Safety and Efficacy of Recombinant Factor VIIa (NovoSeven) Use during ECMO Support in Patients after Cardiac Surgery

Background: Acute postoperative bleeding in cardiac surgical patients is a major cause of morbidity and mortality. Substitution of coagulatory factors may not always provide optimal hemostasis and off label, use of recombinant FVIIa has been proposed. When on ECMO, extra care must be taken during coagulatory substitution as clotting of the system may cause cardiovascular complications and possible ECMO failure, leading to death. In this paper, we examined the safety and efficacy of rFVIIa during ECMO support in postoperative cardio-surgical patients. Methods: We retrospectively examined all patients receiving rFVIIa postoperatively from December 2005 and January 2020. Clinical characteristics, demographics, bleeding, thrombotic complications, mortality, and rFVIIa administration were analyzed. Results: A total of 74 patients received rFVIIa postoperatively due to uncontrollable bleeding after cardiac surgery on our ICU. Of these patients, 23 patients were on ECMO treatment. Twelve patients received rFVIIa during, but not prior to the initiation of ECMO therapy. Six patients (50%) were male; mean age was 46 years (30-72 years). Eleven patients (91.7%) were on venoarterial ECMO, one patient was on central ECMO (8.3%). Dose of administered rFVIIa was corrected for body weight; mean dosage was 82μg/kg. We saw a significant reduction in need for red packed cells, fresh frozen plasma and thrombocyte transfusion after rFVIIa administration. There was no impact on the functionality of the ECMO system, especially regarding the oxygenator after rFVIIa administration. One patient suffered a stroke due thromboembolism (8.3%). One patient developed late thromboembolism in the leg (8.3%), and two cases of pulmonary embolism (16.7%) were recorded. Overall survival was 25% and there was no significant difference in survival between ECMO and non-ECMO patients. Weaning from ECMO could be achieved successfully in 41.7% of our patients. Conclusion: Recombinant Factor VIIa is an effective agent in reducing blood loss during ongoing ECMO therapy in patients with refractory bleeding. Although no direct relation between rFVIIa application and thromboembolic events could be established, its use should be done with the utmost care and in selected patients. However, rFVIIa therapy did not impact ECMO function in our cohort.

Monitoring of Recombinant Activated Coagulation Factor VII (rFVIIa) Therapy in Patients (pts) with Inherited Factor VII (FVII) Deficiency

Introduction and Objectives: Inherited FVII deficiency is a rare hemorrhagic disorder.Clinical bleeding does not correlate with the level of FVII plasma activity. FVII involves in the extrinsic coagulation pathway. ROTEM is point of care method. EXTEM is one of ROTEM screening tests. EXTEM analyses the extrinsic pathway of coagulation. Aim of the study was to evaluate hemostatic effect and safety of rFVIIa treatment in pts with inherited FVII deficiency. Materials and Methods: The results of rFVIIa treatment were investigated in 4 pts (1 male, 3 females) with inherited FVII deficiency. Pts were treated with rFVIIa before gynecological (2), abdominal (1) and orthopedic surgery (1). Pts received 30 mcg/kg of rFVIIa (Koagil VII, Generium, Russia) before surgery. Plasma FVII activity, fibrinogen, INR, APTT, ROTEM and thromboelastography (TEG) parameters were investigated before rFVIIa administration, then in 15 minutes, in 2 hours, in 6 hours and in 12 hours. Results: Before rFVIIa administration median plasma FVII activity was low, CT EXTEM was long and INR was greater than 3. TEG, APTT and fibrinogen were in normal ranges (table 1, fig. 1). Fifteen minutes after rFVIIa administration FVII:C activity increased, INR and CT EXTEM decreased. Hemostatic effect of rFVIIa remained during 12 hours. During this period CT EXTEM correlated with INR (r = 0.97, p<0.001). Other parameters did not change significantly. None patients had hemorrhagic complications. Conclusion: CT EXTEM allowed to evaluate hemostatic effect of rFVIIa in operating room and good correlated with INR in pts with inherited FVII deficiency. Disclosures No relevant conflicts of interest to declare.

