The Benefit of FVIII Measurement: Tailored Treatment with Obi-1, a Recombinant Porcine Sequence Factor VIII, in Subjects with Acquired Hemophilia a

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3509-3509
Author(s):  
Abiola Oladapo ◽  
Joshua Epstein ◽  
Aaron Novack ◽  
Heinrich D. Farin
Keyword(s):  
Dose Reduction ◽  
Initial Dose ◽  
Hemophilia A ◽  
Activity Levels ◽  
Phase 2 ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Fviii Activity ◽  
Treatment Dose ◽  
The Impact

Abstract Introduction: A significant unmet need in the management of acquired hemophilia A (AHA) is a replacement therapy that can be used without consideration of anti-human FVIII titer and allows for the ability to measure FVIII levels. The ability to measure FVIII levels during treatment: (1) identifies treatment response and leads to the ability to individually tailor treatment; (2) reduces treatment safety concerns; and (3) optimizes the utilization of therapy during treatment to minimize cost impact. OBI-1 is a recombinant porcine sequence FVIII developed to meet this need. Objective: To determine the impact of FVIII monitoring on OBI-1’s utilization during the treatment phase in the OBI-1 Phase 2/3 trial in AHA. Methods: A post-hoc analysis of the utilization data from the prospective, open label, Phase 2/3 study of OBI-1 in AHA was conducted. Subjects were administered an initial dose of 200U/kg of OBI-1 and subsequent doses were based on subject’s post-infusion FVIII activity levels and clinical assessments. The impact of FVIII monitoring on OBI-1’s utilization was evaluated by comparing: (A) the initial administered dose to the subsequent doses infused in the treatment period; and (B) the initial total administered dose within the first 24 hours of treatment to the doses infused in the subsequent 24-hour period(s) in the treatment period. The magnitude and the statistical significance of the dose adjustment were determined using non-parametric statistics (signed rank test). Results: Of the 29 subjects enrolled in the study, 65.5% (n=19) were males and median (range) age was 70 (42-90) years. Twenty-eight of the enrolled subjects had AHA while presence of anti-human FVIII titer could not be confirmed in the twenty-ninth subject. Of the subjects with AHA, 27 had a serious bleeding episode while one was enrolled for hemostatic cover for a planned surgery. Two subjects (7.1%) successfully responded requiring only the initial administered dose (100U/kg; 200U/kg). Two additional subjects were successfully treated within the first 24 hours. After the initial dose, subsequent doses indicated a median (IQR) dose reduction of 41.2% (50%) [n=26, p<0.01]. After the first 24-hour period, subsequent 24-hour periods showed a median (IQR) dose reduction of 65.4% (32.5%) [n=24, p<0.0001]. Conclusion: Study data indicate a significant reduction in the treatment dose after the initial dose or subsequent daily dosing after the first 24 hours. The ability to measure and monitor FVIII activity levels allow for the tailoring of OBI-1’s treatment dose and regimen. This measurability likely has a significant impact on dosing decisions to control the bleed. Disclosures Oladapo: Baxter Healthcare Corporation: Employment. Epstein:Baxter Healthcare Corporation: Employment. Novack:Baxter Healthcare: Employment. Farin:Baxter Healthcare: Employment.

scholarly journals Recombinant porcine FVIII for bleed treatment in acquired hemophilia A: findings from a single-center, 18-patient cohort

2020 ◽  
Vol 4 (24) ◽  
pp. 6240-6249
Author(s):  
Patrick Ellsworth ◽  
Sheh-Li Chen ◽  
Raj S. Kasthuri ◽  
Nigel S. Key ◽  
Micah J. Mooberry ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Rescue Therapy ◽  
Severe Bleeding ◽  
Activity Levels ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Fviii Activity ◽  
Hemostatic Efficacy ◽  
Bypassing Agents ◽  
Activated Prothrombin Complex Concentrates

