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.     

Novoseven use in a non-cardiac pediatric ECMO patient with uncontrolled bleeding

Despite the presence of normal coagulation values, refractory bleeding during extracorporeal membrane oxygenation (ECMO) is encountered. Occasionally, hemostasis is not achieved through traditional techniques including surgical exploration, anti-fibrinolytics, increasing fibrinogen level, increasing platelet counts, and decreasing activated clotting time (ACT). We report the case of an infant on veno-arterial ECMO for respiratory syncytial virus with severe bleeding and the use of recombinant activated factor VII (rFVIIa; NovoSeven; Novo Nordisk, Copenhagen, Denmark). This was a retrospective review of the patient's medical records, laboratory values, and chest radiographs. rFVIIa was given to this patient on two separate occasions for bleeding unresponsive to traditional bleeding management. On both occasions, the patient's blood loss returned to zero within 20 minutes of administration and remained there for a minimum of 4 days. Continued bleeding on ECMO unresponsive to current medical management may be an indication for rFVIIa. However, rFVIIa should not be administered without first considering the ECMO circuits conditions to include presence of clot, and documentation of circuit pressures, which, after rFVIIa, may be the first indication of intraoxygenator clot formation. Additionally, rFVIIa should not be a first-line treatment until continued studies allow for approved use in this patient population.     

Is recombinant activated factor VII effective in the treatment of excessive bleeding after paediatric cardiac surgery?

A best evidence topic in paediatric cardiac surgery was written according to a structured protocol. The question addressed was whether recombinant activated factor VII was effective for the treatment of excessive bleeding after paediatric cardiac surgery. Altogether 150 papers were found using the reported search; 13 papers were identified that provided the best evidence to answer the question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these studies were tabulated. A total of 311 children experienced excessive bleeding following cardiac surgery that was refractory to the conventional methods of achieving haemostasis. One hundred and ninety-two patients received the rFVIIa while 116 were in control arm from five studies. The primary end-point was on chest tube drainage, the plasma prothrombin time, the activated partial thromboplastin time after the administration of rFVIIa and the secondary end-point was reduction of blood products transfusion. Thrombosis was a complication in 8 patients (4.2%); three deaths (1.6%) but not attributable to thromboembolic events following the use of rFVIIa. Most of the studies failed to clearly state the doses but the extracted doses ranged between 30 and 180?μg/kg/dose, the interval between doses ranged between 15 and 120?min with a maximum of four doses. However, most of the patients had 180?μg/kg/dose with interval between dose of 2?h and maximum of two doses with dosage moderated with respect to weight, prior coagulopathy and responsiveness. There were two randomized studies with good sample size. One showed no significant differences in the secondary end points between the two arms and noted no adverse complications. However, the rFVIIa was used prophylactically. The other observed that there were no increase in thromboembolic events rather rFVIIa was effective in decreasing excessive bleeding that may complicate cardiac surgery in children. In conclusion, the studies were in support of the notion that the use of rFVIIa was effective in decreasing excessive bleeding which may complicate paediatric cardiac surgery, and care should be exercised when using it in the children on ECMO circuit.     

Usefulness of activated recombinant factor VII for controlling massive bleeding: 4 years' experience in a university hospital

OBJECTIVE: Massive bleeding that cannot be controlled by the usual means, such as transfusion, is a serious medical problem with high associated mortality. Our aim was to assess the efficacy and safety of treatment with activated recombinant factor VII (rFVIIa) to control massive bleeding after the failure of other methods. PATIENTS AND METHODS: This was a retrospective study of all cases of rFVIIa-treated massive bleeding in patients without a history of coagulation disorder from January 2003 through June 2007. RESULTS: The prevalence of rFVIIa treatment for this indication was 1 in 5200 hospitalized patients. Thirty patients were treated. Bleeding was reduced or stopped in 80% and consumption of blood products was reduced after administration of rFVIIa. Mortality was 43% and death was due to continued bleeding in 5 cases. No deaths were due to thromboembolism. CONCLUSIONS: rFVIIa is efficacious for controlling bleeding and reducing transfusion requirements in cases of massive hemorrhage, but mortality unrelated to bleeding is high in patients experiencing this complication. Further study is needed to better assess the utility, dosing, and ideal timing in the use of this drug.     

