No abstract

Unfractionated heparin is often used to prevent thrombosis in microvascular surgery, but a major drawback of heparin therapy is increased bleeding. Low-molecular-weight heparins prevent venous thrombosis as effectively as heparin and have better bioavailability and a longer plasma half-life, which explains the increased use of low-molecular-weight heparins as substitutes for heparin in clinical practice. However, the ability of low-molecular-weight heparins to prevent arterial thrombosis has been debated. In this study, the authors compared the antithrombotic and antihemostatic effects of heparin and the low-molecular-weight heparin dalteparin in a rat model of arterial thrombosis. A segment of the left common carotid artery was isolated between vascular clamps and opened longitudinally. An endarterectomy was performed and the arteriotomy was closed with a running suture. The antithrombotic effect (vascular patency 31 minutes after reperfusion) and the surgical bleeding were measured. Groups of 10 rats were treated in a blind, random fashion with intravenous injection of one of the following substances 1 minute before clamp release. Three groups received a bolus of heparin (20, 60, or 180 IU anti-factor Xa/kg), three groups received dalteparin (60, 180, or 540 IU anti-factor Xa/kg), and one group was treated with vehicle (saline). Heparin 180 IU/kg produced a distinct antithrombotic effect compared with the control group (p = 0.03), but it also significantly increased the surgical bleeding to 2.0 g compared with 1.5 g in the control group (medians, p = 0.01). Dalteparin 180 and 540 IU/kg also produced a powerful antithrombotic effect (p = 0.01 and p = 0.03, respectively). In contrast to heparin, 180 IU/kg dalteparin did not increase the surgical bleeding (median, 1.5 g; p = 0.37 versus controls). Dalteparin 540 IU/kg increased the median surgical bleeding to 2.6 g (p = 0.06 versus controls). The nonsignificant difference may be explained by the great interindividual variation of surgical bleeding in the high-dose dalteparin group. Dalteparin prevented arterial thrombosis as effectively as unfractionated heparin. In contrast to heparin, dalteparin did not increase the surgical bleeding, which indicates that dalteparin instead of heparin can be used to prevent thrombosis in microvascular surgery.

No abstract

The antithrombotic effect of bovine activated protein C (bAPC) given with or without bovine protein S (bPS) was investigated in a rat model of deep arterial injury. A segment of the left common carotid artery was isolated between vascular clamps and opened longitudinally. An endarterectomy was performed and the arteriotomy was closed with a running suture, whereafter the vessel was reperfused by removing the clamps. The antithrombotic effect (vascular patency rates 31 minutes after reperfusion) and the arteriotomy bleeding were measured. Ten treatment groups each containing 10 rats and a control group of 20 animals were in a blind random fashion given intravenous bolus injections of increasing doses of activated protein C, with or without co-administration of protein S. The groups received either bAPC alone (0.8, 0.4, 0.2 or 0.1 mg/kg), bAPC (0.8, 0.4, 0.2, 0.1 or 0.05 mg/kg) combined with bPS (0.6 mg/kg), or bPS alone (0.6 mg/kg) whereas the control group received vehicle only. Administered alone, bAPC or bPS had no antithrombotic effect, regardless of dosage. In contrast, all groups that were treated with bAPC in combination with bPS demonstrated a significant antithrombotic effect, as compared to controls. Neither bAPC, bPS, nor the combination of bAPC and bPS increased the arteriotomy bleeding significantly compared to controls. In vitro clotting assays using bAPC or bPS alone yielded only minor prolongation of clotting time, whereas bAPC combined with bPS prolonged the clotting time considerably, demonstrating the dependence on the APC-cofactor activity of bPS for expression of anticoagulant activity by bAPC. In conclusion, our study shows the in vivo significance of protein S as a cofactor to activated protein C, and that potent anti-thrombotic effect can be achieved by low doses of bAPC combined with bPS, without producing hemorrhagic side effects.

In conclusion, administration of human APC variants having enhanced anticoagulant efficacy together with human PS in a rat model of arterial thrombosis did not give an efficient antithrombotic effect. The lack of effect may be due to species-specific differences between the human protein C system and the rat hemostatic system.