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 pl asma half-life. We have compared the efficacy of PEG-hirudin with unfractio nated heparin (UH) in preventing arterial thrombosis. Arterial thrombus for mation was induced ex vivo in 12 healthy human volunteers by exposing a tis sue factor-coated coverslip positioned in a parallel-plate perfusion chambe r to flowing nonanticoagulated human blood drawn directly from an antecubit al vein. at an arterial wall shear rate of 2600 s(-1) for 3.5 minutes. PEC- hirudin, UH, or saline (as control) were administered ex vivo through a hep arin-coated mixing device positioned proximal to the perfusion chamber. Pla telet and fibrin deposition was quantified by immunoenzymatic measure of th e P-selectin and D-dimer content of dissolved plasmin-digested thrombi, res pectively. UH was administered to a plasma concentration of 0.35 IU/mL. Thi s concentration prolonged the activated partial thromboplastin time from 32 +/-1 seconds to 79+/-4 seconds (P<0.01). UH did not significantly prevent p latelet deposition. However, fibrin deposition was reduced by 39% (P<0.05). PEG-hirudin in plasma concentrations of 0.5, 2.5, and 5 mu g/mL prolonged the activated partial thromboplastin time to 48+/-2, 87+/-4, and 118+/-4 se conds, respectively. In contrast to UH, PEG-hirudin prevented both platelet and fibrin deposition in a dose-dependent manner with a >80% reduction at 5 mu g/mL (P<0.01). Furthermore, the plasma level of PEG-hirudin required t o significantly prevent fibrin deposition (0.5 mu g/mL) corresponded to a m uch shorter prolongation of activated partial thromboplastin time (48+/-2 s econds) than that needed for UH (79+/-4 seconds). Thus, our results are com patible with the view that thrombin is greatly involved in recruitment of p latelets in evolving thrombi, and that PEG-hirudin is an effective agent fo r preventing arterial thrombosis in a human ex vivo experimental model.