Low-Molecular-Weight Heparin (Dalteparin) Effectively Prevents Thrombosis in a Rat Model of Deep Arterial Injury

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.

Anticoagulation Therapy in Microsurgery: A Review

“…Although some studies clearly have found LMWH to be a less effective treatment than traditional heparin in reducing the frequency of arterial thrombosis, 46,47 others have reported better or equal results. 34,48 In a rabbit model Zhang et al 48 observed a 50% increase in the patency of arterial anastomoses with LMWH in comparison with no anticoagulation, but observed no difference in the patency of small venous anastomoses.…”

“…In addition to causing fewer hematomas LMWH has higher bioavailability (85% compared with 10%), a longer plasma half-life, a steady dose-response relationship, 34,49 and causes fewer cases of thrombocytopenia compared with unfractionated heparin. 25,50,51 Thus LMWH produces reliable anticoagulation over a longer period of time without the need for monitoring.…”

“…[31][32][33] Disadvantages of heparin use include its low bioavailability and unpredictable doseresponse relationship. 34 Subcutaneous administration to postoperative patients necessitates close monitoring of fluctuating coagulation levels, which extends the length and increases the cost of the hospital stay. 35 The goal in heparin therapy is the efficient delivery of a minimal therapeutic dose to the site of vascular anastomosis.…”

“…This value was found to be 3-fold lower for the lowest dose of dalteparin with distinct antithrombotic effect (180 U/kg) compared with the same dose of unfractionated heparin. 34 Therefore the level of activity of LMWH is expressed best as units of anti-activated factor X (factor Xa) activity instead of APTT. 52 In a rat model Ritter et al 47 showed that a single injection of either unfractionated heparin or LMWH just before pedicle division results in a similar anastomotic patency and flap survival rate.…”

Comparative study of isovolemic hemodilution with 3% albumin, dextran-40, and prophylactic enoxaparin (LMWH) on thrombus formation at venous microanastomosis in rats

“…Experimental studies in rats have demonstrated better results on prevention of microanastomosis thrombosis using LMWH, but often with a dose greater than the typical human dose. 28,29 We observed that de 0.5 mg/kg/day dosage of enoxaparin (similar that used in prophylaxis of thromboembolism in adult human, 40 mg/day) was not adequate to prevent thrombosis in femoral vein microanastomosis in rats.…”