Single Dose Of rFVIIa Research Articles

EPCR deficiency or function-blocking antibody protects against joint bleeding–induced pathology in hemophilia mice

AbstractWe recently showed that clotting factor VIIa (FVIIa) binding to endothelial cell protein C receptor (EPCR) induces anti-inflammatory signaling and protects vascular barrier integrity. Inflammation and vascular permeability are thought to be major contributors to the development of hemophilic arthropathy following hemarthrosis. The present study was designed to investigate the potential influence of FVIIa interaction with EPCR in the pathogenesis of hemophilic arthropathy and its treatment with recombinant FVIIa (rFVIIa). For this, we first generated hemophilia A (FVIII−/−) mice lacking EPCR (EPCR−/−FVIII−/−) or overexpressing EPCR (EPCR++ FVIII−/−). Joint bleeding was induced in FVIII−/−, EPCR−/−FVIII−/−, and EPCR++FVIII−/− mice by needle puncture injury. Hemophilic synovitis was evaluated by monitoring joint bleeding, change in joint diameter, and histopathological analysis of joint tissue sections. EPCR deficiency in FVIII−/− mice significantly reduced the severity of hemophilic synovitis. EPCR deficiency attenuated the elaboration of interleukin-6, infiltration of macrophages, and neoangiogenesis in the synovium following hemarthrosis. A single dose of rFVIIa was sufficient to fully prevent the development of milder hemophilic synovitis in EPCR−/−FVIII−/− mice. The development of hemophilic arthropathy in EPCR-overexpressing FVIII−/− mice did not significantly differ from that of FVIII−/− mice, and 3 doses of rFVIIa partly protected against hemophilic synovitis in these mice. Consistent with the data that EPCR deficiency protects against developing hemophilic arthropathy, administration of a single dose of EPCR-blocking monoclonal antibodies markedly reduced hemophilic synovitis in FVIII−/− mice subjected to joint bleeding. The present data indicate that EPCR could be an attractive new target to prevent joint damage in hemophilia patients.

EPCR Deficiency Prevents Development of Hemophilic Arthropathy

Recent studies from our laboratory showed that clotting factor VIIa (FVIIa), whose primary function is to initiate the coagulation cascade following its binding to procoagulant cofactor tissue factor (TF), also binds anticoagulant cofactor, endothelial cell protein C receptor (EPCR). EPCR plays a key role in the activated protein C (APC)-mediated anticoagulant pathway by promoting the activation of protein C bound to it. Pharmacological concentrations of rFVIIa could compete with protein C for the EPCR and downregulate APC generation by preventing protein C binding to the EPCR. Our recent studies showed that FVIIa binding to EPCR also induces barrier-protective and anti-inflammatory effects both in vitro and in vivo model systems. Bio-distribution of rFVIIa in mice revealed that a small fraction of rFVIIa administed to mice i.v. accumulates in knee joints and retained there for three to seven days. The present study was conducted to investigate the relevance of FVIIa binding to EPCR in pharmacological FVIIa treatment of joint disease in hemophilia. For this, we first generated hemophilia A mice lacking EPCR or overexpressing EPCR. To generate EPCR deficient FVIII-/- mice, Procrflox/flox and Procr+/floxMeox2+/cre mice were first backcrossed with FVIII-/- mice to generate Procrflox/flox/FVIII-/- and Meox2+/cre/FVIII-/- mice. EPCR deficient FVIII-/- mice (Procr-/-/FVIII-/-) were generated by breeding female Procrflox/flox/FVIII-/- with male Procr+/floxMeox2+/cre /FVIII-/- mice. EPCR- overexpressing FVIII-/- were generated by crossing Tie2-EPCR mice with FVIII-/- mice. We induced joint bleeding in FVIII-/-, EPCR deficient FVIII-/-, and EPCR-overexpressing FVIII-/- mice by needle puncture injury. Right knee joint intra articular space was pierced with 30G needle to induce joint bleeding; left knee joint served as an uninjured control. Injured mice were treated with a single dose of rFVIIa (1 mg/kg) at 20 min following the injury or three doses of rFVIIa (1 mg/Kg) at 20 min, 24 h and 72 h following the injury. In controls, saline was administered in place of rFVIIa. The knee injury was evaluated by measuring knee joint diameter and visual bleeding score. At the end of 14 days post injury, mice were euthanized, and the knee joints were excised and fixed for immunohistochemical analysis. Hemophilic arthropathy was evaluated by scoring a set of pathological parameters (e.g., synovial hyperplasia, neoangiogenesis, presence of blood, iron score, villus formation, and cartilage degeneration). A subset of mice was used to collect synovial fluid at 7 days post injury. Assessment of joint bleeding at 5 h following the needle injury, by extracting and measuring hemoglobin levels in joint tissues and monitoring hematocrit, showed an equal amount of bleeding in all three genotypes of mice (FVIII-/-, EPCR deficient FVIII-/-, and EPCR-overexpressing FVIII-/- mice). Administration of three doses of FVIIa was effective in preventing hemophilic arthropathy in FVIII-/- and EPCR-overexpressing FVIII-/- mice, whereas a single dose of rFVIIa had a minimal effect in reducing hemophilic arthropathy. Interestingly, a single dose of FVIIa fully corrected the needle injury-induced hemophilic arthropathy in EPCR-deficient FVIII-/- mice. More importantly, EPCR-deficient FVIII-/- mice failed to develop full-blown hemophiic arthropathy even in the absence of any treatment. Measurement of inflammatory cytokines in the synovial fluid showed a robust increase in IL-6 levels in FVIII-/- mice and a single dose of FVIIa substantially reduced IL-6 levels. Interestingly, IL-6 levels in the synovial fluid of injured EPCR-overexpressing FVIII-/- mice were markedly higher compared to injured FVIII-/- mice, three doses of rFVIIa was required to attain a significant reduction in IL-6 levels in these mice. In contrast to these data, we found very little IL-6 levels in the synovial fluids of injured EPCR-deficient FVIII-/- mice. Overall, these data indicate that EPCR levels profoundly influence hemophilic arthorpathy. EPCR-deficiency protects from development hemophilic arthropathy because down-regulation of APC generation in EPCR deficiency could allow sufficient thrombin generation in hemophilia to prevent joint bleeding and bleeding-associated inflammation. Disclosures Rao: Takeda: Research Funding.

