Modulation of the Coagulation Cascade Using Recombinant Factor VIIa and Activated Protein C in a Severely Injured Trauma Patient

Abstract Exsanguination after trauma remains a leading cause of early death in severely injured patients [1]. Sepsis and multiple organ failure are significant causes of mortality in severely injured trauma patients who survive their injury and require a prolonged ICU hospitalization [2]. Despite advances in operative technique and critical care medicine, the treatment options for patients with coagulopathic hemorrhage or severe sepsis have remained relatively unchanged. We report a unique case in which pharmacological modulators of coagulation, recombinant Factor VIIa, and activated protein C were successfully used to treat massive hemorr-hage and then severe sepsis in a severely injured trauma patient.     

Recombinant factor VIIa for the treatment of severe postoperative and traumatic hemorrhage

BACKGROUND: The aim of this study was to determine the dose of recombinant factor VIIa (rFVIIa) that has been used in our institution to successfully control hemorrhage in trauma and postoperative patients. METHODS: This was an 8-month retrospective cohort study of 13 patients with acute hemorrhage and no known history of coagulopathic disorders. RESULTS: Administration of factor VIIa resulted in the cessation of life-threatening hemorrhage at dosages approximately one half those recommended for the management of hemophilia. After administration, there was a significant decrease in the total blood-product transfusion requirement (P <0.05). CONCLUSIONS: The use of factor VIIa in patients with life-threatening hemorrhage is a safe and effective therapeutic modality when used as an adjunct to standard interventions for control of severe hemorrhage. Lower-dose regimens were as successful as higher-dose regimens previously reported. The results of this respective study of 13 patients suggests that recombinant factor VIIa therapy for control of life-threatening hemorrhage as an adjunct to standard interventions can be successful at doses <90 mg/kg.     

Recombinant factor VIIa for intraoperative bleeding in a child with hepatoblastoma and review of recombinant activated factor VIIa use in children undergoing surgery

We report a case of a child with a large liver mass who underwent an open liver biopsy and had massive bleeding intraoperatively. Recombinant activated factor VII (rFVIIa) given intraoperatively was successful in stopping the bleeding. We also reviewed the literature on the use of rFVIIa in pediatric surgery.     

Cost-Effectiveness of Recombinant Activated Factor VII as Adjunctive Therapy for Bleeding Control in Severely Injured Trauma Patients in Germany

Abstract Purpose: The purpose of this study was to assess the cost-effectiveness of recombinant activated factor VII (rFVIIa) as adjunctive therapy for the control of bleeding in patients with severe blunt trauma injuries in Germany. The primary outcome measure was incremental cost per quality-adjusted life-year (QALY) gained. Materials and Methods: We developed a cost-effectiveness model based on patient-level data from a 30 day international, randomized, placebo-controlled phase II trial. The data were supplemented with secondary data from the German Trauma Register and German life tables to estimate lifetime costs and benefits. We assumed that the non-significant difference in mortality observed in the phase II trial of 5% in favor of rFVIIa could be verified in the ongoing, much larger follow-up trauma study. We adopted the perspective of third-party payers in Germany, and included all trauma-related healthcare costs. Results: The incremental cost per QALY gained with rFVIIa relative to placebo was e29,451. The probability that this was below e30,000 and e40,000 was 51 and 58%, respectively. The estimates were sensitive to the differences observed in mortality and the applied discount rate. Conclusions: Based on preliminary evidence from a phase II trial, we conclude that, relative to placebo, rFVIIa may be a cost-effective therapy from the thirdparty payer perspective in Germany.     

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.     

The impact of blood product ratios in massively transfused pediatric trauma patients

Background

Few studies have examined the impact of balanced resuscitation in pediatric trauma patients requiring massive transfusions. Adult data may not be generalizable to children.

Methods

Retrospective analysis assessed patients seen at a level I trauma center between 2003 and 2010 aged ≤18 years requiring massive packed red blood cell (PRBC) transfusion, defined as transfusion of ≥50% total blood volume. After excluding mortalities in the first 24 hours, the impact of plasma and platelet ratios on mortality was evaluated.

