Administration Of rFVIIa Research Articles

Recombinant activated factor VII (rFVIIa) in refractory haemorrhage for non-haemophiliacs: an eleven-year single-centre experience

BackgroundMassive bleeding is one of the commonest salvageable causes of death. The search for an ideal haemostatic agent during massive bleeding is still ongoing. One of the novel haemostatic medications is recombinant activated factor VII (rFVIIa). To date, the usage of rFVIIa during massive haemorrhage among non-haemophiliac patients remains off-label. The aim of this study is to report our experience in using rFVIIa to treat refractory bleeding.MethodsMedical records of all patients treated with rFVIIa for massive bleeding over an eleven-year period in a single institution were recorded. Treatment indications, 24-h and 30-day mortality, changes in transfusion needs and coagulation profiles after rFVIIa administration were analysed.ResultsrFVIIa were administered in 76 patients. Of these, 41 (53.9%) were non-surgical bleeding, followed by 22 patients (28.9%) with trauma, other surgery bleedings in 9 patients (11.8%) and 4 patients (5.4%) with peripartum haemorrhage. Total survival rate was 78.9% within 24 h and 44.7% over 30 days. Among all these patients who had received rFVIIa due to life-threatening haemorrhage, blood and blood product requirements were significantly reduced (P < 0.001), and the coagulation profiles improved significantly (P < 0.05). Two patients with preexisting thromboembolism were given rFVIIa due to intractable bleeding, both survived. No thromboembolic events were reported after the administration of rFVIIa.ConclusionsrFVIIa significantly improved coagulation parameters and reduced blood product requirements during refractory haemorrhage. Additionally, usage of rFVIIa in trauma and peripartum haemorrhage patients yield better outcomes than other groups of patients. However, the overall mortality rate remained high.

Nebulised recombinant activated factor VII (rFVIIa) does not attenuate the haemorrhagic effects of blast lung injury

IntroductionPrimary blast lung injury causes intrapulmonary haemorrhage. A number of case reports have suggested the efficacy of recombinant activated factor VII (rFVIIa) in the treatment of diffuse alveolar haemorrhage from...

Recombinant activated factor VII is associated with postoperative thromboembolic adverse events in bleeding after coronary surgery.

To evaluate the impact of recombinant activated factor VII (rFVIIa) administration on thromboembolic adverse events (TAEs) in coronary artery bypass grafting (CABG) surgery patients showing postoperative bleeding. From January 2004 to May 2015, 180 CABG surgery patients with postoperative bleeding were included in the study. All patients were managed conservatively and 81 (45%) also received rFVIIa. Ten patients developed new TAEs (5.6%), 15 (8.3%) were re-explored, 4 (2.2%) had postoperative dialysis and 6 (3.3%) died by day 30 postoperation. Among those with TAEs, 7 experienced cerebrovascular accidents, 2 had myocardial infarction and 1 had pulmonary embolism. A multivariable regression model confirmed rFVIIa as the only independent factor associated with the development of TAEs (odds ratio 6.19, 95% confidence interval 1.197-31.996; P = 0.0296). Fifteen (8.3%) patients were re-explored for bleeding according to our management protocol. No variables to predict the need for re-exploration were identified by the regression model. Chest tube output was statistically significantly lower in patients who received rFVIIa from 3 h [1.9 (Q1-Q3 1.7-2.1) ml/kg/h vs 3.2 (Q1-Q3 3-3.4) ml/kg/h, P = 0.000] through to 12 h after admission [0.6 (Q1-Q3 0.5-0.6) ml/kg/h vs 0.7 (Q1-Q3 0.6-0.9) ml/kg/h, P = 0.000]. rFVIIa for the treatment of post-CABG bleeding resulted in increased incidence of TAEs in spite of rapid control of bleeding. Hence, rFVIIa should only be used for selected patients and with extreme caution.

Recombinant Activated Factor VII as a Second Line Treatment for Postpartum Hemorrhage.

BackgroundSevere or massive postpartum hemorrhage (PPH) has remained a leading cause of maternal mortality for decades across the world and it results in critical obstetric complications. Recombinant activated factor VII (rFVIIa) has emerged as a gold standard adjunctive hemostatic agent for the treatment of life-threatening PPH refractory to conventional therapies although it remains off-licensed for use in PPH. We studied the effects of rFVIIa on coagulopathy, transfusion volume, prognosis, severity change in Korean PPH patients.MethodsA retrospective review of medical records between December 2008 and March 2011 indicating use of rFVIIa in severe PPH was performed. We compared age, rFVIIa treatment, transfusion volume, and Sequential Organ Failure Assessment (SOFA) score at the time of arrival in the emergency department and after 24 hours for patients whose SOFA score was 8 points or higher.ResultsFifteen women with SOFA score of 8 and above participated in this study and eight received rFVIIa administration whereas seven did not. Patients’ mean age was 31.7 ± 7.5 years. There was no statistically significant difference in initial and post-24 hours SOFA scores between patients administered rFVIIa or not. The change in SOFA score between initial presentation and after 24 hours was significantly reduced after rFVIIa administration (P = 0.016).ConclusionsThis analysis aimed to support that the administration of rFVIIa can reduce the severity of life-threatening PPH in patients. A rapid decision regarding the administration of rFVIIa is needed for a more favorable outcome in severe PPH patients for whom there is no effective standard treatment.

