Comparison of the antithrombotic effect of PEG-hirudin and heparin in a human ex vivo model of arterial thrombosis.
Polyethylene glycol (PEG)-hirudin is a derivative of hirudin with a long plasma half-life. We have compared the efficacy of PEG-hirudin with unfractionated heparin (UH) in preventing arterial thrombosis. Arterial thrombus formation was induced ex vivo in 12 healthy human volunteers by exposing a tissue factor-coated coverslip positioned in a parallel-plate perfusion chamber to flowing nonanticoagulated human blood drawn directly from an antecubital vein at an arterial wall shear rate of 2600 s-1 for 3.5 minutes. PEG-hirudin, UH, or saline (as control) were administered ex vivo through a heparin-coated mixing device positioned proximal to the perfusion chamber. Platelet and fibrin deposition was quantified by immunoenzymatic measure of the P-selectin and D-dimer content of dissolved plasmin-digested thrombi, respectively. UH was administered to a plasma concentration of 0.35 IU/mL. This concentration prolonged the activated partial thromboplastin time from 32+/-1 seconds to 79+/-4 seconds (P<0.01). UH did not significantly prevent platelet deposition. However, fibrin deposition was reduced by 39% (P<0.05). PEG-hirudin in plasma concentrations of 0.5, 2.5, and 5 microg/mL prolonged the activated partial thromboplastin time to 48+/-2, 87+/-4, and 118+/-4 seconds, respectively. In contrast to UH, PEG-hirudin prevented both platelet and fibrin deposition in a dose-dependent manner with a >80% reduction at 5 microg/mL (P<0.01). Furthermore, the plasma level of PEG-hirudin required to significantly prevent fibrin deposition (0.5 microg/mL) corresponded to a much shorter prolongation of activated partial thromboplastin time (48+/-2 seconds) than that needed for UH (79+/-4 seconds). Thus, our results are compatible with the view that thrombin is greatly involved in recruitment of platelets in evolving thrombi, and that PEG-hirudin is an effective agent for preventing arterial thrombosis in a human ex vivo experimental model.
D000990:Antithrombin III / Q000032:analysis; D001157:Arterial Occlusive Diseases / Q000188:drug therapy*; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D005337:Fibrin / Q000032:analysis; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005898:Glass; D006207:Half-Life; D006493:Heparin / Q000494:pharmacology*; D006629:Hirudins / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D019007:P-Selectin / Q000032:analysis; D010447:Peptide Hydrolases / Q000032:analysis; D015539:Platelet Activation; D012965:Sodium Chloride / Q000494:pharmacology; D013925:Thromboplastin / Q000494:pharmacology; D013927:Thrombosis / Q000188:drug therapy*; D001620:beta-Thromboglobulin / Q000032:analysis