Recombinant factor VIIa in trauma patients with the 'triad of death'

IntroductionThe use of recombinant factor VIIa (rFVIIa) in trauma patients is usually part of rescue therapy when haemorrhage and coagulopathy have not responded to conventional treatment. In this scenario, trauma patients are likely to have one or more components of the ‘triad of death’ (coagulopathy, acidosis and hypothermia). The aim of this study was to report on the outcome of trauma patients with the ‘triad of death’ immediately prior to receiving rFVIIa.Materials and methodsTrauma patients receiving rFVIIa with the ‘triad of death’ were identified from the Australia and New Zealand Haemostasis Registry (ANZHR) and included in the study. The ‘triad of death’ was defined as an INR of >1.5, serum pH of <7.2 and a core temperature of <35 °C. Pre-dose clinical signs, investigations, adverse events and outcomes were analysed.ResultsThere were 2792 patients in the ANZHR, of which 386 were trauma patients and 45 patients had the ‘triad of death’. Patients with the ‘triad of death’ were significantly older and had higher injury severity scores than other trauma patients, with a mortality of 68.9%. Survivors were significantly less acidaemic (p < 0.001) and had significantly less packed red blood cell (PRBC) transfusion prior to rFVIIa administration (p = 0.041) than non-survivors with the triad of death.DiscussionIn the face of refractory bleeding, coagulopathy, acidosis and hypothermia following conventional resuscitation, the use of rFVIIa in trauma patients was associated with survival in 31% of patients and may be considered as a management option. Administration of rFVIIa in patients with a pH of <6.91 appears futile.     

Recombinant Factor VIIa for Life-Threatening Hemorrhage in Trauma Patients: Review of the Literature

Abstract The control of hemorrhage and coagulopathy is a vital component of trauma care, and failure to achieve hemostasis can contribute to mortality. Recombinant factor VIIa (rFVIIa) is a well-established therapy for bleeding episodes and surgical prophylaxis in hemophilia patients with inhibitors. However, there has been increasing utilization of rFVIIa in the treatment of trauma-related blood loss in patients without pre-existing coagulopathy. This paper reviews published experience in this area. Database searches identified 126 rFVIIa-treated trauma patients reported in 15 publications between November 1999 and November 2004. Ages ranged from 20 months to 88 years, and the majority of patients (68.7%) had suffered blunt injury. In most cases, rFVIIa was used as a salvage therapy when bleeding continued despite the appropriate application of available conventional hemostatic methods. Doses of rFVIIa varied widely (36–178 μg/kg), with patients receiving a single dose or multiple doses separated by an interval of 2–12 h. Efficacy of treatment (reduction in blood loss, transfusion requirements and mortality) was reported for 79.4% of subjects. Most publications also described shortening or normalization of coagulation parameters following rFVIIa administration. No non-thrombotic adverse events were noted in any patient, but five cases (4.0%) of thromboembolic events were recorded. Recently reported clinical trial data offer support to these anecdotal observations. In conclusion, data appear to support the utility of rFVIIa as an adjunctive therapy for the reduction of hemorrhage and transfusion requirements in trauma patients. However, further information relating to the use of rFVIIa in the trauma setting is required.     

The role of recombinant factor VIIa in the treatment of life-threatening haemorrhage in blunt trauma

BACKGROUND: Recombinant factor VIIa (rFVIIa) is a novel haemostatic agent originally developed to treat bleeding in haemophiliacs. Several case reports suggest effectiveness of rFVIIa in the treatment of patients without pre-existing bleeding disorders. The aim of this study is to evaluate treatment with recombinant (rFVIIa) in blunt trauma patients with uncontrolled bleeding. PATIENTS AND METHODS: This study was designed as a retrospective case review. Consecutive patients with life-threatening uncontrolled bleeding due to blunt trauma who were treated with rFVIIa were selected. Data were obtained from medical records. RESULTS: A total of eight blunt trauma patients were treated with rFVIIa for uncontrolled bleeding. After treatment the need for transfusion of red blood cells (RBC) decreased significantly from 31.3 +/- 15.8 to 6.1 +/- 6.8 units (P = 0.003), fresh frozen plasma (FFP) from 13.3 +/- 6.6 to 5 +/- 6.3 units (P = 0.02), and platelets from 3.6 +/- 1.8 to 1.5 +/- 2.3 units (P = 0.01). Three patients died of non-bleeding complications. The other five fully recovered. CONCLUSION: Treatment with rFVIIa reduced or stopped bleeding in all patients. No adverse events were registered. Prospective studies are mandatory to elucidate the role of rFVIIa in blunt trauma.     

