Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates.
The effects on thrombosis and hemostasis of thrombin-induced activation of endogenous protein C (PC) were evaluated in baboons. Thrombosis was induced by placing into arteriovenous shunts a segment of Dacron vascular graft, which generated arterial platelet-rich thrombus, followed by an expansion region of low-shear blood flow, which in turn accumulated fibrin-rich venous-type thrombus. Thrombosis was quantified by 111In-platelet imaging and 125I-fibrinogen accumulation. Intravenous infusion of alpha-thrombin, 1-2 U/kg-min for 1 h, increased baseline activated PC levels (approximately 5 ng/ml) to 250-500 ng/ml (P < 0.01). The lower thrombin dose, which did not deplete circulating platelets, fibrinogen, or PC, reduced arterial graft platelet deposition by 48% (P < 0.05), and platelet and fibrin incorporation into venous-type thrombus by > 85% (P < 0.01). Thrombin infusion prolonged the activated partial thromboplastin clotting time, elevated fibrinopeptide A (FPA), thrombin-antithrombin III complex (T:AT III), and fibrin D-dimer plasma levels (P < 0.01), but did not affect bleeding times. Thrombin's antithrombotic effects were blocked by infusing a monoclonal antibody (HPC-4) which prevented PC activation in vivo, caused shunt occlusion, increased the consumption of platelets and fibrinogen, elevated plasma FPA and T:AT III levels, and reduced factor VIII (but not factor V) procoagulant activity (P < 0.05). We conclude that activated PC is a physiologic inhibitor of thrombosis, and that activation of endogenous PC may represent a novel and effective antithrombotic strategy.
Hanson
S R
SR
Division of Hematology-Oncology, Emory University School of Medicine, Atlanta, Georgia 30322.
Griffin
J H
JH
Harker
L A
LA
Kelly
A B
AB
Esmon
C T
CT
Gruber
A
A
D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D005165:Factor V / Q000378:metabolism; D005167:Factor VII / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005344:Fibrinopeptide A / Q000378:metabolism; D008297:Male; D010215:Papio; D010314:Partial Thromboplastin Time; D011093:Polyethylene Terephthalates; D011486:Protein C / Q000378:metabolism*; D013917:Thrombin / Q000494:pharmacology*; D013927:Thrombosis / Q000503:physiopathology / Q000517:prevention & control*
D011093:Polyethylene Terephthalates; D011486:Protein C; D005344:Fibrinopeptide A; D005165:Factor V; D005167:Factor VII; D005337:Fibrin; D005340:Fibrinogen; D013917:Thrombin