Results

Of 6,675 pediatric trauma patients, 105 were massively transfused (mean age, 12.4 ± 6.3 years; mean Injury Severity Score, 25.8 ± 11.4; mortality rate, 18.1%). All deceased patients sustained severe head injuries. Plasma/PRBC and platelet/PRBC ratios were not significantly associated with mortality.

Conclusions

In this study, higher plasma/PRBC and platelet/PRBC ratios were not associated with increased survival in children. The value of aggressive blood product transfusion for injured pediatric patients requires further prospective validation.     

Liver Rupture in a Patient with HELLP Syndrome Successfully Treated with Extensive Surgery Combined with Recombinant Factor VIIa

Massive gastric dilatation with necrosis and rupture is a very rare event. Here we describe the case of a 13-year-old girl with acute gastric dilatation, infarction, necrosis and perforation. It began with acute abdominal pain, but an absence of vomiting after eating a heavy meal. Laparotomy showed massive gastric dilatation with infarction and perforation.

Early diagnosis is essential to reduce morbidity and mortality, and therefore treatment must be started promptly.     

Recombinant factor VIIa for life-threatening post-partum haemorrhage

The treatment of life-threatening post-partum haemorrhage (PPH)still remains challenging, and hysterectomy may be requiredto control the bleeding. We present 12 cases of severe PPH treatedwith recombinant factor VIIa (rFVIIa). We briefly describe thecauses of the haemorrhage and the medical and surgical interventionsbefore rVIIa administration. In 11 women there was a partialor good response to rFVIIa administration, while in one therewas no response. In the four women undergoing a subsequent selectivearterial embolization, the bleeding was significantly reducedalthough not completely stopped. From our experience with these12 cases, and from previously reported cases, the use of rFVIIamay be of benefit in life-threatening PPH. However, treatmentwith rFVIIa, in addition to standard surgical and medical interventions,may not be definitive in every patient and a selective arterialembolization may be needed.      

The use of factor VIIa in haemorrhagic shock and intracerebral bleeding

Factor VIIa is a revolutionary new pharmaceutical that promises to change the anaesthesia and critical care approach to major trauma. It is an extremely potent pro-coagulant agent, and while it enables haemostasis at the site of tissue injury, it also has the possibility of producing life-threatening thromboembolic complications. New data regarding FVIIa use is published almost every month, leading to a rapidly evolving clinical understanding of the potential indications, and potential pitfalls, of off-label use. Determination of appropriate practice, including the ability to judge the risks and benefits of FVIIa therapy for individual cases, is still some years in the future, and will depend in large part on clinical trials which are just getting underway.     

The successful use of recombinant factor VIIa in a patient with vascular-type Ehlers-Danlos syndrome

Vascular-type Ehlers-Danlos syndrome is an inherited connective tissue disorder resulting in an increased risk of serious peri-operative bleeding during surgery for spontaneous organ or vessel rupture. The excessive bleeding may result in coagulopathy, and thus compound the difficulty in securing surgical haemostasis. With the advent of recombinant factor VIIa, a new therapy has become available for the management of intractable surgical bleeding.     

Treatment of Diffuse Pulmonary Hemorrhage with Factor VIIa

Abstract  Blunt thoracic trauma resulting in lung contusion with severe diffuse pulmonary hemorrhage and massive hemoptysis is rare and has a poor prognosis. Treatment options are limited. We report a case of the successful use of recombinant activated factor VII (NovoSeven™) in the treatment of life-threatening diffuse pulmonary hemorrhage secondary to an isolated blunt force thoracic injury without relevant traumatic coagulopathy.     

