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PubMed2006

An illustrative case and a review on the dosing of recombinant factor VIIa in congenital factor XI deficiency.

Recombinant activated factor VII (rFVIIa) has been used in a very limited number of patients with severe factor XI (FXI) deficiency. The dose and duration of treatment has varied greatly between these case reports. In a few of these cases there was also evidence of thrombotic complications. We present here a report on one additional patient with congenital FXI deficiency. For two major orthopaedic procedures in this patient we used rFVIIa as a single bolus dose followed by continuous infusion at a low rate. The data from these treatment episodes, together with those from a review of the published cases, lend support to the concept of using much lower doses than in haemophilia with inhibitors. A bolus dose of 20 microg kg(-1) and thereafter maintenance of the FVII activity at approximately 3 IU mL(-1) appears effective and safe.

Factor VII↗
PubMed2000

Binding of factor VIIa to tissue factor on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis.

Tissue factor (TF) is the cellular receptor for factor FVIIa (FVIIa), and the complex is the principal initiator of blood coagulation. The effects of FVIIa binding to TF on cell migration and signal transduction of human fibroblasts, which express high amounts of TF, were studied. Fibroblasts incubated with FVIIa migrated toward a concentration gradient of PDGF-BB at approximately 100 times lower concentration than do fibroblasts not ligated with FVIIa. Anti-TF antibodies inhibited the increase in chemotaxis induced by FVIIa/TF. Moreover, a pronounced suppression of chemotaxis induced by PDGF-BB was observed with active site-inhibited FVIIa (FFR-FVIIa). The possibility that hyperchemotaxis was induced by a putative generation of FXa and thrombin activity was excluded. FVIIa/TF did not induce increased levels of PDGF beta-receptors on the cell surface. Thus, the hyperchemotaxis was not a result of this mechanism. FVIIa induced the production of inositol-1,4, 5-trisphosphate to the same extent as PDGF-BB; the effects of FVIIa and PDGF-BB were additive. FFR-FVIIa did not induce any release of inositol-1,4,5,-trisphosphate. Thus, binding of catalytically active FVIIa to TF can, independent of coagulation, modulate cellular responses, such as chemotaxis.

Amino Acid Chloromethyl Ketones↗
PubMed1999

Factor VIIa's first epidermal growth factor-like domain's role in catalytic activity.

Factor VIIa-tissue factor complex formation initiates the extrinsic blood coagulation pathway. We investigated factor VIIa's first epidermal growth factor-like (egf1) domain's role in the catalytic activity increase caused when factor VIIa binds tissue factor. Starting with a factor VIIa with factor IX's egf1 domain (factor VII(IXegf1)a), we made 4 proteins with egf1 residues changed to those in factor VIIa, including E51A, D64Q, FG74-75PA, and K79R. We measured each enzyme's affinity for tissue factor and determined the enzymes' kinetic constants with and without tissue factor. The Kd for factor VII(IXegf1)a binding to tissue factor was 60-200-fold higher than that of factor VIIa depending on the assay employed. Only factor VII(IXegf1)a with the K79R (K79Ra) mutation, among all the mutants, had an effect on binding with a Kd 3-8-fold lower than that of factor VII(IXegf1)a. In kinetic analyses with a small peptide substrate, in the absence of tissue factor, factor VIIa, factor VII(IXegf1)a, and K79Ra had similar kcat's and Km's. With tissue factor, due to a kcat decrease, factor VII(IXegf1)a's catalytic efficiency (kcat/Km) was 2-fold lower than factor VIIa's. K79Ra's catalytic efficiency was intermediate between those of factor VIIa and factor VII(IXegf1)a. With factor X as substrate, in the absence of tissue factor, K79Ra and factor VII(IXegf1)a had catalytic efficiencies 1.5-fold and 2-fold lower than that of factor VIIa. In contrast, with tissue factor and with factor X as substrate, due to higher Km's, factor VII(IXegf1)a and K79Ra had only 9% and 33% of factor VIIa's catalytic efficiency. Our results suggest the egf1 domain's role in tissue factor binding involves critical alignment of tissue factor with factor VIIa's catalytic domain. Proper alignment in turn promotes optimal catalytic activities.

