Factor Eight Inhibitor Bypassing Activity Research Articles

Factor Eight Inhibitor Bypass Activity Use in Cardiac Surgery: A Propensity-matched Analysis of Safety Outcomes.

Bleeding during cardiac surgery may be refractory to standard interventions. Off-label use of factor eight inhibitor bypass activity (FEIBA) has been described to treat such bleeding. However, reports of safety, particularly thromboembolic outcomes, show mixed results, and reported cohorts have been small. Adult patients undergoing cardiac surgery on cardiopulmonary bypass between July 1, 2018, and June 30, 2023, at Stanford Hospital (Stanford, California) were reviewed (n = 3,335). Patients who received FEIBA to treat postcardiopulmonary bypass bleeding were matched with those who did not by propensity scores in a 1:1 ratio using nearest neighbor matching (n = 352 per group). The primary outcome was a composite outcome of thromboembolic complications including any one of deep vein thrombosis, pulmonary embolism, unplanned coronary artery intervention, ischemic stroke, and acute limb ischemia, in the postoperative period. Secondary outcomes included renal failure, reoperation, postoperative transfusion, intensive care unit length of stay, and 30-day mortality. A total of 704 encounters was included in this propensity-matched analysis. The mean dose of FEIBA administered was 7.3 ± 5.5 U/kg. In propensity-matched multivariate logistic regression models, there was no statistically significant difference in odds ratios for thromboembolic outcomes, intensive care unit length of stay, or mortality. Patients who received more than 750 U FEIBA had an increased odds ratio for acute renal failure (odds ratio, 4.14; 95% CI, 1.61 to 10.36; P < 0.001). In multivariate linear regression, patients receiving FEIBA were transfused more plasma and cryoprecipitate postoperatively. However, only the dose range of 501 to 750 U was associated with an increase in transfusion of erythrocytes (β, 2.73; 95% CI, 0.68 to 4.78; P = 0.009) and platelets (β, 1.74; 95% CI, 0.85 to 2.63; P < 0.001). Low-dose FEIBA administration during cardiac surgery does not increase risk of thromboembolic events, intensive care unit length of stay, or mortality in a propensity-matched cohort. Higher doses were associated with increased acute renal failure and postoperative transfusion. Further studies are required to establish the efficacy of activated factor concentrates to treat refractory bleeding during cardiac surgery.

Factor Eight Inhibitor Bypassing Activity as First-line Therapy for Coagulopathy in Cardiac Surgery

ObjectiveTo compare the outcomes of Factor Eight Inhibitor Bypassing Activity (FEIBA) versus Fresh Frozen Plasma (FFP) as the primary treatment for postoperative coagulopathy in cardiac surgery patients. DesignA retrospective, propensity-matched study. SettingA single, tertiary hospital. ParticipantsPatients who underwent non-coronary open-heart surgery with cardiopulmonary bypass between 2015 and 2023. InterventionsNone. Measurements and Main ResultsWe stratified patients into two groups based on whether they received intraoperative FFP or FEIBA, while cases using both were excluded. We analyzed 434 cases, with 197 receiving FFP and 237 receiving FEIBA. After propensity-matching, there was no significant difference in the proportion of the patients who required pRBC transfusions (p=0.08). However, of those who required pRBC transfusions, patients in the FEIBA group required significantly less units of pRBC (p<0.001). Significantly less patients in the FEIBA group required platelet (p<0.001) and cryoprecipitate (p<0.001) transfusions. The FEIBA group showed reduced prolonged postoperative intubation (p=0.05), reduced ICU length of stay (p=0.04), and lower 30-day readmission rates (p=0.03). There were no differences in rates of thrombotic complications between the two cohorts. ConclusionsIn the initial treatment of post-cardiopulmonary bypass coagulopathy, FEIBA may be more effective than FFP in reducing blood product transfusions and readmission rates. Further studies are needed to explore the potential routine use of FEIBA as first line agent in this patient population.

Transplacental Transfer of Emicizumab: Experience with Emicizumab in a Pregnant Female with Severe Hemophilia Α and an Inhibitor

