Acquired Hemophilia A Associated with Venous Thrombosis and Very High Inhibitor Titer: A Challenging Scenario

Abstract Acquired hemophilia due to inhibitor antibodies is a rare entity during childhood period. Moreover, transplacental hemophilia during the newborn period as a result of maternal IgG antibodies (inhibitors) which may cross the placenta into the foetal circulation is very rare and may cause life- threathening neonatal hemorrhages. The occurence of acquired hemophilia during or after delivery may lead bleeding tendencies in both the mother and baby. Here, we want to decribe a newborn baby who delivered from a mother with an initial diagnosis of acquired Hemophilia A and succesfully treated with a prohylactic rFVIIa. Case : A 27 years old women who was diagnosed with an acquired hemophilia A after her first delivery was admitted to our hospital for the second delivery.Her pregnancies were 15 months apart. Her FVIII level was found to be low (<1%) with a very high titer (>100NBU) inhibitor.She was treated with rFVIIa before C/S by adult hematologist and after giving a birth to a term boy without any bleeding complication, newborn baby was referred to our department because of having low FVIII level (0.3 %) with high titer inhibitor(320 NBU) and an abnormal aPTT mixing test on the first day of life. Cranial and abdominal USG was found to be normal and despite having no bleeding event we decide to give IVIG treatment due to very high titer of inhibitor level. On the 3rd day of life some blood in the stool was detected however there is no decrease in the Hb level. Prophylactic rFVIIa with a dose of 90µg/kg/daily was given during the next 4 weeks and inhibitor level was checked regulary. His inhibitor level was decraesed gradually on the first week 256NBU , second week 51 NBU and 4th week 2NBU with a FVIII level 2.7% and propylactic treatment was stopped on the 5th week of life. Although we did not able to detect inhibitor antibodies by trying to do aptt mixing test in the breastmilk, his mother did not have enough breatmilk and baby was supported by infant formula as well. There was a few numbers of cases with neonatal acquired hemophilia due to transplacental transfer of autoantibodies reported in the literature . It was reported that most inhibitors spntaneously disappear over a median 30 months after delivery and FVIII inhibitors are rarely present during labor and delivery in the next pregnancy. However, in our case 15 months after the first pregnacy he was delivered. The outcome of the transplasental acquired hemophilia cases reported in the literature was favorable with a resolution after a median of 3 months (range 0.2-3 months) despite one of them experienced intracranial hemorrhage.. Although peak inhibitor titer was reported to be 150BUin the literature, in our case it was the higher than the reported level (320NBU). However despite a very high peak inhibitor titer, we can speculate that due to limited intake of breastmilk which may also contain inhibitor antibodies may ameoliorate the prompt decrase of inhibitor antibodies. rFVIIa is safe and protect our patient from life-threatening bleeding events without any complication. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood-2021-145618 ◽

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.

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

Blood ◽

10.1182/blood.v122.21.205.205 ◽

2013 ◽

Vol 122 (21) ◽

pp. 205-205 ◽

Cited By ~ 1

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.

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Acquired Hemophilia A. Experience Of a Single Center

Blood ◽

10.1182/blood.v122.21.4781.4781 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4781-4781 ◽

Cited By ~ 1

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

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e17006 ◽

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.

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Rituximab Monotherapy Is Effective for Inhibitor Eradication with Concomitant Porcine Factor VIII Followed By Emicizumab for Bleed Control in Acquired Hemophilia a

Blood ◽

10.1182/blood-2021-154207 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 348-348

Author(s):

Patrick Ellsworth ◽

Sheh-Li Chen ◽

Christopher Wang ◽

Nigel S Key ◽

Alice Ma

Keyword(s):