Amino Acid Substitution↗
PubMed2005

Optimization of a coagulation factor VIIa inhibitor found in factor Xa inhibitor library.

An inhibitor of the complex of factor VIIa and tissue factor (fVIIa/TF), 2-substituted-4-amidinophenylpyruvic acid 1a, was structurally modified with the aim of increasing its potency and selectivity. The lead compound 1a was originally found in our factor Xa (fXa) inhibitor library on the basis of structural similarity of the primary binding sites of fVIIa and fXa. The design was based on computational docking studies using the extracted active site of fVIIa. Compound 1j was found to inhibit factor VIIa/TF at nanomolar concentration with improved selectivity versus fXa and thrombin and it preferentially prolonged the clotting time in the TF-dependent extrinsic pathway.

Antithrombins↗
PubMedDate not supplied

Activity of factor VIIa and von Willebrand factor in non-insulin-dependent diabetic subjects with coronary artery disease.

Atherosclerosis is more extensive and occurs earlier in diabetics compared with the general population. The pathophysiology of atherosclerosis is not fully established. We compared the activity of two blood clotting agents, activated factor VII (VIIa) and von Willebrand factor (vWF), in diabetic and non-diabetic subjects with coronary artery disease. According to clinical features, subjects were placed in one of four groups: Group I, non-insulin-dependent diabetes mellitus (NIDDM) with coronary heart disease (CAD) (n = 16); Group II, NIDDM (n = 15); Group III, CAD with no presence of diabetes (n = 17); and Group IV, healthy volunteers (n = 15). The level of factor VIIa was higher in Group I compared with all other groups, and was significantly higher in Group II compared with Group III and Group IV. Activity of vWF was higher in Group I compared with Group II, Group III and Group IV. There was no statistical difference between Group II and Group III. There was no significant correlation between concentration of blood glucose, total cholesterol or triglyceride, duration of diabetes and either factor VIIa or vWF activity. The results of this study suggest that increased activity of plasma vWF and factor VIIa may be useful markers to identify ischaemic heart disease risk in NIDDM subjects.

Adult↗
PubMed1997

Binding of factor VIIa to tissue factor induces alterations in gene expression in human fibroblast cells: up-regulation of poly(A) polymerase.

Tissue factor (TF) is the cellular receptor for an activated form of clotting factor VII (VIIa) and the binding of factor VII(a) to TF initiates the coagulation cascade. Sequence and structural patterns extracted from a global alignment of TF confers homology with interferon receptors of the cytokine receptor super family. Several recent studies suggested that TF could function as a genuine signal transducing receptor. However, it is unknown which biological function(s) of cells are altered upon the ligand, VIIa, binding to TF. In the present study, we examined the effect of VIIa binding to cell surface TF on cellular gene expression in fibroblasts. Differential mRNA display PCR technique was used to identify transcriptional changes in fibroblasts upon VIIa binding to TF. The display showed that VIIa binding to TF either up or down-regulated several mRNA species. The differential expression of one such transcript, VIIa-induced up-regulation, was confirmed by Northern blot analysis. Isolation of a full-length cDNA corresponding to the differentially expressed transcript revealed that VIIa-up-regulated gene was poly(A) polymerase. Northern blot analysis of various carcinomas and normal human tissues revealed an over expression of PAP in cancer tissues. Enhanced expression of PAP upon VIIa binding to tumor cell TF may potentially play an important role in tumor metastasis.

Base Sequence↗
PubMed2000

The treatment of bleeding in hemophilic patients with inhibitors with recombinant factor VIIa.