Introduction: Severe hemophilia A (HA) in females is incredibly rare particularly if complicated by a high-titer factor VIII (FVIII) inhibitor. We report, to the best of our knowledge, the first-of-its-kind use of emicizumab (emi) ante/post-partum, its effect on the newborn, and its excretion in breast milk. Baseline details: 29-year-old-female was diagnosed with severe HA at age 1 following prolonged bleeding from a venipuncture site. She had no family history of HA. One stage FVIII activity (OSA) was less than 1%. She was compound heterozygous for F8 type 1 and type 2 intron 22 inversions. At 21 months of age, she developed a high-titer inhibitor (peak: 35 Bethesda unit[BU]). She was not treated with immune tolerance induction and had remained on factor eight inhibitor bypassing activity (FEIBA) as prophylaxis until transferring to our center. She was transitioned to monthly emi prophylaxis and recombinant FVIIa (rFVIIa, NovoSeven) for breakthrough bleeding at age 26. She was medically advised against pregnancy due to unclear safety profile of emi in pregnancy and theoretical concerns for an increased risk of bleeding and thrombotic complications associated with the use of bypassing agents in the peripartum setting. Nevertheless, she desired pregnancy and continued on emi prophylaxis every 4 weeks during her pregnancy. Clinical course in pregnancy: She had an uncomplicated antepartum course and did not require rFVIIa for breakthrough bleeds. Blood emi levels and FVIII inhibitor levels were measured in each trimester of pregnancy (Table 1). Her labor was induced with oxytocin while on rFVIIa and tranexamic acid (TXA) support. She had a spontaneous, unassisted vaginal delivery immediately complicated by post-partum hemorrhage resulting in estimated blood loss of 1100cc. She did not require blood transfusion. She continued on 90 mcg/kg rFVIIa support every 2 hours, gradually prolonging the dosing interval by 2 hours every 24 hours (q2, q4, q6, etc.), and experienced no further in-hospital bleeding. She delivered a healthy female newborn. The infant developed cephalhematoma but transcranial ultrasound was negative for intracranial bleeding. Cord blood was collected at the time of delivery and sent for emi level, FVIII activity and FVIII inhibitor titer (Table 2). FVIII inhibitor assay with bovine reagent (CBU) was performed using chromogenic substrate assay (CSA) after pre-analytical heat-inactivation of patient plasma. The infant's CSA FVIII level was measured using a bovine chromogenic FVIII assay, and FVIII was also assayed using a one-stage APTT-based assay. Mother opted to breast-feed the infant. Emi level was measured in breast milk (Table 1). Conclusion: In this highly unusual case, we demonstrate that emi crossed the placenta and is excreted in breast milk. We also demonstrate that the maternal FVIII inhibitor did not cross the placenta into the newborn. Drawing conclusions on the safety of emi despite placental and breast milk transmission and transmissibility of inhibitor based on a single case would be premature. The conglomeration of several rarities in a single case renders our report unique and insightful and provides a baseline experience for future cases.

Factor eight inhibitor bypassing activity for refractory bleeding in coronary artery bypass grafting: A propensity‐matched analysis

BackgroundPerioperative bleeding and transfusion have been associated with major morbidity and mortality after cardiac surgery. As concerns remain regarding potential graft thrombosis following administration of a prothrombin factor concentrate, the use of factor eight inhibitor bypassing activity (FEIBA) in managing refractory postoperative bleeding has never been evaluated in patients undergoing isolated coronary artery bypass grafting (CABG). ObjectivesWe aimed to examine the safety of FEIBA in patients undergoing isolated CABG, with respect to 30‐day mortality, perioperative outcomes, and thrombotic complications. MethodsA retrospective review was undertaken of all consecutive patients who had undergone isolated on‐pump CABG between January 2015 and December 2019 at North Shore University Hospital. Patients requiring intraoperative extracorporeal membrane oxygenator support were excluded. Patients were divided into two groups, dependent upon whether they received FEIBA (n = 63) versus no FEIBA (n = 2493). A 1:5 propensity match analysis was employed, and patients were analyzed with respect to thrombotic complications, reintervention for myocardial ischemia, and short‐term clinical outcomes. ResultsThere was no difference in 30‐day mortality between the two cohorts. There was also no significant difference in a composite of thrombotic complications (composed of deep vein thrombosis, pulmonary embolism, and stroke) between the two groups. Similarly, there was no significant difference in the requirement for postoperative reintervention for myocardial ischemia between patients who received FEIBA versus those who did not. ConclusionsFactor eight inhibitor bypassing activity may be safe when used as rescue therapy for refractory bleeding following isolated CABG.

Factor VIII inhibitor bypass activity (FEIBA) for the reduction of transfusion in cardiac surgery: a randomized, double-blind, placebo-controlled, pilot trial