Five Days of No Anticoagulation or Antiplatelet Therapy and NovoSeven Administration in a HeartWare HVAD Patient

Postoperative bleeding is the most common complication following the implantation of ventricular assist devices. This is a case report of a HeartWare HVAD patient with intractable bleeding following chest tube insertion necessitating massive blood transfusion and multiple thoracotomies. Anticoagulation and antiplatelet therapy were discontinued and intravenous NovoSeven was administered as last resort. Bleeding ceased immediately and no pump-related issues were observed. However, thrombus formation in the right atrium and superior vena cava was detected.     

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 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.     

Recombinant Factor VIIa in Pediatric Cardiac Surgery

ObjectivesRecombinant activated factor VIIa (rVIIa) is used off-label for refractory bleeding after cardiac surgery. This study reviewed the indications, usage rates, and complications of rVIIa.DesignA retrospective case-control observational study.SettingA single quaternary pediatric hospital.ParticipantsAll children undergoing cardiac surgery with cardiopulmonary bypass over a three-year period.InterventionsAdministration of rVIIa as rescue therapy for refractory bleeding after weaning from cardiopulmonary bypass.Measurements and Main ResultsOnethousand, five hundred fifteen cardiopulmonary bypass procedures were reviewed. Patients receiving rVIIa were each matched to two control patients by age, procedure type, and bypass time. Data collected included weight, crossclamp time, anticoagulant and antifibrinolytic dose, return to the operating room for bleeding, thrombotic events, and extracorporeal membrane oxygenation (ECMO) circuit interventions.Forty-two patients received rVIIa (2.8%). Major systemic thrombotic complications were observed in 19% (controls 12.5%) of patients; 80% of recombinant factor VIIa patients requiring postoperative ECMO had interventions for circuit thrombosis (controls 31.25%); 4.76% of rVIIa recipients required reexploration for intractable bleeding (controls 1.39%).ConclusionsThis study added to understanding regarding the use of recombinant factor VIIa in pediatric cardiac surgery and reported increased thrombotic complications, especially for children who progress to ECMO. Prospective studies to better understand the pathophysiology of coagulopathy and hemorrhage in pediatric cardiac surgery and the role of hemostatic agents, such as rVIIa, are required.     

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.     

Venovenous Extracorporeal Membrane Oxygenation With Prophylactic Subcutaneous Anticoagulation Only: An Observational Study in More Than 60 Patients

Extracorporeal lung support and therapeutic anticoagulation are dogmatically linked for most clinicians in fear of clotting of the extracorporeal circuit. In the last decade, however, we have learned that bleeding complications in the course of extracorporeal membrane oxygenation (ECMO) therapy are common and not occasionally limiting or fatal. Even though international guidelines lowered the PTT‐target values, ECMO therapy without anticoagulation has only been reported sporadically in case reports heretofore. This monocentric, observational study was designed to evaluate a protocol for venovenous ECMO therapy without additional anticoagulation. Patients without former thrombotic events solely received thrombosis prophylaxis with 40 mg subcutaneous enoxaparin per day like every critical care patient. After approval by the local ethics committee (Albert‐Ludwigs‐University Freiburg ethics committee, EK 513/14) all consecutive patients treated with venovenous ECMO therapy since introduction of the protocol have been identified. Digital charts of the patients have been evaluated with special regard to bleeding and thrombotic or embolic events or breakdown of the extracorporeal circuit. Sixty‐one patients received venovenous ECMO therapy with prophylactic subcutaneous enoxaparin only. Median duration of ECMO therapy was 7 days (2–32). Overall 560 ECMO days have been observed. No system exchange because of thrombotic occlusion was necessary within the permitted 5 days run time of the centrifugal pump. Overall we identified thrombotic complications in four patients. In three of them centrifugal pump after a runtime of more than 5 days unexpectedly stopped completely because of thrombotic occlusion. In all cases pump exchange was performed promptly and patients did not incur hypoxic deficit. One other patient received substitution of blood products and coagulation factor concentrates because of severe bleeding and sustained myocardial infarction the day after. Only 18% of patients presented with essential clinical bleeding after 7 days of therapy. No fatal bleeding event and no intracranial hemorrhage was observed. Patients required only a third of blood product transfusion compared to published data. Venovenous ECMO therapy with prophylactic anticoagulation only was feasible in this study. It was not associated with an increased rate of system exchanges compared to regimes with therapeutic anticoagulation in registry data. It provides the potential to relevantly decrease the incidence of severe bleeding events and blood transfusion requirements. The apodictic adherence to anticoagulation in therapeutic dosage should be critically scrutinized in every patient.     