Single Low Dose of rFVIIa Combined with Antifibrinolytic Agent is a Simple and Safe Treatment for Factor XI-Deficient Patients undergoing Surgery

Background Factor XI (FXI) deficiency is a rare autosomal bleeding disorder. The rarity of spontaneous bleeding and absence of optimal tools to predict the bleeding risk in FXI-deficient patients hamper the standardization of prophylactic treatment enabling them to undergo major surgeries without blood products. Objectives We explored the effectiveness of a single and very low dose of recombinant factor VIIa (rFVIIa) along with tranexamic acid (TXA) as prophylactic treatment for FXI-deficient patients undergoing various types of surgery at various sites of injury. We studied the potential use of thrombin generation (TG) as a surrogate tool for predicting thrombogenicity. Patients and Methods Our cohort consisted of 10 patients with severe FXI deficiency undergoing 12 interventions. Patients received a single dose of 10 to 15 μg/kg rFVIIa at the end of surgery in addition to TXA initiated 2 hours before surgery at the dose of 4 g/day for 3 to 5 days. TG was tested before and 30 minutes after rFVIIa administration. Results All operations were uneventful and none of the patients bled excessively or required blood products. No thrombotic event was reported, and the postoperative hospitalization duration was comparable to that of patients without bleeding disorders. TG performed at the peak of rFVIIa was below the curve of healthy controls, thus confirming that the administered dose was not thrombogenic. Conclusion A single very low dose of rFVIIa along with TXA is a simple and safe treatment to control hemostasis in severe FXI-deficient patients undergoing diverse type of surgical procedure at various sites.

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

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 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. Figure 1. Parameters of hemostasis before and after rFVIIa administration expressed as a median (IQR) Figure 1. Parameters of hemostasis before and after rFVIIa administration expressed as a median (IQR) Disclosures No relevant conflicts of interest to declare.

Pharmacokinetics of Multiple Doses of rFVIIa in Patients with Hemophilia With and Without Inhibitors

