Determination of Coagulation Functions and Inhibitory Mechanisms In Acquired Hemophilia A with Type 1 and Type 2 Inhibitors.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3666-3666
Author(s):  
Tomoko Matsumoto ◽  
Keiji Nogami ◽  
Kenichi Ogiwara ◽  
Nobuyuki Tsujii ◽  
Midori Shima
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Hemorrhagic Diathesis ◽  
Severe Hemophilia ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Time To Peak ◽  
Inhibitory Mechanisms

Abstract Abstract 3666 Development of factor (F)VIII autoantibody inhibitors results in severe hemorrhagic diathesis known as acquired hemophilia A (AHA). Based on kinetics patterns of FVIII inhibition, these inhibitors are classified into type 1 and type 2 behaviors that inhibit FVIII activity completely and incompletely at saturating concentrations, respectively. We have recently reported on the coagulation functions and inhibitory mechanisms of AHA with type 2 (Blood 2009, 106, Abst), but the mechanism(s) by which hemorrhagic symptoms of AHA are markedly severe are poorly understood. In the present study, we investigated the coagulation function and inhibitory mechanisms for AHA with type 1 as well as type 2. Plasma samples of patients were obtained from congenital severe hemophilia A (S-type; FVIII:C<0.2 IU/dl, FVIII:Ag<1 IU/dl; n=15), AHA with type 1 (<0.2 IU/dl, 3.0±4.2 IU/dl; 167±175 BU/ml; n=9), and AHA with type 2 (2.0±1.9 IU/dl, 12.3±7.5 IU/dl; 202±120 BU/ml; n=8). Thrombin generation test (TGT) was performed using tissue factor (0.5 pM), phospholipids (PL 4 μM), and ellagic acid (0.3 μM). Although FVIII:C in type 1 was similar to that in S-type, TGT parameters in type 1 were significantly decreased than those in S-type and type 2 (type 1/type 2/S-type; ETP: 779±520/1166±880/1125±377 nM×min; Peak thrombin: 37.2±20.1/62.4±35.0/65.0±11.2 nM). Of note, time to peak in both types markedly prolonged compared to that in S-type (type 1/type 2/S-type; 34.7±9.2/31.0±6.8/23.8±4.0 min). Similarly, FXa generation using chromogenic assay were decreased in order of S-type>type 2>type 1, demonstrating that coagulation functions of AHA were much worse than that in congenital severe hemophilia A, and those in type 1 was predominantly lower than those in type 2. Next we compared with inhibitory mechanisms of AHA-type 1 and type 2 inhibitors. The IgGs from AHA's plasmas were immune-purified using protein G-Sepharose. All cases recognized the C2 domain alone, and little recognized other coagulation proteins. Competition binding assays showed that all type 1 competed with anti-C2 mAbESH4 (type 1) by 50–80%, whilst little or slightly competed with anti-C2 mAbESH8 (type 2), and that all type 2 competed with ESH8 by 50–85%, whilst little or mildly competed with ESH4. Type 1 IgGs inhibited the FVIII binding of von Willebrand factor (VWF) and PL by 60–80%, whilst type 2 inhibited both bindings by <5%. In our previous and present studies, a FXa generation assay and SDS-PAGE (and Western blotting) analysis revealed that all type 2 blocked thrombin (and FXa)-catalyzed FVIII activation by 80≂f95% through inhibition of cleavage at Arg372 and Arg1689 in dose- and timed-dependent manners. In contrast, all type 1 did not significantly affect FVIII activation and cleavage by thrombin. It was difficult to evaluate FXa-catalyzed FVIII reaction with type 1, since type 1 inhibited the FVIII-PL binding directly. These findings supported that the inhibitory effects of AHA with type 1 and type 2 on FVIII function were similar to those of ESH4 and ESH8 reported, respectively. Taken together, AHA-type 1 inhibitors interfere FVIII-VWF complexes and inhibit FVIII(a)-PL binding essential for function of tenase complex, whilst type 2 inhibitors decrease FXa generation only through inhibition of thrombin (and FXa)-catalyzed FVIII activation, supporting that these distinct mechanisms of both types result in different serious hemorrhagic symptoms. In addition, we speculate that FVIII(a)-inhibitor complexes might inhibit FIXa-catalyzed FX activation indirectly through steric hindrance, consequently coagulation functions in AHA would be significantly worse than those in congenital severe hemophilia A. Disclosures: Nogami: Bayer hemophilia award program 2009: Research Funding. Ogiwara:Baxter Hemophilia Scientific Research and Education Fund in Japan, 2009: Research Funding.

