Recombinant activated factor VII for adjunctive hemorrhage control in trauma

BACKGROUND: Recombinant activated factor VII (rFVIIa) was approved for treatment of hemorrhages in patients with hemophilia who develop inhibitors to factors VIII or IX. Conditions with increased thromboembolic risk, including trauma with or without disseminated intravascular coagulation, were considered a contraindication for the drug. The mechanism of action of rFVIIa suggests enhancement of hemostasis limited to the site of injury without systemic activation of the coagulation cascade. Therefore, use of the drug in trauma patients suffering uncontrolled hemorrhage appears to be rational. METHODS: Seven massively bleeding, multitransfused (median, 40 units [range, 25-49 units] of packed cells), coagulopathic trauma patients were treated with rFVIIa (median, 120 microg/kg [range, 120-212 microg/kg]) after failure of conventional measures to achieve hemostasis. RESULTS: Administration of rFVIIa resulted in cessation of the diffuse bleed, with significant decrease of blood requirements to 2 units (range, 1-2 units) of packed cells (p < 0.05); shortening of prothrombin time and activated partial thromboplastin time from 24 seconds (range, 20-31.8 seconds) to 10.1 seconds (range, 8-12 seconds) (p < 0.005) and 79 seconds (range, 46-110 seconds) to 41 seconds (range, 28-46 seconds) (p < 0.05), respectively; and an increase of FVII level from 0.7 IU/mL (range, 0.7-0.92 IU/mL) to 23.7 IU/mL (range, 18-44 IU/mL) (p < 0.05). Three of the seven patients died of reasons other than bleeding or thromboembolism. CONCLUSION: The results of this report suggest that in trauma patients rFVIIa may play a role as an adjunctive hemostatic measure, in addition to surgical hemostatic techniques, and provides the motivation for controlled animal and clinical trials.     

Low-dose recombinant factor VIIa for trauma patients with coagulopathy

INTRODUCTION: Coagulopathy in injured patients is common and is generally treated with fresh frozen plasma (FFP). Response can be variable, thus complete correction may take hours and require large volumes of fluids. High-dose recombinant factor VIIa (FVIIa, Novoseven, Novo Nordisk, Bagsvaerd, Denmark) has been used off-label to treat severe coagulopathy following trauma. Expense has limited use. Recently, we began administering low dose FVIIa (1.2mg) to patients with mild to moderate coagulopathy after trauma, hypothesising that it would be effective and safe. PATIENTS AND METHODS: We retrospectively reviewed consecutive patients who received a low dose of 1.2mg of FVIIa over a 2-year period. Factor VIIa is administered after approval by a gatekeeper at the discretion of the treating physician. Demographics, injury and laboratory data were abstracted as were indications for use, source of coagulopathy, effectiveness, and complications. A two-tailed paired t-test was used to determine significant changes in coagulation parameters and blood product utilisation. RESULTS: Eighty-one patients received 84 low doses of FVIIa. The mean age of the patients was 51 (+/-22) with a mean ISS of 29 (+/-11). Seventy-three per cent were male and 67% had a traumatic brain injury (TBI) as their primary injury. The aetiology of the coagulopathy in the study population included; TBI (40%), warfarin use (22%), and cirrhosis (13%). Mean prothrombin time (PT) fell from 17.0s (+/-3.2) to 10.6s (+/-1.4) (p<0.0001). All patients had a good clinical response with no bleeding complications. Utilisation of packed red blood cells and fresh frozen plasma were significantly less in the 24h after FVIIa administration as compared to the 24h prior. Subsequent thromboembolic events were observed in 12 of the 81 patients (15%) and included; cerebrovascular accident (CVA) (6), mesenteric thrombosis (2), myocardial infarction (MI) (1), pulmonary embolism/deep venous thrombosis (PE/DVT) (2), and atrial thrombus (1). Only four of these events were thought to be related to the FVIIa administration, with two of the four contributing to a lethal outcome. CONCLUSIONS: Low dose FVIIa rapidly and effectively treats mild to moderate coagulopathy following injury. This low dose (1.2mg) FVIIa is the smallest available unit dose. It costs approximately the same as 8 units of plasma and may be cost-effective in patients who require high volume factor administration. Low dose FVIIa may be effective in coagulopathic trauma patients who are not in shock but require rapid normalisation of clotting function.     

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.     

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.     