Abstract Acquired hemophilia A (AHA) is a rare bleeding disorder in which acquired autoantibodies to endogenous factor VIII (FVIII) decrease FVIII activity and lead to a bleeding phenotype. A substantial majority of individuals who develop AHA present with severe bleeding. Effective treatment requires both immunosuppressive therapy and prompt hemostatic treatment. Bleeding is commonly treated with bypassing agents (BPAs) such as recombinant activated FVII (rFVIIa) or activated prothrombin complex concentrates Disadvantages to BPAs include the inability to monitor response with standard laboratory assays, inconsistent hemostatic efficacy, and thrombosis. Recombinant porcine FVIII (rpFVIII: Obizur, Baxter, Deerfield, IL) was approved by the US Food and Drug Administration (FDA) for bleed treatment in AHA in 2014, and has the advantage of laboratory monitoring of FVIII activity levels and known hemostatic efficacy in the presence of anti-human FVIII inhibitors and after failure of BPAs. Using an algorithm-based approach, rpFVIII has been used to successfully treat 18 patients with AHA at our center with substantially lower doses than the current FDA-recommended dosing. Additionally, data from our cohort show that the preexposure anti-porcine Bethesda titer does not reliably predict the clinical response to rpFVIII treatment and is not correlated with the anti-human Bethesda titer. We also present data showing lower total rpFVIII use for initial bleed resolution when rpVIII is used upfront, as compared with use as rescue therapy. We validated our dosing algorithm, which uses much lower than FDA-recommended doses with 14 more patients than in our previously reported patient series.

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

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

scholarly journals Postpartum Acquired Hemophilia: A Rare Cause of Postpartum Hemorrhage

2013 ◽  
Vol 2013 ◽  
pp. 1-2 ◽  
Author(s):  
Srikanth Seethala ◽  
Sumit Gaur ◽  
Elizabeth Enderton ◽  
Javier Corral
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Factor Vii ◽  
Normal Vaginal Delivery ◽  
Factor Viii Inhibitor ◽  
Activity Levels ◽  
Factor Viii Activity ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Viii Inhibitor

A 36-year-old female started having postpartum vaginal bleeding after normal vaginal delivery. She underwent hysterectomy for persistent bleeding and was referred to our institution. An elevation of PTT and normal PT made us suspect postpartum acquired hemophilia (PAH), and it was confirmed by low factor VIII activity levels and an elevated factor VIII inhibitor. Hemostasis was achieved with recombinant factor VII concentrates and desmopressin, and factor eradication was achieved with cytoxan, methylprednisolone, and plasmapheresis.

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 &gt;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 &gt;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.

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 Bleeding and Response to Hemostatic Therapy in Acquired Hemophilia A (AHA): Results from the GTH-AH 01/2010 Study

Blood ◽  
2020 ◽  
Author(s):  
Katharina Holstein ◽  
Xiaofei Liu ◽  
Andrea Smith ◽  
Paul Knöbl ◽  
Robert Klamroth ◽  
...  
Keyword(s):  
Partial Remission ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Individual Risk ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Bleeding Rate ◽  
Risk Of Bleeding ◽  
Fviii Activity ◽  
Hemostatic Therapy

Acquired hemophilia A (AHA) is due to autoantibodies against coagulation factor VIII (FVIII) and most often presents with unexpected bleeding. In contrast to congenital hemophilia, the patient's residual FVIII activity does not seem to correlate with the risk of bleeding as suggested from previous studies. Risk factors for bleeding have not been described. We used data from the prospective GTH-AH 01/2010 study to assess the risk of bleeding and the efficacy of hemostatic therapy. FVIII activity was measured at baseline and weekly thereafter. Bleeding events were assessed by treating physicians. A total of 289 bleeds was recorded in 102 patients. 141 new bleeds starting after day 1 were observed in 59% of the patients, with a mean rate of 0.13 bleeds per patient-week in weeks 1 to 12, or 0.27 bleeds per patient-week before achieving partial remission. Weekly measured FVIII activity was significantly associated with the bleeding rate, but only achieving FVIII ≥50% abolished the risk of bleeding. A good WHO performance status assessed at baseline (score 0 vs. higher) was associated with a lower bleeding rate. Hemostatic treatment was reported to be effective in 96% of bleeds. In conclusion, the risk of new bleeds after a first diagnosis of AHA remains high until partial remission is achieved, and weekly measured FVIII activity may help to assess the individual risk of bleeding. These results will help to define future strategies for prophylaxis of bleeding in AHA.

scholarly journals Tinjauan Terkini Hemofilia A yang Didapat : Aspek Diagnosis dan Manajemen