Effects of recombinant activated factor VII in traumatic nonsurgical intracranial hemorrhage

OBJECTIVE: To determine whether treatment with recombinant activated factor VII (rFVIIa) will prevent progression of bleeding in nonsurgical hemorrhagic traumatic brain injury (TBI). METHODS: Chart review from the trauma registry of a level 1 trauma center between January 1, 2002 and December 31, 2004 identified 2 patients who received rFVIIa for progressive hemorrhagic TBI. These patients were given a single dose of rFVIIa (120 mcg/kg) after a repeat head computed tomography (CT) scan showed worsening of intracranial bleeding. Pre-rFVIIa and post-rFVIIa coagulation parameters and postintervention CT scans were performed. A matched convenience sample was drawn from the institution's trauma registry reflecting similar injury patterns. RESULTS: The 2 patients who received rFVIIa were ages 61 and 79 years; the patients in the matched convenience sample were 57 and 63 years. Both sets of patients comprised 1 man and 1 woman who had suffered blunt trauma, including hemorrhagic TBI, and were matched according to age, gender, and injury severity score (ISS). During their hospital course, repeat CT scans documented worsening of intracranial hemorrhage in both cohorts. In the rFVIIa patients, follow-up CT showed overall improvement of head injury compared with the convenience sample. The rFVIIa patients also saw an appreciable decrease in both prothrombin time (PT) and international normalized ratio (INR). CONCLUSIONS: In hemorrhagic TBI, rFVIIa has the potential to limit or even halt the progression of bleeding that would otherwise place growing pressure on the brain. A prospective, randomized multicenter trial is planned to elucidate this hypothesis.     

Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials

BACKGROUND: Uncontrolled bleeding is a leading cause of death in trauma. Two randomized, placebo-controlled, double-blind trials (one in blunt trauma and one in penetrating trauma) were conducted simultaneously to evaluate the efficacy and safety of recombinant factor VIIa (rFVIIa) as adjunctive therapy for control of bleeding in patients with severe blunt or penetrating trauma. METHODS: Severely bleeding trauma patients were randomized to rFVIIa (200, 100, and 100 microg/kg) or placebo in addition to standard treatment. The first dose followed transfusion of the eighth red blood cell (RBC) unit, with additional doses 1 and 3 hours later. The primary endpoint for bleeding control in patients alive at 48 hours was units of RBCs transfused within 48 hours of the first dose. RESULTS: Among 301 patients randomized, 143 blunt trauma patients and 134 penetrating trauma patients were eligible for analysis. In blunt trauma, RBC transfusion was significantly reduced with rFVIIa relative to placebo (estimated reduction of 2.6 RBC units, p = 0.02), and the need for massive transfusion (>20 units of RBCs) was reduced (14% vs. 33% of patients; p = 0.03). In penetrating trauma, similar analyses showed trends toward rFVIIa reducing RBC transfusion (estimated reduction of 1.0 RBC units, p = 0.10) and massive transfusion (7% vs. 19%; p = 0.08). Trends toward a reduction in mortality and critical complications were observed. Adverse events including thromboembolic events were evenly distributed between treatment groups. CONCLUSION: Recombinant FVIIa resulted in a significant reduction in RBC transfusion in severe blunt trauma. Similar trends were observed in penetrating trauma. The safety of rFVIIa was established in these trauma populations within the investigated dose range.     

"Low-dose" recombinant activated factor VII results in less blood and blood product use in traumatic hemorrhage

