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

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Abstract
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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