The use of recombinant activated factor VII in trauma patients: Experience from the Australian and New Zealand haemostasis registry

BACKGROUND: There is increasing use of rFVIIa (eptagog alpha, Novoseven) in injured patients with critical bleeding. The role of rFVIIa is not defined in this group of patients. Registries provide an opportunity to review the patients, reported response and adverse events for rFVIIa. AIM: To determine the pattern of use, reported response and adverse events in patients receiving rFVIIa following injury using the Australian and New Zealand Haemostasis Registry (ANZHR). METHODS: The ANZHR (commenced May 2005) collects data from 53 hospitals on all patients receiving rFVIIa in those hospitals. RESULTS: Of 695 cases in the registry, 108 patients from 19 hospitals were submitted with a primary trauma diagnosis. Most (88) patients received one 90microg/kg dose of rFVIIa. There was a significant reduction in the use of all blood products following rFVIIa (p<0.001) and rFVIIa was thought to have decreased or stopped bleeding in 59% of cases. There was wide variation in the timing of rFVIIa use. There were two adverse events that were considered possibly linked and a total of three thromboembolic events. Following multivariate analysis, pH provided the best model of response to rFVIIa. Patients with a pH<7.05 were significantly less likely to respond (OR=0.3, 95% CI=0.0-0.3). Only two patients would fit the criteria for the present prospective study of rFVIIA in trauma patients. CONCLUSION: The best approach to managing critical bleeding in trauma patients is not agreed. The role of rFVIIa will only be clarified if there is a standardised approach to fluid management and transfusion of blood products. The registry allows tracking of current practice, outcomes and adverse events and will complement present phase 2 and 3 trials.     

Recombinant FVIIa decreases perioperative blood transfusion requirement in burn patients undergoing excision and skin grafting--results of a single centre pilot study

BACKGROUND: Excision of burn wounds is frequently associated with a large volume of blood loss requiring allogeneic blood transfusion. We conducted a pilot study to investigate the effect of activated recombinant coagulation factor VII (rFVIIa) on the reduction of blood transfusion requirements in burn patients undergoing excision and skin grafting. METHODS: Eighteen consecutive patients scheduled for the surgery were randomised to receive either placebo or 40 microg/kg rFVIIa administered at first skin incision, and a second dose (40 microg/kg) at 90 min later. Blood transfusion requirements during, and up to 24h post-surgery per patient and percentage full thickness wound excised were compared. In addition, postoperative complications commonly seen in patients with burns as well as adverse events related to rFVIIa were monitored. RESULTS: rFVIIa significantly decreased the total number of units of blood components transfused per patient and percentage full thickness burn wound excised compared with placebo (0.9 versus 2.2, p=0.0013) including significant fewer red blood cell units (0.5 versus 1.1, p=0.004). We further observed a trend towards improved graft survival (p=0.1) and a reduction in multiple organ failures (p=0.08) in the rFVIIa-treated group. There were no adverse events, in particular thromboembolic events. CONCLUSION: rFVIIa might be useful in decreasing blood transfusion requirements in burn patients undergoing excision and skin grafting.     

Recombinant factor VIIa (NovoSeven) as a hemostatic agent after surgery for congenital heart disease

BACKGROUND: Postoperative bleeding and blood product requirements can be substantial in children undergoing open-heart surgery, and reexploration is required in 1% of cases. Recombinant activated factor VII (rFVIIa, NovoSeven, NovoNordisk, Denmark) is a hemostatic agent approved for the treatment of hemophilic patients with inhibitors to factor VIII or factor IX. It has also been used with success in other conditions. We present our experience with rFVIIa treatment for uncontrolled bleeding after open-heart surgery in five pediatric patients. METHODS: The study group consisted of five patients after open-heart surgery with excessive blood loss. The patients were treated with rFVIIa after failure of conventional treatment to control the bleeding. Blood loss, blood product consumption, and coagulation test results were recorded before and after rFVIIa administration. RESULTS: In all cases, blood loss decreased considerably after rFVIIa administration (mean 7.8 ml x kg(-1) x h(-1)), almost eliminating the need for additional blood products, and the prolonged prothrombin time normalized. In two patients with thrombocytopathy, rFVIIa helped to discriminate surgical bleeding from bleeding caused by a defect in hemostasis. No side effects of rFVIIa treatment were noted. CONCLUSIONS: These cases support the impression that RFVIIa is efficient and safe in correcting hemostasis in children after cardiopulmonary bypass when other means fail. However, the data are still limited, and more extensive research is needed.