To determine whether recombinant factor VIIa (rFVIIa) is associated with increased survival and/or thromboembolic complications.
Uncontrollable hemorrhage is the main cause of early mortality in trauma. rFVIIa has been suggested for the management of refractory hemorrhage. However, there is conflicting evidence about the survival benefit of rFVIIa in trauma. Furthermore, recent reports have raised concerns about increased thromboembolic events with rFVIIa use.
Consecutive massively transfused (≥ 8 units of red blood cells within 12 h) trauma patients were studied. Data on demographics, injury severity scores, baseline laboratory values and use of rFVIIa were collected. Rate of transfusion in the first 6 h was used as surrogate for bleeding. Study outcomes included 24‐hour and in‐hospital survival, and thromboembolic events. A multivariable logistic regression analysis was used to determine the impact of rFVIIa on 24‐hour and in‐hospital survival.
Three‐hundred and twenty‐eight patients were massively transfused. Of these, 72 patients received rFVIIa. As expected, patients administered rFVIIa had a greater degree of shock than the non‐rFVIIa group. Using logistic regression to adjust for predictors of death in the regression analysis, rFVIIa was a significant predictor of 24‐hour survival (odds ratio (OR) = 2.65; confidence interval 1.26–5.59; p = 0.01) but not of in‐hospital survival (OR = 1.63; confidence interval 0.79–3.37; p = 0.19). No differences were seen in clinically relevant thromboembolic events.
Despite being associated with improved 24‐hour survival, rFVIIa is not associated with a late survival to discharge in massively transfused civilian trauma patients.
Coagulopathy; Bleeding; Thromboembolic events; Hemorrhagic shock
Uncontrolled bleeding continues to be a major cause of mortality in trauma, cardiac surgery, postpartum hemorrhage and liver failure. The aim of this paper is to assess the evidence supporting the efficacy of activated recombinant factor VII (rFVIIa) administration in these settings.
Electronic literature search.
Numerous retrospective trials have mostly shown a decrease in blood transfusion requirements with no increase in thromboembolic events (TEE), but major limitations in trial design make generalization difficult. In most retrospective reports rFVIIa has been administered as a last-ditch attempt to control bleeding, when acidosis, hypothermia and coagulation factor depletion may not allow optimal rFVIIa effect. Prospective randomized controlled trials have not shown any effect of rFVIIa on mortality or TEE, although some have shown a reduction in RBC requirement.
Stipulated transfusion protocols in prospective trials have reduced anticipated mortality among controls and make future trials for mortality effect unlikely in view of large sample size requirements. Establishment of these protocols and rapid hemostasis are likely to have greater benefits than administration of a single agent.
Factor VII; Coagulation factors; Bleeding complication
Spinal fusion surgery in children and adolescents with idiopathic scoliosis is often associated with severe haemorrhage. Recombinant coagulation factor VIIa (rFVIIa) has previously been shown to be an effective haemostatic treatment for severe bleeding associated with a variety of coagulopathic and non-coagulopathic indications. The aim of this retrospective study was to assess the safety and haemostatic efficacy of rFVIIa in a series of 26 consecutive adolescent patients with scoliosis (22 females; mean age 16.6 years) undergoing correctional surgery. A second series of 26 consecutive patients (20 females; mean age 16.2 years) who received standard therapy during surgery, represented historical controls. Blood loss, transfusion requirements, duration of surgery, and peri-operative measurements of coagulation parameters were compared between the two groups. Intra-operative and combined intra-operative and post-operative blood losses were significantly smaller in the rFVIIa-treatment group than in the historical controls (P=0.003 and 0.032, respectively); rFVIIa-treated patients also demonstrated significantly reduced blood loss per vertebral segment fused (P=0.032) and per hour of surgery (P<0.001). Intra-operative requirements for packed red blood cells were also significantly lower in the treatment group (P=0.042). Patients in the treatment group demonstrated rapid and maintained reduction of prothrombin time and international normalised ratio; values among rFVIIa-treated patients remained significantly lower than those in the control group at all time points evaluated (P<0.001). There were no deaths and no adverse events. These results suggest that rFVIIa is a safe and effective haemostatic agent for use during spinal fusion surgery in adolescent patients with idiopathic scoliosis; however, further research and randomised, placebo-controlled trials are needed to confirm these findings.