Introduction: Recombinant activated coagulation factor VII (rFVIIa, NovoSeven®) has a well-established efficacy and safety profile, and is currently the only recombinant by-passing agent globally available for the treatment of bleeding episodes in patients with hemophilia and inhibitors. In clinical trials with on-demand treatment of mild and moderate bleeding episodes, both the 3×90 µg/kg repeat dose and the 270 µg/kg single dose dosing regimens have proven to be efficacious with success rates around 90%. This clinical trial is the first direct comparison of the PK of 3x90 µg/kg and 270 µg/kg in patients with hemophilia using two PK assays, and the trial also includes an evaluation of other coagulation parameters, to allow for a comparison of the two regimens from a PK perspective. Aim: To evaluate and compare the pharmacokinetics of rFVIIa administered intravenously after a single 270 µg/kg dose and three 90 µg/kg doses given at three hour intervals to hemophilia patients, using two PK assays (FVIIa activity assay and FVII antigen). In addition, a series of plasma coagulation tests (PT, aPTT, F1+F2, and D-dimer) was performed and correlated to the exposure of rFVIIa. Methods: Six patients with severe hemophilia A and B, with and without inhibitors, were included in a single center randomized cross-over clinical trial. Each patient was randomized to receive both a single injection of 270 µg/kg rFVIIa and 3x90 µg/kg rFVIIa (one administration every three hours; the maximum interval for the treatment of a bleed according to the EU label) in a non-bleeding state. Blood samples were collected pre-dose and 10 min, 1, 3, 6, 9, 12, and 24 hours post-dose. For the multiple-dose regimen, the same post-dose samples were collected after the first 90 µg/kg dose and in addition, 10 min after the 2nd dose, and 10 min and 1 hour after the 3rd dose. The trial was conducted according to ICH GCP and the declaration of Helsinki. Results: The PK based on FVIIa activity was comparable for the two dosing regimens, with AUC of 429.5 and 455.4 IUxh/mL and a half-life of 2.6 and 2.8 hours for the 3x90 and 270 µg/kg dosing regimens, respectively, results which are comparable to previously reported studies (Tiede et al. 2011, Morfini et al. 2012). For the 90 µg/kg dose administered every 3 hours, an accumulation ratio of 1.8 was observed, which resulted in a higher peak activity following the last dose (Figure 1). For rFVIIa PK based on FVII antigen, the results were somewhat different compared to the FVIIa activity results, with a reduced clearance. Previous data (Agersø et al. 2011) have shown that this discrepancy is due to the formation of FVIIa-AT complexes as part of the FVIIa clearance pathway. For PT, aPTT, and D-Dimer, no apparent differences between the two treatment regimens were observed. For both regimens, a rapid reduction of PT followed the first administration of rFVIIa. The PT remained reduced for the duration of sampling, with a slow return towards baseline beginning 9 hours after administration. F1+2 showed a transient increase following rFVIIa administration. The increase was most pronounced after the 270 µg/kg dose, with the peak 1 hour after the injection. In the 3x90 µg/kg dose regime, the F1+2 response was lower, and the most pronounced response was seen 1 hour following the last of the 3 doses of 90 µg/kg (Figure 2.) Figure 1. Mean FVIIa activity over time following rFVIIa administration Figure 1. Mean FVIIa activity over time following rFVIIa administration Figure 2. Prothrombin fragments 1 and 2 over time following rFVIIa i.v. administration Figure 2. Prothrombin fragments 1 and 2 over time following rFVIIa i.v. administration Conclusions: The PK parameters of rFVIIa are consistent and comparable between the two dosing regimens, with low inter-subject variation. The accumulation ratio following 3 doses of 90 µg/kg rFVIIa of 1.8 resulted in a 50% increase in peak activity following the last dose. PK results using the FVII antigen assay showed reduced clearance compared to FVIIa activity, confirming the involvement of AT complexes in rFVIIa clearance. F1+2 followed the FVIIa activity, with the highest peak following administration of 270 µg/kg, and an increase in F1+2 concentration with multiple doses of rFVIIa, but with a delayed response. Disclosures Stenmo: Novo Nordisk: Employment. Fernandez-Bello:Novo Nordisk: Research Funding. Ezban:Novo Nordisk: Employment. Butta:Novo Nordisk: Research Funding. Jiménez-Yuste:novo Nordisk: Consultancy.

Sustained pro-haemostatic activity of rFVIIa in plasma and platelets in non-bleeding pigs may explain the efficacy of a once-daily prophylaxis in humans

SummaryRecombinant factor VIIa (rFVIIa) is registered for treatment of inhibitor-complicated haemophilia, and a once-daily prophylactic administration of rFVIIa is successful in reducing the number of bleeding events. This suggests that a single rFVIIa dose has a pro-haemostatic effect up to 24 hours (h), which is difficult to explain given its half-life of 2 h. In this study, six pigs received a 90 µg/kg rFVIIa bolus. Plasma was collected and platelets were isolated at various time points up to 48 h, and analysed for FVIIa levels and associated haemostatic activity. Elevated plasma FVIIa levels were detected up to 24 h post-administration (36 (32–56) mU/ml [median (interquartile range [IQR]), 24 h] vs 2 (2–14) mU/ml [baseline]). Corresponding prothrombin time (PT) values remained shortened compared to baseline until 24 h post-administration (9.4 (9.3–9.9) seconds (s) [24 h] vs 10.5 (10.2–11.0) s [baseline], p ≤0.01). The lag time in thrombin generation testing as well as clotting times in plasma-based assays were shortened up to 12 or 24 h post-administration, respectively (lag times 1.8 (1.7–2.1) minutes (min) [12 h] vs 2.3 (2.3–2.6) min [baseline], p ≤0.01 and clotting times 3.8 (3.2–3.9) min [24 h] vs 5.2 (4.6–5.5) min [baseline], p ≤0.001). Platelet FVIIa levels were elevated up to 48 h (7.7 (3.4–9.0) ng VIIa/mg actin [48 h] vs 2.5 (0.7–4.8) ng VIIa/mg actin [baseline]). In conclusion, elevated and haemostatically active plasma and platelet FVIIa levels are detectable up to 24–48 h following rFVIIa administration in pigs. This prolonged pro-haemostatic effect of FVIIa may explain the prophylactic efficacy of a once-daily rFVIIa treatment.