Recombinant factor VIIa (rFVIIa) has proven efficacy in the treatment of patients with alloantibodies and autoantibodies to factors VIII and IX. More than 80% of over 2,000 reported bleeding episodes treated with rFVIIa have been controlled in a variety of clinical circumstances. Its theoretical lack of activation of the coagulation system prompted many clinicians to undertake elective surgical procedures using rFVIIa in addition to on-demand treatment of minor bleeding episodes. Hemostatic efficacy has been good for most of these surgical procedures, without serious adverse events. rFVIIa is considered a useful, safe, and effective treatment for bleeding in patients with anti-factor VIII (FVIII) and anti-factor IX (FIX) inhibitors. However, the optimal dose for various clinical situations has yet to be established and requires further investigation. Laboratory monitoring of treatment using plasma FVIIa measurements should be better standardized. Despite the relatively high cost of this new drug, rFVIIa represents a major therapeutic advance in the treatment of hemophilic patients with inhibitors.

Autoantibodies↗
PubMed2004

Monitoring of hemostatic status in four patients being treated with recombinant factor VIIa.

Recombinant Factor VIIa (rVIIa) is a potent hemostatic agent for the management of refractory bleeding in patients with Factor VII deficiency or Factor VIII inhibitors. While the current recommended dose is usually effective, the most appropriate dose remains a subject of debate. Since factor VII levels and shortening of the pro-thrombin time do not appear to correlate with response, an appropriate laboratory marker of clinical response has not been identified. In this article we report changes noted in thrombin generation, platelet function and clot structure in blood from patients treated with rVIIa. Thrombin generation was assessed via a thrombin generation time (TGT) assay using a Hemodyne HAS instrument. Changes in clot structure were assessed as changes in clot elastic modulus in the HAS, changes in maximum amplitude in the TEG and changes in maximum clot firmness in the ROTEG. The cases presented confirmed improvement in thrombin generation with administration of rVIIa. The cases also illustrate that: a) in the factor VII deficient patient, 25% of the 90 microg/kg dose is sufficient to totally correct the defect, b) patients with high level factor VIII inhibitors may require significantly more than the recommended dose of 90 microg/kg, c) thrombin generation may not be completely corrected despite dramatic shortening of the prothrombin time, and d) increasing rVIIa doses does not by itself ensure improved thrombin generation.

Aged↗
PubMed2003

Treatment of bleeding in severe hemorrhagic pancreatitis with recombinant factor VIIa.

Recombinant factor VIIa (rFVIIa) has been used to treat bleeding complications in patients with hemophilia. It acts at the site of vessel injury, forming a complex with tissue factor to activate the clotting cascade. Recent reports have shown rFVIIa may be a useful hemostatic agent in patients after obstetrical, urologic, trauma, or transplant procedures. We report the first documented case of bleeding from hemorrhage pancreatitis treated with rFVIIa.

Factor VIIa↗
PubMed2004

Prevention of beta strand movement into a zymogen-like position does not confer higher activity to coagulation factor VIIa.

Coagulation factor VIIa (FVIIa) belongs to the chymotrypsin family of S1 peptidases, whose members require the cleavage of at least one internal peptide bond to attain an active conformation. FVIIa also requires association with tissue factor (TF) to attain full catalytic competency. Without this, FVIIa has very low activity toward peptide and physiologic substrates. Reregistration of beta strands has been suggested to play a part in the activation of FVII, and their positioning is possibly important for the active conformation of FVIIa. To scrutinize this hypothesis, we have designed FVIIa variants which prevent beta strand movement and lock FVIIa in the alleged active conformation. The V299M mutation, alone or combined with the L280I mutation, was introduced to alter the first of two Leu-X-Val motifs in beta strand B2 and thereby prevent reregistration. Along the same line, C164V/V299C-FVIIa has a new disulfide which would keep beta strand B2 in the registration of active FVIIa. The amidolytic and proteolytic activities of V299M-, L280I/V299M-, and C164V/V299C-FVIIa were indistinguishable from or lower than those of wild-type FVIIa, and none of the mutants displayed an altered exposure of the N-terminal amino group of the protease domain. Moreover, the affinities of mutant and native FVIIa for TF increased to a similar extent upon incorporation of an active site inhibitor, and the enzymatic activities were equally stimulated by TF. In conclusion, we found no evidence that the mutants were in a more active state than native FVIIa. Thus, the proposed beta strand reregistration, if part of the regulatory mechanism governing FVIIa activity, apparently does not suffice for the transformation of FVIIa into an enzymatically active conformation. Our data raise the possibility that the structural differences between enzymatically latent (zymogen-like) and active FVIIa resemble those between trypsinogen and trypsin.