Bleeding; Haemostasis; Scoliosis; Surgery; RFVIIa
Refractory post cardiopulmonary bypass (CPB) bleeding continues to cause concern for cardiac surgeons and intensivists. Massive postoperative hemorrhage following CPB is multifactorial and not fully understood, and it is also associated with increased mortality and morbidity. Activated recombinant factor VII (rFVIIa) has emerged as possible salvage medication in refractory post cardiac surgical bleeding. This observational study sought to identify the pattern of use of rFVIIa in cardiac surgery, its effectiveness, and risk.
This study involved a retrospective case review of medical records of ten patients undergoing a variety of cardiac surgery procedures and who developed life-threatening bleeding during surgery or after surgery despite conventional medical therapy, including transfusion of blood and blood products, and received rFVIIa at a regional center between August 2007 and April 2009.
All ten patients received two consecutive doses of rFVIIa (average dose 65 μg/kg) at a 2-hour interval. Eight patients were re-explored due to massive postoperative bleeding or cardiac tamponade before receiving rFVIIa. Surgical sources of bleeding were not identified in any cases. A second re-exploration was carried out in two cases. Two patients (20%) died in ITU from problems not related to bleeding and thromboembolism. Blood loss was significantly reduced after administration of rFVIIa. Blood loss 6 hours prior to treatment was 1758.5 ± 163.9 mL and blood loss in the 6-hour period post treatment was 405.6 ± 50.5 mL (P < 0.05). Blood and blood products used in the 6-hour period before and after administration of rFVIIa were 19.6 ± 1.5U and 4.4 ± 0.6U, respectively (P < 0.05). No adverse reactions or thrombotic complications related to rFVIIa were noted.
In our limited study, use of rFVIIa in refractory post surgical bleeding was significantly reduced blood loss and use of blood and blood products. We concluded that rFVIIa can be used satisfactorily and safely as a rescue therapy in the management of post cardiac surgical bleeding.
cardiopulmonary bypass; CPB; refractory bleeding; rFVIIa
Recombinant activated coagulation factor VII (rFVIIa) is known to be effective in the management of acquired deficiencies of factor VII and platelet function defects. But recently, rFVIIa has been successfully used to treat ongoing bleeding in disseminated intravascular coagulopathy (DIC) condition. The patient reported here was suspected to be suffering from toxic hepatitis on admission. After percutaneous liver biopsy, bleeding occurred and did not stop even after right hepatic artery embolization. The patient developed a severe hemorrhage that resulted in hypovolemic shock, hemoperitoneum, and a massive subcapsular hematoma. The patient then developed DIC due to massive transfusion, as well as acute liver necrosis. The patient was given 400 μg/kg of rFVIIa. Recombinant factor VIIa was administered in an attempt to control the bleeding. This stabilized the hemoglobin levels of the patient. The patient gradually recovered in 4 months. In conclusion, this case suggests that rFVIIa can be successfully used for the hemostasis of uncontrolled bleeding in DIC.
Recombinant activated coagulation factor VII; Subcapsular hematoma
We conducted a post-hoc analysis on the effect of recombinant factor VIIa (rFVIIa) on coagulopathic patients from two randomized, placebo-controlled, double-blind trials of rFVIIa as an adjunctive therapy for bleeding in patients with severe trauma.
Blunt and penetrating trauma patients were randomly assigned to rFVIIa (200 + 100 + 100 μg/kg) at 0, 1, and 3 hours after transfusion of 8 units of red blood cells (RBCs) or to placebo. Subjects were monitored for 48 hours post-dosing and followed for 30 days. Coagulopathy was retrospectively defined as transfusion of fresh frozen plasma (FFP) (>1 unit of FFP per 4 units of RBCs), FFP in addition to whole blood, and transfusion of platelets and/or cryoprecipitate.