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.

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

Recombinant 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.

Excess Factor XIII (FXIII) Consumption During Cardiopulmonary Bypass Surgery in a Patient with Congenital FXIII Deficiency

Abstract 4632 Background:FXIII is an essential component of normal hemostasis. Congenital deficiency of FXIII activity is a rare autosomal recessive bleeding disorder with an estimated incidence of one in 3–5 million. A fibrin-stabilizing FXIII concentrate that provides both A and B subunits of FXIII was FDA approved last year for routine prophylactic treatment of congenital FXIII deficiency. There are few data available on replacement of FXIII concentrate in patients with congenital deficiency undergoing surgery and there is no published information on managing FXIII deficient patients undergoing cardiopulmonary bypass (CPB) surgery. It is known that FXIII levels decrease in normal individuals who are placed on the cardiopulmonary bypass pump. Patients/Methods:A 52 year old man with congenital FXIII deficiency (baseline level 20%) underwent an aortic valve replacement. On the day of surgery, immediately prior to intubation, he was given a dose of FXIII concentrate (42 U/kg) which had previously been shown to correct his FXIII level to 100%. Early in surgery, the patient became hypotensive and did not respond to vasopressors, so the chest was opened urgently, internal CPR was performed and the patient was placed on cardiopulmonary bypass. He experienced heavy, poorly controlled bleeding intraoperatively. Factor XIII levels were checked intraoperatively at 3 hrs and 7 hrs post administration of the pre-op FXIII dose, and were 40% and 43% respectively. These levels were considerably lower than expected based on FXIII pharmacokinetic studies done 2 weeks prior to surgery. He received an additional dose of FXIII concentrate (42 U/kg) 8 hours after the original pre-op dose. During surgery he also received 9 units of PRBCs, 3 units of platelets, 7 units of FFP and a single dose of rFVIIa (90 mcg/kg) during the period of excessive bleeding, with ultimate control of bleeding; the patient was transferred to the surgical ICU 6 hours after the surgery was started. He recovered uneventfully and his post-operative FXIII levels were consistent with the published FXIII concentrate half-life of 6–8 days. Discussion:Studies have shown that plasma levels of FXIII decrease by 10–33% in a general population of patients undergoing CPB surgery which is presumed to be due to FXIII consumption during extracorporeal circulation. This raises concerns for effective replacement of FXIII in cases of congenital FXIII deficiency. In the case presented, FXIII levels were approximately 60% lower than anticipated based on pre-surgical pharmacokinetic testing of exogenous FXIII concentrate, and likely resulted in significant clinical bleeding intraoperatively. Further information is needed on surgical management, especially in cases involving extracorporeal circulation; collection of such cases in a registry may be helpful to improve our understanding on how to care for these patients. For now, we recommend using an increased dose of FXIII prior to such surgeries as the 100% correction dose determined in a preoperative challenge test was not enough to restore this patient’s FXIII levels during surgery and prevent intraoperative bleeding. Disclosures:Off Label Use: FXIII CONCENTRATE IN SURGERY. Leissinger:CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

US Experience with Recombinant Factor VIIa (rFVIIa) for Surgery in Acquired Hemophilia (AH): Analysis From the Hemophilia and Thrombosis Research Society (HTRS) Registry

