Suppression of intimal hyperplasia with low molecular weight heparin in a sheep model

Background Both unfractionated heparin (UH) and low molecular weight hepari n (LMWH) in therapeutic anticoagulant doses have been shown to inhibit the development of intimal hyperplasia (IH) but with an increased risk of haemo rrhage. In this study we investigated the effect of a "low dose" and "high dose" of UH and LMWH on the inhibition of IH together with their effect on plasma anti-Xa activity (AXa) and activated partial thromboplastin time (AP TT) using a carotid artery sheep model. Methods. A gelatin sealed Dacron patch graft was implanted into the common carotid artery of sheep which were randomly allocated to a control group (G roup 1, n=10) or to one of four treatment groups receiving either low-dose LMWH enoxaparin 1 mg/kg/day (group 2, n=11), high-dose LMWH enoxaparin 2 mg /kg/day (Group 3, n=13), low-dose UH 125 u/kg/day (Group 4, n=10) or high-d ose UH 250 u/kg/day (Group 5, n=10). The LMWH was administered subcutaneous ly once daily for four weeks and the UH in two divided doses per day for fo ur weeks. During the treatment period, AXa and APTT were assayed from blood collected prior to and at 1 and 2 h after heparin administration on day 3, 7, 14, 21 and 28. On day 28, all animals were sacrificed and grafts were c ollected for analysis after taking blood samples prior to, then at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h following the last injection. Measurements of in timal thickness were obtained under light microscopy from eight transverse sections of each grafted artery using an eyepiece graticule. Results. IH measurements (Mean+/-SD) were: Group 1 (controls) 288+/-86 mu m , Group 2 (low-dose LMWH) 222+/-50 mm (p<0.05 compared to Group 1), Group 3 (high-dose LMWH) 203+/-78 mu m (p<0.01), Group 4 (low-dose UH) 275+/-61 mu m, and Group 5 (high-dose UH) 206+/-71 mu m (p<0.01). There was no signifi cant difference between Groups 2, 3 and 5. Groups 2, 3 and 5 demonstrated s ignificant AXa during the 28 days period of which Groups 2 and 5 showed a s ignificant increase in AXa levels with time. In the 24 h study after the la st dose of treatment both Groups 2 and 3 showed longer AXa than group 5 (12 -24 h vs 8 h). When compared to the control group, significant elevation of APTT was demonstrated in Groups 3 and 5. Group 5 had significantly longer APTT than Group 3. In the 24 h study, APTT reflected the changes of AXa in all groups. Conclusions. In this study the LMWH enoxaparin was effective in reducing th e formation of IH both at a standard anticoagulant therapeutic dose of 2 mg /kg/day and also at a lower dose of 1 mg/kg/day.