Clinical Significance of Coagulation Studies in Predicting Response to Recombinant Factor VIIa in Cardiac Surgery Patients

Abstract 4351 INTRODUCTION: While recombinant activated Factor VII (rFVIIa) is increasingly used for management of uncontrolled hemorrhage in a variety of clinical settings, its efficacy appears mixed. Few studies have examined the association between coagulation studies and rFVIIa efficacy in cardiac surgery. DESIGN/METHODS: We performed a retrospective study of all patients at Brigham and Women’s Hospital (BWH) from February 2005 through March 2011 who received rFVIIa for uncontrolled hemorrhage during or after cardiac surgery. rFVIIa-mediated hemostasis was determined based on clinical descriptions in the medical record. Laboratory studies, clinical parameters, blood product transfusions, and chest tube output were compiled from the medical record. RESULTS AND DISCUSSION: Forty-seven patients were identified for this study. The median age was 65 years (range, 16–85). Thirty-one patients were male. Eleven had a perioperative left ventricular ejection fraction < 35%. Of 47 surgeries performed, 30 were emergent or urgent and 16 elective (data was missing in 1 case). Twelve required an intraaortic balloon pump, and 12 placement or removal of a ventricular assist device. Median cardiopulmonary bypass (CPB) time was 281.5 min (range, 104–744; n = 45). Over a median follow-up period of 52 days (range, 0–1673), 22 patients (46.8%) died, 10 within one day of receiving rFVIIa. Median survival was 443 days (90% confidence interval (CI) [30, not-yet-reached]). The median dose of rFVIIa was 40.2 mcg/Kg. rFVIIa-mediated hemostasis was achieved in 23 patients (48.9%), while continued bleeding was observed in 24 (51.1%). Thromboembolic complications attributed to rFVIIa developed in 9 patients (arterial, 5; venous, 4). Median transfusion requirements decreased after rFVIIa administration for the entire population, although the differences were not statistically significant. Survival status could not be reliably incorporated into models of transfusion requirements in this retrospective study, prohibiting further analysis. Mean coagulation studies before vs after rFVIIa were: PT, 24.9 sec +/− 18.3 (n = 44) vs 15.4 sec +/− 4.9 (n = 47); INR, 2.3 +/− 2.5 (n = 44) vs 1.2 +/− 0.5 (n = 47); and PTT, 57.3 sec +/− 27.2 (n = 40) vs 48.4 sec +/− 17.8 (n = 44), respectively. Plasma fibrinogen was excluded from the analysis, as levels were not measured in over one-third of cases. Univariate analyses identified several clinical or laboratory variables associated with rFVIIa-mediated hemostasis: PT after rFVIIa administration (p = 0.02 by Fisher’s exact test), INR before rFVIIa (p = 0.05), INR after rFVIIa (p = 0.05), PTT after rFVIIa (p = 0.008), pH after rFVIIa (p = 0.04), and survival status (p = 0.008). In stepwise multivariable logistic regression analyses, only normalization of PTT after rFVIIa was significantly associated with rFVIIa-mediated hemostasis (odds ratio (OR) = 0.169, 95% CI [0.041,0.694], p = 0.01). Stepwise multivariable regression models of PT, INR, and PTT after rFVIIa showed a strong association of PTT and only a marginal association of PT with rFVIIa-mediated hemostasis (PTT: OR = 0.181, 95% CI [0.047,0.722], p = 0.02; PT: OR = 0.10, 95% CI [0.01,0.98], p = 0.05). Chest tube output was recorded for 14 patients who received rFVIIa in the CSICU rather than in an operating room. Of these, 8 (57.1%) had a reduction in chest tube output of ≥ 25% and 5 (21.4%) a reduction of ≥ 50%. While none of the variables examined showed a significant association with reduced chest tube output, concordance with rFVIIa-mediated hemostasis among this small subset of patients was poor (for ≥ 25% reduction: concordance 64.3%, 90% CI [39,84.7], p = 1.0 by McNemar’s test; for ≥ 50% reduction: concordance 57.1%, 90% CI [32.5,79.4]), p = 0.2). CONCLUSION: In cardiac surgery patients who receive rFVIIa for uncontrolled hemorrhage, normalization of PTT after rFVIIa appears to be strongly correlated with rFVIIa-mediated hemostasis. This suggests that optimal hemostasis with rFVIIa occurs following concomitant repletion of other coagulation factors in both extrinsic and intrinsic pathways, although the possibility that normalization of coagulation studies in both pathways is a marker of rFVIIa-mediated hemostasis has not been ruled out. Prospective trials may help to determine whether correction of PTT and other coagulation parameters can improve rFVIIa efficacy in cardiac surgery. Disclosures: No relevant conflicts of interest to declare.