AbstractAbstract 3372 Background:AH is a rare disorder caused by autoantibodies against factor VIII (FVIII). Patients can present with peri-operative bleeding, and a prolonged aPTT that doesn’t correct with 1:1 mixing after 2 hours (37°C). The Hemostasis and Thrombosis Research Society (HTRS) Registry was established to support the society’s research needs and monitor the safety of recombinant activated factor VII (rFVIIa). In October 2006, the FDA approved rFVIIa for the treatment of bleeding and prevention of bleeding during surgery in AH at 70–90 mcg/kg every 2–3 hours. In 2007, a new case report form (CRF) for capturing information about surgeries was added. Methods:Data on treatment during surgical procedures was collected from the HTRS registry surgical CRF. For each rFVIIa-treated surgery, the initial dose, total dose per procedure (prior to and post surgery), average infused dose, number of doses, and treatment duration were calculated. Queries were issued to verify any procedures lacking treatment data or where treatment was listed as “none”. Efficacy was assessed on a 4 point scale and an investigator assessed adequacy of hemostasis on the “planned regimen” immediately and at 24 and 72 hours. Results:Of 166 registered AH patients, 36 patients underwent 58 surgeries. There were 24 (43%) rFVIIa-treated procedures (17 rFVIIa only). The mean (range) age of all patients undergoing surgery was 69 (14–89), and for rFVIIa-treated patients was 77.8 (28–89). rFVIIa-treated patients were mostly female (71%) and Caucasian (59%). Approximately 33% (19/58) of all surgeries were elective, including 54% (13/24) of rFVIIa-treated surgeries. The most common procedures overall were central line placement (12), endoscopy (12) and orthopedic (5). rFVIIa-treated surgeries included: central venous access (6), endoscopy (5), incision, drainage and grafting of hand hematomas (3), AVM embolization (2), orthopedic procedures (2) cholecystectomy (1), colon biopsy (1), catheter removal (1), exchange of prostate brachytherapy implant (1), venipuncture (1) and IVC filter placement (1). rFVIIa was used pre-op in 19 procedures and post-surgery in 15. In 9/24 procedures (8/24 pre-op), a single rFVIIa dose was used. Median (range) for rFVIIa treatment is described in the table below:Prior to SurgeryPost SurgeryAll TreatmentsInitial Dose (mcg/kg)90.0 (44–187)106.0 (56–270)96.1 (44–270)Average Infused Dose90.0 (44–155)93.0 (43–200)91.5 (43–200)Total Dose120.0 (44–4802)1770 (96–6229)399.0 (44–6229)Number of Injections1.0 (1–31)15.0 (1–77)4.0 (1–77)rFVIIa Tx Duration (days)0 (0–9)4.5 (0–19)0 (0–19)Total Tx Duration0 (0–9)5.0 (0–41)2 (0–41)rFVIIa efficacy was rated as excellent/good in 17 (77.3%), fair/partially effective in 2 (9.1%), and poor/ineffective in 3 (13.6%). For those rated fair/partially effective, one received only one pre-op rFVIIa dose of 75 mcg/kg with antifibrinolytics (no post-surgery treatment) and the other received 1 pre-op and 2 post-op rFVIIa 106 mcg/kg doses at 2 hour intervals with no other treatments. For those rated poor/ineffective, one received rFVIIa and PRBCs only, one received rFVIIa 81 mcg/kg initially every 4–6 hrs then plasma-derived activated prothrombin complex concentrate (pd-aPCC) then rFVIIa, and one had resolution of a neck hematoma with rFVIIa (subsequently switched to pd-aPCC) but could not maintain an airway and was transferred to hospice. No thromboembolic events were reported in rFVIIa-treated patients.Two patients underwent 6 follow-up procedures during ongoing post-op rFVIIa-treatment. Eleven patients used hemostatic agents other than rFVIIa in 12 surgical procedures. These included use of pd- aPCC in 5 cases (3 pre-op; 2 pre-op and post-op) and use of desmopressin in 2 cases, and recombinant FVIII in 3 cases. Blood products (FFP, PRBCs) were used post-op in 2 cases. Thirteen patients underwent 16 surgeries with no reported treatment. Conclusions:rFVIIa provided adequate hemostasis for almost all rFVIIa-treated AH surgeries at doses largely conforming to the package insert. There were no safety concerns and no thromboembolic complications reported in this population of older patients. Lack of hemostatic therapy reported for some procedures may reflect surgery as a presenting AH symptom, surgery during ongoing treatment not requiring additional treatment, or surgery performed following immune suppression/tolerization. Disclosures:Ma:Novo Nordisk Inc.: Consultancy, Speakers Bureau. Kessler:Novo Nordisk: Consultancy, Research Funding. Fisher:Novo Nordisk Inc.: Employment. Gut:Novo Nordisk Inc.: Employment. Cooper:Novo Nordisk Inc.: Employment.

EComment. Activated recombinant factor VII in intractable bleeding after cardiac surgery

I read with great interest the paper by Muzzi et al. [1] concerning the salvage use of Celox gauze (MedTrade Products Ltd, Cheshire, UK) in two patients and the postoperative course was uneventful. Celox gauze is a very effective haemostatic agent and it is capable of clotting heparinised blood [2]. However, its use is limited in controlling haemorrhage in a military trauma setting on the battlefield. The authors stated that despite the use of fresh frozen plasma, platelets, desmopressin and epsilon-aminocaproic acid, control of the bleeding was not achieved. I would like to ask the authors why they did not make use of activated recombinant factor VII or rFVIIa (NovoSeven®, Novo Nordisk, Denmark). Bleeding is a troublesome situation and carries a dismal prognosis in postoperative extracorporeal membrane oxygenation (ECMO) implantation for post-cardiotomy cardiogenic shock. Since 1999, rFVIIa has been used after cardiac surgery as a compassionate therapy for life- threatening haemorrhage [3]. Dramatic bleeding secondary to consumptive coagulopathy post-cardiopulmonary bypass has been shown to be successfully managed by the infusion of a single dose of 60-90 µg/kg of rFVIIa. However, previous compensation with fibrinogen (>1 g/l) and platelets (>50 g/l) is mandatory to ensure an effective clotting cascade. In a recent multicentre observational study [3] assessing the efficacy of rFVIIa in cardiac surgery, the authors concluded that a single dose of rFVIIa was sufficient to stop or decrease bleeding in 80% of their patients, of whom 34% (n = 37) were assisted by mechanical devices. Thrombotic events were the major drawback especially in patient with assist devices and occurred in 27% of them. A review of the literature published in 2006 [4] showed that rFVIIa was an effective homeostatic agent for intractable bleeding after cardiac surgery and the risk of serious, adverse thrombotic events was estimated to be under 1%. The usage of Celox in combination with a vacuum assisted closure device seems to be lifesaving and represents an effective and safe (thrombotic event-free) tool. It should be considered in the armamentarium of every cardiac surgeon.

Recombinant factor VIIa as last‐resort treatment of desperate haemorrhage

Studies are inconclusive regarding clinical outcomes after administration of recombinant activated coagulation factor VII (rFVIIa) during severe haemorrhage. The circumstances encountered during desperate haemorrhage make it difficult to include the most critically ill patients that could possibly benefit the most from such treatment into randomized controlled trials. We report our experience with rFVIIa as last-resort treatment of desperate haemorrhage when all standard treatment has failed. Hospital charts of all consecutive patients treated with rFVIIa for desperate non-haemophilic bleeding over a 10-year period at the single institution administering rFVIIa were surveyed for treatment indications, clinical outcome, transfusion need and coagulation profiles. Fifty-five rFVIIa treatment occasions of desperate bleeding were identified in 54 patients (median age 54 years). A single rFVIIa dose was used in 86%, and haemorrhage was considered effectively contained by immediate clinical response on 81% of occasions. Overall, 38 patients (71%) survived for over 30 days. Two thromboembolic events occurred (3.6%). The 24-h mortality in 45 rFVIIa immediate clinical responders and 10 non-responders was 2% and 50%, respectively (P = 0.0004), and the 30-day mortality was 25% and 60%, respectively (P = 0.05). Blood product use decreased with rFVIIa (P < 0.01) as did the prothrombin time (20.0-13.3 s, P < 0.0001). The majority of unselected consecutive patients receiving rFVIIa as last-resort treatment for desperate haemorrhage were considered to have immediate clinical response as well as reduced transfusion requirements and correction of coagulation parameters. An immediate clinical response to rFVIIa may possibly be predictive of survival.