BACKGROUND: This study was designed to compare mortality and blood product use in patients who received recombinant activated factor VII (rFVIIa) for traumatic hemorrhage to a matched historic control. METHODS: Trauma registry data of bleeding trauma patients who received rFVIIa (40 microg/kg, repeated once if needed) included 28-day mortality; pre- and post-rFVIIa international normalized ratio; and packed red blood cell (PRBC), fresh frozen plasma, platelet, and cryoprecipitate requirements. A control group was created of bleeding patients who did not receive rFVIIa by matching for Injury Severity Score and age. The chi2 and Student's t tests were used to test for significance. RESULTS: Twenty-nine patients, well matched to 72 control patients, made up the rFVIIa group. rFVIIa corrected international normalized ratio within 4 hours (from 4.4 to 1.2; p < 0.0001). There was no difference in mortality (control, 40.3%; rFVIIa, 41.4%). The rFVIIa group required significantly fewer PRBC transfusions than the control group (18.3 +/- 7.5 vs. 22.0 +/- 9.7; p = 0.036). Compared with the control group, the rFVIIa group required fewer platelet transfusions (1.4 +/- 1.2 vs. 2.3 +/- 2.1; p = 0.01) and less cryoprecipitate (0.59 +/- 0.54 vs. 1.5 +/- 1.8; p = 0.006). CONCLUSION: rFVIIa resulted in significantly less PRBC, platelet, and cryoprecipitate use and equivalent mortality when compared with the matched control group, with no increase in complications.     

Use of recombinant factor VIIa for adjunctive hemorrhage control in trauma and surgical patients

Recombinant factor VIIa (rFVIIa) has recently been described for patients with ongoing massive bleeding in a number of different clinical scenarios. A retrospective chart review was conducted at a public level I trauma center in order to describe the use of rFVIIa in trauma and surgical patients with massive bleeding despite surgical control. Fifteen trauma and general surgical patients underwent major operative procedures and developed coagulopathy requiring massive blood product transfusion. All patients had continued life-threatening hemorrhage despite surgical control of bleeding. The mean base deficit was 6 and arterial lactate was 9.0 mmol/L. An initial dose of rFVIIa was given intravenously, followed by a second dose if there was evidence of at least a partial response. Twelve of 15 patients who had been expected to die from hemorrhage survived for greater than 48 hours, and 7 survived to hospital discharge. A partial or complete hemostatic response to rFVIIa was noted in 12 of 15 patients. The number of blood products received after administration of rFVIIa was significantly reduced and the International Normalized Ratio (INR) decreased. Our experience demonstrates that rFVIIa may reduce or completely arrest coagulopathic bleeding in trauma and surgical patients after vascular control.     

Use of recombinant factor VIIa in pediatric patients with liver failure and severe coagulopathy

BACKGROUND: Several reports have suggested a benefit for recombinant Factor VIIa (rFVIIa) in nonhematological conditions, including liver disease and transplantation. However, there are few reports of its use in children with liver failure. Recently, we used rFVIIa in four patients with liver failure and severe coagulopathy with bleeding who demonstrated significant laboratory and clinical improvement following its use with no side effects. PATIENTS AND METHODS: All four patients were hospitalized with liver failure, coagulopathy, and bleeding that was controlled with fresh frozen plasma, platelets, and other therapies, as indicated. Their international normalization ratios (INR) ranged from 1.7 to 5.8 (normal 0.9-1.1). All four patients received rFVIIa for bleeding episodes that were not responding to their usual therapy, for procedures with a high risk of bleeding, or both. The dose of rFVIIa ranged from 0.067 to 0.3 mg/kg. The INR improved to normal or near normal in all four patients. In all cases, bleeding stopped within 10 minutes of receiving the rFVIIa, and there were no complications observed. CONCLUSIONS: rFVIIa provided significant benefit in these children with liver failure and severe coagulopathy, in terms of clinical and laboratory improvement in their bleeding and coagulation profiles. There were no obvious side effects from the rFVIIa. This drug may be an important tool in the treatment of children with liver failure and more study is needed to define the optimal dosing for children.     

Recommandations européennes pour l'utilisation du facteur VII activé recombinant comme thérapeutique adjuvante du saignement majeur

Objective

To develop consensus guidelines for use of recombinant activated factor VII (rFVIIa) in massive hemorrhage.

Methods

A guidelines committee derived the recommendations using clinical trial and case series data identified through searches of available databases. Guidelines were graded on a scale of A-E according to the strength of evidence available. Consensus was sought among the committee for each recommendation.

Results

A recommendation for use of rFVIIa in blunt trauma was made (grade B). rFVIIa might also be beneficial in post-partum hemorrhage (grade E), uncontrolled bleeding in surgical patients (grade E) and bleeding following cardiac surgery (grade D). rFVIIa could not be recommended for use: in penetrating trauma (grade B); prophylactically in elective surgery (grade A) or liver surgery (grade B); or in bleeding episodes in patients with Child-Pugh A cirrhosis (grade B). Efficacy of rFVIIa was considered uncertain in bleeding episodes in patients with Child-Pugh B and C cirrhosis (grade C). Monitoring of rFVIIa efficacy should be performed visually and by assessment of transfusion requirements (grade E), while thromboembolic adverse events are a cause for concern. rFVIIa should not be administered to patients considered unsalvageable by the treating medical team.