SINGLE CENTRE EXPERIENCE WITH LONG-TERM FOLLOW-UP OF RECOMBINANT FACTOR VIIA IN PATIENTS UNDERGOING CARDIAC SURGERY

Peri-operative haemorrhage requiring massive transfusion represents a major challenge in cardiac surgery and is associated with significant morbidity and mortality. Recombinant Factor VIIa (rFVIIa) administration remains a controversial rescue therapy for intractable non-surgical bleeding. Variability in reported complications by small retrospective studies has led to a disparity in recommendations found in the literature. We report a single centre experience of 103 consecutive patients who received rFVIIa for intractable non-surgical haemorrhage after cardiac surgery from 2010 to 2014. Retrospective data analysis was performed. The primary end point was a combined incidence of major adverse thromboembolic events (MATEs), which included CVAs, post-operative MI, acute mesenteric ischemia, and significant peripheral arterial ischemia. Secondary end points included chest tube loss and blood product utilization 24 hours pre- and post-rFVIIa administration, and 30-day mortality. All reported CVAs were reviewed by a single neuroradiologist to confirm diagnosis, location, and extent. A total of 103 consecutive cardiac surgery patients received rFVIIa for intractable non-surgical bleeding: 10 isolated AVR, 27 isolated CABG, 31 combined CABG/valve, 14 Bentall/Root procedure, 5 Type A aortic dissection and 16 other categorized. A median dose of 6.7mg of rFVIIa was administered (Range 2.4 to 14.8mg). rFVIIa administration occurred both in the OR (46.6%) and in the ICU (53.4%). The median age was 66 yrs (±11.9) with 71% being male. The overall incidence of MATEs was 14.6% and was comprised of 8.7% CVA, 2.9% MI, and 2.9% ischemic gut. There were no acute peripheral arterial vascular events requiring intervention. Chest tube drainage before and after rFVIIa decreased from 1300ml/hr to 376.5ml/hr (p < 0.001). Blood product utilization was significantly decreased in the 24 hours after rFVIIa administration (p < 0.001): PRBCs 5.1 to 2.7 units; platelets 1.3 to 0.5 units; FFP 6.2 to 2.2 units. The rate of re-exploration due to bleeding was 42%. Overall 30-day mortality was 21%. A survival curve was created for a subset of patients (N=66) who had surgery between 2010 and 2013. In this subset the mortality rate was 24.2% with a mean survival time of 12.5 months (Range 0-46). This large case series of Canadian cardiac surgery patients with intractable life-threatening bleeding demonstrates that administration of rFVIIa is an effective rescue therapy with an acceptable rate of MATEs, given the likely alternative outcomes, in salvage situations when conventional therapies have failed.

Outcomes Following Three-Factor Inactive Prothrombin Complex Concentrate Versus Recombinant Activated Factor VII Administration During Cardiac Surgery

To compare outcomes following inactive prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) administration during cardiac surgery. Retrospective propensity-matched analysis. Academic tertiary-care center. Patients undergoing cardiac surgery requiring cardiopulmonary bypass who received either rFVIIa or the inactive 3-factor PCC. Outcomes following intraoperative administration of rFVIIa (263) or factor IX complex (72) as rescue therapy to treat bleeding. In the 24 hours after surgery, propensity-matched patients receiving PCC versus rFVIIa had significantly less chest tube outputs (median difference -464 mL, 95% confidence interval [CI] -819 mL to -110 mL), fresh frozen plasma transfusion rates (17% v 38%, p = 0.028), and platelet transfusion rates (26% v 49%, p = 0.027). There were no significant differences between propensity-matched groups in postoperative stroke, deep venous thrombosis, pulmonary embolism, myocardial infarction, or intracardiac thrombus. Postoperative dialysis was significantly less likely in patients administered PCC versus rFVIIa following propensity matching (odds ratio = 0.3, 95% CI 0.1-0.7). No significant difference in 30-day mortality in patients receiving PCC versus rFVIIa was present following propensity matching. Use of rFVIIa versus inactive PCCs was significantly associated with renal failure requiring dialysis and increased postoperative bleeding and transfusions.

Recombinant Factor VIIa Is Associated With Increased Thrombotic Complications in Pediatric Cardiac Surgery Patients.