Recombinant Activated Factor VII (rFVIIa) Treatment of Refractory Bleeding in Cardiac Surgical Patients

Objective: Our aim to evaluate the efficacy and safety of rFVIIa in cardiac surgical patients with refractory bleeding. Design: The study was a retrospective study. Setting: Prince Sultan cardiac center, Saudia Arabia. Participants: Data were collected in patients who had undergone cardiac surgery and complicated by refractory bleeding. The study included 35 patients adults and 8 children. Interventions: rFVIIa administration. Measurements and main results: The rFVIIa effect was assessed by the decrease in the chest blood loss (The amount of bleeding was < 3ml/kg/hr without accumulation of blood inside the chest) and number of blood products (Packed red blood cells, platelets, fresh frozen plasma, and cryoprecipitate) given before and after rFVIIa administration was recorded. The dose of rFVIIa was 93.72 ± 17.39 μg/kg. All patients received single dose of rFVIIa, but nine patients received a second dose through half to one hour following the initial dose. The blood losses before rFVIIa administration was 7.47 ± 1.53 ml/kg/hr and decreased significantly to 2.37 ± 0.67 and 1.08 ± 0.42 ml/kg/hr in the next six and eighteen hours respectively (P=0.001)[paired test]. Before rFVIIa administration, the number of transfused packed RBC, fresh frozen plasma, platelets and cryoprecipitates were 11.25 ± 3.57, 11.35 ± 4.15, 11.77 ± 4.40 and 10.16 ± 3.76 units and decreased significantly to 5.930 ± 1.704, 3.86 ± 1.52, 3.65 ± 1.42 and 2.91 ± 2.11 units respectively after rFVIIa (P=0.00). Conclusion: In patients undergoing cardiac surgery exhibiting refractory bleeding, rFVIIa at a mean dose of 93.7 ± 17 μg/kg improved significantly hemostasis and decreased additional administration of blood products, without any complication related to rFVIIa.

Recombinant Activated Factor VII for Bleeding In the Setting of Malignancy or Hematopoietic Stem Cell Transplantation: The Australian and New Zealand Experience, 2000–2009,

Abstract 3311▪▪This icon denotes a clinically relevant abstract BackgroundHemorrhage from disease processes or their therapy commonly complicates the course of patients with malignancies. Recombinant activated factor VII (rFVIIa) was developed for prevention or treatment of bleeding in hemophilia patients who have factor inhibitors, but may also have a role in enhancing coagulation and augmenting conventional therapies in refractory bleeding. However, outcomes are not defined for this indication, and randomized studies are challenging. We explored the safety and efficacy of rFVIIa in the treatment of hemorrhage associated with malignancy or stem cell transplantation (SCT) using prospective clinical registry data. MethodsThe Australia and New Zealand Haemostasis Registry (ANZHR) documented all rFVIIa use in non-hemophilia patients in both countries. More than 90 institutions participated in its operation from 2000 to 2009, capturing an estimated 85% of use in these countries. Participating institutions obtained approval from local institutional review boards to provide de-identified data. They were required to report all usage to limit bias and registry data were audited regularly. We identified episodes of rFVIIa use where the primary diagnosis at the time of hemorrhage was a malignancy or SCT. Response to rFVIIa reported by the treating clinician, transfusion requirements, adverse events and 28 day survival were analyzed. Logistic regression and multiple linear regression models were used to identify factors associated with response. ResultsOf 3446 episodes reported to ANZHR, 362 eligible episodes were identified in 325 patients (10.5% the total). Median patient age was 56 years (IQR 39–67); 205 (63%) were male. Episodes were reported from 51 institutions (57% of participating), median 5 (IQR 3–8) per institution. Primary diagnosis was hematological in 173 cases (48%); non-hematological malignancy in 189 (52%). 321 (88.6%) were receiving disease-directed therapy (initial therapy in 200 [55% of the total], 19 [5%] supportive care, unreported in 22 [6%]). Intent of care was curative in 218 (60%), palliative in 122 (34%), 22 (6%) unreported. 33 (9.1%) were undergoing allogeneic SCT and 5 (1.4%) autologous SCT. Primary sites of bleeding were gastrointestinal in 165 (46%), pulmonary 47 (13%), intracranial 36 (10%), genitourinary 34 (9%), hepatic 28 (8%), others 52 (14%). Causes of bleeding were 116 (34%) surgical (including resection of tumor or metastases), disease-induced coagulopathy 48 (14%), disease invasion 62 (18%), mucositis (including graft-versus-host disease) 53 (15%), others 65 (19%); 6 (2%) received rFVIIa prophylactically prior to procedures. In 255 episodes (70%) a single dose of rFVIIa only was administered. Median dose was 90μg/kg (IQR 77–100). Prior to administration median (IQR) hemoglobin was 82 g/L (69–93); platelet count 82 × 109/L (43–127), fibrinogen 2.1 g/L (1.4–3.1), INR 1.4 (1.2–1.8), pH 7.3 (7.2–7.4), temperature 36.7°C (36.0–37.1), and patients had received 5 (2–12) units red cells, 2 (0–4) platelet doses, 4 (0–8) plasma units, and 0 (0–8) cryoprecipitate doses. Bleeding stopped or decreased in 175 (60%) of cases where response was reported (prophylactic cases were excluded from response assessment). Transfusion requirements fell to 2 (0–4) red cells, 0 (0–2) platelets, 0 (0–3) plasma, and 0 (0–8) cryoprecipitate following the first dose. Response decreased with low pH in univariate analysis (p=0.014). In multivariate analysis, low pH and hematological malignancy were independent predictors of poor response (p=0.001). 18 patients (5.5%) had thromboembolic events reported within 28 days of administration. 202 patients (57%) survived to 28 days. Survival was significantly higher in rFVIIa responders (71% vs 38% p<0.001, Figure 1). [Display omitted] ConclusionsThis is the first comprehensive exploration of rFVIIa in hemorrhage associated with malignancy. Usage in this setting was higher than anticipated. Reported efficacy and safety were promising in this heterogeneous group with severe refractory bleeding and elevated baseline risk of thrombosis. Clinician-reported bleeding response was supported by reduced transfusion requirements and survival benefit. Response was associated with pH and type of malignancy, suggesting that these factors may assist in patient selection. Use of rFVIIa may be an effective adjunct to conventional therapies in carefully selected cancer patients with refractory hemorrhage. Disclosures:Off Label Use: Recombinant Activated Factor VII, for bleeding associated with malignancy.