BackgroundUncontrolled bleeding after cardiac surgery can be life-threatening. Factor eight inhibitor bypassing activity (FEIBA) is a prothrombin complex concentrate empirically used as rescue therapy for correction of refractory bleeding diathesis post-cardiopulmonary bypass (CPB). FEIBA used as rescue therapy for bleeding diathesis after CPB has been associated with a low incidence of complications and a reduction in transfusion requirement and re-exploration. The feasibility and efficacy of early administration of FEIBA after the termination of CPB have not been studied in a prospective randomized trial.MethodsWe designed a small randomized, double-blinded, placebo-controlled pilot trial to determine the feasibility of a larger trial testing the hypothesis that FEIBA decreases transfusion requirements after CPB. The study was designed to evaluate the feasibility of a larger pivotal trial to determine the effectiveness of FEIBA in reducing the total volume of blood products transfused perioperatively, and its safety profile. Study participants were adult patients undergoing elective major aortic cardiovascular surgery at a tertiary referral hospital, who were equally randomized to receive a single dose of either FEIBA or matched placebo intraoperatively at the end of CPB.ResultsTwenty patients were screened and 12 were randomized and included in the analysis. Protocol adherence was high, and all patients received the study drug per intention-to-treat except one patient. There were no protocol deviations or events of unblinding, and adverse events were not different between groups. Patients in the FEIBA group were older and more likely to be female and had higher BMI, lower hematocrit, and longer hypothermic circulatory arrest. There were no differences in post-randomization blood product transfusions (difference FEIBA vs. placebo −899 mL; 95% CI −5206 to 3409) or in the administration of open-label FEIBA.ConclusionsThis pilot trial confirmed the adequacy of the trial design that involved the early, blinded administration of FEIBA, by demonstrating excellent protocol adherence. We conclude that a larger trial establishing the effectiveness of early prothrombin complex concentrate administration to reduce the use of blood products in the setting of high-risk cardiac surgery is feasible.Trial registrationClinicalTrials.gov, NCT02577614. Registered 16 October 2015

The Use of Factor Eight Inhibitor Bypass Activity (FEIBA) for the Treatment of Perioperative Hemorrhage in Left Ventricular Assist Device Implantation

To test the hypothesis that factor eight inhibitor bypassing activity (FEIBA) can be used to control bleeding following left ventricular assist device (LVAD) implantation without increasing the 14-day composite thrombotic outcome of pump thrombus, ischemic cerebrovascular accidents, pulmonary embolism, and deep venous thrombosis. Retrospective cohort study. Academic hospital. Three hundred nineteen consecutive patients who underwent LVAD implantation (December 1, 2009 to December 30, 2018). FEIBA administered to control perioperative hemorrhage. The 82 patients (25.7%) in the FEIBA cohort had more risk factors for perioperative hemorrhage, such as lower preoperative platelet count (169 ± 66 v 194 ± 68 × 103/mL, p = 0.004), prior cardiac surgery (36.6% v 21.9%, p = 0.008), and longer cardiopulmonary bypass (CPB) time (100.3 v 75.2 minutes, p = 0.001) than the 237 controls. After 16.6 units (95% CI: 14.3-18.9) of blood products were given, 992 units (95% CI: 821-1163) of FEIBA were required to control bleeding in the FEIBA cohort. Compared to the controls, there were no differences in the 14-day composite thrombotic outcome (11.0% v 7.6%, p = 0.343) or mortality rate (3.7% v 1.3%, p = 0.179). Multivariate logistical regression identified preoperative international normalized ratio (odds ratio [OR]: 1.30, 95% CI: 1.04-1.62) and CPB time (OR: 1.11, 95% CI: 1.02-1.20) as risk factors for 14-day thrombotic events, but FEIBA usage was not associated with an increased risk. In this retrospective cohort study, the use of FEIBA (∼1,000 units, ∼13 units/kg) to control perioperative hemorrhage following LVAD implantation was not associated with increases in mortality or composite thrombotic outcome.

Acquired Haemophilia Associated with Urticarial Vasculitis.

Acquired haemophilia (AHA) is a rare autoimmune disorder caused by circulating autoantibodies that inhibit the activity of factor VIII (FVIII). Acquired inhibitors against FVIII are rarely seen, with a reported incidence of approximately 1 case per million/year. Clinical conditions and contexts associated with AHA include autoimmune diseases, lymphoproliferative malignancies, drug treatment, pregnancy and infections. An association with urticarial vasculitis is even more rare. Here, we report a case of a 59-year-old woman presenting with cutaneous and muscle haematomas secondary to AHA in association with urticarial vasculitis, who was successfully treated with factor eight inhibitor bypassing activity (FEIBA) and prednisolone.LEARNING POINTSAcquired haemophilia (AHA) is a rare autoimmune disease.AHA predisposes to severe, potentially life-threatening haemorrhage.An association with urticarial vasculitis is even more rare.

