A review of the off-label use of recombinant activated factor VII in a developing country tertiary care center.

Recombinant activated factor VII (rFVIIa) was first approved for treatment of congenital hemophilia. It could, however, also have a role in management of patients without pre-existing coagulopathies who undergo surgical procedures, have life-threatening hemorrhages, or sustain traumas associated with major blood loss. A retrospective chart review was performed for all cases given rFVIIa at American University of Beirut Medical Center (AUB MC). Patients with a previous medical history of thrombophilia were excluded. There were four pediatric patients with a mean age younger than 1 year. Adult patients' mean age was 64.5 +/- 17.4 years. The most common off-label uses for rFVIIa are control of hemorrhage during the repair of aortic dissection (4/17 cases) or following intracerebral hemorrhage (4/17 case). One trauma patient received the medication. Complications included cerebral ischemia in one patient. Three of the patients died but their death was not related to the bleeding or the medication. Based on the prognostic score proposed by Biss and Hanley, seven patients were low risk, four intermediate risk, and six high risk. Although off-label use of rFVIIa at AUB MC was supported by published reports, and associated with few complications, guidelines are required to control use of this medication.     

Evaluation of off-label recombinant activated factor VII for multiple indications in children.

Despite a paucity of safety and efficacy data, the use of recombinant activated factor VII in children for off-label indications has now surpassed its use in hemophilia. A retrospective chart review was conducted of 46 subjects (age, 6.7 +/- 6 years; weight, 26 +/- 20 kg) who received recombinant activated factor VII for nonhemophiliac indications between January 1, 2004, and September 1, 2005. Indications for use included prevention (n = 6) or treatment (n = 40) of bleeding due to general surgery, hepatic failure, gastrointestinal bleeding, severe traumatic brain injury, bone marrow transplant, cardiac, acetaminophen overdose, and multiorgan system failure. Decreases in prothrombin time, partial thromboplastin time, and international normalized ratio were observed. No inappropriate thrombotic events were noted. Administration of recombinant activated factor VII was associated with a reduction in coagulation markers without obvious adverse thrombotic events at cost of $4189 per dose. These findings should be confirmed in a prospective trial.     

Successful use of activated recombinant factor VII in life threatening bleeding after thoracic surgery

We present three patients in whom life-threatening haemorrhage following lung resection was successfully managed using activated recombinant factor VII (NovoSeven). In one case, activated recombinant factor VII was the only therapy administered to manage bleeding, and in the two remaining cases, activated recombinant factor VII was administered after patients failed to respond to conventional therapy. All patients demonstrated effective haemostasis and improved coagulation parameters as a result of treatment with activated recombinant factor VII. Our experience with the clinical use of rFVIIa suggests that this agent may provide effective hemostasis following lifethreatening postoperative bleeding after major thoracic surgery. Despite these favorable results, randomized, placebo - controlled trials are needed to identify optimal treatment strategy, patient selection, and safety of treatment in patients with massive bleeding following major thoracic surgery.     

"Off-license" use of recombinant activated factor VII

Recombinant factor VIIa (rFVIIa) has been widely used in the treatment of bleeding episodes in haemophiliac patients with inhibitors. In haemostatic circles it has also been assessed in reversing oral anticoagulant therapy. Over the last few years, it has been used "off-label" in patients with uncontrolled bleeding due to haemostatic abnormalities due to trauma and/or massive blood loss, thrombocytopenia, platelet dysfunction or liver dysfunction. This review examines the proposed mechanism of action of rFVIIa in the context of current concepts of haemostasis and its pharmacological properties. The "off-license" use of rFVIIa is reviewed. The latter are reported mainly as case reports, case series. There is an overwhelming need for randomized controlled trials to assess rFVIIa's efficacy, dosing and safety in current "off-license" use.     

The use of recombinant activated factor VII in platelet-associated bleeding

Recombinant activated factor VII (rFVIIa) was originally developed for the treatment of spontaneous and surgical bleeding of hemophiliacs with inhibitors. Along with the elucidation of its molecular mechanism of action, rFVIIa has been successfully used over the last few years in a wide range of non-hemophilic bleeding conditions. The aim of this review is to summarize the current clinical experience on the use of rFVIIa in the management of bleeding associated with congenital or acquired platelet disorders.     