Allosteric Site↗
PubMed2006

Challenges in the therapeutic use of a "so-called" universal hemostatic agent: recombinant factor VIIa.

Recombinant factor VIIa (rFVIIa) was developed in the early 1990s to provide "bypassing" hemostatic therapy for hemophilia A and B patients with inhibitors. More recently, it has been licensed for use in patients with inherited deficiency of factor VII. Since it was licensed for use in hemophilia with inhibitors in the US, Europe, and other countries for these specific indications, it has been used selectively but in a wide array of clinical settings for uncontrolled hemorrhage in individuals without an inherited bleeding disorder. Many of these uses have been described in the medical literature as case reports or small, uncontrolled series. Several randomized clinical trials (RCT) for these "off-label" medical uses have been published in recent months and will serve as the focus of this review. In particular, a review of an RCT for spontaneous intracranial hemorrhage that has demonstrated clinical efficacy in reducing both mortality and volume of central nervous system hemorrhage will be offered. A brief discussion of hypothesized physiologic mechanisms of supraphysiologic doses of rFVIIa will introduce the clinical discussion of these broad off-label uses. Since rFVIIa is a very expensive therapy, possible strategies for optimizing its use in the these settings will be presented.

Factor VII↗
PubMed2004

Safety profile of recombinant factor VIIa.

Recombinant factor VIIa (rFVIIa; NovoSeven(R), Novo Nordisk, Bagsvaerd, Denmark) has been used for many years in the successful management of bleeding episodes in patients with hemophilia and inhibitors. More recently, rFVIIa has also shown considerable success as a hemostatic agent in trauma and surgery patients without pre-existing coagulopathy. Despite extensive and varied usage of rFVIIa, the incidence of serious adverse events associated with its use is less than 1%; however, there remain concerns regarding the agent's potential to induce thrombosis. This paper will review the safety profile of rFVIIa by examining existing clinical evidence, and will demonstrate that the isolated thrombotic events reported following rFVIIa treatment are due primarily to an improvement in the coagulation mechanism rather than rFVIIa treatment per se. The demonstrated safety of rFVIIa is probably due to its localization to injured areas of the vascular tree by binding to tissue factor (TF) and activated platelets at the bleeding site, thus avoiding systemic activation of coagulation. Finally, those situations in which rFVIIa therapy may not be safe, such as disseminated intravascular coagulation (DIC) and sepsis, will also be discussed.

Blood Coagulation↗
PubMed2001

Successful outcome of a cirrhotic patient with postoperative haematuria treated with a single high dose of recombinant factor VIIa.

Recombinant factor VIIa (rfVIIa) has been widely used for the treatment and prevention of bleeding episodes in haemophiliacs with high-titre inhibitors. High single doses are the treatment of choice for joint and muscle bleeds in those patients. There are only a few reports on the value of rfVIIa in cirrhotic patients with haemostatic impairment but this drug can consistently correct the prothrombin time in these individuals. We report a case of a good response to a single high dose of rfVIIa in a patient with advanced liver disease who suffered from severe refractory postoperative haematuria.

Factor VII↗
PubMed2004

Antidotes to haemorrhage: recombinant factor VIIa.

Recombinant Factor VIIa (rFVIIa) concentrates were originally developed to treat the refractory bleeding complications associated with allo-antibody inhibitors in hemophilias A and B. As experience was gained in the hemophilias, the physiology of rFVIIa and its successes in controlling bleeds stimulated rFVIIa use in other challenging medical conditions complicated by bleeding. Thus, rFVIIa has assumed the role of a 'universal pancoagulant' without sufficient evidence-based data from well-designed, adequately powered clinical trials. This chapter discusses the anecdotal experience with rFVIIa based upon the few controlled trials that do exist, and emphasizes that these empirical dosing strategies have not yielded the best approach to achieve effective control of bleeding. Evidence-based data are necessary to establish the cost-benefit and risk-benefit profiles of rFVIIa, and to establish it as a standard treatment for bleeding.

