Elisabeth Erhardtsen

Potential role for rFVIIa in transfusion medicine

R ecombinant FVIIa (rFVIIa) was developed for treatment of bleeding in hemophilia patients with inhibitors and has also been successfully used in nonhemophilia patients with acquired antibodies against FVIII (acquired hemophilia). Pharmacological doses of rFVIIa have been found to enhance the thrombin generation on already activated platelets and, therefore, will also likely be of benefit in providing hemostasis in other situations characterized by profuse bleedings and an impaired thrombin generation. In fact, limited clinical experience already exists, indicating a hemostatic effect in patients with thrombocytopenia and those with functional platelet defects.1,2 In addition, it has been used successfully in less well-characterized bleeding situations,3-5 as well as in patients with impaired liver function.6,7 By using recombinant products, the risk of transferring human blood-borne pathogenic virus is avoided. Accordingly, rFVIII was approved in the late 1980s and recombinant F IX was approved in 1997 for treatment of hemophilia A and hemophilia B, respectively.

Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease

Orthotopic liver transplantation (OLT) can be associated with excessive blood loss. As a result, there may be increased risk of adverse outcomes. Activated recombinant factor VII (rFVIIa) has demonstrated the ability to improve hemostasis in a variety of disorders; however, there has been a limited amount of research into its use in OLT. The purpose of this dose‐finding study was to examine the efficacy and safety of rFVIIa in the reduction of bleeding in patients undergoing OLT. In this double‐blind trial, patients with end‐stage liver disease scheduled for OLT were randomized to 1 of 4 parallel study groups. They received a single intravenous bolus of rFVIIa (20, 40, or 80 μg/kg) or placebo prior to surgery. The primary assessment endpoint was the total number of red blood cell (RBC) units transfused perioperatively. Safety was evaluated by adverse events reported. Eighty‐three comparable patients were randomized to receive study product, with 82 ultimately undergoing OLT. There were no significant differences in required RBC units between the placebo and rFVIIa study groups. The number of adverse events was comparable between study groups. In conclusion, rFVIIa has a good safety profile in patients undergoing OLT. However, the doses studied did not have any effect on the number of RBC transfusions required. (Liver Transpl 2005;11:895–900.)

Recombinant coagulation factor VIIa in major liver resection: a randomized, placebo-controlled, double-blind clinical trial.

Background:Prevention of bleeding episodes in noncirrhotic patients undergoing partial hepatectomy remains unsatisfactory in spite of improved surgical techniques. The authors conducted a randomized, placebo-controlled, double-blind trial to evaluate the hemostatic effect and safety of recombinant factor VIIa (rFVIIa) in major partial hepatectomy. Methods:Two hundred four noncirrhotic patients were equally randomized to receive either 20 or 80 &mgr;g/kg rFVIIa or placebo. Partial hepatectomy was performed according to local practice at the participating centers. Patients were monitored for 7 days after surgery. Key efficacy parameters were perioperative erythrocyte requirements (using hematocrit as the transfusion trigger) and blood loss. Safety assessments included monitoring of coagulation-related parameters and Doppler examination of hepatic vessels and lower extremities. Results:The proportion of patients who required perioperative red blood cell transfusion (the primary endpoint) was 37% (23 of 63) in the placebo group, 41% (26of 63) in the 20-&mgr;g/kg group, and 25% (15 of 59) in the 80-&mgr;g/kg dose group (logistic regression model; P = 0.09). Mean erythrocyte requirements for patients receiving erythrocytes were 1,024 ml with placebo, 1,354 ml with 20 &mgr;g/kg rFVIIa, and 1,036 ml with 80 &mgr;g/kg rFVIIa (P = 0.78). Mean intraoperative blood loss was 1,422 ml with placebo, 1,372 ml with 20 &mgr;g/kg rFVIIa, and 1,073 ml with 80 &mgr;g/kg rFVIIa (P = 0.07). The reduction in hematocrit during surgery was smallest in the 80-&mgr;g/kg group, with a significant overall effect of treatment (P = 0.04). Conclusions:Recombinant factor VIIa dosing did not result in a statistically significant reduction in either the number of patients transfused or the volume of blood products administered. No safety issues were identified.

Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: Review of safety profile

BACKGROUND:  In recent years, the hemostatic agent recombinant factor VIIa (rFVIIa) has emerged as a potentially new therapeutic agent for management of coagulopathy in patients with cirrhosis or following severe traumatic injury, a complex problem for clinicians in which standard treatment strategies are not always effective. As with other hemostatic agents, a primary safety concern of rFVIIa therapy is the theoretical possibility that systemic administration could confer an increased risk of thrombotic complications. So far, clinical experience indicates rFVIIa to be a safe treatment for currently approved indications within hemophilia. Little information is available, however, for patient populations outside this clinical setting.

Ongoing NovoSeven® trials

Recombinant activated factor VII (rFVIIa, ‘NovoSeven®’) was initially developed for the treatment of bleeding in patients with haemophilia and inhibitors, and is currently licensed in most countries worldwide. The mechanism of action suggests that its enhancing effects in haemostasis are limited to the site of injury and that systemic activation of the coagulation cascade does not occur. These properties, together with anecdotal reports of its beneficial effects in different patient populations with severe bleeds, suggest that rFVIIa may be valuable as a general haemostatic agent. In case reports, rFVIIa has been reported to reduce bleeding in patients with liver disease, thrombocytopenia or thrombocytopathia, trauma those undergoing radical prostatectomy or receiving oral anticoagulant therapy. A number of clinical trials have recently been initiated to collect data on the safety and efficacy of rFVIIa in these patient groups. The beneficial effects of rFVIIa occurring in these studies will support the potential use of rFVIIa as a universal haemostatic agent.

Pharmacodynamics of active site‐inhibited factor VIIa in endotoxin‐induced coagulation in humans

Inhibition of the tissue factor‐factor VIIa pathway attenuated the activation of coagulation and prevented death in a gram‐negative bacteremia primate model of sepsis. This lethal animal model suggested that tissue factor also influences inflammatory cascades.

A study of the pharmacokinetics and safety of recombinant activated factor VII in healthy Caucasian and Japanese subjects

In this randomized, placebo-controlled, double-blind, single-centre, dose escalation study, we report the first evaluation of the pharmacokinetics and safety of recombinant activated factor VII (rFVIIa) in healthy Caucasian and Japanese subjects. Thirty-two healthy subjects were stratified according to sex and ethnic group to receive single bolus intravenous injections of three different doses of rFVIIa (40, 80, 160 μg/kg rFVIIa) or placebo, each separated by a 7-day wash-out period. Blood samples were taken up to 24 h after dosing. The factor VII clotting activity appeared to be dose dependent, but independent of sex and ethnic group. Statistical analyses demonstrated no significant effect of dose, sex or ethnicity on the dose-normalized mean area under the plasma concentration–time curve AUC0–t, indicating dose proportionality. No serious adverse events or thromboembolic events were reported. Analyses of coagulation parameters did not suggest induction of systemic coagulation when dosing rFVIIa up to 160 μg/kg. In conclusion, the pharmacokinetics of rFVIIa in Caucasian and Japanese subjects are similar, and no safety issues were identified.

Recombinant human factor VIIa (rFVIIa) in a rabbit stasis model

The thrombogenicity of recombinant human FVIIa (rFVIIa) and FEIBA was studied in a rabbit stasis model. Only minor thrombus formation in isolated vein segments during 10 min. of stasis was seen following the administration of rFVIIa 100-1000 micrograms/kg or FEIBA 50-100 U/kg whereas both compounds caused clear thrombus formation during 30 min. of stasis. RFVIIa caused no change in platelet counts or plasma fibrinogen 3 hours after administration, whereas a small decrease of APTT was seen due to the direct effect of rFVIIa in this assay. In contrast, FEIBA caused a significant and dose-dependent decrease of platelet counts as well as of fibrinogen, and an increase of APTT which demonstrate a general consumption of coagulation factors. In conclusion the study demonstrated a local pharmacological effect of rFVIIa in the absence of a general activation of the coagulation cascade.