Recombinant factor VIIa (rFVIIa) is routinely used as an off-label hemostatic agent in children undergoing cardiac surgery. Despite evidence that rFVIIa use is associated with an increased incidence of thrombotic complications in adult cardiac surgery, the safety of rFVIIa as a rescue hemostatic agent in the pediatric cardiac surgical population is less definitively delineated. In this retrospective study, we used propensity score matching to compare the incidence of thrombotic complications between children treated with rFVIIa and their matched controls. We retrospectively reviewed medical records and pharmacy data from all neonates and children who underwent congenital cardiac surgery between May 1, 2011, and October 31, 2013, at Boston Children's Hospital, and identified those who received rFVIIa during the perioperative period. Using existing knowledge, we chose 10 factors associated with bleeding after cardiac surgery to be used in our propensity score: age, sex, body weight, neonates, prematurity, previous sternotomy, cardiopulmonary bypass time, deep hypothermic circulatory arrest time, aortic cross-clamp time, and the operative surgeon. We then used propensity-matched analysis to match children treated with rFVIIa with 2 controls. The primary outcome was thrombotic complications. Secondary outcomes included reexploration for bleeding, length of cardiac intensive care unit stay, length of hospital stay, and 30-day mortality. One hundred forty-nine patients received perioperative rFVIIa during the study period. Propensity matching yielded 143 rFVIIa patients matched to 2 control patients each (n = 286). Three control patients were found to have received rFVIIa during the perioperative course and were removed from the analysis, for a total of 283 control patients. The administration of rFVIIa was associated with an increased incidence of thrombotic complications (20% vs 8%; odds ratio [OR]: 3.9 [95% confidence interval {CI}: 2.6-5.9], P < .001). Administration of rFVIIa was associated with a prolonged median length of cardiac intensive care unit stay (8 days [interquartile range {IQR}: 4-24] vs 5 days [IQR: 2-10], P < .001) and prolonged length of hospital stay (20 [IQR: 9-44] vs 11 days [IQR: 7-23], P < .001). No difference in reexploration for bleeding (rFVII = 14% vs controls = 9%; OR: 1.7 [95% CI, 0.92-3.1], P = .12) or 30-day mortality was observed (8% vs 6%; OR 1.3 [95% CI, 0.60-2.89], P = .51). This retrospective analysis confirmed that perioperative administration of rFVIIa is associated with an increased incidence of postoperative thrombotic complications in neonates and children undergoing cardiac surgery, without increase in 30-day mortality. In conclusion, rFVIIa should be used with extreme caution in pediatric patients undergoing cardiac surgery.

Use of an innovative syringe pump to deliver bolus rFVIIa for patients with haemophilia and inhibitors undergoing surgery

Abstract Aim: To evaluate the efficacy and safety of using a syringe driver perfusor pump to deliver frequent regular bolus doses of rFVIIa peri- and postoperatively to patients with severe haemophilia and inhibitors. Background: The provision of surgical haemostatic coverage with rFVIIa requires regular bolus doses, initially every two hours and subsequently three-hourly, moving to four- to six-hourly post-operatively. This has implications for safety and nursing time, and can influence clinical decision-making. We investigated the use of an infusion pump to deliver timed and accurate rFVIIa bolus doses during the postoperative period. Methods: Two patients with severe haemophilia A and inhibitors undergoing three procedures were managed with a pre-surgical bolus infusion of 120mcg/kg of rFVIIa, followed by postoperative doses of 90mcg/kg every two hours for the first 72 hours, and every three hours subsequently, with increasing dose intervals thereafter. All postoperative bolus doses were delivered via a pre-programmed infusion pump. The pump also required a constant background infusion set at 0.1ml/ hour for the first patient, and reduced to 0.01ml/hour for the second patient. Results: The pump was simple to use and readily accepted by patients and nursing staff. There were no delayed or missed doses, and good haemostasis was maintained. Overall nursing time involved in reconstituting and administering rFVIIa was reduced from three to six hours per treatment day (with conventional bolus dosing) to just one to two hours per day with the pump. Conclusions: The syringe pump successfully delivered the correct doses at the specified time intervals for all three procedures. The technique met the centre’s safety and efficacy criteria and resulted in a significant reduction in the amount of nursing time needed over a 24-hour period. This novel method of rFVIIa administration appears to be safe and effective in the elective surgery setting, and should be further investigated.