Clinical Trial ◽

Factor Viii ◽

Research Funding ◽

Hemophilia A ◽

Effective Strategy ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

Trial Investigator ◽

Fviii Activity ◽

Inhibitor Titer

Abstract Introduction Acquired hemophilia A (AHA) is a rare bleeding disorder in which acquired auto-antibodies to endogenous Factor VIII (FVIII) resulting in decreased FVIII activity. AHA can lead to life-threatening bleeding, with effective treatment requiring both immunosuppressive therapy (IST) and bypassing agents such as recombinant activated Factor VII (rFVIIa) or activated prothrombin complex concentrates (APCC) (Tiede et al. Haematologica 2020). Some, including our group, have begun using emicizumab as well (Knoebl et al. Blood 2020). IST is required for inhibitor eradication, but regimens are heterogenous and have not been systematically compared in the literature. While there is no standard of care IST in these patients, most patients in the literature receive multiple agents, including corticosteroids, mycophenolate mofetil, cyclosporine, and/or rituximab in combination. We report in a prospective cohort that for IST, rituximab monotherapy is an effective strategy. An updated treatment algorithm is offered that has been effective for treatment of these patients at our institution, which adds emicizumab therapy after initial bleed control. Methods We analyzed clinical, pharmacy, and laboratory data from 24 patients treated with rpFVIII at the University of North Carolina for AHA from July 2015 to June 2021. All patients were initially treated according to our previously established dosing algorithm with recombinant porcine FVIII, and the last five patients have received emicizumab after initial factor dosing (see Figure 1). 17 of the patients who received rituximab and were followed at our center subsequently attained inhibitor eradication, six of those received only rituximab therapy. Investigational review board approval was obtained for our data collection and analysis. Patients who did not receive rituximab, failed to reach an inhibitor level <0.5 BU, or who were lost to follow up were excluded from the analysis. For patients that fit the inclusion criteria, the time between date of the first rituximab infusion and the date of inhibitor eradication was calculated. Results All patients in our cohort who we followed until inhibitor eradication (17 of 24 patients) had eradication of inhibitors after a median of 143 days from initiation of immunosuppression. For patients treated with rituximab monotherapy for inhibitor eradication (6 of 17), this goal was reached in a median of 134.5 days (range 76-191 days). For those who received agents in addition to rituximab and have reached inhibitor eradication to date (9 of 17 patients), median days from initiation of immunosuppression to inhibitor eradication was 137.5 days (range 11-485) (P = 0.43 on Mann-Whitney test). Patients were treated as previously reported by our group per an algorithm that starts recombinant porcine FVIII without waiting for a porcine inhibitor and at lower than FDA recommended dosing. Subsequent doses for bleed control are titrated according to one-stage, clot based FVIII activity. This report also includes 5 new patients who, after initial bleed control per our algorithm, were initiated on emicizumab while awaiting inhibitor eradication. There was no correlation between time to rituximab initiation and time to inhibitor eradication in both those who received rituximab monotherapy and those who had multiple IST agents. There was also no significant difference in initial inhibitor titer between groups with median initial inhibitor titer of 104 BU in the rituximab monotherapy group, and 70 BU in the multiple IST agents group (see Figure 3). Conclusions Rituximab monotherapy appears to be an effective strategy for inhibitor eradication in acquired hemophilia A. In the context of bleed treatment with porcine factor, followed by emicizumab, a standardized, algorithmic approach can be effectively employed for these patients. Though any patients have inhibitor recurrence, as is described in the literature, with emicizumab available, bleeding can be avoided with regular monitoring. Emicizumab given while re-eradicating an inhibitor can prevent morbidity of this disease. Figure 1 Figure 1. Disclosures Ellsworth: Takeda: Other: Salary supported as part of NHF-Takeda Clinical Fellowship Award. Key: Uniqure: Consultancy, Other: Participation as a clinical trial investigator; Grifols: Research Funding; Takeda: Research Funding; BioMarin: Honoraria, Other: Participation as a clinical trial investigator; Sanofi: Consultancy. Ma: Accordant: Consultancy; Takeda: Honoraria, Research Funding. OffLabel Disclosure: Emicizumab is not approved for use in Acquired Hemophilia A and this represents an OFF LABEL use of the drug.

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Simultaneous Deep Venous Thrombosis and Acquired Factor VIII Inhibitor

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/107602960200800410 ◽

2002 ◽

Vol 8 (4) ◽

pp. 375-379 ◽

Cited By ~ 4

Author(s):

Steven R. Deitcher ◽

Teresa L. Carman ◽

Kandice Kottke-Marchant

Keyword(s):

Venous Thrombosis ◽

Factor Viii ◽

Deep Venous Thrombosis ◽

Hemophilia A ◽

Duplex Ultrasound ◽

Factor Viii Inhibitor ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

Prolonged Aptt ◽

Life Threatening

Acquired hemophilia A is a life-threatening immune-mediated hemorrhagic disorder that is most often found in individuals older than 50 who present with an unexplained activated partial thromboplastin time (aPTT) prolongation and clinically significant bleeding. The prolonged aPTT associated with acquired hemophilia A reflects factor VIII activity deficiency due to neutralizing or clearing autoantibodies. Deep venous thrombosis, in contrast, is a veno-occlusive disorder associated with several distinct hypercoagulable states that can result in significant morbidity and mortality due to pulmonary embolism, thrombus extension, and the post-thrombotic syndrome. A prolonged a PYI in the setting of thrombosis may reflect the presence of a lupus anticoagulant. In the absence of accurate diagnosis and the immediate institution of specific therapy, both disorders can be fatal. Three cases of acquired factor VIII inhibitors that included a prolonged aPTT, bleeding, and duplex ultrasound evidence of deep venous thrombosis are presented. The diagnostic and therapeutic challenges posed by these cases as well as a proposed mechanism by which pathologic thrombosis can develop in a patient with a life-threatening bleeding disorder are discussed.