Six Year, Single Institution, off-Label Use of Recombinant Factor VIIa

Abstract 1402 Objective: Recombinant factor VIIa (rFVIIa) is used for hemophiliac patients with inhibitors against coagulation factor VIII or IX, but there is varied off-label use of rFVIIa for other patients. The aim of the present study was to examine our institution's off-label use of rFVIIa in an adult population. Methods: We performed an IRB-approved retrospective review of rFVIIa administrations since its first use in January 2003 through December 2008. Patients were identified using an inpatient pharmacy database capturing all rFVIIa administrations. Blood product transfusion (packed red blood cells, pRBCs; fresh frozen plasma, FFP; platelets; cryoprecipitate), adjunctive hemostatic agent use (epsilon aminocaproic acid, protamine, desmopressin, estrogen, or vitamin K), and operative or vascular interventional procedures were examined before and after administration. Laboratory data including pH, temperature, prothrombin time (PT/INR), partial thromboplastin time (PTT), and fibrinogen were also collected by chart review. Outcome measures included mortality at 24h, 48h, and 30d, as well as thrombotic complications. Two-tailed paired T-tests were used for statistical comparisons. Results: A total of 256 consecutive adult patients received rFVIIa. Of these, 20 (8%) received rFVIIa for FDA-approved on-label use. Thus, 236 off-label rFVIIa administrations were confirmed, with an average patient age of 58± 19y. The annual number of doses administered increased from 2003 to 2005, after which rFVIIa utilization remained constant (52 ± 5 patients/year from 2005–2008). rFVIIa was administered for head injury or hemorrhagic stroke (41%), cardiothoracic surgery (23%), gastrointestinal bleeding (14%), trauma (10%), off-label hematologic disorders (4%), vascular surgery (4%), transplantation (2%), orthopedics (2%), and obstetrics (2%). Administration locations consisted of the intensive care unit (70%), operating room (20%), emergency room (6%), and ward (2%). Single doses (79 ± 28 mcg/kg) comprised 79% of administrations. Extremely high and low single dose regimens (> ±1 standard deviation) were used in neurologic and cardiothoracic surgical populations. Immediately before rFVIIa administration, temperature was 36.9 ± 1.0 °C, pH 7.38 ± 0.10, platelets 141 ± 101 × 109/L, PT/PTT 2.7/44 s, and fibrinogen 243 ± 131 mg/dL. These parameters did not clinically change at 24h or 48h after rFVIIa administration, though PT/INR stabilized at 1.28 ± 0.80 and 1.32 ± 0.41, respectively. Mortality rates were 13%, 17%, and 38% at 24h, 48h, and 30d respectively. 80% of deaths at 24h were related to either uncontrolled or intracranial hemorrhage. 2 deaths >48h after administration were stroke related in a post-cardiopulmonary bypass setting. 25 thromboembolic complications occurred at any point following administration and through hospital discharge. Greater than 75% of the complications were deep vein thromboses, none resulting in death. Of the 60 patients requiring massive transfusion (>10 pRBCs) in the 24h prior to rFVIIa administration, the pRBC, FFP and platelet usage significantly decreased within 24h (pRBC: 20.6 ± 9.9 to 8.4 ± 8.6; FFP: 12.0 ± 7.3 to 6.9 ± 8.1; platelets: 3.5 ± 2.8 to 2.1 ±2.0, all p<0.0001). 24h after rFVIIa in massively transfused patients, the number of patients requiring operation or vascular intervention procedures decreased from 27 to 14. This was also associated with a 38% decrease for the need of adjunctive hemostatic agents. There were no meaningful changes in laboratory coagulation parameters. Conclusion: Analysis of this large retrospective cohort of single institution rFVIIa administration reveals 92% off-label use. The majority (64%) of indications are for cardiothoracic surgery and intracranial hemorrhage. Although thromboembolism rates are 10%, mortality at 24h does not seem to be associated with thromboembolism. In those requiring a massive transfusion, rFVIIa use may decrease transfusion requirements, need for operative or vascular intervention, and the need for hemostatic adjunct use. Disclosures: Off Label Use: Recombinant factor VIIa and its off-label use in hemostasis. Lawson:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees.

