Recombinant nematode anticoagulant protein c2, an inhibitor of tissue factor/factor VIIa, attenuates coagulation and the interleukin-10 response in human endotoxemia.
The tissue factor-factor (F)VIIa complex (TF/FVIIa) is responsible for the initiation of blood coagulation under both physiological and pathological conditions. Recombinant nematode anticoagulant protein c2 (rNAPc2) is a potent inhibitor of TF/FVIIa, mechanistically distinct from tissue factor pathway inhibitor. The first aim of this study was to elucidate the pharmacokinetics and pharmacodynamics of a single intravenous (i.v.) dose of rNAPc2. The second aim was to study its effect on endotoxin-induced coagulation and inflammation. Initially, rNAPc2 was administered to healthy volunteers in three different doses. There were no safety concerns and the pharmacokinetics were consistent with previous studies, in which rNAPc2 was administered subcutaneously. rNAPc2 elicited a dose-dependent reduction of the endogenous thrombin potential and a selective prolongation of prothrombin time. Subsequently, the effect on endotoxin-induced coagulation and inflammation was studied. The administration of rNAPc2 completely blocked the endotoxin-induced thrombin generation, as measured by plasma prothrombin fragment F1+2. The endotoxin-induced effect on fibrinolytic parameters such as plasmin-antiplasmin complexes and plasminogen activator inhibitor type 1 was not affected by rNAPc2. The administration of rNAPc2 attenuated the endotoxin-induced rise in interleukin (IL)-10, without affecting the rise in other cytokines. In conclusion, rNAPc2 is a potent inhibitor of TF/FVIIa, which was well tolerated and could safely be used intravenously in this Phase I study in healthy male volunteers. A single i.v. dose rNAPc2 completely blocked endotoxin-induced thrombin generation without affecting the fibrinolytic response. In addition, rNAPc2 attenuated the endotoxin-induced rise in IL-10, without affecting the rises in other cytokines.
de Pont
A C J M
AC
Department of Intensive Care, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. a.c.depont@amc.uva.nl
Moons
A H M
AH
de Jonge
E
E
Meijers
J C M
JC
Vlasuk
G P
GP
Rote
W E
WE
Büller
H R
HR
van der Poll
T
T
Levi
M
M
D000293:Adolescent; D000328:Adult; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D005342:Fibrinolysis / Q000187:drug effects; D015801:Helminth Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis*; D008297:Male; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D012449:Safety; D013917:Thrombin / Q000096:biosynthesis; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D016207:Cytokines; D015801:Helminth Proteins; D011994:Recombinant Proteins; C400226:anti-coagulant protein C2, Ancylostoma caninum; D016753:Interleukin-10; D013925:Thromboplastin; D015942:Factor VIIa; D013917:Thrombin