Efficacy Of Factor VIIa Research Articles

Platelet binding and activity of a factor VIIa variant with enhanced tissue factor independent activity

Platelet binding and activity play important roles in the efficacy of factor VIIa (FVIIa) as a bypassing agent for hemophilia treatment. An analog of FVIIa with increased tissue factor (TF)-independent activity, NN1731, has been produced by introducing three amino acid changes in the protease domain. NN1731 has a conformation similar to TF-bound FVIIa, even in the absence of TF. This results in much greater intrinsic proteolytic activity, but similar activity in the presence of TF. We hypothesized that these changes would not alter binding to platelets or phospholipid, a characteristic thought to be localized to the Gla domain. The goal of the current work was to compare platelet binding and activity of NN1731 and wild-type FVIIa. FVIIa and NN1731 bound identically to phospholipid vesicles as assessed by both activity assays and electrophoretic quasielastic light scattering techniques. However, NN1731 bound to a greater number of sites on activated platelets than FVIIa, as assessed by flow cytometry. Removal of the Gla domain abolished binding of both FVIIa and NN1731. Inhibition of the active site did not reduce NN1731 binding to the level of FVIIa. When corrected for the amount of protein bound, NN1731 had greater activity than FVIIa on platelet surfaces. While the Gla domain is essential for FVIIa binding to platelets, changes in the protease domain in NN1731 enhanced platelet binding as well as proteolytic activity. Features in addition to lipid composition appear to contribute to binding of rFVIIa and, especially, NN1731 to platelets.

Unlabeled uses of factor VIIa (recombinant) in pediatric patients

Unlabeled uses of factor VIIa (recombinant) in pediatric patients are reviewed. Factor VIIa (recombinant) is currently approved for the treatment and prevention of bleeding in patients with hemophilia A or B and inhibitors of coagulation factors, acquired hemophilia, or congenital factor VII deficiency. Use of this agent has expanded to include unlabeled indications, including bleeding unrelated to coagulation factor deficiencies in infants, children, and adolescents without congenital hemophilia. Results of a search of the English-language medical literature for relevant articles primarily included case reports and retrospective reviews, with few randomized clinical trials. Reasons for use of factor VIIa (recombinant) included bleeding associated with acquired coagulopathies or congenital disorders resulting in coagulopathies, hepatic failure, surgery, and bleeding associated with prematurity, malignancies, and trauma. In most reports, conventional therapies were used with limited or no success. Factor VIIa (recombinant) was most commonly used in patients with coagulopathies or hemorrhage secondary to surgical procedures, primarily cardiopulmonary bypass and liver transplantation, as well as intracranial hemorrhage. In general, higher mortality rates were reported in medical versus surgical patients. The lowest rates of complete response were seen in younger patients and patients with trauma. A decrease in the requirement of blood product transfusion after the use of factor VIIa (recombinant) versus standard therapies or placebo was commonly observed but was not statistically significant in many cases. Given the lack of well-designed controlled studies, current evidence is inconclusive regarding the safety and efficacy of factor VIIa (recombinant) for unlabeled indications in pediatric patients.

The Efficacy of Factor VIIa in Emergency Department Patients With Warfarin Use and Traumatic Intracranial Hemorrhage

The objective was to compare outcomes in emergency department (ED) patients with preinjury warfarin use and traumatic intracranial hemorrhage (tICH) who did and did not receive recombinant activated factor VIIa (rFVIIa) for international normalized ratio (INR) reversal. This was a retrospective before-and-after study conducted at a Level 1 trauma center, with data from 1999 to 2009. Eligible patients had preinjury warfarin use and tICH on cranial computed tomography (CT) scan. Patients before (standard cohort) and after (rFVIIa cohort) implementation of a protocol for administering 1.2 mg of rFVIIa in the ED were reviewed. Glasgow Coma Scale (GCS) score, Revised Trauma Score (RTS), Injury Severity Score (ISS), INR, and Marshall score were collected. Outcome measures included mortality, thromboembolic complications, and INR normalization. Forty patients (median age=80.5 years, interquartile range [IQR]=63.5-85) were included (20 in each cohort). Age, GCS score, ISS, RTS, initial INR, and Marshall score were similar (p>0.05) between the two cohorts. Survival was identical between cohorts (13 of 20, or 65.0%, 95% confidence interval [CI]=40.8% to 84.6%). There were no differences in rate of thromboembolic complications in the standard cohort (1 of 20, 5.0%, 95% CI=0.1% to 24.9%) than the rFVIIa cohort (4 of 20, 20.0%, 95% CI=5.7% to 43.7%; p=0.34). Time to normal INR was earlier in the rFVIIa cohort (mean=4.8 hours, 95% CI=3.0 to 6.7 hours) than in the standard cohort (mean=17.5 hours, 95% CI=12.5 to 22.6; p<0.001). In patients with preinjury warfarin and tICH, use of rFVIIa was associated with a decreased time to normal INR. However, no difference in mortality was identified. Use of rFVIIa in patients on warfarin and tICH requires further study to demonstrate important patient-oriented outcomes.