2020 ◽  
Vol 3 (2) ◽  
pp. 79
Author(s):  
Ibnu Purwanto
Keyword(s):  
Partial Thromboplastin Time ◽  
Hemophilia A ◽  
Underlying Disease ◽  
Activated Partial Thromboplastin Time ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Fviii Activity ◽  
Life Threatening ◽  
Hemostatic Therapy ◽  
Hemofilia A

<p>Hemofilia A yang didapat adalah penyakit yang jarang terdiagnosis dan seringkali salah terdiagnosis namun berpotensi menyebabkan perdarahan yang mengancam nyawa. Penyakit autoimun akibat pembentukan autoantibodi (inhibitor) terhadap FVIII ini hampir setengahnya memiliki gangguan lain yang mendasari. Pemanjangan activated partial thromboplastin time, mixing test yang tidak terkoreksi, rendahnya aktivitas FVIII, dan bukti inhibitor FVIII mendukung penegakan diagnosis Hemofilia A yang didapat. Rintangan dalam manajemen pasien dimulai dari penegakan diagnosis hingga penentuan terapi, baik terapi hemostatik, imunosupresi, serta pengobatan penyakit penyerta. Pemilihan terapi serta pengendalian terhadap efek samping dari pengobatan memerlukan perhatian khusus agar tercapai hemostasis dan remisi yang bertahan lama.</p><p>Acquired Hemophilia A can potentially cause life-threatening conditions due to profuse bleeding, but this autoimmune disease is mostly underdiagnosed. Hemophilia A occurs due to the development of an antibody against FVIII, moreover up to half of these cases have underlying conditions. Prolonged activated partial thromboplastin time, uncorrected mixing test, low FVIII activity, and detection of FVIII inhibitors support the diagnosis of acquired Hemophilia A. However, several challenges lay within patients’ management strategy, such as diagnosis workup and therapeutical choices. Treatment for acquired hemophilia A encompasses hemostatic therapy, immunosuppression, and treatment of underlying disease. Moreover, therapeutical choice and side effects control require special consideration to achieve hemostasis and durable remission.</p>

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.

scholarly journals A Case of a Patient Who Is Diagnosed with Mild Acquired Hemophilia A after Tooth Extraction Died of Acute Subdural Hematoma due to Head Injury

2018 ◽  
Vol 2018 ◽  
pp. 1-3 ◽  
Author(s):  
Tomohisa Kitamura ◽  
Tsuyoshi Sato ◽  
Eiji Ikami ◽  
Yosuke Fukushima ◽  
Tetsuya Yoda
Keyword(s):  
Factor Viii ◽  
Subdural Hematoma ◽  
Tooth Extraction ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Acute Subdural Hematoma ◽  
Factor Viii Inhibitor ◽  
Activity Levels ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia

Background. Acquired hemophilia A (AHA) is a rare disorder which results from the presence of autoantibodies against blood coagulation factor VIII. The initial diagnosis is based on the detection of an isolated prolongation of the activated partial thromboplastin time (aPTT) with negative personal and family history of bleeding disorder. Definitive diagnosis is the identification of reduced FVIII levels with evidence of FVIII neutralizing activity. Case report. We report a case of a 93-year-old female who was diagnosed as AHA after tooth extraction at her home clinic. Prolongation of aPTT and a reduction in factor VIII activity levels were observed with the presence of factor VIII inhibitor. AHA condition is mild. However, acute subdural hematoma of this patient occurred due to an unexpected accident in our hospital. Hematoma was gradually increased and the patient died 13 days after admission. Discussion. Although AHA is mild, intracranial bleeding is a life-threatening condition. We also should pay attention to the presence of AHA patients when we extract teeth.

scholarly journals Recombinant Porcine Factor VIII, Obi-1, Successfully Controlled Gastrointestinal Bleeding in a Patient with Acquired Hemophilia A

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4676-4676
Author(s):  
Muhammad Kashif Riaz ◽  
Saulius Girnius ◽  
Joseph Edward Palascak
Keyword(s):  
Gastrointestinal Bleeding ◽  
Factor Viii ◽  
Hemophilia A ◽  
Factor Vii ◽  
Gastric Body ◽  
Activate Factor ◽  
Phase 2 ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Fviii Inhibitor