Conclusion

There is a rationale for using rFVIIa to treat massive bleeding in certain indications, however, only adjunctively to the surgical control of bleeding once conventional therapies have failed. Lack of data from randomized, controlled clinical trials, and possible publication bias of the case series data, limits the strength of the recommendations that can be made.     

Safety and hemostatic effect of recombinant activated factor VII in cirrhotic patients undergoing partial hepatectomy: a multicenter, randomized, double-blind, placebo-controlled trial

BACKGROUND: Coagulopathy caused by cirrhosis may contribute to excessive bleeding during hepatectomy. We evaluated the hemostatic effect and safety of recombinant factor VIIa (rFVIIa) in cirrhotic patients undergoing partial hepatectomy. METHODS: Patients were randomized to rFVIIa 50 or 100 mug/kg or placebo, administered intravenously 10 minutes before surgery and every second hour during surgery. The primary efficacy end points were the proportion of patients receiving red blood cell (RBC) transfusions and the amount of RBCs transfused. The RBC transfusion trigger was blood loss of 500 mL. Safety end points included thromboembolic and adverse events. RESULTS: No statistically significant effect of rFVIIa treatment on efficacy end points was observed. Serious and thromboembolic adverse events occurred at similar incidences in the study groups. CONCLUSIONS: Using blood loss as a transfusion trigger, the efficacy of rFVIIa in reducing the requirement for RBC transfusion was not established in this study. No safety concerns were identified.     

Early versus late recombinant factor VIIa in combat trauma patients requiring massive transfusion

BACKGROUND: Coagulopathy is a consequence of severe trauma, especially in massively transfused patients (>or=10 units of red blood cells in 24 hours), and is associated with increased mortality. We hypothesized that recombinant factor VIIa (rFVIIa) administered to massive transfusion patients before transfusion of 8 units of blood (early) would reduce transfusion requirements compared with rFVIIa after 8 units (late). METHODS: We retrospectively reviewed records for trauma admissions to combat support hospitals in Iraq between January 2004 and October 2005. Patients requiring a massive transfusion and receiving rFVIIa were identified. Groups were divided into those who received rFVIIa early or late. RESULTS: Of 5,334 trauma patients (civilian and military), 365 (6.8%) required massive transfusion. Of these, 117 (32%) received rFVIIa. Complete records for blood transfusions were available for 61 patients: 90% had penetrating trauma, 17 received rFVIIa early, and 44 received it late. At admission, temperature, heart rate, blood pressure, Glasgow Coma Scale score, base deficit, hemoglobin, platelets, prothrombin time/International Normalized Ratio, and Injury Severity Score were similar in both groups as were administered units of fresh frozen plasma, fresh whole blood, cryoprecipitate (cryo), and crystalloid. The early rFVIIa group required fewer units of blood during the first 24-hour period (mean 20.6 vs. 25.7, p=0.048) and fewer units of stored red blood cells (mean 16.7 vs. 21.7, p=0.049). Early and late mortality (33.3% vs. 34.2%, p=NS), acute respiratory distress syndrome (5.9 vs. 6.8%, p=NS), infection (5.9% vs. 9.1%, p=NS), and thrombotic events (0% vs. 2.3%, p=NS) were similar. CONCLUSIONS: Early administration of rFVIIa decreased red blood cell use by 20% in trauma patients requiring massive transfusion.     

Off-label use of recombinant activated factor VII in surgical and non-surgical patients at 16 Canadian hospitals from 2007 to 2010 (Canadian Registry Report)

Purpose

Recombinant activated factor VII (rFVIIa) is a pro-hemostatic drug that is approved for treatment of bleeding in hemophilia patients, but it is frequently used off-label in non-hemophiliacs. The purpose of this study was to determine if the off-label use of rFVIIa is expanding and whether this poses a net harm to patients.

Methods

For this historical cohort study, data were collected on all non-hemophilia patients who received rFVIIa from 2007 to 2010 at 16 Canadian centres, and the pattern of use was examined. Logistic regression was used to determine the prognostic importance of severity of bleeding and the presence of an rFVIIa dose-effect relationship with major adverse events.