Coagulation factor VIIa (recombinant) for warfarin-induced intracranial hemorrhage

The use of coagulation factor VIIa (recombinant) for the treatment of warfarin-induced intracranial hemorrhage (ICH) is described. ICH is a devastating disorder that can be exacerbated by the use of oral anticoagulation. The treatment of warfarin-associated ICH involves the prompt reversal of anticoagulation to allow for surgical procedures, if necessary. Despite limited labeled indications, factor VIIa (recombinant) has been used to reverse warfarin-induced anticoagulation in patients with active hemorrhage, partly due to the rapid effect of factor VIIa on the International Normalized Ratio and the ability to administer the drug quickly in acute settings. The efficacy of factor VIIa (recombinant) for the reversal of anticoagulation in patients with warfarin-associated ICH has been described in several case reports, case series, and retrospective cohort studies. Based on these reports, the use of factor VIIa (recombinant) for the treatment of warfarin-associated ICH may be a viable alternative or adjunct therapy to standard treatment with fresh-frozen plasma and vitamin K. However, due to the nature of these reports, future controlled trials should be conducted to verify the exact place for factor VIIa (recombinant) for this indication. Thromboembolic complications are rare but serious complications secondary to the use of factor VIIa (recombinant). Though differences exist in the reported rate of thromboembolic complications associated with factor VIIa (recombinant), factor VIIa (recombinant) should be used with caution in patients with a predisposition to thromboembolic complications. Use of factor VIIa (recombinant) may be considered for reversal of anticoagulation in patients with warfarin-associated ICH. However, patients should be screened for increased risk of thrombosis before administration of the drug.

453: The Efficacy of Factor VIIa in Emergency Department Patients With Warfarin Use and Traumatic Intracranial Hemorrhage

The use of recombinant activated factor VII (rFVIIa) is gaining popularity in coagulopathic trauma patients. Its utility in patients on warfarin with traumatic intracranial hemorrhage (tICH) is unclear. The objective of this study was to compare outcomes in emergency department patients with pre-injury warfarin use and tICH who did and did not receive rFVIIa for reversal of their coagulopathy.

Cofactor-induced and mutational activity enhancement of coagulation factor VIIa.

Coagulation factor VIIa (FVIIa) is an atypical member of the trypsin family of serine proteases. It fails to attain spontaneously its catalytically competent conformation and requires its protein cofactor tissue factor (TF) to accomplish this. Over a number of years, this unique behaviour of FVIIa has prompted investigations of the TF-induced activation mechanism and the zymogenicity determinants in factor VIIa. Factor VIIa has gained additional interest in the past decade because of its development into a clinically useful haemostatic agent. Here, we present an overview of the current knowledge about the TF-induced allosteric activation of FVIIa and the various molecular approaches to enhance the intrinsic activity and efficacy of FVIIa.

Dosing factor VIIa (recombinant) in nonhemophiliac patients with bleeding after cardiac surgery

The dosing of factor VIIa (recombinant) in nonhemophiliac patients with cardiac-surgery-associated bleeding (CSAB) is discussed. Factor VIIa (recombinant) is a vitamin K-dependent glycoprotein that is FDA-approved for use in patients with hemophilia A or B with inhibitors to factor VIII or IX and for patients with factor VII deficiency. Case reports and observational studies indicate that factor VIIa (recombinant) may be efficacious for the treatment of acute bleeding episodes related to trauma, surgery, and coagulopathies. The use of factor VIIa (recombinant) for CSAB is increasing. No controlled clinical trials have been conducted to determine the safety and efficacy of factor VIIa (recombinant) in the treatment of CSAB; therefore, the appropriate dosing scheme remains unclear. In addition, thromboembolic events associated with factor VIIa (recombinant) have been reported, so the safety of factor VIIa (recombinant) in patients with normal coagulation systems is unclear. Data from one randomized, controlled, clinical trial of the use of factor VIIa (recombinant) in intracerebral hemorrhage showed a dose-related trend toward adverse events when factor VIIa (recombinant) was compared with placebo. No particular dose of factor VIIa (recombinant) is strongly supported in the literature for off-label use, and thromboembolic events may be dose dependent. Use of the smallest possible dose is warranted because of the high cost of factor VIIa (recombinant) and the potential for thromboembolic events. A single dose of 2.4 or 4.8 mg or 45 microg/kg should be considered.

Real efficacy of factor VIIa in the treatment of the postpartum hemorrhage

Real efficacy of factor VIIa in the treatment of the postpartum hemorrhage

Mechanism of factor VIIa–dependent coagulation in hemophilia blood: Presented in part at the 42nd Annual Meeting of the American Society of Hematology, December 1-5, 2000, San Francisco, CA.

AbstractThe ability of factor VIIa to initiate thrombin generation and clot formation in blood from healthy donors, blood from patients with hemophilia A, and in anti–factor IX antibody–induced (“acquired”) hemophilia B blood was investigated. In normal blood, both factor VIIa–tissue factor (TF) complex and factor VIIa alone initiated thrombin generation. The efficiency of factor VIIa was about 0.0001 that of the factor VIIa–TF complex. In congenital hemophilia A blood and “acquired” hemophilia B blood in vitro, addition of 10 to 50 nM factor VIIa (pharmacologic concentrations) corrected the clotting time at all TF concentrations tested (0-100 pM) but had little effect on thrombin generation. Fibrinopeptide release and insoluble clot formation were only marginally influenced by addition of factor VIIa. TF alone had a more pronounced effect on thrombin generation; an increase in TF from 0 to 100 pM increased the maximum thrombin level in “acquired” hemophilia B blood from 120 to 480 nM. Platelet activation was considerably enhanced by addition of factor VIIa to both hemophilia A blood and “acquired” hemophilia B blood. Thus, pharmacologic concentrations of factor VIIa cannot restore normal thrombin generation in hemophilia A and hemophilia B blood in vitro. The efficacy of factor VIIa (10-50 nM) in hemophilia blood is dependent on TF.