Sixty rFVIIa-treated and 76 placebo subjects were retrospectively identified as being coagulopathic. No significant differences were noted in baseline characteristics. The rFVIIa-treated coagulopathic subgroup consumed significantly less blood product: RBC transfusion decreased by 2.6 units for the whole study population (P = 0.02) and by 3.5 units among patients surviving more than 48 hours (P < 0.001). Transfusion of FFP (1,400 versus 660 ml, P < 0.01), platelet (300 versus 100 ml, P = 0.01), and massive transfusions (29% versus 6%, P < 0.01) also dropped significantly. rFVIIa reduced multi-organ failure and/or acute respiratory distress syndrome in the coagulopathic patients (3% versus 20%, P = 0.004), whereas thromboembolic events were equally present in both groups (3% versus 4%, P = 1.00).
Coagulopathic trauma patients appear to derive particular benefit from early adjunctive rFVIIa therapy.
The objective of this study is to evaluate the effectiveness of rfVIIa in reducing blood product requirements and re-operation for postoperative bleeding after major abdominal surgery.
Hemorrhage is a significant complication after major gastrointestinal and abdominal surgery. Clinically significant bleeding can lead to shock, transfusion of blood products, and re-operation. Recent reports suggest that activated rfVIIa may be effective in correcting coagulopathy and decreasing the need for re-operation.
This study was a retrospective review over a 4-year period of 17 consecutive bleeding postoperative patients who received rfVIIa to control hemorrhage and avoid re-operation. Outcome measures were blood and clotting factor transfusions, deaths, thromboembolic complications, and number of re-operations for bleeding.
Seventeen patients with postoperative hemorrhage following major abdominal gastrointestinal surgery (nine pancreas, four sarcoma, two gastric, one carcinoid, and one fistula) were treated with rfVIIa. In these 17 patients, rfVIIa was administered for 18 episodes of bleeding (dose 2,400-9,600 mcg, 29.8-100.8 mcg/kg). Transfusion requirement of pRBC and FFP were each significantly less than pre-rfVIIa. Out of the 18 episodes, bleeding was controlled in 17 (94%) without surgery, and only one patient returned to the operating room for hemorrhage. There were no deaths and two thrombotic complications. Coagulopathy was corrected by rfVIIa from 1.37 to 0.96 (p < 0.0001).
Use of rfVIIa in resuscitation for hemorrhage after non-traumatic major abdominal and gastrointestinal surgery can correct dilutional coagulopathy, reducing blood product requirements and need for re-operation.
Reoperation; Factor VII; Postoperative complications; General surgery; Coagulopathy
To evaluate the use of recombinant factor VIIa (rFVIIa) for the treatment of bleeding in nonhemophiliac children.
This was a retrospective chart review of all patients < 18 years of age who received rFVIIa over a 2 year period.
Twenty-four pediatric patients received a total of 240 doses of rFVIIa for treatment of bleeding. Recombinant factor VIIa was effective in achieving bleeding resolution in 54% of patients. The mean age of patients in the bleeding non-resolution versus resolution group was 50% younger (5.5 vs. 10.3 years, P = 0.104).
Bleeding resolution can be achieved with recombinant factor VIIa using similar doses to those recommended for children with hemophilia. Widespread use of rFVIIa for bleeding in children without hemophilia is not warranted given this efficacy data. Further safety studies are needed with rFVIIa in this population to clarify thrombotic risks.
children; factor VIIa; bleeding; hemophilia; non-hemophiliac
In 2006, the Canadian National Advisory Committee on Blood and Blood Products (NAC) developed a transfusion policy framework for the use of off-label recombinant factor VIIa (rFVIIa) in massive bleeding. Because the number of randomised controlled trials has doubled, the NAC undertook a review of the policy framework in 2011. On the basis of the review of 29 randomised controlled trials, there remains little evidence to support the routine use of rFVIIa in massive bleeding. Mortality benefits have not been demonstrated. Contrarily, an increase in arterial thromboembolic events has been observed with the use of off-label rFVIIa. Given the absence of evidence of benefit and with evidence of the risk of harm, the NAC recommends that recombinant VIIa no longer be used for the off-label indications of prevention and treatment of bleeding in patients without haemophilia.
massive transfusion; off-label use; recombinant factor VIIa
Recent studies and case reports have shown that recombinant factor VIIa (rFVIIa) treatment is effective for reversing coagulopathy and reducing blood transfusion requirements in trauma patients with life-threatening hemorrhage. The purpose of this study is to evaluate the effect of rFVIIa treatment on clinical outcomes and cost effectiveness in trauma patients.