Activated Recombinant Factor VIIa for Intractable Extra-Cranial Hemorrhage in 55 Consecutive Patients

Abstract 1264 Background:Recombinant activated coagulation factor VII (rFVIIa) has been increasingly used in non-hemophiliac patients for unapproved indications. We undertook a 10 year nation-wide retrospective survey in order to evaluate the use of rFVIIa in Iceland in patients with intractable extra-cranial hemorrhage. Material and methods:Hospital charts of all patients that received rFVIIa between 1999–2008 at Landspitali, the single institution administering rFVIIa in Iceland, were reviewed and indications, coagulation profiles and clinical outcome were evaluated. This analysis focuses on patients treated off-label for desperate (intractable) extra-cranial hemorrhage (IH), ie only patients in who all other measures were considered to have failed to stop hemorrhage. Results:rFVIIa was used for IH in 55 patients (median age 53 yrs, range; 0–84, 51% males). This included IH in open heart surgery (n=23), non-cardiac surgery (n=7), post-partum hemorrhage (n=9), multitrauma (n=8) and miscellaneous (n=8). A single rFVIIa dose was used in 86% of cases and hemorrhage was considered effectively contained by immediate clinical response to rFVIIa in 81% of the IH cases. Survival at 30 days for all patients was 68%. Out of 55 patients with IH, six died within 24 hours of administration of rFVIIa (five assessed clinically as rFVIIa non-responders) and 11 other patients (total 17 patients, 31%) died within 30 days (six non-responders). The 24-hour mortality in rFVIIa clinical responders and non-responders was 2% and 50% respectively (p=0.0004) and the 30 day mortality was 25% and 60% respectively (p=0.05). The need for transfusion of blood products was significantly decreased (p<0.01) and also the prothrombin time (20.0 to 13.3 sec, p<0.0001). Conclusion:The majority of unselected consecutive patients receiving rFVIIa as last resort treatment for IH were considered to have favorable immediate clinical response as well as reduced transfusion requirements and normalisation of coagulation parameters. Also, patients deemed with clinical response to rFVIIa may have had lower mortality. Disclosures:Off Label Use: Activated recombinant factor VII for use in desperately bleeding patients.

Experience with a single dose of recombinant activated factor VII for the management of mild-to-moderate bleeds in haemophilia

Experience with a single dose of recombinant activated factor VII for the management of mild-to-moderate bleeds in haemophilia

Efficacité du facteur VII activé recombinant dans l’hémorragie alvéolaire diffuse

Alveolar haemorrhage is a serious complication of a range of different pathologies. Published recent literature has reported only cases unresponsive to the usual treatment (steroids, transfusions, immunosuppressors and mechanical ventilation) as well as multiple secondary complications of these kinds of therapies. Recombinant activated factor VII (rF VIIa) is a new class of agent, which appears to be a successful adjunct therapy in the case of failure of conventional treatments. We describe two cases of alveolar haemorrhage treated with rF VIIa. The first patient had leukaemia and the second had ANCA-associated granulomatous vasculitis. Both were admitted to the intensive care unit for mechanical ventilation with persistent diffuse alveolar haemorrhage that responded only to a single dose of rF VIIa (90 μg/kg). rF VIIa is a promising treatment for diffuse, persistent alveolar haemorrhage, with only a small dose required to be effective. Future studies are needed in order to establish a clear protocol for the administration of this novel agent.

Ten Years and Over 3600 Cases of Recombinant Activated Factor VII Use: What Does the Haemostasis Registry Data Tell Us?

AbstractAbstract 3352 Background:Recombinant activated factor VII (rFVIIa, NovoSeven®) is approved for the treatment of spontaneous and surgical bleeding in patients with haemophilia A or B and with antibodies to either factor VIII or factor IX. However rFVIIa has increasingly been used for indications outside the approved areas as a last resort treatment in trauma, cardiac surgery and other critical bleeding episodes despite the absence of conclusive randomized clinical trial (RCT) data. Aims:The aim of the Haemostasis Registry was to collect data (including dose, adverse events and outcome) on the off-license use of rFVIIa in Australia and New Zealand. Methods:Monash University established the Haemostasis registry in 2005 with an educational grant from Novo Nordisk Pharmaceuticals. More than 100 hospitals (including all major users of rFVIIa in Australia and New Zealand) contributed data to the Registry covering a ten year period (2000 to 2010). Results:More than 3600 off-license rFVIIa cases have been reported to the Registry. 65% of cases were male and the median age was 56 years. Major areas of use were cardiac surgery (∼43%), other surgery (18%) and trauma (13%). The majority (∼77%) of patients received a single dose of rFVIIa with a median (IQR) dose of 91 (73-103) mcg/kg. Seventy-four percent of cases documented a response (decrease or cessation of bleeding) following rFVIIa. Patient mortality rate at 28 days was lower if bleeding was reportedly stopped or decreased (88% or 82% vs. 39% no change, respectively) (χ22=533, p<0.001). Stepwise logistic regression analysis identified the number of units of RBC's, pH and context of bleeding as significant independent predictors of patient response to rFVIIa administration and pH, context of bleeding and units of FFP were included in the best predictive model of patient outcome at 28 days. Thromboembolic adverse events were reported in 7.5% of all patients however risk-adjusted adverse event rates in Haemostasis Registry cardiac patients were not significantly different from those seen in non-rFVIIa treated cardiac patients recorded in the ASCTS registry (www.ascts.org). Conclusions:The Haemostasis Registry is the largest dataset of its kind and provides critical observational data on the importance of pH, temperature and coagulopathic state in determining the response to rFVIIa. Although the role of rFVIIa in critical bleeding is still not clear, the Haemostasis Registry has been an invaluable resource for rigorously tracking adverse events and helping to guide clinical practice in an arena unlikely to be supported by new RCT data. Disclosures:Phillips:Novo Nordisk: Educational Grant. Off Label Use: rFVIIa; used for the treatment of critical bleeding in trauma, cardiac surgery, liver and obstetrics. Zatta:Novo Nordisk: Educational Grant. McNeil:Novo Nordisk: Educational Grant. Cameron:Novo Nordisk: Educational Grant.