Protocolized use of Factor Eight Inhibitor Bypassing Activity (FEIBA) for the reversal of warfarin induced coagulopathy

IntroductionCoagulopathy due to warfarin in patients with major bleeding was traditionally reversed with fresh frozen plasma and intravenous (IV) vitamin K, but prothrombin complex concentrates (PCC) are increasingly used in the treatment of these patients. Factor Eight Inhibitor Bypassing Activity (FEIBA) is an activated four-factor PCC most commonly used in patients with hemophilia. We aimed to evaluate the efficacy and safety of FEIBA and IV vitamin K for the reversal of warfarin-associated coagulopathy in patients with major bleeding, by measuring the percentage of patients who achieved target INR ≤ 1.5 and the incidence of thrombotic adverse events (TAE). MethodsIn this prospective observational study, we enrolled patients presenting to the Emergency Department (ED) with warfarin associated coagulopathy (INR > 1.5) and major bleeding. Patients received FEIBA using an INR based dosing strategy and IV vitamin K. ResultsIn 43 patients, median initial INR was 4.0 (2.7, 7.3 interquartile range (IQR)). Median time to result the second INR was 45 min (38, 55 IQR) and the median INR was 1.4 (1.3, 1.6 IQR). Out of the 43 patients, 93% achieved the target INR of ≤1.5. In-hospital mortality was 40% (17 patients). There were 11 TAEs in 6 patients (14%); 4 events in 2 patients (5%) were attributed to FEIBA. ConclusionA protocolized use of FEIBA and IV vitamin K resulted in the efficacious reversal of warfarin-induced coagulopathy in patients with major bleeding. TAEs occurred in 14% of patients and were attributed to FEIBA in 5% of patients.

Combination of Novoseven and Feiba in Hemophiliac Patients with Inhibitors.

The aim of this study is to investigate the effective therapeutic combination of recombinant VIIa(Novoseven) and factor eight inhibitor bypass activity(FEIBA) drugs for the bleedings of adult hemophiliac patients with inhibitors.19 bleeding episodes of 5 hemophilia A patients who were using bypassing agents and followed-up between 2008 and 2016 in Hacettepe Hematology Department were analyzed retrospectively. In 11, 5 and 3 bleeding episodes, FEIBA, recombinant factor VIIa and FEIBA+recombinant factor VIIa were given to the patients, respectively. The treatment durations differed between 1 and 14 days depending on the bleeding and clinical course of the patients. Generally the treatment with bypassing agents was successful, and only in one patient who had elbow hematoma encountered serious bleeding which was taken under control by switching the bypass agent. We offer a different approach because of three reasons. Firstly, in our protocol we start the treatment with recombinant factor VIIa for the first three days. Secondly, our protocol is adjusted to consider health economics. Thirdly, we extended the time interval between doses of both bypassing agents without increasing bleeding risks because the half-life of both agents enables us to modify the protocol with more flexibility. To conclude, we have evaluated our clinic’s data about hemophilia A patients with inhibitors and we offer a different protocol in the management of bleeding episodes for these patients.

Management of Odontogenic Fascial Space Infection in Hemophilia Patients: A Proposed Protocol.

The purpose of this study was to suggest a protocol for the management of odontogenic space infections in patients with hemophilia which is often incompletely addressed by clinicians because of the fear of excessive bleeding leading to prolonged morbidity. Six diagnosed cases of hemophilia (four cases of hemophilia A and two cases of hemophilia B) with odontogenic fascial space infection were included in the study. Apart from routine investigations, assessments were also done to identify inhibitors to factor VIII/IX. Factor VIII/IX was replaced along with infusion of factor eight inhibitor bypass activity (FEIBA) one hour before incision and drainage. All the cases were treated by incision and drainage along with removal of foci under local anesthesia. The postoperative outcome was uneventful in all cases except one in which postoperative bleeding was noted from the extraction site on the third day which was again managed following the designed protocol. Maintaining good oral hygiene and seeking early dental care are of prime importance in patients with hemophilia to avoid invasive procedures. However, if odontogenic infection develops in these patients, performing timely incision and drainage using our protocol will minimize the complications and give successful outcome.

Incomplete dabigatran reversal with idarucizumab

Context: With increasing use of direct oral anticoagulants (DOACs), urgent reversal of these agents becomes a growing concern. Idarucizumab is a humanized monoclonal antibody fragment that specifically binds to dabigatran with higher affinity than thrombin, rapidly neutralizing its anticoagulant effect without increased risk of thrombosis.Case details: We describe two cases in which the recommended dose of idarucizumab was unsuccessful in completely reversing the anticoagulant effects of dabigatran. Both of these patients were noted to have supratherapeutic international normalized ratios (INRs) and high dabigatran concentrations. In the first case, an 86-year-old male underwent an emergent procedure and experienced excessive hemorrhaging refractory to blood product repletion, idarucizumab, and factor eight inhibitor bypass activity (FEIBA). In the second case, a 62-year-old female in shock was found to have elevated dabigatran concentrations despite two doses of idarucizumab, continuous renal replacement therapy (CRRT), blood product repletion, and FEIBA. Both patients ultimately expired from their coagulopathies.Discussion: These cases illustrate the potential for incomplete reversal of dabigatran with the recommended 5 g of idarucizumab and emphasize the importance of early detection of dabigatran toxicity. While direct dabigatran serum concentrations are not readily available, the INR may be a useful surrogate marker for supratherapeutic dabigatran concentrations.