The use of thromboelastography, thrombin generation test and clotting tests to evaluate the efficacy of hemostatic therapy with recombinant activated factor VII in hemophilia patients with inhibitor

Introduction . The Problem of the use of recombinant activated factor VII (rFVIIa) in hemophilia patients with inhibitors is the complexity of the laboratory evaluation of the therapy. After rFVIIa administration standard clothing tests are changing, however, are not normalized. The aim of this study was to investigate the possibility of using standard clothing tests (activated partial thromboplastin time (APTT) and prothrombin time (PT)) to assess the efficiency of hemostatic therapy with rFVIIa in hemophilia patients with inhibitors. The aim of this work is to investigate the possibility of using standard clothing tests (activated partial thromboplastin time (APTT), prothrombin time (PT)) to assess the efficiency of hemostatic therapy with rFVIIa in patients with inhibitory hemophilia. Materials and methods. 20 male hemophilia patients with inhibitors were included in the study. At the time of study inclusion none patients had signs of bleeding. Plasma levels of FVIII were < 1 %, FVIII inhibitor titers were from 5 BU/ml to 463 BU/ml. All patients received rFVIIa (Coagil-VII) at a dose of 90 μg/kg. Before the administration of rFVIIa and then in 15, 30 and 60 min, 2 and 24 h the APTT, the PT, the endogenous thrombin potential (ETP) and thromboelastography (TEG) parameters (reaction time – R, maximum amplitude – MA) were evaluated. Results. Before rFVIIa administration all patients had prolonged APTT. 15 min after administration of rFVIIa APTT shortened and remained shorter than baseline level, but 2 times longer than normal ranges during 2 hours. The PT also significantly decreased in 15 min after the rFVIIa administration. Prior to treatment patients had minimal to no clotting detectable by TEG. Administration of rFVIIa led to normalization of TEG traces in the most of the patients in 15 min. Elevated by TEG hemostatic effects persisted for 2 h. The ETP increased in 15 min after rFVIIa administration. This increase of ETP persisted for 60 min. There were strong correlations between R and APTT (r = 0.74; p = 0.001), between MA and APTT (r = 0.70), between PT and R (r = 0.79; p = 0.01), PT and MA (r = 0.76; p = 0.01). There were no correlations between ETP and APTT, and between ETP and R. The shortening of the APTT after rFVIIa administration for 17 s and more or for 22 % and more from the baseline levels were associated with the normalization of R and MA. Changes of the PT poorly allowed to discriminate normal values of TEG. Conclusion . Shortening of the APTT after rFVIIa administration in hemophilia patients with inhibitor for 17 s and more or for 22 % and more from the initial value can be used to assess the hemostatic efficiency of rFVIIa therapy.

Use of the UKHCDO Database for a postmarketing surveillance study of different doses of recombinant factor VIIa in haemophilia.

Recombinant factor VIIa (rFVIIa) is recommended in Europe at standard (3 × 90 μg kg-1 ) or high (1 × 270 μg kg-1 ) doses. When granting the license for the high dose, the European Medicines Agency (EMA) requested postmarketing surveillance for thrombosis. This was conducted by the United Kingdom National Haemophilia Database (NHD) on behalf of Novo Nordisk and the EMA. To assess the use and safety of rFVIIa utilizing prospective data collected by the NHD (1 January 2008 to 30 June 2011). Data were obtained from 67 haemophilia A/B patients with inhibitors treated for 1057 bleeds and 31 acquired haemophilia patients treated for 70 bleeds. Initial rFVIIa dose was categorized post hoc as low (<90 μg kg-1 ), intermediate (≥90-<180 μg kg-1 ) or high (≥180-<270 or ≥270 μg kg-1 ). For haemophilia A/B, high and lower initial rFVIIa dose was used for 38.4% and 51.4% of episodes, respectively, while for acquired haemophilia, the values were 11.4% and 77.1% respectively. Median initial doses were higher for haemophilia A/B (146.3 μg kg-1 ) than acquired haemophilia (90.5 μg kg-1 ). A single administration of rFVIIa was the most frequently used regimen for haemophilia A/B, in contrast with standard recommendations and previous reports. For acquired haemophilia, most episodes were treated with multiple doses. No adverse drug reactions or thromboembolic events were reported for any rFVIIa dose. The novel use of a national database for postmarketing surveillance has demonstrated acceptable safety for all recommended doses of rFVIIa.

Primary prophylaxis for children with severe congenital factor VII deficiency — Clinical and laboratory assessment

Severe congenital factor VII (FVII) deficiency is a rare bleeding disorder. Prophylaxis with replacement therapy has been suggested to patients, yet the most beneficial dosing regimens and therapy intervals are still to be defined. Due to the lack of evidence-based data, we hereby present our experience with long-term administration and monitoring primary prophylaxis in children with severe FVII deficiency and an extremely high bleeding risk.Four children with familial FVII deficiency, treated by prophylactic recombinant activated factor VII (rFVIIa), 15–30μg/kg/dose, given 2–3 times weekly since infancy, are discussed. Clinical follow up and monitoring laboratory assays, including thrombin generation, measured at various time points after prophylactic rFVIIa administration are presented.Among our treated patients neither FVII activity nor thrombin generation parameters (both already declined 24h post rFVIIa administration) were able to predict the impact of prophylaxis, and could not be used as surrogate markers in order to assess the most beneficial treatment frequency. However, the long clinical follow-up and comprehensive laboratory assessment performed, have shown that early primary prophylaxis as administered in our cohort was safe and effective.