Prophylaxis In Congenital Factor VII Deficiency, Indications, Efficacy and Safety: Results of the STER

AbstractAbstract 665 IntroductionProphylaxis is considered a difficult endeavour in FVII deficiency, especially because of the very short FVII zymogen and FVIIa half-lives, mainly in childhood. The Seven Treatment Evaluation Registry (STER, www.targetseven.org) is a prospective observational, multi-centre, web-based registry concerned with the evaluation of treatments for spontaneous bleeding episodes, surgery and prophylaxis in patients with FVII deficiency. As regards prophylaxis, STER provides the frame for a structured and detailed data capture aiming at: a) identifying patients in whom prophylaxis is advisable, b) defining clinical settings in which prophylaxis is necessary and c) describing effective and safe dosing schedules. Materials and MethodsTogether with basic clinical and laboratory data related to the patient, the following information has been collected for each prophylaxis treatment course: i. Type (primary or secondary, short- and long-term), ii. Indication iii. Start/stop date iv. Schedule, v. Concomitant medications and illness vi. Bleeding episodes, vii. Other complications. The prophylactic regimen adopted reflected the decision of each enrolling physician as was the type of replacement therapy. FVIIc assays were performed at each centre lab, whereas inhibitor assays were centralized. ResultsNineteen patients with FVII deficiency (12 females, 7 males, age ranging from new born to 71 y.) were enrolled as a long-term prophylaxis was deemed necessary by the treating physician. FVIIc levels ranged from <1% to 4.9 of normal, median 1.5). Patients' disease severity was characterized by a striking prevalence of the severest symptoms (CNS and GI bleeding bleeding, hemarthrosis) as disease hallmark. Twelve subjects received recombinant FVIIa (rFVIIa), six received plasma-derived (pd) products (pdFVII concentrates [n=3], Fresh Frozen Plasma (FFP) [n=3]); 1 subject was given both pdFVII and an APCC. The 12 patients who were prophylaxed with rFVIIa (7 for a primary and 5 for a secondary course) were treated for the following reasons: recurrent hemarthrosis (n=4), CNS bleeding (3), menorrhagia (2), other (3). The 3 patients treated with pdFVII were reported for secondary prophylaxis courses after hemarthrosis (n=2) and hematuria, and the 3 patients treated with FFP were reported for courses after CNS bleeding (n=1), GI (1) and menorrhagia (1). Reported treatment schedules were quite various: the commonest frequency of rFVIIa administrations was “3 times a week” (n=5) ranging from daily (n=1) to once weekly (n=2); for menorrhagia, one dose on the 1st & 2nd days of the cycle were administered. The single dose of rFVIIa ranged from 14 to 80 μg/kg. Clinical efficacy of the rFVIIa prophylaxis regimens was excellent (n=10) with small intervals and medium or high dosing (14-80μg/kg). The regimens based on a dose of 30μg/kg once/week or on a dose of 16.5μg/kg 3 times/week, were considered partially effective. Prophylaxis with pdFVII was performed at a mean dose of 17 IU/kg (range: 9–30 U) 2 to 3 times /weekly: only the outcomes of the 3 times weekly regimen were reported as excellent. FFP was given at a mean dose of 15 ml/Kg twice a week but was only effective in preventing provoked bleeds. Long term prophylaxis courses carried out in 2 patients who had previously developed an inhibitor to FVII (both following multiple treatments) deserve a special mention: one received a long-term rFVIIa prophylaxis course with excellent results, while the other was given pdFVII and the APCC in association with satisfactory results. In none of the described prophylaxis courses spontaneous or catheter-related thromboses were reported. ConclusionsWe have identified a subset of patients with a FVII deficiency who may need a continuous, long-term prophylaxis treatment; these patients have a severe disease characterized by CNS or GI bleeding, hemarthrosis (mostly as presenting symptoms) or menorrhagia associated with low to very low FVIIc levels. Reported dosing and schedules varied widely so it is difficult to ascertain which is the optimal prophylaxis schedule but the 3 dose weekly regimens associated with medium to high replacement therapy doses appear the most efficacious. We have also shown that long-term prophylaxis is feasible in patients with an inhibitor to FVII. Disclosures:Knudsen:Novonordisk: Employment.

