Ability of recombinant factor VIIa to generate thrombin during inhibition of tissue factor in human subjects

In view of the central role of the tissue factor-factor VIIa pathway in the initiation of blood coagulation, novel therapeutic strategies aimed at inhibiting this catalytic complex are currently being evaluated. A limitation of this new class of anticoagulants may be the lack of an appropriate strat...

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Bibliographic Details
Published in:	Circulation (New York, N.Y.) Vol. 103; no. 21; pp. 2555 - 2559
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott Williams & Wilkins 29-05-2001 American Heart Association, Inc
Subjects:	Adult Animals Anticoagulants - pharmacology Biological and medical sciences Blood. Blood coagulation. Reticuloendothelial system Cross-Over Studies Double-Blind Method Factor IX - drug effects Factor IX - metabolism Factor VIIa - metabolism Factor VIIa - pharmacology Factor X - drug effects Factor X - metabolism Helminth Proteins - blood Helminth Proteins - pharmacology Humans Male Medical sciences Partial Thromboplastin Time Pharmacology. Drug treatments Prothrombin Time Recombinant Proteins - pharmacology Thrombin - drug effects Thrombin - metabolism Human Thrombin(drug) Tissue factor Anticoagulant Inhibitor Recombinant protein Biological activity Factor VII
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Summary:	In view of the central role of the tissue factor-factor VIIa pathway in the initiation of blood coagulation, novel therapeutic strategies aimed at inhibiting this catalytic complex are currently being evaluated. A limitation of this new class of anticoagulants may be the lack of an appropriate strategy to reverse the effect if a bleeding event occurs. The aim of this study was to investigate the in vivo potential of recombinant factor VIIa (rVIIa) to induce thrombin generation in healthy subjects pretreated with recombinant nematode anticoagulant protein c2, a specific inhibitor of the tissue factor-factor VIIa complex, in a double-blind randomized crossover study. Administration of nematode anticoagulant protein c2 (3.5 microgram/kg) caused a prolongation of the prothrombin time from 13.7+/-0.6 to 16.9+/-1.2 seconds. The subsequent injection of rVIIa (90 microgram/kg) resulted in an immediate and complete correction of the prothrombin time and a marked generation of thrombin, reflected by increased levels of prothrombin activation fragment F1+2 and thrombin-antithrombin complexes from 0.75+/-0.64 to 3.29+/-6.3 nmol/L and from 2.4+/-0.6 to 10.7+/-3.9 microgram/mL, respectively. Factor X and IX activation peptides showed a 3.5-fold and a 3.8-fold increase, respectively, after the administration of rVIIa in the presence of nematode anticoagulant protein c2. 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 ObjectType-News-3 content type line 23
ISSN:	0009-7322 1524-4539
DOI:	10.1161/01.CIR.103.21.2555