SeveN BleeP Registry – 5 Years Later: An Update.

Abstract 3651 Introduction: SeveN Bleep (Seven A in Nonhemophilia Bleeding in Pediatrics) is a web-based registry for collecting data on the use of rFVIIa in the treatment of severe and/or life threatening bleeding in children without hemophilia. The registry was endorsed by the Paediatric/Perinatal SSC subcommittee of ISTH. Methods: The registry was established in 2005. During the five years of its existence, 191 cases were recorded, of which 164 (86%) records fulfilled the validation criteria and were eligible for further analyses. For the purpose of analysis, the patients were stratified into two groups: neonates and infants <1 year, and children >1 yr old. Statistical methods were used as appropriate. Results: Fifty nine (36%) valid records described the treatment with rFVIIa in neonates and infants, and 105 (64%) in older children. Of these, 27(16%) were for the prevention of severe bleeding. In the rest (84%) of cases, rFVIIa was used to treat severe bleeding. Those 137 cases (42 neonates+infants and 95 older children) were further analysed for the purpose of this report. The median weight in the <1 year old was 2.4 kg. The reasons for administration of rFVIIa included: bleeding during “non-trauma” surgery (17%), cardiac surgery (12%), trauma (12%) and intracranial haemorrhage (12%). Overall survival rate was 50%. Only one neonate experienced a thrombembolic event as a possible SAE from the treatment with rFVIIa. There were no deaths related to rFVIIa treatment. In those older than 1 year, the median age was 10 years and median weight 30 kg. The reasons for administration of rFVIIa included trauma (45%), “non-trauma” surgery (14%) and bleeding related to malignancy and/or its treatment (11%). Survival rate in this group was 72%. 17% of deaths were related to the underlying hemorrhage treated. There were no thrombotic event or death related to rFVIIa treatment recorded in this group. There was a trend towards using a higher total dose (median 160ug/kg) in patients that died compared to a lower dose (median 120 ug/kg) in those who survived (p=0.078). In addition, those who survived needed lesser number of doses as compared to the deceased patients (median number of doses 1 and 2, respectively; p=0.052). Use of rFVIIa led to a significant decrease in the consumption of blood products in the 24 hour period after rFVIIa administration compared to the 24 hours prior to the use of rFVIIa - packed red cells (280 ml vs. 560 ml; p=0.001), FFP (250 ml vs. 500 ml; p=0.003). There were also significant changes in certain laboratory parameters related to rFVIIa administration also. Estimated blood loss decreased from 30 ml/kg prior to rFVIIa administration to 3 ml/kg after the use of rFVIIa (p=0.002). Conclusion: SevNBleep registry has proven to be a useful international tool for collection of relevant clinical data on the use of rFVIIa. rFVIIa appears to be beneficial in the management of bleeding in the pediatric population. The prevalence of adverse events related to use of rFVIIa was very low, though not absent. To minimize the potential bias related to reporting of SAEs, all major contributing centers has been contacted for further information with regards to consecutive reporting of patients treated with rFVIIa. Disclosures: Off Label Use: rFVIIa use in life threatening bleeding in children.