Determination for Coagulation Functions and Novel Inhibitory Mechanisms in Acquired Hemophilia A with Type 2 Inhibitors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3483-3483
Author(s):  
Tomoko Matsumoto ◽  
Keiji Nogami ◽  
Kenichi Ogiwara ◽  
Katsumi Nishiya ◽  
Masahiro Takeyama ◽  
...  
Keyword(s):  
Heavy Chain ◽  
Hemophilia A ◽  
Hemorrhagic Diathesis ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Time To Peak ◽  
Coagulation Function ◽  
Inhibitory Mechanisms ◽  
Dose Dependent

Abstract Abstract 3483 Poster Board III-420 The development of factor (F)VIII autoantibody inhibitors results in severe hemorrhagic diathesis known as acquired hemophilia A (AHA), although many inhibitors with type 2 behavior incompletely inhibit FVIII activity at saturating concentrations. However, the mechanisms of AHA with type 2 behavior remain to be fully understood. In this study, we evaluated the detailed coagulation function and clarified inhibitory mechanisms for AHA with type 2. Plasma samples of patients were obtained from congenital hemophilia A with severe type {(FVIII:C<0.2 IU/dl; S1-type, n=9) and (0.2-1.0 IU/dl; S2-type, n=6)}, with moderate type (2.1 ± 0.9 IU/dl; M-type, n=10), and AHA-type 2 (2.0 ± 1.9 IU/dl, 201 ± 120 BU/ml; type 2 n=8). Thrombin generation test (TGT) was performed using tissue factor (0.5 pM), phospholipids (PL 4 μM) and ellagic acid (0.3 μM). Although the levels of FVIII:C in M-and S2-types were similar and low compared to those in type 2, TGT parameters in type 2 were significantly decreased than those in M-and S2-types (M/S2/type 2: ETP: 2719±725/1613±684/1352±971 nM*min, peak thrombin: 155±52/110±25/62±35 nM, time to peak: 17.4±2.4/19.3±2.8/31.0±6.8 min). Of note, time to peak in type 2 significantly prolonged than that in S1-type (23.0±4.0 min, p<0.05), suggesting that coagulation function in AHA-type 2 was much worse than that in congenital severe hemophilia A (<0.2 IU/dl). Next, we examined on these inhibitory mechanisms of AHA-type 2 inhibitors. The IgGs from 6 cases were immune-purified from plasmas using protein G-Sepharose. All cases recognized the C2 domain alone of FVIII, whilst any little recognized other coagulation proteins. Competition binding assays showed all anti-C2 cases competed with anti-C2 mAbESH8 (type 2 behavior), whilst little or mildly competed with anti-C2 mAbESH4 (type 1 behavior). FVIII was activated by thrombin, followed by measuring the FVIIIa/FIXa-dependent FX activation in the presence of inhibitors. The addition of purified IgG prior to FVIII activation inhibited the FXa generation by 80∼95% in dose-dependent manners, whilst that of IgG post to FVIII activation little inhibited, supporting these inhibitors affected the cofactor activity for FVIII, but not that for FVIIIa. SDS-PAGE and Western blot revealed that all cases inhibited thrombin cleavage of the FVIII heavy chain at Arg372 by 50∼80% in similar timed- and dose-dependent manners. Furthermore, effects of inhibitors on FVIII/FIXa-dependent FX activation were examined. The presence of all IgGs inhibited the FXa generation by 70∼95% in these circumstances, and these effects were timed- and dose-dependent manners. These also blocked FXa-catalyzed cleavage of the heavy chain at Arg372 by 60∼70%. However, all cases did not inhibit the binding of either von Willebrand factor or PL to FVIII. We concluded that the coagulation functions of AHA-type 2 inhibitors with a C2 epitope like ESH8 were markedly decreased by which inhibitory mechanisms that these inhibitors blocked FVIII activation and cleavage by thrombin and FXa, and these might result in serious hemorrhagic symptoms. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Diagnostic and Prognostic Value of Factor VIII Binding Antibodies in Acquired Hemophilia A: Data from the GTH-AH 01/2010 Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3515-3515
Author(s):  
Andreas Tiede ◽  
Sonja Werwitzke ◽  
Ulrich Geisen ◽  
Ulrike Nowak-Göttl ◽  
Hermann Eichler ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Gold Standard ◽  
Research Funding ◽  
Prognostic Value ◽  
Hemophilia A ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Advisory Committees ◽  
Cox Regression Analysis ◽  
Diagnostic And Prognostic Value