Antithrombin replacement during extracorporeal membrane oxygenation

Heparin remains the predominant anticoagulant during extracorporeal membrane oxygenation (ECMO). Heparin acts by potentiating the anticoagulant effect of antithrombin (ATIII). Acquired ATIII deficiency, common in pediatric patients requiring ECMO, may result in ineffective anticoagulation with heparin. ATIII replacement may result in increased bleeding. Our objective is to determine ATIII's effect on anticoagulation and blood loss during ECMO. A retrospective chart review was performed of all patients at Children's Hospital of Wisconsin who received ATIII while supported on ECMO in 2009. ATIII activity levels, heparin drip rate, and activated clotting times (ACT) were compared before, 4, 8, and 24 h after ATIII administration. Chest tube output and packed red blood cell (pRBC) transfusion volume were compared from 24 h before ATIII administration to 24 h after. Twenty-eight patients received ATIII as a bolus dose during the course of 31 separate times on ECMO support. The median age of these patients was 0.3 years (range 1 day-19.5 years). ATIII activity increased significantly at 8 and 24 h after administration. No significant difference was noted in heparin drip rate, ACT levels, chest tube output, or pRBC transfusion volume. ATIII administration resulted in higher ATIII activity levels for 24 h without a significant effect on heparin dose, ACT, or measures of bleeding.     

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.     

"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.     

Audit of factor VIIa for bleeding resistant to conventional therapy following complex cardiac surgery

PURPOSE: There are an increasing number of anecdotal reports and trials of recombinant activated factor VII (rFVIIa) for bleeding during surgery. The reports of rFVIIa during cardiac surgery are limited. We report our experience using rFVIIa, in the operating room; to treat bleeding that prevented chest closure, despite appropriate conventional treatment, following complex cardiac surgery. METHODS: Retrospective chart review, at an Australian University hospital and associated private hospital, of cardiac surgery patients given rFVIIa (usual dose 90 microg.kg(-1)). We used rFVIIa for bleeding that prevented closure of the chest despite administration of blood products, protamine, and surgical attempts to secure hemostasis. RESULTS: Recombinant activated factor VII was administered on 55 occasions to 53 patients. Most patients had complex aortic or valve surgery. Median bypass time was 266 min. Before administering rFVIIa, patients received (median): packed red cells four units; platelets 15 units; fresh frozen plasma eight units; and cryoprecipitate ten units. After administering rFVIIa the median doses of donor blood products up to 12 hr after intensive care unit admission were: packed red cells one unit; platelets zero units; fresh frozen plasma zero units; and cryoprecipitate zero units. The decrease in doses of all blood products was significant (P < 0.001). We could not determine if rFVIIa played a role in significant mortality (19%) and morbidity (17%). CONCLUSION: Use of rFVIIa in cardiac surgery may be effective, but definitive clinical trials are needed to clarify its role in clinical practice and safety. We present an rFVIIa guideline developed during the audit period.     

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.     