Abstract Introduction: Acquired hemophilia A (AHA) is a rare, life-threatening bleeding diathesis categorized by low levels of Factor VIII (FVIII) due to an acquired auto-antibody against FVIII. Treatment for AHA requires both control of the bleeding and eradication of the inhibitor. Recombinant activated factor VII (rFVIIa) maybe used to control the bleeding, but with only mixed results in controlling gastrointestinal bleeding (GIB). rFVIIa is associated with thrombosis risk and lack of ability to monitor. The recombinant porcine FVIII (rpFVIII), OBI-1, recently obtained regulatory approval based on the results of Phase 2/3 trial, but the patients in this cohort did not have GIBs. Here we present a patient with AHA admitted with a GIB and successfully treated with OBI-1. Case: A 69 year old African American female with T1N0M0 infiltrative ductal carcinoma of the left breast and Stage IVA Squamous cell carcinoma of the cervix, treated in 1997 and 2007 respectively, presented to the emergency department with two days of painless bright red blood per rectum. She was orthostatic (supine: HR 79, BP 112/77 and standing: HR 111, BP 100/72) with hemoglobin (Hb) of 5.7gms/dl. An EGD demonstrated a bleeding vessel and multiple arteriovenous malformations (AVM) in the gastric body that were secured with clipping. Over the next 5 days EGD was repeated twice and multiple endoclips were placed in an attempt to achieve hemostasis. She subsequently underwent angiography to identify a target vessel for embolization, but one could not be found. On hospital day 11, hematology was consulted for a prolonged aPTT (113.8 seconds) and inadequate correction with mixing studies (63.7 seconds). FVIII level was <1% with factor VIII inhibitor titer of 245 Bethesda Units/ml (BU). Prior to starting OBI-1, she received 9 units of packed red blood cells and 2 units of fresh frozen plasma. OBI-1 was started at 200u/kg q4h for first 2 days and then decreased to q8h, with cessation of bleeding within 24 hours. Upon completion of the bolus of OBI-1, her FVIII level was 14%, then 38% at 8 hours, 48% at 16 hours and 62% at 24 hours. Rituximab (375mg/m2 weekly) and corticosteroids (prednisone 1mg/kg daily x7 days) were given in an attempt to eliminate the inhibitor. She remained stable for 6 days but subsequently developed abdominal pain. A CT of the abdomen revealed free air prompting emergent surgical intervention. She had internal hernia in the pelvis, ischemic small bowel and perforated jejunum requiring extensive resection. During this time she remained on rpFVIII (200u/kg q8h) with FVIII pre-infusion levels ranging from 2% - 14% and post-infusion levels from 80% to 217% and had only 25ml estimated blood loss during surgery. Unfortunately, 1 day after surgery she developed multi-organ failure and expired on hospital day 19. Discussion: OBI-1 is a glycosylated, B-domain deleted recombinant porcine factor VIII that retains the ability to interact with Factor IXa and activate Factor X, but it is less inhibited by auto-antibodies to human FVIII. For FVIII inhibitor titers >5 BU, an inhibitor bypassing agent is usually necessary because human FVIII products are not able to overcome the inhibitor. Given the high FVIII inhibitor titers in this patient, administration of rFVIIa or OBI-1 was necessary. Our own institutional experience of treating GIBs in patients with AHA had poor outcomes. The efficacy of rFVIIa in treating GIB is inconclusive, with response rate ranging from 53% to 71%. However, rFVIIa is associated with a risk of thrombosis approaching 9.4%, especially in older patients and those with vasculopathy, a common demographic in AHA. Unlike rFVIIa, OBI-1 allows close monitoring of FVIII and in the aforementioned Phase 2/3 trial, there were no thrombotic complications or serious adverse events. We were successful in controlling the bleeding within 24 hours with OBI-1 and were able to achieve therapeutic levels of FVIII despite high Bethesda titers. Unfortunately, our patient died from an ischemic bowel and perforated jejunum that was likely related to hernia or repeated instrumentation in an attempt to stop the bleeding prior to the diagnosis of AHA. Conclusion: OBI-1 appears to effectively and rapidly overcome a high titer FVIII inhibitor and control bleeding in a patient with AHA and GIB. While this is a promising therapy, additional study is necessary to determine safety, efficacy, and cost-effectiveness. Disclosures No relevant conflicts of interest to declare.

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