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

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.

scholarly journals five Int22h Homologous Copies in Association with Intron22 Inversion Type 3

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5033-5033
Author(s):  
Nathalie Lannoy ◽  
Marie Ravoet ◽  
Bernard Grisart ◽  
Mathilde Fretigny ◽  
Cedric R. Hermans
Keyword(s):  
Hemophilia A ◽  
Conflicts Of Interest ◽  
Severe Hemophilia ◽  
Causative Gene ◽  
International Consortium ◽  
Intron 1 ◽  
Intrachromosomal Rearrangement ◽  
Type 3

Abstract Introduction F8 intron22 inversion is the causative gene defect in up to 45% of severe hemophilia A (HA) patients mediated by recombination between three highly homologous copies located in intron 22 (int22h-1) and two other extragenic copies (int22h-2 and int22h-3) positioned more telomerically outside the gene. Intrachromosomal rearrangement between int22h-1 and int22h-3 provide the F8 type 1 inversion while the F8 type 2 inversion could be explained by the participation of the int22-h2 sequence in the homologous recombination. However, a third type, known since 1993*, was explained by the existence of a duplicated copy of int22h-3 or int22h-2 in case of intron22 inversion type 3A or 3B respectively. Methods Three unrelated HA patients with intron22 type 3A/3B were identified by southern blotting. To appreciate the length of the int22h extragenic duplicated, genomic hybridisation was performed using Affimetrix CytoScan High-Density array. Results Breakpoint analyses by CGH-array in all patients show same duplication of approximately 180kb delimited between intron 1 of CLIC2 gene and distal repeat int22h-3reflecting the presence of five genomic int22 copies. A fourth non-hemophiliac case was added since analysis by CGH technique identified duplication delineated by same boundaries. Conclusion This study suggests the existence of genotypes harboring five int22h copies mediated by 180 kb duplication at Xq28 locus probably not associated with HA. We propose that this duplication has happened by tandem inversed duplication. Such genotype is to be considered as polymorphism and could be associated with the two kinds of F8 intron22 inversion type 3 when intrachromosomal recombination has occurred between homologous copies. *Antonarakis SE and the international consortium study. Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood 1995; 86: 2206-2212 Disclosures No relevant conflicts of interest to declare.

scholarly journals Orihime Study: Real World Treatment Patterns and Clinical Outcomes of 338 Patients with Acquired Hemophilia a from a Japanese Health Claims Database

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1042-1042
Author(s):  
Yoshiyuki Ogawa ◽  
Kagehiro Amano ◽  
Yukari Matsuo-Tezuka ◽  
Norihiro Okada ◽  
Yoichi Murakami ◽  
...  
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Disease Diagnosis ◽  
Health Claims ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Claims Database ◽  
Chugai Pharmaceutical ◽  
Hemostatic Therapy ◽  
The Mean