Between January 2007 and December 2010, we reviewed the medical records of patients who were treated with rFVIIa (N=18) or without rFVIIa (N=36) for life-threatening hemorrhage due to multiple traumas at the Emergency Department of Pusan National University Hospital in Busan, Korea. We reviewed patient demographics, baseline characteristics, initial vital signs, laboratory test results, and number of units transfused, and then analyzed clinical outcomes and 24-hr and 30-day mortality rates. Thromboembolic events were monitored in all patients. Transfusion costs and hospital stay costs were also calculated.
In the rFVIIa-treated group, laboratory test results and clinical outcomes improved, and the 24-hr mortality rate decreased compared to that in the untreated group; however, 30-day mortality rate did not differ between the groups. Thromboembolic events did not occur in both groups. Transfusion and hospital stay costs in the rFVIIa-treated group were cost effective; however, total treatment costs, including the cost of rFVIIa, were not cost effective.
In our study, rFVIIa treatment was shown to be helpful as a supplementary drug to improve clinical outcomes and reduce the 24-hr mortality rate, transfusion and hospital stay costs, and transfusion requirements in trauma patients with life-threatening hemorrhage.
Recombinant factor VIIa; Multiple trauma; Clinical outcome; Mortality rate; Treatment cost
In this article we describe the current use of recombinant activated factor VII (rFVIIa; NovoSeven®) in trauma patients. Emphasis is placed on current uses as defined by key studies, efficacy data, and safety data. Most published studies in trauma patients are retrospective case studies and reports, although an international, double-blind, randomized, controlled, phase II study has been conducted that reported on the efficacy of rFVIIa in reducing the amount of blood products transfused in blunt trauma patients. That study demonstrated the efficacy and safety profile of this hemostatic agent as compared with placebo as adjunctive therapy in the management of severe bleeding associated with trauma. Further prospective, randomized, and placebo-controlled clinical trials will yield more information on the role of rFVIIa in the management of traumatic bleeding.
Recently, there has been an increased use of recombinant activated factor VII (rFVIIa) to promote hemostasis in various hemorrhagic conditions. The objective of this study was to determine the outcome of patients treated with rFVIIa who had intractable bleeding associated with cardiac surgery (CSP) or as a result of other causes (OBP).
The medical records of 40 consecutive patients treated with rFVIIa were retrospectively reviewed for blood product use before and after treatment. In all patients, rFVIIa was given only after all other measures to stop bleeding had failed. The number of transfused units of red cells (R), platelets (P), fresh frozen plasma (F), and cryoprecipitate (C) were determined both before and after administration of rFVIIa, and the results compared. Mortality at 4 hours and 30 days was assessed. Patients dying within 4 hours of rFVIIa administration were not evaluable for response. Patient characteristics were also assessed as risk factors for mortality.
Twelve of 24 CSP survived for more than 4 hours. These 12 patients required an average of 17 units (U) of R, 18 U of P, 18 U of F and 15 U of C pre-treatment compared to an average of 6 U, 10 U, 9 U and 4 U of R, P, F and C respectively, post-treatment. These differences were statistically significant. For the OBP, 11 of 16 survived more than four hours. These 11 patients required an average of 10 U of R, 11 U of P, 14 U of F and 10 U of C pretreatment compared to an average of 1 U, 2 U, 2 U and 0 U of R, P, F, and C respectively, post-treatment. With the exception of C, there was a statistically significant decrease in blood product use following treatment with rFVIIa. Of the survivors in each group, 6 of 12 CSP and 2 of 11 OBP died between 3 and 30 days post-treatment from causes other than bleeding. Mortality at 30 days for CSP and OBP survivors was 50% and 18% respectively, whereas overall 30 day mortality was 75% for CSP and 44% for OBP.
rFVIIa is effective in decreasing blood product use and promoting hemostasis in patients with intractable bleeding associated with cardiac surgery and a variety of other causes.