Recombinant Activated Factor VIIa (rFVIIa) Treatment in Very-Low-Birth-Weight (VLBW) Premature Infants with Acute Pulmonary Hemorrhage: A Single-Center, Retrospective Study.

We aimed to evaluate the efficacy of intravenous administration of recombinant activated factor VIIa (rFVIIa) for acute pulmonary hemorrhage treatment in very-low-birth-weight (VLBW) premature infants. This study was carried out retrospectively in premature infants with pulmonary hemorrhage that were ≤30weeks gestational age or <1250g birth weight. The data of all VLBW premature infants with pulmonary hemorrhage who were hospitalized in our neonatal intensive care unit between 01 January 2013 and 31 December 2015 were evaluated. Group 1 (n=21) received rFVIIa support within the first 30min of pulmonary hemorrhage plus conventional treatment, while Group 2 (n=21) received conventional treatment only. The number of patients whose pulmonary hemorrhage was stopped within the first 2h was significantly higher in Group 1 than Group 2 (n=14 vs n=4; p=0.002). After pulmonary hemorrhage, hemoglobin values of Group 1 were higher than Group 2 (11.12±1.06 vs 10.14±1.59g/dL; p=0.024). Erythrocyte suspension (1.43±4.51 vs 5.71±7.46mL/kg; p=0.030) and fresh frozen plasma use (5.71±8.10 vs 19.52±12.44mL/kg; p<0.001) in Group 1 were lower than those of Group 2. Prothrombin time, activated partial thromboplastin time, and international normalized ratio values in Group 1 were lower than those of Group 2 (p<0.05). No statistically significant difference was identified in recurrence of pulmonary hemorrhage after 72h, overall mortality, mortality from pulmonary hemorrhage, surfactant use, intubation time, hospitalization duration, intraventricular hemorrhage (IVH), severe IVH, patent ductus arteriosus rates, or short-term complication rates. rFVIIa administration was observed to be effective in stopping pulmonary hemorrhage, reducing blood product requirement, and improving coagulation test parameters. Prospective studies are needed to evaluate the efficacy, reliability, and long-term results of rFVIIa in the prevention and treatment of pulmonary hemorrhage in premature infants.

Treatment of bleeding in acquired hemophilia A with the proper administration of recombinant activated factor VII: single-center study of 7 cases

Recombinant activated factor VII (rFVIIa) is the bypassing agent used in the first-line hemostatic therapy for acquired hemophilia A (AHA); however, the occurrence of thrombotic complications in rFVIIa-treated AHA patients was recently reported to be 2.9–6.5%. Therefore, the investigation of the proper administration of rFVIIa for AHA is needed. In the present study, we retrospectively investigated the clinical features of AHA with regards to the use of rFVIIa (presence or absence of use and total amount) in 7 AHA patients encountered in our department for 7 years between January 2008 and December 2014. Ages were 63–89 years old (median: 79 years old), and there were 5 male and 2 female patients. The coexistence of cardiovascular risk factors and arteriosclerotic diseases, such as hypertension, diabetes mellitus, and cerebral infarction were present in 6 patients. Anemia progressed to less than 7 g/dL of hemoglobin and required red blood cell transfusion in 5 patients, showing “severe” hemorrhage. Factor VIII inhibitors were removed by immunological treatments in 6 patients. As a hemostatic therapy, rFVIIa was used in 4 patients. rFVIIa was not administered or was administered at a very low dose (20 mg) to 3 and 1 patient, respectively, and bleeding stopped as inhibitor titers decreased and disappeared in these patients. Inhibitors did not disappear in 1 patient and the control of hemostasis became poor and was accompanied by intestinal hemorrhage. Although a large amount of rFVIIa (265 mg in total) was administered, the patient bled to death. Therefore, bleeding may be stopped without the administration of rFVIIa in some AHA cases, while the dose of rFVIIa is not necessarily related to hemostatic effects in other cases. Since the main aim of AHA treatments is the removal of inhibitors, caution is needed to ensure that more than the necessary amount of rFVIIa is not administered.

Pharmacological concentrations of recombinant factor VIIa restore hemostasis independent of tissue factor in antibody‐induced hemophilia mice

