Effects of Heparin, Dermatan Sulfate and of their Association on the Inhibition of Venous Thrombosis Growth in the Rabbit

Summary

This study compares the ability of unfractionated heparin, of dermatan sulfate, and of their simultaneous administration delivered as continuous intravenous infusion or as a single bolus injection to inhibit the growth of a standardized venous thrombosis in the rabbit.

When delivered as continuous intravenous infusion for 4 h, heparin and dermatan sulfate inhibited thrombus growth in a dose dependent manner. The maximum antithrombotic effect of heparin was achieved at the dose of 0.15 mg kg^–1 h^–1 (25 U kg^–1 h^–1) which generated a mean plasma concentration of 1.8 µg ml^–1 (0.31 U ml^–1) and a 1.8 fold prolongation of the activated partial thromboplastin time (APTT) in comparison to the pretreatment value. A comparable antithrombotic effect was obtained with dermatan sulfate at the dose of 2 mg kg^–1 h^–1. This dose generated a mean plasma concentration of 30 µg ml^–1 and a 1.3 fold APTT prolongation. Increasing these doses up to 10 fold did not improve the antithrombotic effect which did not overpass 60–70% of the controls. When the compounds were delivered simultaneously, the maximum antithrombotic effect (64%) was obtained with the following association: 0.06 mg kg^–1 h^–1 (10 U kg^–1 h^–1) for heparin and 1 mg kg^–1 h^–1 for dermatan sulfate. Increasing these doses up to 4 to 5 fold did not improve the antithrombotic effect. Heparin, dermatan sulfate and the association of both were also delivered as single bolus injections and the resultant antithrombotic effect was determined 4 h after saline infusion. Bolus doses of 0.15 and 0.30 mg kg^–1 (25 and 50 U kg^–1) of heparin or of 1 and 2 mg kg^–1 of dermatan sulfate were ineffective. In contrast, the association of dermatan sulfate (2 mg kg^–1) to heparin (0.15 or 0.30 mg kg^–1) generated antithrombotic effects of 61 and 64% respectively in the absence of detectable residual plasma anticoagulant activities, 1 h after the bolus injections. These studies indicate that: (1) under continuous intravenous regimen, dermatan sulfate is as effective as heparin to inhibit venous thrombus growth when delivered at a 13 fold higher dose on a weight basis; (2) the coadministration of the two compounds under the same regimen does moderately improve the antithrombotic effect; (3) while each of these compounds were ineffective when delivered as a single bolus, their coadministration generated a dramatic antithrombotic effect for at least 4 h; (4) simultaneous activation of antithrombin III and of heparin cofactor II may therefore represent a valuable strategy to treat an established deep vein thrombosis.

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