Recombinant activated factor VII (rFVIIa) has been used as adjunctive therapy in trauma patients with severe bleeding. However, its pharmacokinetics profile remains unknown.
In two placebo-controlled studies in patients with blunt and penetrating trauma, the pharmacokinetics of rFVIIa given at an initial dose of 200 μg.kg-1 after transfusion of eight red blood cell units, followed by additional doses of 100 μg.kg-1, one and three hours later, have been studied, based on the FVII coagulant activity assay. Both non-compartment and population pharmacokinetic analyses were performed. A two-compartment, population pharmacokinetic model was used to estimate a population profile for the rFVIIa dosing regimen. Data are population means (percent coefficient of variation (CV)).
Based on the two-compartment population model, the estimated pharmacokinetic parameters were: clearance 40 (30% CV) ml.kg-1.h-1; central volume of distribution 89 (32% CV) ml.kg-1; inter-compartmental clearance 24 ml.kg-1.h-1; and peripheral compartment volume 31 ml.kg-1. Baseline FVII coagulant activity was estimated at 0.29 (39% CV) U.ml-1, initial half-life was 0.6 (34% CV) hours, and terminal half-life 2.4 (50% CV) hours. High intra- and inter-patient variability was noted in volume of distribution and clearance, which was in part correlated with the transfusion requirements as the single significant covariate. The non-compartmental analysis led to almost identical estimates of key parameters.
A high intra- and inter-patient variability was noted in the volume of distribution and clearance of rFVIIa in trauma patients with severe bleeding, mainly related with the transfusion requirements and thus blood loss and/or bleeding rate.
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.
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.
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).
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.
The hemostatic properties of recombinant activated factor VII (rFVIIa) are established in patients with inherited or acquired hemophilia with inhibitors and in patients with congenital factor VII deficiencies. Emerging clinical evidence suggests that there may be a wider role for rFVIIa in the management of hemorrhage associated with traumatic injury/accident and severe bleeding associated with critical surgery. This article considers recent data from studies in which rFVIIa was used in an attempt to control bleeding in clinical situations as diverse as coagulopathy associated with chronic liver disease, massive perioperative bleeding and bleeding during prostatectomy, organ transplantation and orthopedic surgery, uncontrollable obstetric hemorrhage, and intracerebral hemorrhage. In nontrauma settings involving acute and potentially life threatening bleeding, there may be a place for rFVIIa as adjunctive therapy in the control of hemostasis.
Ventricular assist devices(VAD) implantation/removal is a complex surgical procedure with perioperative bleeding complications occurring in nearly half of the cases. Recombinant activated factor VII (rFVIIa) has been used off-label to control severe hemorrhage in surgery and trauma. We report here our experience with rFVIIa as a rescue therapy to achieve hemostasis in patients undergoing orthotopic heart transplant (OHT) and/or VAD implantation.
A retrospective review was conducted from Jan 03 to Aug 05 for patients who received rFVIIa for the management of intractable bleeding unresponsive to standard hemostatic blood component therapy. Blood loss and the quantity of blood products, prior to, and for at least 12 hours after, administration of rFVIIa were recorded.
Mean patient age was 53, (38–64 yrs), mean dose of rFVIIa administered was 78.3 μg/kg (24–189 μg/kg) in 1–3 doses. All patients received the drug either intraoperatively or within 6 hours of arrival in ICU. Mean transfusion requirements and blood loss were significantly reduced after rFVIIa administration (PRBC's; 16.9 ± 13.3 to 7.1 ± 6.9 units, FFP; 13.1 ± 8.2 to 4.1 ± 4.9 units, platelets; 4.0 ± 2.8 to 2.1 ± 2.2 units, p < 0.04 for all). 5 patients expired including 3 with thromboembolic cause. One patient developed a lower extremity arterial thrombus, and another deep vein thrombosis.
In this review, there was a significant decrease in transfusion requirement and blood loss after rFVIIa administration. Although, 5/17 developed thromboembolic complications, these patients may have been at higher risk based on the multiple modality therapy used to manage intractable bleeding. Nevertheless, the exact role of rFVIIa with respect to development of thromboembolic complications cannot be clearly determined. Further investigation is needed to determine rFVIIa's safety and its effectiveness in improving postoperative morbidity and mortality.