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Low-Dose Combined Immunosuppression Results In Rapid Remission In Patients With Acquired Hemophilia A

Blood ◽

10.1182/blood.v122.21.3589.3589 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3589-3589 ◽

Cited By ~ 1

Author(s):

Andrea Várkonyi ◽

Attila Szederjesi ◽

János Dolgos ◽

Péter Farkas ◽

Júlia Galgóczi ◽

...

Keyword(s):

Low Dose ◽

Hemophilia A ◽

Bleeding Control ◽

Off Label Use ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

Off Label ◽

Bypassing Agents ◽

Inhibitor Titer

Abstract Introduction Acquired hemophilia A (AHA) is a rare severe disorder caused by autoantibodies against FVIII resulting in significant morbidity and mortality up to 20 % in some studies. The two pillars of treatment include acute bleeding control, and immunosuppressive therapy which aims to stop the underlying autoimmune phenomenon. Although critical for long-term disease-free survival, there is currently no consensus for the best immunosuppressive regimen. Most authors use steroids first line, followed by cyclophosphamide and/or rituximab in steroid failures. However, upfront low-dose combined regimens offer the theoretical advantage of reduced steroid-exposure and toxicity as well as increased effectiveness. In the current retrospective analysis, we aim to review our institutional experience with such a regimen. Patients and Methods We identified 16 (7 males and 9 females) AHA patients newly diagnosed between October 2009 and June 2013; all treated with an identical regimen on an institutional protocol. Patient age varied between 53-86 (median 76,4) years. Mean initial inhibitor titer was 30.5 Bethesda units (BU; range 2 - >500). In 4 out of 16 patients (26,7 %) an underlying disease was identified, the remaining 12 cases were considered idiopathic. Low-dose combined immunosuppression consisted of the following regimen: 1000 mg cyclophosphamide on day 1 and 22, 40 mg dexamethasone on day 1, 8, 15 and 22, and 100 mg rituximab on day 1, 8, 15 and 22 (the regimen was termed CyDRi). Simultaneous use of bypassing agents was left to the discretion of the treating physician (8/16 patients, 50 %). All patients received at least 1 cycle of CyDRi. If complete remission (CR, defined as cessation of bleeding and an undetectable FVIII inhibitor in the Bethesda assay) was not achieved, the CyDRi therapy was repeated every 6 weeks until remission. Laboratory follow-up included CBC, routine chemistry and APTT (with a mixing study when prolonged), as well as FVIII levels and the Bethesda assay. Clinical monitoring varied according to the localization of bleeding. Results 50 % of patients presented with severe active bleeding symptoms, and they all received bypassing agents simultaneously with the CyDRi regimen. The remaining 8 patients had a recent history of bleeding but were not actively bleeding at the time of admission, and were given CyDRi without concurrent bypassing agents – none of them had a subsequent episode of bleeding (time to bleeding control = 0; Figure) Bleeding control was also rapidly achieved in the other patients with >90 % of patients free of bleeding within 3 weeks (Figure). CR was achieved in 15/16 patients (93,75 %). The time to CR was short with more than 75% of patients in CR by week 7 (Figure). Toxicity and side effects were infinitesimal compared to commonly used prolonged steroid therapies: One patient acquired pneumonia three weeks after discharge from the hospital, and two patients developed Clostridium difficile colitis during hospitalization. All three patients responded to antibiotic treatment. 8 of 16 patients (50 %) required more than one cycle of CyDRi to achieve a durable CR, either due to slow response or a laboratory relapse (6 and 2 patients, respectively). Two of the 8 patients required a third cycle of CyDRi (one for a very slow response, the other for a second relapse). CyDRi was equally effective in treating relapses. One patient died from a cause deemed unrelated to AHA (elderly patient with a femoral neck fracture). Her inhibitor titer was falling rapidly, but she died before achieving CR. Follow-up of our cohort is median 21 (range 2-45) months. Conclusion The CyDRi low-dose combined immunosuppression produced higher complete remission rates with a remarkably rapid cessation of bleeding and a significantly improved side-effect profile and mortality rate in this retrospective AHA cohort, compared to regimens previously described in the literature. A prospective randomized comparison seems warranted to confirm these results. Disclosures: Off Label Use: Cyclophosphamide, dexamethasone and rituximab are all off label use for the treatment of acquired hemophilia A.

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Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2)

Blood ◽

10.1182/blood-2012-02-409185 ◽

2012 ◽

Vol 120 (1) ◽

pp. 47-55 ◽

Cited By ~ 146

Author(s):

Peter Collins ◽

Francesco Baudo ◽

Paul Knoebl ◽

Hervé Lévesque ◽

László Nemes ◽

...

Keyword(s):

Complete Remission ◽

Factor Viii ◽

Hemophilia A ◽

First Line ◽

Acquired Hemophilia A ◽

Acquired Hemophilia ◽

First Line Therapy ◽

Line Therapy ◽

Fatal Hemorrhage ◽

Inhibitor Titer

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

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