Results

One thousand three hundred seventy-eight patients received rFVIIa off-label, and 987 (72%) of these patients underwent cardiac surgery. The median [interquartile range] dose was 57 [36-85] µg·kg^?1. Usage increased from 2007 to 2008 (n = 341 and 380, respectively) but decreased in 2009 and 2010 (n = 350 and 307, respectively). Dose of rFVIIa and bleeding severity were associated with measured adverse events (P < 0.05). After adjusting for bleeding severity, dose was not associated with any of the adverse events.

Conclusions

The off-label use of rFVIIa in Canada remains stable. Since severity of bleeding is prognostically important, the benefits of rapidly gaining control of bleeding that is non-responsive to conventional therapies may at times warrant the use of potent hemostatic drugs with established risk profiles, such as rFVIIa.     

Recombinant factor VIIa for control of hemorrhage: early experience in critically ill trauma patients

STUDY OBJECTIVE: To examine our institutional experience with recombinant Factor VIIa (rFVIIa) as a treatment for exsanguinating hemorrhage in critically ill trauma patients. DESIGN: Retrospective case review. SETTING: A specialized trauma and critical care hospital, serving as the quaternary referral center for trauma and surgical shock in the state of Maryland. PATIENTS: All patients with diffuse coagulopathy and impending exsanguination, given rFVIIa in an effort to control life-threatening hemorrhage. Patients were in the intensive care unit (ICU) or operating room (OR) and included both acute admissions and late-stage patients with multiple organ system failure. INTERVENTIONS: Patients of interest were those that had received rFVIIa. MEASUREMENTS: Examination of medical records, including pharmacy data, laboratory results, and the institutional trauma registry. MAIN RESULTS: Administration of rFVIIa contributed to successful control of hemorrhage in three of five patients. Failure in two patients was mostly likely due to overwhelming shock and acidosis. CONCLUSIONS: Administration of rFVIIa shows promise in the treatment of exsanguinating hemorrhage. Prospective, controlled clinical trials of this therapy are strongly recommended.     

Treatment of critical bleeding in trauma patients

AIM: Massive haemorrhage after trauma is a big challenge for care-givers, being a leading cause of early in-hospital mortality. Surgical bleeding may be easily controlled with several techniques. Otherwise, consumptive coagulopathy is often extremely difficult to stop. An adjunctive strategy to treat traumatic coagulopathic bleeding is recombinant activated factor VII (rFVIIa) (NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark). METHODS: All major trauma victims haemodinamically unstable (systolic blood pressure < 90 mmHg or > 90 mmHg with massive infusions or vasopressors) admitted to the Emergency Department of the Niguarda Ca' Granda Hospital in Milan from October 2002 to September 2005 were reviewed. Mechanical bleeding was controlled with interventional techniques when indicated. Blood derivatives were administrated to maintain haemoglobin> 7 g/dL, INR < 1.5, fibrinogen > 1 and platelet count > 50 x 109. Off-label administration of rFVIIa was performed in the last year in any coagulopathic salvageable patient when all other strategies failed to control bleeding. RESULTS: Major trauma were 942, mean age 32.49+/-18.44 years, 94% blunt trauma, 25.13% haemodynamically unstable. Deaths occurred in 17.02% of cases before any procedure. Emergency invasive treatments were performed in 72.34% of cases. Infusions restored haemodynamic stability in 10.63% of patients. In average 9.4+/-4.1 units of red blood cells were transfused in unstable patients. rFVIIa (dosing 60-100 mg/kg) was administrated in 12 patients. Mortality occurred in 33.33% of cases. The principal cause of death was brain injury. A femoral artery thrombosis was observed in a mangled leg. No other adverse effects due to rFVIIa were documented. CONCLUSIONS: Off-label administration of rFVIIa was able to reverse life-threatening bleeding not manageable with standard strategies in our series of major trauma patients without systemic adverse effects.     

