Recombinant activated factor VII use in critically ill infants with active hemorrhage

Introduction

Recombinant activated factor VII (rFVIIa) is infrequently used off-label in infants despite a paucity of data in this population. We report a retrospective review of rFVIIa use in infants focusing on safety and efficacy.

Method

Between 2002 and 2007, 32 critically ill nonhemophiliac infants less than 1 year old received rFVIIa at our institution. Indications of rFVIIa and post-rFVIIa venous thrombosis were reviewed. Transfusion requirements were calculated 8 hours before and after rFVIIa administration.

Results

Infants received on average 2 doses of rFVIIa at a mean dosage of 90 μg/kg. Active hemorrhage was the indication for rFVIIa in 24 infants, which included postoperative bleeding in 16 and nonsurgical bleeding in 8. The remaining 8 infants had preoperative coagulopathy. Thrombosis was noted in 4 infants (13%) and was not related to transfusion requirements, the number of doses, or dosage of rFVIIa. For infants who had active hemorrhage, rFVIIa was able to significantly reduce the requirements of packed red blood cells by 36.17 mL/kg (P < .005), platelets by 10.31 mL/kg (P < .01), and cryoprecipitates by 2.19 mL/kg (P < .05).

Conclusion

This is the first large case series demonstrating the efficacy of rFVIIa in critically ill infants with active hemorrhage by reducing their transfusion requirements. Furthermore, venous thrombosis was not associated with increase in either the number of doses or dosage of rFVIIa.     

Recombinant factor VIIa for treatment of massive liver fracture in a premature infant

Recombinant factor VIIa (rFVIIa) is a highly efficacious therapy initially used to treat the bleeding diathesis of hemophiliac patients that has recently gained a wider role in the treatment of liver disease, thrombocytopenia, and intracerebral and traumatic hemorrhage. Data with regard to the use of rFVIIa within the pediatric population for the treatment of liver injury, however, are limited. We present a case report of successful treatment using rFVIIa of an iatrogenic liver injury in a 1200-g infant who was undergoing resection of a large sacrococcygeal teratoma. In addition, we review the issues of surgical relevance to the pediatric surgeon relating to rFVIIa's mechanism of action and dosages for clinical application.     

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.     

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.     

Small-dose recombinant activated factor VII (NovoSeven) in cardiac surgery

Recombinant activated factor VII (rFVIIa) has been used at different doses in cardiac surgery patients. We tested the efficacy of small-dose rFVIIa in patients with intractable bleeding after cardiac surgery. The study group comprised 15 cardiac surgery patients with intractable bleeding treated with small-dose (1.2 mg) rFVIIa as a slow IV bolus at the end of complete step-by step transfusion protocol. Fifteen matched patients undergoing the same transfusion protocol in the pre-rFVIIa era represented the control group. Blood loss at the end of the transfusion protocol was a primary outcome. Median, 25th-75th 24-h blood loss percentiles were 1685 (1590-1770) mL versus 3170 (2700-3850) mL in study group and controls, respectively (P = 0.0004). Transfused red blood cells, fresh-frozen plasma, and platelets in the study group and controls were as follows: 7 (4-8) U versus 18 (12-21) U (P = 0.001); 7.5 (6-11) U versus 11 (9-15) U (P = 0.003); 0 (0-4) U versus 9 (6-13) U (P = 0.001). In addition, significant improvements of prothrombin time (P = 0.015), international normalized ratio (P = 0.006), activated partial prothrombin time (P = 0.01), and platelet count (P = 0.003) were detected in the study group versus controls. Finally, patients receiving rFVIIa showed a reduced intensive care unit length of stay (chi2 = 15.9, P = 0.0001) and had infrequent surgical re-exploration (chi2 = 16.2,P < 0.0001). Small-dose rFVIIa showed satisfactory results in cardiac patients with intractable bleeding. Further randomized studies are necessary to confirm our findings.     

Recombinant factor VIIa for life-threatening bleeding in high-risk cardiac surgery despite full-dose aprotinin

We report the case of an orthotopic heart transplant in a patient with multiple previous cardiac surgeries. The case was prolonged and complicated by severe coagulopathy and bleeding despite the use of full-dose aprotinin throughout. Bleeding was not controlled after 30 U of platelets, 20 U of fresh frozen plasma, and 10 U of cryoprecipitate. However, after the administration of recombinant factor VIIa 90 microg/kg, the rate of bleeding slowed dramatically and no further factor replacement was required. There was no evidence of unwanted clot formation within the newly transplanted heart or around the intraaortic balloon pump that remained in situ for 72 h postoperatively. With the combined risks of coagulopathy and bleeding as well as acute right ventricular failure with increases in pulmonary vascular resistance, the re-do sternotomy for heart transplant seems to be an ideal situation in which to consider the use of recombinant factor VIIa.     

Successful use of recombinant factor VIIa (NovoSeven) in children with compartment syndrome: two case reports

Compartment syndrome (CS) is an uncommon bleeding manifestation in patients with liver failure and end-stage renal disease (ESRD). Although prompt intervention is paramount in preventing the tissue necrosis and the permanent functional deficits that may be associated with untreated CS, the indications for initiating therapies for children with CS are not standardized. In this report, we present 2 children, one with ESRD and the other with liver failure, who have CS related to life-threatening bleeding complications and were treated with recombinant factor VIIa (rFVIIa). In conclusion, treatment decisions for patients with CS should be made on a case-by-case basis. The use of rFVIIa is an effective and safe treatment in children with liver failure and ESRD. Surgical treatment should be preferred in patients with CS. However, in patients who have a coagulation defect, the first priority is to correct the clotting deficiency. The use of rFVIIa is a treatment option in children with CS due to a coagulation defect.     