Variation in the use of recombinant activated factor VII in critical bleeding

Background: Recombinant activated factor VII (rFVIIa) is being increasingly used as a treatment option in settings of uncontrolled bleeding. Despite this, national practice guidelines are lacking, resulting in widespread practice variation between providers. This investigation aimed to describe the differences in use of rFVIIa across Australian and New Zealand hospitals. Methods: Data were extracted from the Haemostasis Registry that collects both contemporaneous and retrospective cases of off‐licence (i.e. in non‐haemophilia patients) rFVIIa use in participating institutions. Hospitals were classified according to geographical location and service provision. Results: 2075 cases from 87 hospitals were recorded on the Haemostasis Registry. Across all hospital categories, over 41% of cases received rFVIIa in relation to cardiac surgery. Case complexity varied between providers, with large urban centres treating more severely ill patients. This was reflected in significant differences in the use of blood components and products before rFVIIa administration. Despite differences in patient complexity and use of blood products between hospital categories, response to treatment and patient outcomes remained similar across providers, with survival rates ranging from 68.29% to 70.41%. Conclusion: This is the largest study of off‐licence use of rFVIIa. There is significant regional variation in the administration of rFVIIa in Australian and New Zealand hospitals, with little documentation of adherence to guidelines. National consensus guidelines based on available evidence should be developed and promulgated to ensure optimal outcomes.     

Use of recombinant activated factor VII in cardiac surgery for an effective treatment of severe intractable bleeding

Experience gained with administration of supranormal-therapeutic doses (90 microg/kg) of recombinant activated factor VII in 7 cardiac surgery patients is presented. The patients were given recombinant activated factor VII postoperatively for intractable bleeding, 5 of them after surgical revision. Administration of recombinant activated factor VII was associated with significant reduction in blood loss (P < 0.05) and shortening of INR and aPTT in laboratory tests. None of the patients needed reoperation. Administration of recombinant activated factor VII proved highly effective in management of massive hemorrhage in cardiac surgery.     

Standardization of factor VII/activated factor VII measurement in plasma of patients treated with recombinant factor activated VII.

To improve the standardization of the factor VII clotting activity (FVII:C) assay in patients treated with recombinant activated factor VII (rFVIIa), we conducted a multicentre study on plasma samples from four patients with haemophilia A, before and at various times after injection of a single dose of rFVIIa. FVII:C and prothrombin time were measured with the methods and reagents routinely used in each laboratory. Strong inter-laboratory variability of FVII:C values was found. The main source of variability was the type of thromboplastin. FVII:C values measured using rabbit thromboplastin were very close to activated factor VII clotting activity values (FVIIa:C) measured with a commercial assay (Staclot VIIa-TF). FVII:C values obtained with human placental thromboplastin were about three times lower than those obtained with rabbit and recombinant thromboplastins, and with the FVIIa:C assay. There was a good relationship between FVIIa:C and activated factor VII antigen values measured using a commercial immunoassay (Imubind FVIIa ELISA). In conclusion, rFVIIa at pharmacological concentrations can be easily monitored on the basis of FVII:C, using rabbit and probably also recombinant thromboplastin; equivalent results are obtained with a specific activated factor VII bioassay.     

The use of recombinant activated factor VII in the circumcision operation in the case of a congenital factor VII deficiency.

Congenital factor VII deficiency is a rare autosomal recessive hemorrhagic disorder and surgery is normally the cause of excessive bleeding. In this report, we describe the first case with congenital factor VII deficiency admitted to our clinics for the sunnet operation (circumcision), in which recombinant activated factor VII (rFVIIa; NovoSeven) was used to manage the bleeding. The patient was an 8-year old boy with moderate factor VII deficiency (factor VII level, 4%), and rFVIIa was administered at a dose of 20 microg/kg per dose during the circumcision operation. The same dose was repeated at 2, 4, 6, 9, 12, 15, 18, 21 and 24 h post operation. The circumcision operation could therefore be safely performed in patients with congenital factor VII using rFVIIa.     