Intraoperative use of recombinant activated factor VII (rFVIIa)

Recombinant activated factor VII (rFVIIa, Novoseven, Novo Nordisk, Denmark) was introduced as a prohemostatic agent in the early 80s: the only indication approved in USA by Food and Drug Administration (FDA) is the spontaneous bleeding in congenital hemophilia patients who developed inhibitors to FVIII and FIX. Recently, EMEA approved the use of rFVIIa in congenital hemophilia patients with inhibitors undergoing surgery, in subjects with congenital FVII deficiency undergoing surgical or invasive procedures, in patients with acquired hemophilia and in case of Glanzmann's thromboasthenia. Out of these approved indications, the off label use of rFVIIa is rapidly expanding, particularly in surgical patients with acquired coagulation disorders in order to manage severe, uncontrolled bleeding nonresponsive to conventional therapeutic measures or to reduce blood loss and transfusion requirements in potentially bleeding surgical procedures (major liver surgery, liver transplantation, major abdominal or obstetric surgery, trauma surgery). This paper reviews the more recent data coming from retrospective or prospective studies performed in different surgical settings: so far, the major point to be addressed is the place for rFVIIa as an adjunctive but sometimes lifesaving treatment to control haemostasis and critical bleeding in surgery and critically ill patients.     

Recombinant activated coagulation factor VII and bleeding trauma patients

BACKGROUND: Recombinant activated coagulation factor VII (rFVIIa) is increasingly being administered to massively bleeding trauma patients. rFVIIa has been shown to correct coagulopathy and to decrease transfusion requirements. However, there is no conclusive evidence to suggest that rFVIIa improves the survival of these patients. The purpose of this study was to determine whether or not rFVIIa has an effect on the in-hospital survival of massively bleeding trauma patients. METHODS: A retrospective cohort study was conducted from January 1, 2000 to January 31, 2005, at a Level I trauma center in Toronto, Canada. Inclusion criteria included trauma patients requiring transfusion of 8 or more units of packed red cells within the first 12 hours of admission. The primary exposure of interest was the administration of rFVIIa. Primary outcome was a 24-hour survival and secondary outcome was overall in-hospital survival. RESULTS: There were 242 trauma patients identified who met inclusion criteria; 38 received rFVIIa. rFVIIa patients were younger, had more penetrating injuries, and fewer head injuries. However, rFVIIa patients required more red cell transfusions initially, and were more acidotic. Administering rFVIIa was associated with improved 24-hour survival, after adjusting for baseline demographics and injury factors. The odds ratio (OR) for survival was 3.4 (1.2-9.8). Furthermore, there was a strong trend toward increased overall in-hospital survival. The OR of in-hospital survival was 2.5 (0.8-7.6). Also, subgroup analysis of rFVIIa patients showed that 24-hour survivors required a slower initial rate of red cell transfusion (4.5 vs. 2.9 units/hr, p = 0.002), had higher platelet counts (175 vs. 121 [x10(-9)/L], p = 0.05) and smaller base deficits (7.1 vs. 14.3, p = 0.001) compared with rFVIIa patients who died during the first 24 hours. CONCLUSION: rFVIIa may be able to improve the early survival of massively bleeding trauma patients. However, surgical control of massive hemorrhage still has primacy, as rFVIIa did not appear efficacious if extremely high red cell transfusion rates were required. Also, correction of acidosis and thrombocytopenia may be important for rFVIIa efficacy. Prospective studies are required.     

Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease.

Orthotopic liver transplantation (OLT) can be associated with excessive blood loss. As a result, there may be increased risk of adverse outcomes. Activated recombinant factor VII (rFVIIa) has demonstrated the ability to improve hemostasis in a variety of disorders; however, there has been a limited amount of research into its use in OLT. The purpose of this dose-finding study was to examine the efficacy and safety of rFVIIa in the reduction of bleeding in patients undergoing OLT. In this double-blind trial, patients with end-stage liver disease scheduled for OLT were randomized to 1 of 4 parallel study groups. They received a single intravenous bolus of rFVIIa (20, 40, or 80 microg/kg) or placebo prior to surgery. The primary assessment endpoint was the total number of red blood cell (RBC) units transfused perioperatively. Safety was evaluated by adverse events reported. Eighty-three comparable patients were randomized to receive study product, with 82 ultimately undergoing OLT. There were no significant differences in required RBC units between the placebo and rFVIIa study groups. The number of adverse events was comparable between study groups. In conclusion, rFVIIa has a good safety profile in patients undergoing OLT. However, the doses studied did not have any effect on the number of RBC transfusions required.     