Abstract TP328: Ischemic Stroke Following Prothrombin Complex Concentrates Administration for Intracerebral Hemorrhage

Intro: There have been case reports of ischemic infarcts after treatment with prothrombotics for anticoagulation reversal following spontaneous intracerebral hemorrhage (ICH), though there have been no systematic studies evaluating MRI infarction following prothrombin complex concentrate (PCC) or factor eight inhibitor bypassing activity (FEIBA) administration. We evaluated the prevalence of ischemic infarcts on diffusion-weighted imaging (DWI) in ICH patients who received prothrombotics compared to those who did not. Methods: We performed a retrospective review of patients admitted with ICH between January 2013 and April 2016 in whom MRI brain with DWI imaging was performed within 2 weeks of admission and prior to digital subtraction angiography. PCC (4-factor Kcentra, weight, and INR based dosing) was administered to patients on warfarin at the time of ictus with a INR≥1.4 and FEIBA (50 u/kg) was given to patients exposed to an oral Factor Xa inhibitor or direct thrombin inhibitor if ICH occurred within 3-5 half lives of the last dose. Acute ischemia was defined as DWI hyperintensity with corresponding apparent diffusion coefficient hypointensity. Perihematoma lesions, and procedure-related infarctions were excluded from analysis. Groups were compared using chi-square and Wilcoxon Rank Sum tests. Results: A total of 254 patients were enrolled. Of these, 41 (16%) received either 4-factor PCC (n=33) or FEIBA (n=8). Comparing those who received prothrombotics to those who did not, there was no difference in age (median 68 with prothrombotics and without; p=0.724), sex (44% female in both groups; p=0.977), initial NIH Stroke Scale (median 6 versus 8, p=0.838), or hematoma volume (median 15ml versus 10ml; p=0.207). Patients who received prothrombotics were more likely to have lobar ICH than deep ICH (71% versus 47%; p=0.005). DWI infarctions were found in 16% of patients who receive PCC or FEIBA compared with 22% who did not (p=0.404). Conclusions: Our data suggests prothrombotics do not increase the risk of acute ischemic infarcts within two weeks of administration.

Postpartum-acquired hemophilia: A challenging disease to manage

Acquired hemophilia is a severe bleeding diathesis that affects both males and females. It is caused by suddenly appearing autoantibodies that interfere with the coagulation factor VIII activity. This disorder is characterized by spontaneous and post-traumatic subcutaneous bleeds and massive mucosal hemorrhages. We report a case of postpartum-acquired hemophilia with a compartment syndrome of right (Rt.) forearm in a 29-year-old woman. Hemostatic tests indicated a prolonged activated partial thromboplastin time (APTT) to 99 s (normal 30.4–40 s), the prothrombin time was 7.8 s (normal 12–14 s), and the platelet count was 271,000 (normal 155,000–450,000). Further workup demonstrated the presence of autoantibody against factor VIII in a titer of 15 Bethesda Units/ml (BU/ml) and a decreased factor VIII activity to 0.04 IU/ml (normal 0.6–1.5 IU/ml). Immunosuppressive treatment with oral prednisone at 60 mg/24 h was initiated, but she was refractory to steroids; therefore, rituximab was added on a weekly basis for 4 weeks. At the same time, factor eight inhibitor bypassing activity (FEIBA), an anti-inhibitor coagulant complex, has been used as a bypassing agent. Reduction of the factor VIII inhibitor titer to 0 BU/ml and an increase of factor VIII activity to 0.38 were achieved. This led to normalization of hemostatic parameters (APTT 38.9 s, factor VIII activity 0.38).