Surgical complications and procedures in neonates on extracorporeal membrane oxygenation.

We report our experience from May 1985 to January 1991 with surgical complications and procedures performed in neonates on extracorporeal membrane oxygenation (ECMO) (218 venoarterial and 7 venovenous bypass). Eleven children older than 1 month were excluded. Total complications were 96 in 67 patients and included: bleeding (37), problems with initial cannula placement (17), thrombus formation (15), hemothorax, pneumothorax, or effusions (11), mechanical problems (11), and miscellaneous (5). Forty-eight procedures were performed in 37 patients while on ECMO. These were recannulation or reposition of cannulas (14), tube thoracostomy (11), cardiac surgery (6), cardiac catheterization (4), repair of congenital diaphragmatic hernia (5), thoracotomy (4), and others. Twenty-eight complications occurred in 15 of the 27 patients who died. Mortality rate was 12% for the entire group. Primary causes of death were hypoplastic lung (11), cardiac (8), sepsis (4), intraventricular hemorrhage (2), and pulmonary hypertension (2). No deaths were due solely to complications except for the two patients with intraventricular hemorrhage. Mortality in neonates who had complications while on ECMO was significantly higher (P less than .005) than in patients without complications. Hemorrhagic and thoracic complications were associated with higher mortality (P less than .001). Mortality was not affected by mechanical problems, thrombus formation, or catheter-related problems. While on ECMO cardiac defects, diaphragmatic hernia, lobar emphysema, and other conditions can be safely corrected. The use of echocardiography to position the cannulas, better control of coagulation factors and improvement in equipment may ultimately decrease complications.     

Critical bleeding in pregnancy: a novel therapeutic approach to bleeding

AIM: In the developed countries the frequency of life threatening post-partum hemorrhages (PPH) is 1 in 1,000 deliveries with a risk of death of 1-2/100,000 deliveries. Hysterectomies for intractable bleeding are carried out in approximately 50% of the cases. The majority of PPH have obstetrical causes, most frequently atony of the uterus. Hereditary and acquired hemostatic defects are very rare. Guidelines of standard surgical and medical measures are available. In this paper we focus on the use of activated recombinant factor VII (rFVIIa) in PPH. METHODS: A computerized literature search was carried out in PubMed and Ovid for papers published between 2001 and 2005 in the English literature reporting on life-threatening PPH treated with rFVIIa after failure of conventional therapy, including hysterectomy. RESULTS: We identified 11 papers including 39 patients; in 18 of them the laboratory data were indicative for disseminated intravascular coagulation and in 24 hysterectomy was carried out. Controlled or reduced bleeding was reported in 38 out of 39 treated patients. CONCLUSIONS: The bleeding can occur in a series of events conductive to metabolic complications, hypoxia, disseminate intravascular coagulation, organ damage and multiorgan failure, progressively exhaustive. The therapeutic intervention must be instituted as early as possible before successive complications ensue. These preliminary reports in PPH after failure of conventional standard therapy suggest that rFVIIa is an active agent but should be administered as early as possible before the consequences of severe and intractable bleeding.     

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.     

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.     

Probable right atrial thrombus immediately after recombinant activated factor VII administration

We report the finding of a probable right atrial thrombus ina 33-yr-old male patient with severe head, chest, and abdominaltrauma. Refractory coagulopathy and gross haemodynamic instabilityensued, which was only partially controlled with massive bloodproduct transfusion and high-dose inotropic support during laparotomy.Continuous transoesophageal echocardiography revealed a probableatrial thrombus partially occluding the right ventricular inflowtract, which appeared immediately after the patient received100 µg kg^–1 of recombinant activated factor VII(rFVIIa) via a left internal jugular central line. This is thefirst report documenting an immediate temporal relationshipbetween rFVIIa administration and a space-occupying lesion compatiblewith localized thrombosis, despite ongoing severe systemic coagulopathy.We review the clinical use of rFVIIa and discuss possible factorscontributing to this event.