Prevention of thrombus growth by antithrombin III-dependent and two direct thrombin inhibitors in rabbits: implications for antithrombotic therapy.
We compared the abilities of heparin and two direct thrombin inhibitors to prevent fibrin accretion onto pre-existing thrombi in rabbits. Inhibition of thrombus growth was measured as the ability of each test compound to inhibit the accretion of 125I-fibrin onto thrombi pre-formed in jugular veins of rabbits. When administered as a continuous infusion, the two direct (i.e. antithrombin III-independent) thrombin inhibitors, r-hirudin and a tripeptide, Ac(D)-Phe-Pro-bor-Arg (P-8714) inhibited fibrin accretion as effectively as heparin, but did so in doses which generated little systemic anticoagulation, as compared to the marked anticoagulation associated with the heparin effect. However, both r-hirudin and P-8714 were more effective when they were administered as a single bolus injection than as a continuous infusion. Under the former conditions, there was only a transient systemic anticoagulant effect. We conclude that direct or antithrombin III-independent thrombin inhibitors are more effective than heparin in preventing thrombus growth. The limited effect of heparin is likely due to fibrin impairing the ability of heparin/antithrombin III to inactivate thrombin.
Brill-Edwards
P
P
Department of Medicine, McMaster University Medical Centre, Hamilton, Ontario, Canada.
Van Ryn-McKenna
J
J
Cai
L
L
Ofosu
F A
FA
Buchanan
M R
MR
D000595:Amino Acid Sequence; D000818:Animals; D000990:Antithrombin III / Q000502:physiology; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006493:Heparin / Q000627:therapeutic use*; D024764:Hirudin Therapy; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000627:therapeutic use*; D011817:Rabbits; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013924:Thrombophlebitis / Q000517:prevention & control*
D005343:Fibrinolytic Agents; D009842:Oligopeptides; C078378:acetylphenylalanyl-prolyl-bor-arginine; D000990:Antithrombin III; D006493:Heparin; D013917:Thrombin