Failure of recombinant activated factor VII during surgery in a hemophiliac with high-titer factor VIII antibody

Recombinant activated factor VII (rFVIIa) was used before and after inguinal hernioplasty to prevent bleeding in a patient with hemophilia A complicated by a high-potency antifactor VIII inhibitor. rFVIIa (75 micrograms/kg) was given before and after surgery, first by bolus infusions at intervals of 2-3 h for 47 h and then by continuous intravenous infusion at a rate of 38 micrograms/h for an additional period of 12 h. Although no undue bleeding was observed during and for the first 26 h after surgery, the patient subsequently developed wound bleeding and hematomas that necessitated blood transfusion and infusion of porcine factor VIII. This case indicates that rFVIIa is not always successful in patients with antifactor VIII inhibitor and that more experience is needed to establish the optimal doses at surgery.     

Experience of recombinant activated factor VII usage during surgery in patients with haemophilia with inhibitors

Inhibitor development is one of the most challenging complications of haemophilia management. Haemostatic control in patients with haemophilia with inhibitors can be difficult, and is especially risky in those undergoing surgical interventions. Most haemophilia patients with inhibitors suffer from chronic joint disease requiring surgical correction due to recurrent bleeding episodes. The aim of this study was to assess the use of recombinant activated factor VII (rFVIIa) as haemostatic therapy during orthopaedic surgery in haemophilia patients with inhibitors. A series of case reports was retrospectively collected to describe clinical experience of rFVIIa use in inhibitor patients undergoing a range of orthopaedic surgical procedures at a single centre. All surgeries were performed using standard methods. All patients received rFVIIa at a starting dose of 120 μg kg^?1 with the subsequent regimens depending on the type of surgery. rFVIIa provided effective haemostasis in 23 patients with haemophilia A and inhibitors (15 with high inhibitor titres) undergoing orthopaedic surgery. The majority (70%) of surgical procedures were major (joint and extra‐articular surgery). The doses and intervals of rFVIIa treatment used varied depending on the severity of bleeding, and the type (major or minor) or site of surgery. In all cases, administration of rFVIIa achieved good haemostasis. In all 23 patients with haemophilia with inhibitors, rFVIIa treatment in orthopaedic interventions proved to be an efficient haemostatic agent, providing effective intra‐operative and postoperative haemostasis.     

Pharmacokinetics of recombinant activated factor VII (rFVIIa)

Recombinant coagulation factor VIIa (NovoSeven, Novo Nordisk Pharmaceuticals, Inc., Princeton NJ, USA) is a new drug for treatment of bleeding in patients with hemophilia and inhibitors. The pharmacokinetic profiles of rFVIIa have been evaluated in healthy adult volunteers who were pretreated with acenocoumarol, in adult and pediatric patients with hemophilia A or B, and in adult patients with cirrhosis and a prolonged prothrombin time (PT). The clearance (CL) and half-life (t1/2) values of rFVIIa after bolus injection were in the same range in the adult populations studied: patients with hemophilia, patients with cirrhosis, and healthy volunteers. The volume of distribution at steady state (Vss), on the other hand, was slightly smaller in healthy adult volunteers than in patients with hemophilia. The pharmacokinetic profile of rFVIIa seems to be independent of bleeding or nonbleeding conditions in adult hemophilic patients; however, the patients in these studies did not suffer from major bleeding episodes. The values of CL and t1/2 were also dose independent in adult patients with hemophilia and in patients with cirrhosis. Pediatric patients with hemophilia had shorter t1/2 and higher CL values than the adults with hemophilia. The administration of rFVIIa by continuous infusion is still experimental and a number of practical issues remain to be resolved.     

The use of recombinant activated factor VII in congenital and acquired von Willebrand disease.