Mapping T-Cell Peptide Epitopes on Activated Recombinant Factor VII (rFVIIa) Contributing to Inhibitor Antibody Response

Bypassing agents such as activated recombinant factor VII (rFVIIa) are used to treat acute bleeding episodes in patients with hemophilia and inhibitors to coagulation factors VIII (FVIII) or IX. BAY 86-6150 is a modified rFVIIa protein with 6 amino acid substitutions in the rFVII molecule that prolong half-life and improve potency compared with the currently available rFVIIa.In a dose-escalation clinical study, 1 patient out of a cohort of 10 treated with 6.5 μg/kg BAY 86-6150 developed low-titer neutralizing antibodies that were detected after the third exposure. The patient's anti-BAY 86-6150 antibodies also cross-reacted with and neutralized wild-type FVIIa (WT-FVIIa) in vitro. T-cell epitope mapping was performed to identify BAY 86-6150 sequence(s) that may have contributed to the immunogenic response in the patient by measuring CD4+ T-cell response to individual 15-mer peptides spanning BAY 86-6150.The epitope mapping study did not identify any of the 14 peptides unique to BAY 86-6150 as epitopes recognized by the patient's T cells. However, strong responses were detected against 2 WT-FVIIa peptides, WT p6-20 (EELRPGSLERECKEE) and WT p156-170 (GKVCPKGECPWQVLL), indicating that CD4+ T helper cells recognizing these WT peptides may have contributed to the immune response that resulted in the production of anti-BAY 86-6150 antibodies during treatment. It should be noted that although the patient had no detectable anti-FVIIa antibodies before the start of the study, he had been treated with factor eight inhibitor bypassing activity (FEIBA), which contains active FVII, on 3 consecutive days 3 months before entry into the study. Hence it is possible that the patient had been primed for a response against FVIIa that was triggered by the subsequent exposure to BAY 86-6150.The fact that the patient's T cells only responded to WT-FVIIa peptides might be explained if the WT-FVIIa peptides were seen as foreign/non-self peptides by his T-cell repertoire. Unfortunately, the patient's FVII gene sequence was not obtainable, and this possibility remains unanswered.The Universal Protein Resource (UniProt) database reports 2 natural FVII gene variants that encompass the WT p6-20 sequence (Millar, et al. Hum Genet. 2000;107:327-42; Herrmann, et al. Haemophilia. 2009;15:267-280) and one for the WT p156-170 sequence (Wulff and Herrmann. Hum Mutat. 2000;15:489-496) that resulted from single amino acid substitutions. Hence the possibility exists that the patient's T-cell repertoire sees WT-FVIIa sequences as foreign and immunogenic. T cells from 40 healthy donors were also tested for reactivity against the peptide panel to assess relative immunogenicity of BAY 86-6150 vs WT-FVIIa. Seven BAY 86-6150 neoepitopes were stimulatory for 8 unrelated healthy donor T cells, but their mean stimulation indices were not statistically higher than those observed against WT FVIIa peptides. Mean % stimulation values of the positive responses against the 7 BAY 86-6150 neoepitopes versus 39 WT FVIIa peptides were 1.09 (N=13 responses) vs 1.01 (N=70 responses; P =0.5059). Statistical analysis of the in vitro T-cell response indicates that specific mutations to BAY 86-6150 do not result in BAY 86-6150 being more immunogenic than WT FVIIa. This would suggest that BAY 86-6150 will not elicit stronger or higher frequency of anti-FVIIa antibody response than WT FVIIa in patients with hemophilia. DisclosuresPaz:Bayer HealthCare: Employment. Schroeder:Bayer Pharma AG: Employment. Mathew:Bayer HealthCare Pharmaceuticals: Employment. Hardtke:Bayer Pharma AG: Employment. Aswad:Bayer HealthCare: Employment.

The Role of FEIBA in Reversing Novel Oral Anticoagulants in Intracerebral Hemorrhage.

Activated prothrombin complex concentrates factor eight inhibitor bypassing activity (FEIBA) has been recommended for reversing novel oral anticoagulants (NOAC) in the context of intracerebral hemorrhage (ICH), though few clinical studies report its use. A prospective study of patients with spontaneous ICH was conducted from May 2013 to May 2015. Hospital complications including hemorrhage (gastrointestinal bleeding, anemia requiring transfusion, and surgical site bleeding) and thrombosis (pulmonary embolus, deep vein thrombosis, ischemic stroke, and myocardial infarction) were recorded. All ICH patients underwent baseline head CT and a follow-up stability scan in 6h. NOAC taken within 48h of presentation was reversed with FEIBA (50u/kg) per protocol. Three-month outcomes were assessed using the modified rankin score (mRS). Of 127 ICH patients enrolled, 6 (5%) had NOAC-related ICH including: oral factor XA inhibitor N=5 (4%; N=4 rivaroxaban, N=1 apixaban] and direct thrombin inhibitor N=1 (0.8%; dabigatran). The indication for NOAC was atrial fibrillation in all patients and the median CHADS2-VASC score was 4 (range 2-5). The median admission NIHSS was 2 (range 0-14) and the median ICH volume was 8mL (range 1-20). Five patients (3 rivaroxaban, 1 apixaban, 1 dabigatran) presented within 48h and received FEIBA within a median of 13h (range 10-29h) from their last NOAC dose and 8h (range 4.5-20) from the time last known well. None of the patients had ICH expansion, hemorrhagic, or thrombotic complications. Three-month median mRS was 1 (range 0-6). In this small case series, reversal of NOAC with FEIBA was not associated with ICH expansion or any thrombotic or hemorrhagic complications.