ESSENTIALS: The role of tissue factor (TF) in recombinant factor VIIa (rFVIIa) therapy in hemophilia is unclear. An acquired mouse hemophilia model with very low or normal levels of human TF was used in the study. rFVIIa is equally effective in correcting the bleeding in mice expressing low or normal levels of TF. Pharmacological doses of rFVIIa restore hemostasis in hemophilia independent of TF. Recombinant factor VIIa (rFVIIa) has been used widely for treating hemophilia patients with inhibitory autoantibodies against factor VIII or IX. Its mechanism of action is not entirely known. A majority of in vitro studies suggested that pharmacological concentrations of rFVIIa restore hemostasis in hemophilia in a phospholipid-dependent manner, independent of tissue factor (TF). However, a few studies suggested that a TF-dependent mechanism has a primary role in correction of bleeding by rFVIIa in hemophilia patients. Here, we investigated the potential contribution of TF in rFVIIa-induced hemostasis in hemophilia employing a model system of FVIII antibody-induced hemophilia in TF transgenic mice. Mice expressing low levels of human TF (LTF mice), mice expressing relatively high levels of human TF (HTF mice) and wild-type mice (WT mice) had neutralizing anti-FVIII antibodies administered in order to induce hemophilia in these mice. The mice were then treated with varying concentrations of rFVIIa. rFVIIa-induced hemostasis was evaluated with the saphenous vein bleeding model. Administration of FVIII inhibitory antibodies induced the hemophilic bleeding phenotype in all three genotypes. rFVIIa administration rescued the bleeding phenotype in all three genotypes. No significant differences were observed in rFVIIa-induced correction of bleeding between LTF and HTF mice that had FVIII antibodies administered. Our results provide strong evidence supporting the suggestion that the hemostatic effect of pharmacological doses of rFVIIa stems from a TF-independent mechanism.

Analysis of Outcomes Using Low-Dose and Early Administration of Recombinant Activated Factor VII in Cardiac Surgery

Although not currently approved for postoperative cardiac surgical bleeding, recombinant activated factor VII (rFVIIa) has been used for this purpose. This study sought to analyze outcomes in patients who had cardiac surgical bleeding and received low-dose and early administration of rFVIIa versus outcomes in patients who had cardiac surgical bleeding and did not receive rFVIIa. Fifty-one patients receiving rFVIIa were matched, using The Society of Thoracic Surgeons morbidity and mortality scores, with 51 patients who underwent cardiac surgical procedures and met criteria for surgical bleeding. Primary outcomes were ventilator hours and intensive care unit length of stay. Secondary outcomes included 30-day mortality, acute kidney injury, postoperative hospital length of stay, thromboembolic events, postoperative pneumonia, and sternal wound infections. Reoperations for bleeding were analyzed for each group to assess for achievement of hemostasis. The median total dose of rFVIIa was 12 mcg/kg. rFVIIa was given as the first and only treatment for bleeding in 7 of 51 (13%) patients, whereas 13 of 51 patients receiving rFVIIa (25%) also received up to 1 unit of anyblood product. Patients who received rFVIIa had increased duration of mechanical ventilation (p= 0.002) and increased length of stay in the intensive care unit (p=0.02). There were no differences in hospital length ofstay, 30-day mortality, acute kidney injury, postoperative pneumonia, sternal wound infections, postoperative thromboembolic events, or rate of reoperations for bleeding. Low-dose and early administration of rFVIIa (median total dose 12 mcg/kg) for cardiac surgical bleeding shows potential in achieving hemostasis without increased risk of thromboembolism or acute kidney injury.

The Comparison of Hemostatic Effects of Recombinant Activated Factor VII (rFVIIa) in Thrombocytopenic Patients (pts) and Hemophilia Pts with Inhibitors

Background: Administration of rFVIIa is used as a method of choice in the treatment of hemophilia pts with inhibitors. Besides, rFVIIa may be useful in thrombocytopenic pts with inefficiency or impossibility of platelet transfusions due to alloimmunization or religious beliefs.Aim: The aim of the present study was to compare the effects of rFVIIa on hemostasis in thrombocytopenic pts and hemophilia pts with inhibitors.Patients and Methods: rFVIIa was used in 20 pts with thrombocytopenia (I group) and in 20 hemophilia pts with inhibitors (II group). Indications for use of rFVIIa in thrombocytopenic pts were: gastrointestinal and intra-abdominal bleeding, intracranial hemorrhage, insertion of the central venous catheter, lumbar puncture, bleeding from the femoral artery puncture site, epistaxix and pulmonary hemorrhage. In thrombocytopenic pts blood platelet count varied from 1*109/l to 72*109/l (median 15 *109/l). The media dose of rFVIIa in thrombocytopenic pts was 79 μg/kg (ranges from 50 to 144 μg/kg). All hemophilia pts received a single dose of rFVIIa (90 μg/kg). All pts received rFVIIa (Generium, Russia). APTT, Quick prothrombin test (QPT), FVII:C level, endogen thrombin potential (ETP) and Thromboelastography (TEG) parameters (R, MA) were evaluated before and after rFVIIa administration.The median and interquartile range (IQR) were calculated as descriptive statistics. Mann-Whitney U test and Mood's median test were used to evaluate group differences. Statistical analyses were performed with SAS 9.1 (using the Npar1way procedure).Results: rFVIIa was effective in all hemophilia pts. Administration of rFVIIa in 15 min shortened but did not correct APTT, increased QPT and ETP, FVII:C (Table 1). Prior to treatment the hemophilia pts have no clotting determined by TEG, but after rFVIIa administration TEG demonstrated close to normal pattern. In thrombocytopenic pts after rFVIIa administration bleeding stopped in 51% pts, decreased in 44% and did not change in 4% pts. In thrombocytopenic pts maximal hemostatic effect was achieved within 1 hour after rFVIIa administration (Table 1). 1 case of ischemic stroke was obtained. The maximum effect of rFVIIa in thrombocytopenic pts coincided with decrease of plasma activity of FVII perhaps due to its consumption.Conclusion: In the most hemophilia pts with inhibitors the response was achieved within 15 min of administration of rFVIIa. In thrombocytopenic pts haemostatic effect of rFVIIa was delayed and reached within 1 hr, good response was achieved in 51% pts. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pharmacological Concentrations of Recombinant Factor VIIa Restores Hemostasis in Acquired Hemophilia Primarily Independent of Tissue Factor