Recombinant activated factor VII (NovoSeven), a novel hemostatic agent originally developed for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors, has been recently employed with benefit for the management of hemorrhages in other nonhemophilic congenital and acquired hemostatic abnormalities. This review focuses on the use of this drug in acquired and congenital von Willebrand disease. The analysis of the literature data shows that recombinant activated factor VII is an effective agent for the treatment of refractory bleeding in von Willebrand disease patients and for the treatment or prevention of bleeding in those patients with alloantibodies or autoantibodies against von Willebrand factor. Further studies are needed, however, to assess its safety and to optimize the dosages and regimens of therapy in such patients.     

Pharmacokinetic evaluation of recombinant, activated factor VII in patients with inherited factor VII deficiency.

BACKGROUND AND OBJECTIVES: Recombinant factor VIIa (rFVIIa) has been widely used in the treatment of bleedings occurring in hemophiliacs with inhibitors. Very few reports exist on the use of rFVIIa in patients with inherited FVII deficiency. Pharmacokinetic studies on rFVIIa have been performed exclusively in hemophiliacs, patients with cirrhosis or volunteers pretreated with acenocoumarol. The aim of this study was to evaluate the kinetics of rFVIIa in patients naturally deficient of FVII. DESIGN AND METHODS: A single dose kinetic study with rFVIIa was performed in 5 patients affected by severe congenital deficiency of factor VII in order to evaluate the true kinetic parameters of rFVIIa without the interference of FVII. Two dosages, 15 and 30 microg/kg, were used in a crossover schedule. FVII:C and FVIIa concentration/time curves were analyzed by a model-independent method. Antithrombin (AT), prothombin fragment 1+2 (F1+2) and tissue factor pathway inhibitor (TFPI) were assayed. RESULTS: No differences emerged between the dosages with respect to dose-independent parameters [total body clearance (CL), volume of distribution area (VdArea), mean residence time (MRT)]. No significant changes of AT, TFPI, and F1+2 were observed. Comparing the results with those of other studies performed in adult hemophiliacs, in patients affected by cirrhosis or in volunteers on oral anticoagulant therapy (OAT), CL and VdArea of rFVIIa were definitely higher and in vivo recovery was lower. INTERPRETATION AND CONCLUSIONS: These findings suggest that the kinetics of rFVIIa are not dose-dependent. In the absence of FVII, the changes of VdArea and CL may be in agreement with a mechanism of competition between FVII and rFVIIa for tissue factor binding.     

Use of recombinant activated factor VII in patients with Glanzmann's thrombasthenia: a review of the literature

Glanzmann's thrombasthenia (GT) is a rare bleeding disorder characterized by a quantitative or qualitative defect of glycoprotein IIb/IIIa on the platelet membrane. Managing bleeding episodes is often difficult, and a variety of modalities have been used, including platelet transfusions, recombinant factor VIIa (rFVIIa), and other supportive care. The aim of this review was to present the clinical experience with rFVIIa bolus infusion (rFVIIa BI) for treatment of bleeding episodes and prevention of bleeding during surgical procedures in patients with GT. A literature search was performed to identify rFVIIa‐treated patients with GT. Overall, one international survey, one open‐label study, and 40 case reports identified 172 bleeding episodes treated with rFVIIa and 62 procedures covered with rFVIIa. In the international survey, rFVIIa BI was used for 96 bleeding episodes in 59 patients. Recombinant FVIIa was effective in 76 bleeding episodes (79%). Of 34 surgical procedures, 25 procedures received rFVIIa BI with 92% bleeding‐prevention efficacy. The open‐label study reported 28 patients with 28 rFVIIa BI‐treated bleeds, and 26 (93%) bleeding episodes responded to rFVIIa. Published case reports revealed that 25 (69%) of 36 bleeds and 27 (96%) of 28 surgeries responded to rFVIIa BI treatment. Overall, 26 adverse events were reported in 19 patients, including five thromboembolic events in two patients where a possible relationship with rFVIIa could not be excluded. Two large studies and 40 case reports provide a literature base to support the efficacy and safety of rFVIIa BI in patients with GT.