INHIBITORY EFFECTS OF ACTIVATED PROTEIN-C AND HEPARIN ON THROMBOTIC ARTERIAL-OCCLUSION IN RAT MESENTERIC-ARTERIES

Effects of human activated protein C (APC) and heparin on thrombus formation were examined using small mesenteric arteries of rats and video-recording system attached to a microscope. To induce thrombosis we damaged the vessel wall over a short segment by compression and exposed the damaged media to the blood stream. Platelet-rich thrombus enlarged gradually at the damaged site, occluded the vascular lumen for a short period and then flowed away. Such thrombus formation was observed several times after a compression damage. An intravenous administration of APC significantly decreased the total occlusion time from 6.4 +/- 0.7 min at control to 2.2 +/- 0.4 min at 0.9 mg/kg given over 1 min (mean +/- SEM, n = 6, p < 0.01), and from 6.5 +/- 1.0 min to 1.0 +/- 0.3 min at 3.0 mg/kg (n = 6, p < 0.01). An intravenous heparin (300 and 1000 U/kg) also decreased the total occlusion time significantly from 6.2 +/- 0.8 to 2.2 +/- 0.8 min (n = 6, p < 0.05) and from 5.4 +/- 0.8 to 0.8 +/- 0.7 min (n = 6, p < 0.01), respectively. APC prolonged APTT from 11 +/- 1 sec (n = 5) at control to 50 +/- 5 sec (n = 5) at 0.9 mg/kg and to 87 +/- 8 sec (n = 5) at 3.0 mg/kg, while heparin prolonged APTT to more than 120 sec in all 5 rats at both doses. APTT prolongation by APC was significantly attenuated by inhibiting its residual activity in the plasma samples using monoclonal antibody. We conclude that APC inhibits arterial thrombosis developing at the damaged vascular wall with minor effects on APTT.