High doses of recombinant FVIIa (rFVIIa) are used successfully to treat hemophilia patients with inhibitory antibodies against FVIII and FIX. Despite its widespread and successful use of treating bleeding disorders for many years, the understanding of the mechanism of rFVIIa action in hemophilia therapy is incomplete. A majority of the studies, mostly in vitro studies, suggested that activation of FX by rFVIIa bound to phospholipids exposed on the activated platelets is responsible for the hemostatic effect of rFVIIa in hemophilia patients. However, other in vitro studies and mathematical modeling indicated that the action of rFVIIa at therapeutic doses is dominated by the TF-dependent pathway, partly because of the need to overcome the inhibitory effect of zymogen FVII, with a minor contribution from phospholipid-dependent mechanism. In the present study, we investigated whether TF plays a role in rFVIIa-mediated hemostasis in hemophilia by employing transgenic mice expressing low levels of human TF (Low TF mice) or normal levels of human TF (HTF mice; breeding pairs for these mice were provided by Nigel Mackman). Mice were administered with FVIII mAb to induce acquired hemophilia. The saphenous vein incision bleeding model was used to evaluate the hemostasis. In this model, saphenous vein was exposed and bleeding was induced by a sharp incision of the vein with a fine scissors. The bleeding from the cut was monitored for 30 min while blood was collected onto a filter paper by capillary action. After each hemostasis incident, the clot was disrupted gently to reinitiate a new bleeding episode, and average time to achieve hemostasis (ATH) was calculated.First, we investigated the role of TF in hemostasis by comparing the bleeding episodes in low TF and HTF mice following the saphenous vein incision. In the saphenous vein bleeding model, control wild-type mice had a median ATH of 60 sec (n=6) and hemophilia A mice failed to achieve hemostasis within 30 min experimental time frame (n=6). HTF mice had essentially very similar ATH compared to that of the wild-type mice, i.e., 64 sec (n=5). In contrast, low TF mice had a substantially longer median ATH, 90 sec (n=6), which is statistically significantly longer than that of ATH of wild-type or HTF mice. Administration of TF antibodies (1 mg/kg) to neutralize remaining traces of TF in Low TF mice further prolonged the bleeding time to a median ATH of 309 sec (n=6). These data clearly illustrates the role of TF in hemostasis.Next, we created acquired hemophilic condition in low TF and HTF mice by injecting FVIII mAb (1 mg/kg). Low TF mice also received TF antibodies. Administration of FVIII mAb markedly prolonged the bleeding time in both groups of mice (between 300 to 1800 sec), with a median ATH of 900 sec. Administration of rFVIIa (4 mg/kg) to HTF hemophilic mice reduced the ATH to a median of 51 sec (mean ± SD, 50 ± 5 sec, n=6). The same concentration of rFVIIa also restored hemostasis in hemophilic low TF mice with a median ATH of 66 sec (mean ±SD, 70 ± 18 sec, n=6). This value is not statistically significantly different from that of ATH of wild-type mice. Although rFVIIa restored the hemostasis in both HTF and low TF mice, it appears that rFVIIa is slightly, but statistically significantly, more effective in HTF mice compared to low TF mice in restoring the hemostasis (p = 0.025). However, we did not observe any significant differences between these two groups in the volume of blood loss following rFVIIa administration. In summary, our data strongly support the hypothesis that high concentrations of rFVIIa restore hemostasis in hemophilia primarily in TF-independent manner. More detailed studies are needed to completely eliminate the role of TF in rFVIIa mediated hemostasis. DisclosuresNo relevant conflicts of interest to declare.

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

▪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. DisclosuresNo relevant conflicts of interest to declare.

