Ability of Recombinant Factor VIIa to Generate Thrombin During Inhibition of Tissue Factor in Human Subjects

Friederich, Philip W.; Levi, Marcel; Bauer, Kenneth A.; Vlasuk, George P.; Rote, William E.; Breederveld, Daan; Keller, Tijmen; Spataro, Marco; Barzegar, Samad; Büller, Harry R.

doi:10.1161/01.cir.103.21.2555

Cited by 78 publications

(45 citation statements)

References 25 publications

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“…However, phase I studies suggest that recombinant fVIIa can reverse anticoagulant effects of rNAPc2 in normal volunteers. 11 Several methodological features of the present study warrant discussion. First, a concurrent control group was not included because providing an active control group for each of the rNAPc2 regimens tested would have increased substantially the total sample size, and the thrombotic and bleeding events rates for LMWHs, considered by most clinicians to be the best prophylactics available, are already well established in patients undergoing TKR.…”

Section: Discussionmentioning

confidence: 90%

Dose-Response Study of Recombinant Factor VIIa/Tissue Factor Inhibitor Recombinant Nematode Anticoagulant Protein c2 in Prevention of Postoperative Venous Thromboembolism in Patients Undergoing Total Knee Replacement

et al. 2001

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Background —With the best prophylactics now available, venous thromboembolism after total knee replacement remains substantial (25% to 27%). Recombinant nematode anticoagulant protein c2 (rNAPc2) is a potent inhibitor of factor VIIa/tissue factor complex that has the potential to reduce this risk. The present study was performed to determine an efficacious and safe dose of rNAPc2 for prevention of venous thromboembolism after elective, unilateral total knee replacement. Methods and Results —This open-label, sequential dose-ranging study was conducted in 11 centers in Canada, Europe, and the United States. Five regimens were tested. Injections were administered subcutaneously on the day of surgery (day 1) and days 3, 5, and optionally, day 7. Primary efficacy outcome was a composite of overall deep vein thrombosis based on mandatory unilateral venography (day 7±2) and confirmed symptomatic venous thromboembolism recorded ≤48 hours after the last dose of rNAPc2. Primary safety outcome was major bleeding ≤72 hours after the last dose. An independent, blinded Central Adjudication Committee assessed all outcome events. Of 293 patients studied, 251 (86%) could be evaluated for primary efficacy analysis. A dosage of 3.0 μg/kg administered within 1 hour after surgery provided the best observed results, with an overall deep vein thrombosis rate of 12.2%, a proximal deep vein thrombosis rate of 1.3%, and a major bleeding rate of 2.3%. Conclusions —A randomized, double-blind trial that compared rNAPc2 with current best prophylactics is warranted based on encouraging, first-reported clinical results for a factor VIIa/tissue factor inhibitor evaluated for thrombosis prophylaxis.

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Section: Discussionmentioning

confidence: 90%

Dose-Response Study of Recombinant Factor VIIa/Tissue Factor Inhibitor Recombinant Nematode Anticoagulant Protein c2 in Prevention of Postoperative Venous Thromboembolism in Patients Undergoing Total Knee Replacement

et al. 2001

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“…12 Higher dose of rFVIIa, older age, and the use of antiplatelet agents were independently associated with higher risk of arterial TEs (Table 6). A stronger association was found with signs of ischemia at baseline (ORϭ4.19).…”

Section: Discussionmentioning

confidence: 99%

Thromboembolic Events With Recombinant Activated Factor VII in Spontaneous Intracerebral Hemorrhage

Diringer

Skolnick

Mayer

et al. 2010

Stroke

108

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Background and Purpose-Patients with intracerebral hemorrhage have a high risk of thromboembolic events (TEs) due to advanced age, hypertension, atherosclerosis, diabetes, and immobility. Use of recombinant activated factor VII (rFVIIa) could increase TEs in high-risk patients. Factor Seven for Acute Hemorrhagic Stroke (FAST) trial data were reviewed to define the frequency of and risk factors for TE with rFVIIa. Methods-Eight hundred forty-one patients presenting Ͻ3 hours after spontaneous intracerebral hemorrhage were randomized to 20 or 80 g/kg of rFVIIa or placebo. Those with Glasgow Coma Scale score Ͻ5, planned early surgery, coagulopathy, or recent TE were excluded. Myocardial, cerebral, or venous TEs were subject to detailed reporting and expedited local review. Additionally, a blinded Data Monitoring Committee reviewed all electrocardiograms, centrally analyzed troponin I values, and CT scans. Results-There were 178 arterial and 47 venous TEs. Venous events were similar across groups. There were 49 (27%) arterial events in the placebo group, 47 (26%) in the 20-g/kg group, and 82 (46%) in the 80 g/kg group (Pϭ0.04).Of the myocardial events, 38 were investigator-reported and 103 identified by the Data Monitoring Committee. They occurred in 17 (6.3%) placebo and 57 (9.9%) rFVIIa patients (Pϭ0.09). Arterial TEs were associated with: receiving 80 g/kg rFVIIa (ORϭ2.14; Pϭ0.031), signs of cardiac or cerebral ischemia at presentation (ORϭ4.19; Pϭ0.010), age (ORϭ1.14/5 years; Pϭ0.0123), and prior use of antiplatelet agents (ORϭ1.83; Pϭ0.035). Ischemic strokes possibly related to study drug occurred in 7, 5, and 8 patients in the placebo, 20 g/kg, and 80-g/kg groups, respectively. Conclusions-Higher doses of rFVIIa in a high-risk population are associated with a small increased risk of what are usually minor cardiac events. Demonstration of the ability of rFVIIa to improve outcome in future studies should be driven by its effectiveness in slowing bleeding outweighting the risk of a small increase in arterial TEs. (Stroke. 2010; 41:48-53.)