Variability of thromboelastographic responses following the administration of rFVIIa to haemophilia A dogs supports the individualization of therapy with a global test of haemostasis

The efficacy of recombinant factor VIIa (rFVIIa) therapy in haemophilia A is challenged by the lack of a reliable monitoring tool for treatment response. This is further complicated by the significant inter-patient variability associated with this response. Thromboelastography (TEG), a real time global haemostatic test has shown superiority over conventional tests of haemostasis and has proven efficiency in the monitoring of bypass agents such as rFVIIa and FEIBA™. However, this evaluation has been limited to a few case studies or very small patient series. In this study, six severe haemophilia A dogs were treated with a clinically relevant single dose of rFVIIa, and therapy was monitored by thromboelastography predrug and at 15, 30 and 60 min postdrug administration using citrated whole blood samples activated with tissue factor and compared with non-tissue factor-activated samples. Despite the homogeneity of the tested dogs, a clear inter-individual variation was observed in the pre-and post-rFVIIa Thromboelastography analyzes. The improvement of global haemostatic parameters was seen as early as 15 min following drug administration, with a peak for factor VIIa activity in plasma at the same time. There is a significant correlation between plasma FVIIa and TEG parameters 15 min postinjection, and the baseline TEG profile influences the individual postdrug administration outcome. Together, these data support the value of TEG not only as an effective monitoring haemostatic test, but also as a tool for individualization of therapy to achieve the best haemostatic and cost effectiveness of rFVIIa therapy.

Differences in Global Hemostasis Following rFVIIa Dosing: A Focus On Responders Versus Poor Responders.

Abstract 3485Poster Board III-422 IntroductionThe clinical response of hemophilia patients with inhibitors to bypassing agent therapy can be unexpectedly poor. Indeed, there are reports of “poor responders” who either require alternative treatment or dose escalation. The lack of correlation between routine coagulation assays or factor antigen/activity levels with clinical efficacy contributes to the problem in these patients. Analysis of the clotting characteristics of “poor responders” is limited. In a recent study of rFVIIa PK in 10 non-bleeding hemophilia A and B patients, we noted that four of the ten had a remarkable attenuated response as seen in whole blood assays. We report here a comparison of clotting parameters in the “poor responders” versus robust responders to rFVIIa infusion, and attempt to define what might be the source of the altered response. Patients and MethodsTen severe FVIII or FIX deficient patients in a non-bleeding state were infused with a single-dose of rFVIIa (90 μg/kg). Platelet contractile force (PCF), clot structure (CEM,MA,MCF), and clot formation time (FOT,R,CT) were analyzed in whole blood by Hemodyne HAS, Thromboelastography, and Rotation Thromboelastography before, and at 0.5,1,2,4 and 6 hours following rFVIIa dosing. Thrombin generation parameters (Tlag, Cmax) were measured in PRP by the Calibrated Automated Thrombogram. Plasma concentrations of FVII:C and FVII:Ag were measured at each time point. Patients with a clot formation time (FOT, R, CT) ≥ 15 minutes following rFVIIa dosing were termed “Poor Responders”. ResultsThere were few inter-group differences in baseline clotting characteristics. The values for all parameters are provided in Table 1. FVII PK were not different between the Responders and Poor-Responders. This can be appreciated from the PK parameters listed in the table as well as from relative lack of variability for the composite rFVIIa levels seen for the entire group of 10 patients (Figure 1, panels 1 and 2). Both groups had similar FVIIa Cmax and total body clearance values. However, the responders made significantly stronger clots (PCF, CEM) as can be appreciated in table 1 and even more dramatically in panels 3 and 4 of figure 1. In these panels, the responders and poor responders are plotted as separate groups. Even though the groups are small (n=6 vs 4) the minimal response (both in magnitude and duration) to rFVIIa in terms of platelet function (PCF) and clot structure (CEM) is grossly apparent. All three whole blood assays revealed significantly shorter time to clot formation (R, FOT, CT) in the responders. However, the MA (TEG) and MCF (ROTEG), and thrombin generation parameters (Tlag, max) failed to show significant inter-group differences following rFVIIa dosing.Table 1ParameterResponders (N=6)Poor-Responders (N=4)P-ValueFVII:C (IU/mL) Cmax44.1 (13.9)34.0 (4.2)NSFVII:Ag (ng/mL) Cmax984.2 (194.4)865.3 (67.0)NSFVII:C Clearance (mL/h*kg)43.1 (17.1)62.2 (5.3)NSFVII:Ag Clearance (mL/h*kg)23.6 (6.3)26.9 (2.7)NSPCF (Kdynes)6.6 (1.5)1.5 (1.0)<0.001CEM (Kdyne/cm2)20.0 (4.7)3.4 (2.6)<0.001FOT (minutes)8.6 (1.0)17.5 (2.4)<0.001CT (seconds)513.2 (68.3)1128.0 (228.9)0.001MCF (mm)61.6 (4.2)58.3 (2.3)NSR (minutes)7.9 (0.7)14.5 (2.8)0.002MA (mm)62.7 (3.3)59.2 (3.0)NSThrombin Tlag (minutes)10.2 (0.9)11.4 (1.1)NSThrombin Cmax(nM)2039.5 (541.1)1508.3 (152.4)NS [Display omitted] ConclusionsThese data suggest that the differences observed between Responders and Poor Responders are not due to PK influences, but may be related to differences in the effects of thrombin on platelet function. It is possible that whole blood assays may serve as a tool to monitor the clinical effects of rFVIIa. Changes in clot stiffness were better characterized by CEM compared to MA and MCF. There was good correlation between FOT, R and CT parameters to detect onset of clot formation. The thrombin parameters were highly dependent on sample type and triggering agent and did not significantly vary between the two groups. Further studies are needed to clarify the clinical significance of these findings. Disclosures:Ezban:NovoNordisk A/S: Employment. Hedner:NovoNordisk A/S: Employment.

Evaluation of Clotting Parameters in a Patient with Hemophilia A and Inhibitors Who Has a Poor Clinical Response to Standard Dose rFVIIa.