Use of recombinant factor VIIa for uncontrolled bleeding in neonates after cardiopulmonary bypass

Background:  Increasingly, recombinant activated factor VII (rFVIIa) is used adjunctively in nonhemophiliacs to control hemorrhage unresponsive to conventional therapy in a variety of settings including postcardiopulmonary bypass (CPB). Studies examining rFVIIa administration to neonates after CPB are limited. The goal of this study was to evaluate retrospectively the clinical outcomes of neonates treated at our institution with rFVIIa for uncontrolled post-CPB bleeding.
Methods:  We retrospectively identified eight neonates undergoing complex congenital cardiac surgery who received rFVIIa, either intraoperatively or postoperatively, for uncontrolled post-CPB bleeding. Transfusion trends and prothrombin times (PT) were assessed both pre- and post-rFVIIa administration. Chest tube drainage volumes were recorded pre- and post-rFVIIa administration in those neonates receiving rFVIIa postoperatively in the intensive care unit. We documented such adverse events as thrombosis, dialysis (hemodialysis and peritoneal dialysis), extracorporeal membrane oxygenation (ECMO) and in-hospital mortality.
Results:  The mean amount of transfused packed red blood cells, platelets and fresh frozen plasma decreased significantly after the administration of rFVIIa. Transfusion of cryoprecipitate trended towards a decrease but did not reach statistical significance. PT values also decreased significantly after the administration of rFVIIa. A high mortality was found in neonates exposed to both rFVIIa and ECMO; however, this was not significantly different from the mortality of neonates exposed to ECMO alone.
Conclusions:  Administration of rFVIIa to neonates for the treatment of uncontrolled post-CPB bleeding significantly reduced transfusion requirements and normalized PT values. Future randomized, controlled trials are needed to evaluate the potential hemostatic benefit and adverse effects of rFVIIa administration to neonates following CPB.     

Recombinant factor VIIa as an adjunct in nonoperative management of solid organ injuries in children

Background

Ongoing bleeding after blunt solid organ injury in children may require invasive therapy in the form of either angiographic or operative control. We report our experience in the use of a procoagulant, recombinant activated factor VII (rFVIIa), for controlling persistent bleeding in blunt abdominal trauma in children.

Methods

After institutional review board approval, the records of 8 children with blunt abdominal trauma, persistent bleeding, and managed nonoperatively with rFVIIa were reviewed.

Results

All 8 patients presented to our institution after sustaining blunt abdominal trauma and solid organ injury. All children had evidence of persistent bleeding with a drop in hematocrit and elevation in heart rate. Patients received a single dose of rFVIIa at 75 to 90 μg/kg (1 patient had 24 μg/kg) and had successful control of their bleeding without any further therapeutic intervention. Only 3 patients required a blood transfusion after rFVIIa administration—2 who had subarachnoid hemorrhages and the third during pelvic fixation. There were no cases of thromboembolic events after treatment with rFVIIa.

Conclusions

Recombinant factor VIIa is a useful adjunctive therapy in pediatric patients with evidence of ongoing hemorrhage from blunt abdominal injury and may reduce the need for invasive therapeutic procedures and transfusions.     

An open non-randomized study of recombinant activated factor VII in major postpartum haemorrhage

BACKGROUND: Empirical off-label use of recombinant activated factor VII (rFVIIa) has been reported to be effective in some cases of severe postpartum haemorrhage (PPH). Successful management of these patients has lead to more wide-spread use of rFVIIa in less severe cases without any evidence for the advantages of its administration. METHODS: Until November 2006, we had administered rFVIIa to 38 parturients. Based on our initial experience with the first 12 patients, we prepared guidelines for the use of rFVIIa. During the existence of these guidelines, we made a retrospective comparison of the 26 women who received rFVIIa with another 22 women who were treated during the same time period without using rFVIIa. RESULTS: The total amount of blood loss was significantly higher (11.3 +/- 4.5 vs. 8.0 +/- 3.1 l), and the coagulation screen revealed significantly longer partial thromboplastin time (APTT) and prothrombin time (PT) values and significantly lower fibrinogen values in patients receiving rFVIIa. The need for red blood cells, platelets and fibrinogen concentrate was significantly higher in these women. Although the response was considered good in two-thirds of the women, several patients received rFVIIa with a poor or no response as a result of arterial bleeding. CONCLUSION: The decision to use rFVIIa resulted from a more profound haemorrhage. We did not gain any evidence to extend the use of rFVIIa into less severe cases of PPH. Furthermore, this policy would result in a profound increase in the overall costs of the treatment. Randomized placebo-controlled trials are urgently needed to optimize the use of rFVIIa in obstetric haemorrhage.