Determinants of futility of administration of recombinant factor VIIa in trauma

BACKGROUND: "Off-label" use of human coagulation factor VIIa (FVIIa) is presently restricted to patients in extremis at our institution. Although bleeding will diminish in most patients, some will still die early as a result of irreversible shock and/or rebleeding. Futile administration of FVIIa significantly increases the economic burden of this expensive therapy and therefore limits its availability. On the basis of both human and in vitro studies, profound acidosis may be expected to predict lack of response. In addition, the depth of hemorrhagic shock, as defined by the degree of hypoperfusion over a given period of time, may be predictive of failure of FVIIa administration. We hypothesized that retrospective review of FVIIa use would identify variables associated with clinical futility. METHODS: Characteristics of patients receiving FVIIa for acute traumatic hemorrhage were identified. Patients were retrospectively stratified into two groups; those who died as a result of acute hemorrhagic shock (nonresponders) and those in whom hemostasis was achieved and sustained (responders). Demographics, laboratory values, transfusion requirements, and outcomes were recorded for all patients. Data were analyzed using the Student's t test to identify the clinical characteristics of nonresponders and stepwise logistic regression was then used to identify independently predictive factors. A classification and regression tree analysis was conducted to develop a decision tree on the basis of our results. RESULTS: Eighty-one patients received FVIIa therapy over a 3-year period. Among the 46 patients treated for acute hemorrhage, there were 26 with blunt and 20 with penetrating mechanisms of trauma. Average age was 35 +/- 15 years, 72% were male, and the average Injury Severity Score was 36 +/- 15. Revised Trauma Score (RTS), lactate, and preadministration prothrombin time (PT) each predicted lack of response (p < 0.05 for each). RTS and PT were independently predictive of failure of response. An RTS of less than 4.09 and a PT of greater than or equal to 17.6 seconds were significantly associated with futile administration of FVIIa. Age was a significant factor in patients with a PT greater than or equal to 17.6 seconds, whereas ISS was significant in patients with an RTS greater than or equal to 4.09. CONCLUSION: Profound acidosis and coagulopathy may predict failure of FVIIa therapy. Depth of hemorrhagic shock, as described by the RTS, was also associated with futile administration. These variables should be considered as potential contraindications to the use of FVIIa. Earlier administration of FVIIa, before the development of massive blood loss and severe shock, may increase the rate of clinical response.     

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.     

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.     

The utility of recombinant factor VIIa as a last resort in trauma

Introduction

The use of recombinant factor VII (rFVIIa) as a last resort for the management of coagulopathy when there is severe metabolic acidosis during large bleedings in trauma might be deemed inappropriate. The objective of this study was to identify critical degrees of acidosis and associated factors at which rFVIIa might be considered of no utility.

Methods

All massively transfused (≥ 8 units of red blood cells within 12 hours) trauma patients from Jan 2000 to Nov 2006. Demographic, baseline physiologic and rFVIIa dosage data were collected. Rate of red blood cell transfusion in the first 6 hours of hospitalization (RBC/hr) was calculated and used as a surrogate for bleeding. Last resort use of rFVIIa was defined by a pH≤ 7.02 based on ROC analysis for survival. In-hospital mortality was analyzed in last resort and non-last resort groups. Univariate analysis was performed to assess for differences between groups and identify factors associates with no utility of rFVIIa.

Results

71 patients who received rFVIIa were analyzed. The pH> 7.02 had 100% sensitivity for the identification of potential survivors. All 11 coagulopathic, severely acidotic (pH ≤ 7.02) patients with high rates of bleeding (4RBC/hr) died despite administration of rFVIIa. The financial cost of administering rFVIIa as a last resort to these 11 severely acidotic and coagulophatic cases was $75,162 (CA).

Conclusions

Our study found no utility of rFVIIa in treating severely acidotic, coagulopathic trauma patients with high rates of bleeding; and thus restrictions should be set on its usage in these circumstances.

     

Recombinant factor VIIa in trauma patients without coagulation disorders

Recombinant activated factor VIIa (rFVIIa) has many clinical applications for patients with congenital bleeding disorders and in a variety of clinical settings. Additional studies in the future are ongoing and should provide the clinical anesthesiologist an additional option during certain bleeding states. Specific recommendations as to timing of administration and frequent monitoring of ionized calcium status are suggested at this time. Optimization of fibrinogen levels, platelet levels, pH, and body temperature will enhance efficacy of rFVIIa.     

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.     

Administration of recombinant factor VIIa decreases blood loss after blunt trauma in noncoagulopathic pigs

BACKGROUND: Activated factor VII catalyzes the activation of clotting factors IX and X within the clotting cascade, and has been used clinically to decrease bleeding in patients with hemophilia and other bleeding disorders. Studies suggest the use of recombinant VIIa (rVIIa) may decrease bleeding after injury in the presence of a coagulopathy, but there is conflicting evidence regarding its use in the absence of coagulopathy. This study was performed to determine whether a single dose of rVIIa would reduce blood loss in noncoagulopathic pigs after blunt trauma. METHODS: Anesthetized pigs were subject to multiple blunt injuries consisting of a femur fracture, liver laceration, and soft-tissue crush injury. Fifteen minutes after the trauma, pigs were randomized to receive a single 120 microg/kg dose of rVIIa or placebo. Mean arterial pressure, heart rate, temperature, and hematocrit (Hct) were measured during a 2-hour period of standardized fluid resuscitation. The primary endpoint was blood loss. RESULTS: The degree of trauma in the two groups was similar. Animals in the treated group had a mean blood loss of 19.6 mL/kg (13.5-25.7) versus 30.0 mL/kg (24.8-35.3) in the control group (p = 0.037). CONCLUSIONS: A single dose of 120 microg/kg of rVIIa can significantly decrease blood loss in traumatized pigs with no preexisting coagulopathy. Further studies are required to determine the lowest effective dose of this medication.     

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.     

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.