p<0.01). Baseline FVIII:C activity was also a predictor of PR and CR when other cutoffs were used (2 or 3 IU/dl instead of 1 IU/dl), or when it was analyzed as a continuous variable in Cox regression analysis. In contrast, FVIII:C inhibitor titer assessed by the local laboratory did not affect time to PR or CR significantly. OS after 300 days, estimated by the Kaplan Meier method, was 69%. Age, WHO performance status, and FVIII:C activity at baseline were independent predictors of OS. In summary, GTH-AH 01/2010 is the largest prospective study of patients with AHA treated according to a standardized protocol. The study demonstrated a robust effect of baseline FVIII:C activity on the time needed to achieve PR and CR. Baseline FVIII:C activity, together with age and performance status, also affected OS. Therefore, baseline FVIII:C activity may be considered to guide individually tailored immunosuppression in future studies. Disclosures: Tiede: Baxter: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy; CSL Behring: Consultancy, Honoraria, Research Funding. Off Label Use: Prednisolone, cyclophosphamid, and rituximab for immunosuppression in acquired hemophilia. Klamroth:Bayer: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding. Gottstein:Novo Nordisk: Honoraria; Baxter: Honoraria. Holstein:Baxter: Honoraria, Speakers Bureau. Scharf:CSL Behring: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Biotest: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Baxter: Consultancy, Honoraria, Research Funding. Huth-Kühne:SRH Kurpfalz Hospital and Hemophilia Center: Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Greil:Roche: Consultancy, Honoraria, Research Funding. Miesbach:Novo Nordisk: Consultancy, Honoraria, Research Funding; Baxter: Consultancy, Honoraria, Research Funding. Trappe:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel Other; AMGEN: Research Funding, Travel, Travel Other; CSL Behring: Honoraria, Research Funding, Speakers Bureau, Travel, Travel Other; Mundipharma: Research Funding, Travel, Travel Other; Takeda: Consultancy, Research Funding, Travel Other; Novartis: Consultancy, Research Funding, Travel, Travel Other; Novartis: Research Funding, Travel Other; Cellgen: Travel, Travel Other. Knoebl:Novo Nordisk: Consultancy, Honoraria; Baxter: Consultancy, Honoraria.

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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