ACE910 Facilitates Its Hemostatic Effect with the Lower Concentration of Factor X Than That Required for Factor VIIa-Driven Coagulation

The hemostatic effect of bypassing agents such as recombinant (r) factor (F)VIIa and activated prothrombin complex concentrates (aPCC) for hemophilia A with inhibitors (HA-inh) is not always stable (Berntope, Haemophilia 2009). The mechanism(s) of its instability remain unclear, however. We have recently reported the HA-inh case showing the attenuated responsiveness to aPCC (Ogiwara, Int J Hematol. 2014). Some groups reported the hemostatic effects of the complex concentrates of FVIIa and FX (Shirahata, Haemophilia 2012) in HA-inh, suggesting that FX would play the key role in the hemostatic effect by FVIIa. ACE910, a humanized bispecific antibody to FIXa and FX mimicking the functions of FVIIIa, exerting FXase activities without FVIII(a) (Kitazawa, Nature Medicine 2012). In this study, we attempted to elucidate the dependency on FX of the FVIIa- and/or ACE910-driven coagulation. Firstly, the global hemostatic potentials in the whole blood samples obtained from the four HA-inh cases (Case 1, 2, 3 and 4) under perioperative hemostatic treatment with the intermittent administration of rFVIIa every 2-3hr were evaluated by Ca2+-triggered viscoelastometric assay with ROTEM. The first infusion of rFVIIa shortened CT (from 5,087 ± 1,261 to 1,157 ± 208 sec) and increased MCF (from 17 ± 8.7 to 58.8 ± 1.3 mm) in each case. Additional rFVIIa after the 7th administration in Case 1, the 13th in Case 2 and the 12th in Case 3 little affected CT and MCF as well as clinical symptom, indicative of poor responsiveness, while Case 4 showed the improvement of the parameters even after the frequent infusion of rFVIIa, identified as a responsive case. Thrombin generation (TG) triggered by TF (1pM) or TF (1pM) together with ellagic acid (0.3μM) was evaluated in the plasma from the cases with poor response. Peak thrombin (PeakTh) was little changed between pre- and post-additional infusion of rFVIIa in the cases with poor response, similar to the pattern of ROTEM. The level of FX antigen measured by an ELISA in the plasma was 90.5 ± 9.6 nM, showing 67% of normal control (~140 nM), of little difference among the four cases at the first administration of rFVIIa, while that in Case 1, 2 or 3 at the 7th, 13th or 12th administration, respectively, decreased to 39.1 ± 7.0 nM, equivalent to ~45% of that (86.8 ± 12.9 nM) kept in the responsive Case 4. Addition of FX (300nM) in the plasma of poor response to rFVIIa ex vivo increased PeakTh to ~80% of normal control, suggesting that FVIIa-driven hemostatic effect would be dependent upon FX. Furthermore, to investigate the FX-dependency of FVIIa- and ACE910-driven coagulation, TG in the reconstituted HA-inh model plasmas consisting of FX-deficient plasma in which FVIII was inactivated by an anti-FVIII polyclonal antibody (10BU/ml) with/without rFVIIa (50 and 150 nM) or ACE910 (10, 30 and 60 μg/ml) was evaluated in the presence of various concentrations of FX (f.c. 0 - 300 nM). The control experiment without rFVIIa or ACE910 showed the FX dose-dependent increase of PeakTh. In the plasmas with FX ranged from 50 to 300nM, PeakTh improved to almost normal level by rFVIIa as well as ACE910. Of note, with the lower concentration of FX (10-20 nM), PeakTh improved to almost normal level in the presence of ACE910, increased by 38 ± 2.4%, 45 ± 1.7% and 48 ± 0.8% compared to those in its absence, respectively, in an ACE910 dose-dependent manner, whilst the presence of rFVIIa little affected TG compared to those in its absence. Taken together, ACE910 could exert its hemostatic effect with the lower amount of FX than that required for the rFVIIa-driven coagulation. DisclosuresYada:Chugai Pharmaceutical Co., ltd: Research Funding. Nogami:Bayer, NovoNordisk, Baxalta, Chugai, Kaketsuken, Pfizer, Biogen: Honoraria; Bayer, Novo Nordisk, Baxalta. Biogen: Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees. Kitazawa:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership, Patents & Royalties. Hattori:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership, Patents & Royalties. Shima:Biogen: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Kaketsuken: Honoraria.

Successful use of recombinant activated factor VII (eptacog alfa, Novoseven®) in a refractory bleeding during pediatric cardiac surgery: a case report.

A 2-year-and-7-month-old boy underwent an emergent reconstruction surgery of the right ventricle-pulmonary artery (RV-PA) conduit. Although he was successfully weaned from cardiopulmonary bypass (CPB) after reconstruction of the RV-PA conduit, the bleeding continued despite the massive transfusion of red blood cell (RBC), fresh frozen plasma (FFP), and platelets. Because of persistent bleeding and abnormal coagulation laboratory results, we administered the recombinant activated factor VII (rFVIIa), which was not approved for use in the treatment of post-CPB coagulopathy. After administration of rFVIIa, his coagulation data dramatically improved, the bleeding decreased, and the operation was able to be finished.