Trauma is a leading cause of mortality and morbidity, with traumatic brain injury (TBI) and uncontrolled hemorrhage responsible for the majority of these deaths. Recombinant activated factor VIIa (rFVIIa) is being investigated as an adjunctive hemostatic treatment for bleeding refractory to conventional replacement therapy in trauma patients. TBI is a common component of polytrauma injuries. However, the combination of TBI with polytrauma injuries is associated with specific risk factors and treatment modalities somewhat different from those of polytrauma without TBI. Although rFVIIa treatment may offer added potential benefit for patients with combined TBI and polytrauma, its safety in this population has not yet been assessed. We conducted a post hoc sub analysis of patients with TBI and severe blunt polytrauma enrolled into a prospective, international, double-blind, randomized, placebo-controlled study.
A post hoc analysis of study data was performed for 143 patients with severe blunt trauma enrolled in a prospective, randomized, placebo-controlled study, evaluating the safety and efficacy of intravenous rFVIIa (200 + 100 + 100 μg/kg) or placebo, to identify patients with a computed tomography (CT) diagnosis of TBI. The incidences of ventilator-free days, intensive care unit-free days, and thromboembolic, serious, and adverse events within the 30-day study period were assessed in this cohort.
Thirty polytrauma patients (placebo, n = 13; rFVIIa, n = 17) were identified as having TBI on CT. No significant differences in rates of mortality (placebo, n = 6, 46%, 90% confidence interval (CI): 22% to 71%; rFVIIa, n = 5, 29%, 90% CI: 12% to 56%; P = 0.19), in median numbers of intensive care unit-free days (placebo = 0, rFVIIa = 3; P = 0.26) or ventilator-free days (placebo = 0, rFVIIa = 10; P = 0.19), or in rates of thromboembolic adverse events (placebo, 15%, 90% CI: 3% to 51%; rFVIIa, 0%, 90% CI: 0% to 53%; P = 0.18) or serious adverse events (placebo, 92%, 90% CI: 68% to 98%; rFVIIa, 82%, 90% CI: 60% to 92%; P = 0.61) were observed between treatment groups.
The use of a total dose of 400 (200 + 100 + 100) μg/kg rFVIIa in this group of hemodynamically unstable polytrauma patients with TBI was not associated with an increased risk of mortality or with thromboembolic or adverse events.
This report discusses a case of unsuccessful treatment with recombinant factor VIIa (rFVIIa) in off-label use. The need for international guidelines concerning the off-label use of rFVIIa is outlined as well as the need for methods to control the efficacy of rFVIIa objectively.
54 year old male with severe polymicrobial sepsis due to a perforated diverticulitis of the sigmoid colon and consecutive overt disseminated intravascular coagulation. He suffered severe intraabdominal bleeding after abdominal surgery despite conventional haemostatic support. Repeated applications of factor VIIa temporarily improved coagulation essays but did not stop clinical bleeding. The patient died in multiorgan failure due to septic and haemorrhagic shock.
Off-label use of rFVIIa could result in more side effects than could be expected from literature because of a publication bias. However for most off-label applications large prospective, randomised and controlled trials to confirm the positive findings are missing. For the future, not only guidelines concerning the off-label use of rFVIIa are urgently needed but also guidelines for monitoring the efficacy of rFVIIa.
For patients with a normal coagulation system, who experience serious bleeding, sound evidence for recombinant activated factor VII (rFVIIa) as an effective haemostatic agent is only scarcely available so far from controlled clinical trials. In systematic reviews on the clinical use of rFVIIa, treatment failures were only rarely reported.
We present a 45-year old, Caucasian male with persistent intestinal bleeding due to enterocolitis associated with cytomegalovirus infection and acute graft-versus-host-disease. He had received allogeneic peripheral blood stem cell transplantation from an unrelated HLA-identical donor because of chronic myelogenous leukaemia diagnosed two years earlier. Bleeding started at day 18 after transplantation with bloody diarrhea, which was treated with multiple transfusions of fresh frozen plasma, platelet, and red blood cell concentrates, and continued relentlessly, despite all efforts, including continued transfusions, high-dose prednisolone, broad antibiotic and antiviral coverage, and tranexamic acid. Recombinant FVIIa was started at boluses of 90–120 μg/kg every 4–8 hours. Despite more than 10 doses, recurrent severe bleeding progressed to refractory shock, multiorgan failure and death.