Abstract 4440It is known that some FVIII deficient patients who develop high titer FVIII inhibitors do not respond as expected to inhibitor bypassing agents. During an IRB approved study of laboratory monitoring of rFVIIa infusion in hemophilia patients, we had the opportunity to extensively study a patient who was known to respond poorly to standard dose (90 mg/kg) rFVIIa. We present here results from this patient included in this study and question whether it might be possible to predict poor response from in vitro measurements. Case historyThe patient is a 43 year old male with severe hemophilia A (FVIII<1%) and a high titer FVIII antibody (10.4 BU). In 2003, attempts were made to treat spontaneous joint bleeds with standard (90 mg/kg) dose rFVIIa. Responses were poor and the patient was switched to FEIBA (>6000 IU per infusion) to which he responded. He continues to bleed frequently with 7 documented bleeds requiring 21 infusions of FEIBA for treatment during the first six months of 2009. MethodsThis patient was one of 10 hemophiliacs participating in a clinical study of rFVIIa. Blood samples were drawn at baseline and at 0.5, 1, 2, 4 and 6 hours after a single dose of rFVIIa 90 mg/kg. Parameters measured included PT, PTT, fibrinogen level and whole blood assays (Hemodyne HAS, TEG®, and ROTEG®). Thrombin generation was measured in PPP and PRP by CAT. Plasma samples were analyzed for Prothrombin Fragment 1.2, FVII:C, FVII:Ag, FVIIa:ATIII and D-dimer. In addition, in this patient an in vitro spiking study of rFVIIa corresponding to doses of 90, 180 and 270 mg/kg was performed to determine the clotting parameters. ResultsAt baseline, his PT was 9.6 seconds, PTT was 112 seconds, and fibrinogen was 238 mg/dl. Samples for TEG, HAS and ROTEG analysis all failed to clot when re-calcified and monitored for up to 60 minutes. Thirty minutes post infusion of rFVIIa, HAS parameters slightly improved (FOT=16 min, PCF 2.0 Kdyn) but quickly reverted to grossly abnormal at one hour. This is in marked contrast to the typical response of most patients in the study as demonstrated in (Fig.1). [Display omitted] The R for TEG shortened to 14.4 min and CT for ROTEM decreased to 1094 sec after 30 minutes and remained measurable but grossly abnormal (30 min and 2000 sec) for the next six hours. MA (60 mm) and MCF (60 mm) normalized at 30 min and remained normal for the next six hours. Results of CAT were dependent on the sample type and clot triggering agent. Re-calcification in PRP resulted in shortening of T-lag to 21.5 minutes and a C-max of 15.8 nM both of which were grossly abnormal. T-lag for PRP clotted with 1pm TF was 9.9 min and shortened to 5 min post rFVIIa infusion. ETP when measurable was very low. For PPP clotted with 0.5 pM TF and 4mM phospholipid, the T-lag decreased from a baseline of 5 to <3 min post rFVIIa infusion and remained <3 for six hours. Baseline antigen and coagulant rFVIIa, D-Dimer and F1+2 levels were normal in the patient and the pattern of response did not differ from those seen with patients who had normal responses to rFVIIa. The pharmacokinetics of rFVIIa in this patient were determined, and were consistent with other study participants (Cltot: 66.3, mean= 50.8 ml/hr*kg).During the in vitro experiment, addition of rFVII produced HAS results equivalent to those seen 30 minutes after rFVIIa infusion (Table). Addition of concentrations equivalent to 180 and 270 mg/Kg doses produced additional correction.PCF (Kdyn)CEM (Kdyn/cm2)FOT (min)In-vitro rFVIIa Spiking StudyBaseline0.260.0>20.090 μg/Kg1.526.616.0180 μg/Kg5.0122.511.5270 μg/Kg7.7230.67.0In-vivo rFVIIa Infusion StudyBaseline0.200.0>20.030 min post 90 μg/Kg2.015.516.0Normal Ranges: PCF (4.8-9.5 Kdyn); CEM (14.0-35.0 kdyn/cm2); FOT (3.0-8.0 min) ConclusionWe have analyzed the response to rFVIIa infusion using multiple clotting parameters in a patient with known poor clinical response to standard dose rFVIIa. The clotting lag times of whole blood assays including the HAS, TEG and ROTEG appear to be sensitive to varying degrees to the decreased response to rFVIIa. Thrombin generation was grossly abnormal in PRP but appeared relatively insensitive in PPP to the decreased rFVIIa effect. Spiking studies in the HAS correlated with results from infusion and also indicated that the patient might respond to higher dose rFVIIa. This possibility has not been clinically confirmed, but these results raise the possibility of identifying poor responders and perhaps helping to predict doses that might be effective. Disclosures:Ezban:NovoNordisk A/S: Employment. Hedner:NovoNordisk: Employment.

Prophylactic Use of Factor IX Concentrate in a Jehovah's Witness Patient

In Jehovah's Witness patients, the use of red blood cells, platelets, and fresh frozen plasma is not optional. Various blood conservation techniques are available, but complex cardiac surgery remains a major challenge. The feasibility of fractions of "primary components" has not been fully considered in published case reports. For Jehovah's Witness patients who preoperatively give consent, factor IX concentrates may be acceptable for hemostatic therapy. We hereby describe a combination of "secondary components" to prevent excessive bleeding in a Jehovah's Witness patient undergoing complex replacement of the aortic arch.

The Response of Hemostatic Marker Levels to Activated Factor VII in a Neonate following Cardiopulmonary Bypass

The primary function of recombinant activated factor VII (rFVIIa) is to increase thrombin formation which leads to increased fibrin and less “bleeding.” As a result, most of literature utilizes “bleeding” as the outcome measure with respect to rFVIIa. However, we report the actual effect of rFVIIa on changes in hemostatic markers such as prothrombin activation peptide F1.2, thrombin antithrombin complex (TAT), D-dimer, tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI) in a neonate after cardiopulmonary bypass. A single dose of rFVIIa caused a 5.5-fold increase in F1.2, 3.5-fold increase in TAT, and a small increase in d-dimer compared to only a 1.5-fold increase, no increase, and a decrease, respectively, in two neonates undergoing the same procedure having not received rFVIIa. The patterns of change for tPA and PAI were similar.