Anticoagulants↗
PubMed1998

Clinical experience with recombinant factor VIIa.

Recombinant factor VIIa (rFVIIa) represents a major therapeutic advance in the treatment of haemophilia patients with inhibitors. The efficacy and safety of rFVIIa has been extensively studied in over 1900 surgical and non-surgical bleeding episodes in over 400 patients with haemophilia A or B (with or without inhibitors) or acquired haemophilia. Of 103 evaluable surgical bleeding episodes, the response to treatment with rFVIIa was considered to be either excellent or effective in 81%, 86% and 92% of major, minor and dental bleeding episodes, respectively. Treatment has been evaluated in 518 serious bleeding episodes and the response was considered either excellent or effective in 62% of muscle, 80% of ear, nose and throat, 88% of central nervous system, 76% of joint, and 75% of internal or retroperitoneal bleeding episodes. An excellent safety profile has also been demonstrated: of 1957 treatments with rFVIIa, only 16 serious adverse events have been reported that were considered to be possibly, but not necessarily, related to treatment.

Clinical Trials as Topic↗
PubMed1997

Ca2+ binding to the first epidermal growth factor-like domain of factor VIIa increases amidolytic activity and tissue factor affinity.

Coagulation factor VIIa belongs to a family of homologous enzymes, including factors IXa and Xa and activated protein C, composed of two epidermal growth factor-like domains located between an N-terminal domain rich in gamma-carboxyglutamic acid residues and a C-terminal serine protease domain. The first epidermal growth factor-like domain in factor VIIa contains a Ca2+ binding site, the function of which is largely unknown. Site-directed mutagenesis of two Ca2+-liganding Asp residues in this domain abolished Ca2+ binding and resulted in a 2-3-fold decrease in amidolytic activity at optimal Ca2+ concentrations. The lower amidolytic activity persisted in complex with soluble tissue factor, apparently due to a lower kcat of the mutant factor VIIa. Mutant and wild-type factor VIIa bound to lipidated tissue factor were equally efficient activators of factor X. The dissociation constants, derived from amidolytic activity and surface plasmon resonance measurements, were 2-5 nM and 50-60 nM for the interactions between wild-type and mutant factor VIIa, respectively, and soluble tissue factor. Binding to lipidated tissue factor was characterized by dissociation constants of 7.5 pM for factor VIIa and 160 pM for the factor VIIa mutant. Hence, a functional Ca2+ binding site in the first epidermal growth factor-like domain added 7-8 kJ/mol to the total binding energy of the interaction with both lipidated and soluble tissue factor.

Aspartic Acid↗
PubMed2001

Active site blockade of factor VIIa alters its intracellular distribution.

Factor VIIa binding to tissue factor on cell surfaces not only triggers the coagulation cascade but also induces various intracellular responses that may contribute to many pathophysiological processes. Active site-inhibited factor VIIa, similar to factor VIIa, binds to tissue factor on cell surfaces and subsequently gets internalized and degraded. At present, it is unknown whether factor VIIa and active site-inhibited factor VIIa undergo a similar intracellular processing. The data presented herein show that although a fraction of both the internalized factor VIIa and active site-inhibited factor VIIa recycle back to the cell surface, the amount of active site-inhibited factor VIIa recycled back to the cell surface was substantially higher than that of factor VIIa. Furthermore, internalized factor VIIa and not active site-inhibited factor VIIa associates with nuclear fractions. Factor VIIa associated with the nuclear fraction was intact and functionally active. In contrast to factor VIIa, tissue factor is not found in the nuclear fraction. Additional studies show that the internalized factor VIIa specifically associates with cytoskeletal proteins, actin, and tubulin. In summary, the present data reveal that despite the common pathway of tissue factor-mediated processing, considerable differences exist in the trafficking of factor VIIa and active site-inhibited factor VIIa in fibroblasts.

Actins↗