Little can be concluded from single case reports of clinical improvement, because publication bias in favour of positive effects is likely. Our case suggests that rFVIIa is not a panacea, in particular for severe bleeding after bone-marrow transplantation. As long as rigorous, controlled studies or comprehensive registries are lacking, conventional interventions remain the standard of care in non-haemophilic patients with severe bleeding.
Rotational thromboelastography (ROTEG) has been proposed as a monitoring tool that can be used to monitor treatment of hemophilia with recombinant factor VIIa (rFVIIa). In these studies special non-standard reagents were used as activators of the coagulation. The aim of this study was to evaluate if standard ROTEG analysis could be used for monitoring of effects of recombinant factor VIIa (rFVIIa) on Hydroxy Ethyl Starch-induced dilutional coagulopathy.
The study was performed in vitro on healthy volunteers. Prothrombin time (PT) and ROTEG analysis were performed after dilution with 33% hydroxy ethyl starch and also after addition of rFVIIa to the diluted blood.
PT was impaired with INR changing from 0.9 before dilution to 1.2 after dilution while addition of rFVIIa to diluted blood lead to an overcorrection of the PT to an International Normalized Ratio (INR) value of 0.6 (p = 0.01). ROTEG activated with the contact activator ellagic acid was impaired by hemodilution (p = 0.01) while addition of rFVIIa had no further effects. ROTEG activated with tissue factor (TF) was also impaired by hemodilution (p = 0.01) while addition of rFVIIa lead to further impairment of the coagulation (p = 0.01).
The parameters affected in the ROTEG analysis were Clot Formation Time and Amplitude after 15 minutes while the Clotting Time was unaffected. We believe these effects to be due to methodological problems when using standard activators of the coagulation in the ROTEG analysis in combination with rFVIIa.
Recent clinical studies suggest that the prophylactic use of recombinant factor VIIa (rFVIIa) markedly reduces the number of bleeding episodes in hemophilic patients with inhibitors. Given the short biological half-life of rFVIIa, it is unclear how rFVIIa could be effective in prophylactic treatment.
To examine the extravascular distribution of pharmacologically administered rFVIIa to obtain clues on how rFVIIa could work in prophylaxis.
Recombinant mouse FVIIa tagged with AF488 fluorophore (AF488-FVIIa) was administered into mice via the tail vein. At different time intervals following the administration, mice were exsanguinated and various tissues were collected. The tissue sections were processed for immunohistochemistry to evaluate distribution of rFVIIa.
rFVIIa, immediately following the administration, associated with the endothelium lining of large blood vessels. Within 1 h, rFVIIa bound to endothelial cells was transferred to the perivascular tissue surrounding the blood vessels and thereafter diffused throughout the tissue. In the liver, rFVIIa was localized to sinusoidal capillaries and accumulated in hepatocytes. In bone, rFVIIa was accumulated in the zone of calcified cartilage and some of it was retained there for a week. The common finding of the present study is that rFVIIa in extravascular spaces was mostly localized to regions that contain TF expressing cells.
The present study demonstrates that pharmacologically administered rFVIIa readily associates with the vascular endothelium and subsequently enters into extravascular spaces where it is likely to bind to TF and is retained for extended time periods. This may explain the prolonged pharmacological effect of rFVIIa.
bio-distribution; endothelial cell protein C receptor; hemophilia; prophylaxis; rFVIIa; tissue factor
Recombinant activated factor VII (rFVIIa, NovoSeven®) was introduced in 1996 for the treatment of hemophilic patients with antibodies against coagulation factor VIII or IX.
To review the evidence supporting the use of rFVIIa for the treatment of patients with congenital bleeding disorders.
Patients and methods:
English-language databases were searched in September 2009 for reports of randomized controlled trials (RCTs) evaluating the ability of rFVIIa to restore hemostasis in patients with congenital bleeding disorders.