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.     

Use of thromboelastograph and factor VII for the treatment of postoperative bleeding in a pediatric patient on ECMO after cardiac surgery

This report describes a case of possibly fatal bleeding treated successfully with an "overdose" of recombinant factor VII (rFVII; Novo7). A 3.5-year-old boy had surgery for aortic stenosis and aortic arch repair and was placed on extracorporeal membrane oxygenation (ECMO) after a prolonged cardiopulmonary bypass time (CPB); there was subsequent failure to wean from CPB because of right ventricular failure. Subsequently, a severe coagulopathy developed, and despite large volume transfusions with blood and blood products, this was unresolved. Thromboelastograph (TEG) measurements were obtained, and on the advice of the Hematology Department, Novo7 (recommended dose: 15-30 microg/kg) was administered at a dose of 200 microg/kg because of the severity of the bleeding. TEG was repeated, and a further dose of Novo7 was administered at 500 microg/kg; a further TEG after 15 minutes showed normalization, and the remaining bleeding was treated surgically. The patient was weaned from ECMO 48 hours later and was subsequently discharged home with no further problems. Novo7 in an "overdose" can apparently correct major coagulopathy even in patients on ECMO support with no dire effects on the ECMO circuit or the patient in a life-threatening scenario.     

Recombinant activated factor VII (rFVIIa) treatment in infants with hemorrhage

BACKGROUND: Recombinant activated factor VII (rFVIIa) is approved by the FDA for the treatment of bleeding episodes in patients with hemophilia A or B with inhibitors to factor VIII or factor IX. In addition to the FDA-approved indications, rFVIIa has been anecdotally reported effective for profound bleeding episodes in adult patients without hemophilia, and proven beneficial for adults with intracranial hemorrhage. In the pediatric literature, case reports have been made with apparent clinical improvement seen after the use of rFVIIa for acute life-threatening bleeding; however, there are limited data regarding its use in infants<4 months of age. We report our experience with rFVIIa in nine infants with severe hemorrhage of diverse etiologies. METHODS: This case series of infants under 4 months with coagulopathy and bleeding treated with rFVIIa was collected from two institutions. We report the age, weight and pre-rFVIIa laboratory values of the patients as well as the clinical scenario and outcomes. RESULTS: The nine infants all suffered acute life-threatening hemorrhage. Two patients were postoperative from cardiac surgery, two with Vitamin K deficiency and intracranial hemorrhage, three with suspected necrotizing enterocolitis and abdominal hemorrhage, and two with pulmonary hemorrhage. The patients ranged in age from 2 days to 4 months, (average age 1 month and average weight 3.3+/-1.0 kg). Seven of the nine patients had frozen plasma, cryoprecipitate, or platelet administration in failed attempts to correct the coagulation defect prior to receiving rFVIIa. The dose range used in this series was 90-100 microg.kg-1, with 90 microg.kg-1 being the most commonly used dose. The average pre-rFVIIa INR was 8.7+/-5.1. Four patients had an immeasurably high INR. All patients had clinical resolution of bleeding after receiving rFVIIa, and seven of nine patients survived. CONCLUSIONS: rFVIIa is a powerful hemostatic drug whose mechanism of action provides a theoretical specificity to sites of tissue injury. In addition to its FDA-approved uses in hemophiliac patients, this drug has a potential role in the treatment of life-threatening hemorrhage from multiple causes.     

The use of recombinant factor VIIa (NovoSeven) for treatment of active or impending bleeding in brain injury: broadening the indications

We report three patients with severe traumatic brain injury, both open and closed, who were treated with recombinant activated factor VII. This treatment was given in a desperate, last-ditch effort to save the life of patient 1, as a preventive or early treatment of a developing hematoma in patient 2, and as treatment of a threatening hematoma in patient 3. One of the three patients survived. During the past few years we have broadened the indications for recombinant activated factor VII and started using it as a preventive measure rather than as a "last line of defense." However, the potential complications of disseminated intravascular coagulation and thrombotic events, as well as the cost-effectiveness in view of the available evidence-based medicine, should be considered.     

Recombinant activated factor VII administration in a patient with congenital lack of factor VII undergoing laparoscopic hysterectomy: A case report

Introduction and importanceCase report of patient with congenital lack of factor VII, suffering from recurrent hematomas and massive menstrual bleedings resulting in severe anemia and multiple hospitalization.Case presentationPatient was diagnosed with endometrial hyperplasia and not responding to hormonal treatment and substitution with recombinant factor VII was not effective to reduce the bleedings. This case describes successful laparoscopic technique of using bipolar coagulation and non-absorbable clips.Clinical discussionWe describe premedication and post-surgical management – which we had to modify from this found in very scarce literature. Despite previous vaginal deliveries without any complications during the puerperium, 20 days after the surgery patient presented with intraperitoneal bleeding after stopping rFVIIa therapy. It was treated medically without the need for re-laparoscopy.ConclusionLaparoscopic surgery is possible in patients with lack and deficiency of FVIIa, but they need close post-operative surveillance and prolonged supplementation with recombinant FVIIa.     

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.