Inhibition of factor VIIa/tissue factor with nematode anticoagulant protein c2: from unique mechanism to a promising new clinical anticoagulant.
Recombinant nematode anticoagulant protein c2 (rNAPc2) is a potent (K(i) = 10 pM) inhibitor of the factor VIIa/tissue factor complex (fVIIa/TF) that involves the pre-requisite binding to either zymogen or activated factor X (fX) prior to the formation of the final quaternary complex with fVIIa/TF. The formation of the binary complex with circulating fX governs the pharmacokinetic profile of rNAPc2 in humans, resulting in a prolonged elimination half-life of >50 h. The clinical antithrombotic potential of rNAPc2 has been evaluated in a phase-II trial in which the incidence of deep-vein thrombosis was reduced over 50% compared to historic controls with low-molecular-weight heparin in patients undergoing knee replacement surgery. A second phase-IIa trial demonstrated the safety of rNAPc2 and the significant suppression of thrombin generation in patients undergoing elective percutaneous coronary intervention treated with standard anticoagulant and antiplatelet therapies. Overall, rNAPc2 is a unique inhibitor of the fVIIa/TF complex and a promising new clinical anticoagulant.
Vlasuk
George P
GP
Corvas International, Inc., San Diego, California 92121, USA. george_vlasuk@corvas.com
Rote
William E
WE
D000925:Anticoagulants / Q000494:pharmacology*; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D015801:Helminth Proteins / Q000494:pharmacology*; D006490:Hemostatics / Q000037:antagonists & inhibitors*; D006801:Humans; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000187:drug effects*
D000925:Anticoagulants; D015801:Helminth Proteins; D006490:Hemostatics; C400226:anti-coagulant protein C2, Ancylostoma caninum; D013925:Thromboplastin; D015942:Factor VIIa