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“…However, inhibition of VIIa-TF by NAPc2 bound to either factors X or Xa occurs with far greater affinity than the inhibition of prothrombinase (17). The plasma concentrations of NAPc2 achieved in clinical studies suggest that the efficacy of NAPc2 as a therapeutic antithrombotic in humans (54,55) probably derives from inhibition of VIIa-TF.…”

Section: Discussionmentioning

confidence: 99%

Nematode Anticoagulant Protein c2 Reveals a Site on Factor Xa That Is Important for Macromolecular Substrate Binding to Human Prothrombinase

Buddai¹,

Toulokhonova²,

Bergum³

et al. 2002

Journal of Biological Chemistry

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The binding of recombinant nematode anticoagulant protein c2 (NAPc2) to either factor X or Xa is a requisite step in the pathway for the potent inhibition of VIIa tissue factor. We have used NAPc2 as a tight binding probe of human Xa to investigate protein substrate recognition by the human prothrombinase complex. NAPc2 binds with high affinity (K d ϳ1 nM) to both X and Xa in a way that does not require or occlude the active site of the enzyme. In contrast, NAPc2 is a tight binding, competitive inhibitor of protein substrate cleavage by human Xa incorporated into prothrombinase with saturating concentrations of membranes and Va. By fluorescence binding studies we show that NAPc2 does not interfere with the assembly of human prothrombinase. These are properties expected of an inhibitor that blocks protein substrate recognition by targeting extended macromolecular recognition sites (exosites) on the enzyme complex. A weaker interaction (K d ‫؍‬ 260-500 nM) observed between NAPc2 and bovine X was restored to a high affinity one in a recombinant chimeric bovine X derivative containing 25 residues from the COOH terminus of the proteinase domain of human X. This region implicated in binding NAPc2 is spatially adjacent to a site previously identified as a potential exosite. Despite the weaker interaction with bovine Xa, NAPc2 was a tight binding competitive inhibitor of protein substrate cleavage by bovine prothrombinase as well. Extended enzymic surfaces elucidated with exosite-directed probes, such as NAPc2, may define a unique region of factor Xa that is modulated following its assembly into prothrombinase and in turn determines the binding specificity of the enzyme complex for its protein substrate.The proteolytic activation of prothrombin is catalyzed by the prothrombinase complex of coagulation (2-5). Prothrombinase assembles through membrane-dependent interactions between the serine proteinase, factor Xa, and the protein cofactor, factor Va (2, 3). Although solution-phase Xa is a competent enzyme, its incorporation into prothrombinase yields a profound increase in the rate of thrombin formation (2, 3).Prothrombin is the only known protein substrate cleaved efficiently by prothrombinase (2, 6). Such stringent selectivity is not evident in the action of factor Xa on oligopeptidyl substrates, nor is the rate of peptidyl substrate hydrolysis significantly enhanced upon assembly of factor Xa into prothrombinase (7,8). Thus, the narrow and defined specificity of prothrombinase toward its protein substrate is unlikely to be solely explained by the specific recognition of residues surrounding the scissile bond by the active site of factor Xa within the enzyme complex.Mechanistic studies of bovine prothrombinase function have borne out this suggestion (9 -11). A series of studies indicate that recognition of the biological substrate is achieved through stepwise interactions of the protein substrate at an extended macromolecular recognition site (exosite) in prothrombinase removed from the catalytic site of Xa, followed b...

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Ability of Recombinant Factor VIIa to Generate Thrombin During Inhibition of Tissue Factor in Human Subjects

Abstract: During treatment with an inhibitor of the tissue factor-factor VIIa complex, the infusion of rVIIa resulted in thrombin generation. Our results indicate that rVIIa may be a good candidate as an antidote for inhibitors of tissue factor.

Cited by 78 publications

References 25 publications

Dose-Response Study of Recombinant Factor VIIa/Tissue Factor Inhibitor Recombinant Nematode Anticoagulant Protein c2 in Prevention of Postoperative Venous Thromboembolism in Patients Undergoing Total Knee Replacement

Dose-Response Study of Recombinant Factor VIIa/Tissue Factor Inhibitor Recombinant Nematode Anticoagulant Protein c2 in Prevention of Postoperative Venous Thromboembolism in Patients Undergoing Total Knee Replacement

Thromboembolic Events With Recombinant Activated Factor VII in Spontaneous Intracerebral Hemorrhage

Nematode Anticoagulant Protein c2 Reveals a Site on Factor Xa That Is Important for Macromolecular Substrate Binding to Human Prothrombinase

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