Successful use of Kinesio tape to treat an acute muscle haematoma

Abstract A 73-year-old woman presented with recent onset significant spontaneous bruising. She also had a recent diagnosis of type 2 diabetes mellitus and was undergoing investigations for biochemical hyperthyroidism. A diagnosis of acquired haemophilia A was confirmed with laboratory testing in addition to thyrotoxic Graves’ disease. She had significant bruising of her left thigh and restricted mobility of the left leg. A significant left vastus lateralis haematoma was diagnosed by ultrasound scan. A course of FEIBA (Factor Eight Inhibitor Bypassing Activity) was commenced and physiotherapy input provided. Kinesio tape was applied to the thigh using a lymphatic drainage technique with the aim of reducing swelling and bruising. Eight days after the initial application of tape, bruising had significantly reduced and her range of movement had returned to normal. This case history demonstrates how kinesio tape may be used as a useful adjunct to standard therapy.

Factor VIII inhibitor bypass activity and recombinant activated factor VII in cardiac surgery.

Postcardiopulmonary bypass hemorrhage remains a serious complication of cardiac surgery. Given concerns regarding adverse effects of blood product transfusion and limited efficacy of current antifibrinolytics, procoagulant medications, including recombinant factor VIIa (rFVIIa) and factor eight inhibitor bypass activity (FEIBA), increasingly have been used in managing refractory bleeding. While effective, these medications are associated with thromboembolic complications. This study compared the efficacy and risk of adverse events of rFVIIa and FEIBA in cardiac surgical patients with refractory bleeding. This retrospective study evaluated 168 patients who underwent cardiac surgery and received either FEIBA or rFVIIa to manage postbypass hemorrhage. Demographic, clinical, and outcomes data were collected and statistical analysis performed to compare thromboembolic event rates, relative efficacy, and 30-day mortality following administration of these medications. Single university hospital. Patients undergoing cardiac surgery. None. Sixty-one patients received rFVIIa, and 107 received FEIBA. Demographics, surgical procedures, and preoperative anticoagulation were similar between the cohorts; however, the rFVIIa cohort had longer durations of cardiopulmonary bypass (305.1 v 243.8 min, p<0.01). There were no significant differences in the number of thromboembolic events, 30-day mortality, or rates of revision surgery. Neither group demonstrated a clear relationship between dosage and occurrence of thromboembolic events. The rFVIIa cohort received more platelets than the FEIBA cohort (3.13 v 1.67 units, p = 0.01), but transfusion rates of other blood products were similar. This study suggests that rFVIIa and FEIBA have similar efficacy and adverse event profiles in managing intractable postbypass hemorrhage in cardiac surgical patients. Further prospective studies are required.

Prophylaxis with anti‐inhibitor coagulant complex improves health‐related quality of life in haemophilia patients with inhibitors: results from FEIBA NF Prophylaxis Study

The Pro-FEIBA study reported health-related quality of life (HRQoL) improved following 6-month of Factor Eight Inhibitor Bypassing Activity (FEIBA) prophylaxis. This study investigates whether 12-month of FEIBA prophylaxis improved HRQoL in haemophilia patients with inhibitors. Thirty-six subjects in a 1-year prospective, randomized, open-label, parallel-design study were randomized to prophylaxis (85±15Ukg(-1) every other day) or on-demand treatment. HRQoL was assessed at screening, 6 and 12-month termination using the EQ-5D, Haem-A-QoL, Haemo-QoL and a general pain visual analog scale (VAS). To evaluate changes, paired t-tests and criteria for minimally important differences were applied. Repeated measures regression tested the association between annualized bleeding rate (ABR) and physical HRQoL. At 6 and 12months, prophylaxis subjects reported clinically meaningful improvement in EQ-5D index (mean improvement, 0.10 and 0.08, respectively) and both clinically meaningful and statistically significant improvements in EQ-VAS scores (16.9 and 15.7, respectively; P<0.05) vs. baseline. General pain was significantly reduced during prophylaxis at each follow-up (mean improvement, 20.3 and 23.2, respectively; both P<0.05). At 12months, prophylaxis subjects achieved significant improvements in Haem-A-QoL Total Score and in four domains: Physical Health, Feeling, View, and Work and School (all P<0.05). No statistically significant changes, except for Haem-A-QoL Physical Health at 6months, were observed with on-demand treatment. ABR was decreased by 72.5% with prophylaxis vs. on-demand treatment (P=0.0003) and reduced ABR was associated with better physical HRQoL (P<0.05). FEIBA prophylaxis significantly reduced ABR and improved HRQoL in inhibitor patients. Subjects with lower ABR reported better physical HRQoL.