To General Haemostasis – the Evidence-Based Route

Recombinant factor VIIa (rFVIIa) was developed for the treatment of bleeding in haemophilia patients with inhibitors and has also been used successfully in non-haemophilia patients with acquired antibodies against FVIII (acquired haemophilia). Based on dose-finding trials and a compassionate-use programme, rFVIIa was approved for use in haemophilia patients with inhibitors in 1996. At pharmacological doses, rFVIIa has been found to enhance thrombin generation on already activated platelets. Therefore, it is likely that rFVIIa will also be beneficial in providing haemostasis in other situations characterised by profuse bleedings and an impaired thrombin generation. Patients with thrombocytopenia have a decreased number of platelets and thus an impaired thrombin generation. A reduction in bleeding time was reported in approximately 50% of patients with thrombocytopenia and a prolonged bleeding time who participated in a trial of rFVIIa. Moreover, in 8 patients with 9 overt bleeds who were involved in the study, bleeding stopped in 7 episodes after rFVIIa administration. Case reports on the haemostatic effect of rFVIIa in thrombocytopenia have also been published. Reports have also been published on the successful use of rFVIIa in patients with platelet function deficiencies such as Glanzmann’s thrombasthenia and Bernard-Soulier syndrome. A number of haemostatic changes occur after extensive trauma, surgery and bleeding, all of which potentially contribute to an impaired thrombin generation. The effect of rFVIIa has been demonstrated in a number of patients after trauma and bleeds and upper gastrointestinal bleeding episodes. Reports on the beneficial use of rFVIIa in liver transplantation have also been published. Several randomised blinded studies are now underway in e.g. hepatectomy, upper gastrointestinal bleedings, transplantations and intra-cerebral bleeds. In summary, rFVIIa may be an effective and safe method to induce haemostasis in patients within areas of coagulation factor deficiency or platelet disorders and the ongoing and planned randomised studies may lead the way to the use of rFVIIa in general haemostasis.

Pharmacokinetics and Safety of FFR-rFVIIa after Single Doses in Healthy Subjects

FFR‐rFVIIa is an antithrombotic agent, which has also proven to have antirestenotic properties in animal models. FFR‐rFVIIa is a modified recombinant FVIIa in which the catalytic site is irreversibly inactivated by a synthetic tripeptide covalently bound with the FVIIa molecule. The modified rFVIIa retains its tissue factor (TF) binding capacity but is otherwise enzymatically inactive. A double‐blind, placebo‐controlled, randomized dose escalation trial was conducted to investigate eight single i.v. doses of FFR‐rFVIIa (0.01, 0.02, 0.05, 0.08, 0.12, 0.18, 0.27, or 0.40 mg/kg body weight) in healthy male volunteers (n = 62). Safety, pharmacokinetics, and pharmacodynamics of FFR‐rFVIIa were assessed. Mean (SD) AUC0‐∞ ranged from 0.35 (0.11)to 28.8 (3.5) g•h/ml, and mean Cmax ranged from 0.078 (0.019) to 4.8 (0.7) g/ml. The mean elimination half‐life ranged from 3.8 to 5.8 hours. Mean AUC0‐∞ increased with increasing dose levels. Cmax appeared to be proportional to the dose level, with the exception of the lowest dose level. A dose‐dependent prolongation of the prothrombin time was found, demonstrating that FFR‐rFVIIa inhibited coagulation via the TF‐dependent pathway. FFR‐rFVIIa was generally well tolerated at all dose levels studied.