Eight RCTs involving 256 hemophilic patients with antibodies against coagulation factors, also known as inhibitors, were identified. The evidence supporting the use of rFVIIa in these patients was weak with regard to dose, clinical setting, mode of administration, efficacy, and adverse events, given the limited sample size of each RCT and the heterogeneity of the studies.
The authors suggest that rFVIIa therapy in hemophilic patients with inhibitors should be based on the individual’s ability to generate thrombin and form a clot, and not on the patient’s weight alone. Therefore, assays for thrombin generation, such as whole-blood thromboelastography, have the potential to significantly improve the treatment of these patients.
hemophilia; inhibitors; coagulation factor VIII; coagulation factor IX; rFVIIa; NovoSeven; FEIBA; hemostasis; RCT
One of the last remaining clinical hurdles in the treatment of people with hemophilia is the development of inhibitors. Alloantibodies or autoantibodies directed at coagulation factors render the infusion of coagulation factor concentrates ineffective, and alternative means must be used to achieve hemostasis. Recombinant factor VIIa (rFVIIa) was developed to control bleeding episodes in hemophilic patients with inhibitors. Clinical efficacy in achieving hemostasis in inhibitor patients was demonstrated by a compassionate-use protocol, as well as in randomized controlled trials. To date, over 1.5 million doses of rFVIIa have been given to inhibitor patients, with an excellent efficacy and safety record. Because of its short half-life, alternative means of dosing and infusing rFVIIa have been explored and are reviewed here.
hemophilia; inhibitor; recombinant; factor VIIa; inhibitors
Major obstetric haemorrhage remains a significant cause of maternal morbidity and mortality. Previous case reports suggest the potential benefit of recombinant activated factor VII (rFVIIa: NovoSevenR) as a haemostatic agent. We performed a retrospective review of the use of rVIIa in major obstetric haemorrhage in the Northern Region between July 2004 and February 2007. Fifteen women received rFVIIa. The median patient age was 34 years. Major haemorrhage occurred antepartum (5 patients), intrapartum (1), and postpartum (9). All women received an initial dose of 90 mcg/kg rFVIIa and one received 2 further doses. Bleeding stopped or decreased in 12 patients (80%). Additional measures included antifibrinolytic and uterotonic agents, Rusch balloon insertion, uterine curettage/packing, and vessel embolisation. Eight patients required hysterectomy. All women survived to discharge from hospital. No adverse events, including thrombosis, were recorded. This study provides further support for the safety and efficacy of rFVIIa as adjunct therapy in major obstetric haemorrhage.
There have been recent reports on the successful use of recombinant factor VIIa (rFVIIa) in non-hemophiliac patients who have experienced heavy blood loss due to trauma with extensive organ damage and who have received multiple blood transfusions with hemostatic changes without success. The timing of administration, dosage, mortality, units of blood transfusion saved, risk of thrombotic events, and the risk/benefit ratio are still poorly defined.
PATIENTS AND METHODS:
We conducted a retrospective review of all medical records of patients who received rFVIIa between January 2003 and March 2008. Data collection included demographic characteristics, diagnosis, indications, comorbidities, and amount of blood products used with rFVIIa, dose of rFVIIa, mortality, and adverse events.
We identified 45 patients, 27 (60%) males and 18 (40%) females, with a median age of 52 years. The median dose of rFVIIa was 40 μg/kg (range, 20-120 μg/kg). Five (11.1%) patients needed a second dose of rFVIIa (dose range of 20-85 μg/kg) whereas three patients (6.7%) needed a third dose of rFVIIa (dose range of 40-60 μg/kg). There was a marked and significant reduction in transfusion requirements for packed red blood cells (P=.0078). Overall transfusion requirements significantly decreased after the infusion of rFVIIa (P=.0323). Nineteen patients (42.2%) died and thrombosis was documented in 3 patients (6.7%).
Use of rFVIIa should be based on sound clinical evidence to balance the risks, benefits, and cost if used among non-hemophiliacs. Prospective randomized studies are needed to investigate the efficacy and cost-effectiveness of rFVIIa for this indication and to allow a final assessment of the importance of this treatment.