Reversal Of Dabigatran By Recombinant Factor VIIa Is Dependent On The Amount Of Tissue-Factor

BackgroundDabigatran is a new oral anticoagulant that specifically and reversibly inhibits thrombin. Its predictable pharmacokinetics and pharmacodynamics allow for minimal monitoring. However, there is currently no specific antidote to reverse its anticoagulant effects. Instead, activated prothrombin complex concentrate (aPCC) or recombinant Factor VIIa (rFVIIa) has been used to stop bleeding complications in patients on dabigatran. Both were originally used to treat hemophilia patients with inhibitors. Currently, Factor Eight Inhibitor Bypass Activity (FEIBA) is the only clinically approved aPCC, which contains Factors II, IX, X, and VII in both active and non-active forms. In contrast, rFVIIa is a human recombinant protein which can initiate clotting via the tissue factor (TF) pathway. It has been controversial which of these hemostatic agents is more efficient at reversing the effect of dabigatran, as animal models have failed to yield consistent results. We hereby utilized a modified Hemoclot turbdity assay to determine the equivalent concentrations of FEIBA and rFVIIa that can reverse the anticoagulant effect of dabigatran. MethodsA mixture was prepared by incubating normal pooled plasma (NPP) with 382 nM dabigatran and varying concentration of hemostatic agents (FEIBA or rFVIIa), in the absence or presence of TF (Thrombosel®). The mixture was diluted 1:8 in TSP buffer, from which a 50 µL-aliquot was then incubated with 100 µL of NPP at 37°C for 5 min. Clotting was initiated with 100 µL of another mixture containing 10 mM Ca2+ and 2.5 nM thrombin in TSP. Turbidity was measured at 350 nm using a SpectraMax Pro spectrophotometer at 37°C for 2 hr. Clotting time (CT) was defined as the time to reach half of the maximum turbidity. ResultsIn this modified Hemoclot turbidity assay, the CT without dabigatran was 101 s and it linearly increased dependent on the dabigatran concentration up to 1500 nM. Dabigatran at 382 nM, the therapeutic plasma concentration, prolonged CT 5-fold to 505 s. Addition of 1 U/mL FEIBA reduced the CT approximately 35% to 328 s. The reversal effect of FEIBA plateaued at 2.5 U/mL to 5 U/mL because there was minimal further reduction in the CT even with 10 U/mL FEIBA. In contrast, rFVIIa at a therapeutic concentration of 50 nM barely reduced the CT by <10% to 469 s. The reversal effects of rFVIIa were drastically enhanced by the addition of extrinsic tissue factor. With TF at 1.5 pM, the rFVIIa reduced the CT to a level similarly achieved by 1 U/mL of FEIBA, but the CT could not be reduced further despite the concentration of rFVIIa increased 10-fold to 400 nM. Finally, although both FEIBA and rFVIIa/TF reached an eventual plateau in the reversal of dabigatran, none of them could lower the CT to the baseline level. Summary/ConclusionsOur in vitro study shows that reversal of dabigatran by rFVIIa is dependent on the concentration of TF. Higher levels of TF augment the reversal effects of rFVIIa to the extents similarly achieved with FEIBA. The data may, in part, explain the inconsistency of results obtained from in vivo studies using various animal models to compare rFVIIa and FEIBA for the reversal of dabigatran. The circulating TF levels in vivo are much lower than the amount of TF used in this study, thus its availability in the microenvironment for hemostasis varies depending on the methods used to induce bleeding. The data in this study also explain the variable clinical efficacy of rFVIIa reported in the literature when it is used to reverse the bleeding complications in patients on dabigatran. Disclosures:No relevant conflicts of interest to declare.

Diagnosis and management of acquired coagulation inhibitors: a guideline from UKHCDO

A United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) guideline approved by the British Committee for Standards in Haematology Peter W Collins, Elizabeth Chalmers, Daniel Hart, Ian Jennings, Ri Liesner, Savita Rangarajan, Kate Talks, Michael Williams and Charles R. M. Hay School of Medicine, Cardiff University, University Hospital of Wales, Cardiff, Royal Hospital for Sick Children, Glasgow, Royal London Hospital, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK NEQAS Blood Coagulation, Sheffield, Great Ormond Street NHS Trust, London, Hampshire Hospital NHS Foundation Trust, Basingstoke & North Hampshire Hospital, Basingstoke, Newcastle upon Tyne Hospital NHS Foundation Trust, Newcastle, Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, and Manchester University Dept of Haematology, Manchester Royal Infirmary, Manchester, UK