Abstract Introduction: Acquired hemophilia A (AHA) is a rare disorder characterized by severe, spontaneous bleeding caused by autoantibodies against factor (F)VIII (inhibitors). It is known that onset of AHA is triggered by malignancy, autoimmune disease, dermatological disease, and pregnancy/delivery. As the standard therapy, immunosuppressive therapy (IST) should be started immediately to eliminate inhibitors and hemostatic therapy is also necessary in case of bleeding. Many patients require prolonged bed rest because of the bleeding risk; therefore, it is difficult to determine the best time to start rehabilitation. Additionally, the early deaths and high thrombotic rates are frequently reported in AHA. Since it is a rare disorder, the actual situation has not been fully clarified. This study was to describe the epidemiology and clinical practice of AHA in the real world using a large health claims database in Japan. Methods: This was a retrospective observational study using a health claims database provided by Medical Data Vision Co., Ltd. The data period was Apr. 2008-Mar. 2020. Patients who met all of the following criteria were included; patients with disease diagnosis of AHA; patients were hospitalized on the day of AHA diagnosis; and patients had immunosuppressants on/after the date of the first hospitalization. The first date of hospitalization was set as an Index date. Patients with disease diagnosis code of antiphospholipid syndrome, lupus anticoagulant, acquired factor XIII deficiency, acquired von Willebrand disease, or acquired factor V deficiency were excluded. Treatment/procedure patterns (IST, hemostatic therapy, and rehabilitation) and clinical outcome (Activities of Daily Living [ADL], death, and thromboembolism in the hospitalization) in AHA patients were investigated. Results: The study population of 338 patients (214 males: 124 females) was with the mean age of 75.7 (21-96) years. A total of 105 patients (pts) (31.1%) had concurrent diseases, including malignancy (61 pts, 18.0%), autoimmune diseases (40 pts, 11.8%), and dermatological diseases (18 pts, 5.3%). In bypassing agent use (153 pts, 45.3%), recombinant activated factor VII (rFVIIa) was the most frequently used (129 pts, 38.2%) followed by activated prothrombin complex concentrate (aPCC) (36 pts, 10.7%), and plasma-derived factor VIIa and factor X (FVIIa/FX) (14 pts, 4.1%). FVIII agent uses (8 pts) were very few. Median duration of treatment for bypassing agents ranged from 2.5 (FVIIa/FX) to 6.0 (aPCC) days. Steroids alone were used predominantly in the first line for immunosuppression (292 pts, 86.4 %) and oral prednisolone was the most frequently used. The category of rehabilitation most commonly implemented in AHA patients was disuse syndrome (104 pts, 30.8%) followed by locomotor (73 pts, 21.6%) and cerebrovascular (49 pts, 14.5%). Median time (days) from Index date to initiating rehabilitation was 16.5 for disuse syndrome, 23.0 for locomotor, 19.0 for cerebrovascular. In the total ADL scores (Barthel Index) in 196 patients with all 10 items, the proportions of patients with less than 70 points were high at both initial admission and final discharge (47.4% and 38.8%, respectively). The median number of times and length of hospitalization were 1.0 time and 62.0 days, respectively. Of evaluable population (328 pts), thromboembolism during hospitalization was recorded in 15 patients, by type of which disseminated intravascular coagulation (10 pts, 3.0%) was the most frequently recorded. Acute coronary syndrome (3 pts, 0.9%), pulmonary embolism and other (1 pt, 0.3%, each) were fewly recorded. The proportion of deaths during hospitalization was 18.6% (63 pts). Table 1 shows study result summary. Conclusions: This was the first study in a large AHA population using a health claims database in Japan. From an epidemiological point of view, the number of male patients was slightly larger and the mean age was slightly higher compared to the demographics in previous reports. The possible reason is regional variance or data source, whereas, the treatment patterns and the proportion of deaths during hospitalization are mostly aligned with the previous studies. Also this was the first report publishing the data on ADL and rehabilitation in AHA patients. The results showed that it took median 2-3 weeks to start rehabilitation. Further development of treatment strategies to enable early start of rehabilitation is awaited. Figure 1 Figure 1. Disclosures Ogawa: Chugai Pharmaceutical Co., Ltd.: Consultancy. Amano: Chugai Pharmaceutical Co., Ltd.: Consultancy, Speakers Bureau; KM Biologics Co., Ltd.: Research Funding, Speakers Bureau; Bioverativ Inc.: Speakers Bureau; Bayer AG: Speakers Bureau; Shire Plc: Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Speakers Bureau; Sanofi S.A.: Speakers Bureau; Novo Nordisk A/S: Speakers Bureau; CSL Behring: Speakers Bureau; Pfizer Inc.: Speakers Bureau; Japan Blood Products Organization: Speakers Bureau. Matsuo-Tezuka: Chugai Pharmaceutical Co., Ltd.: Current Employment. Okada: Chugai Pharmaceutical Co., Ltd.: Current Employment. Murakami: Chugai Pharmaceutical Co., Ltd.: Current Employment. Nakamura: Chugai Pharmaceutical Co., Ltd.: Current Employment. Yamaguchi-Suita: Chugai Pharmaceutical Co., Ltd: Current Employment. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk A/S: Honoraria, Research Funding, Speakers Bureau; Bayer AG: Honoraria, Research Funding, Speakers Bureau; Sanofi S.A.: Honoraria, Research Funding, Speakers Bureau; KM Biologics Co., Ltd.: Honoraria, Research Funding, Speakers Bureau. OffLabel Disclosure: Data on the uses of cyclophosphamide, cyclosporin A, and rituximab for acquired hemophilia may be included in the poster presentation. However, with regard to these drugs, treatments for other diseases may also be included because this study was conducted with a secondary use of a health claims database. Off-label drug use is explained in the poster.

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.

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

Blood ◽  
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 &lt;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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