Inhibition of Mannose Receptor-mediated Clearance of Tissue-type Plasminogen Activator (t-PA) by Dextran: a New Explanation for Its Antithrombotic Effect

F Noorman; M M Barrett-Bergshoeff; M Bekkers; J J Emeis; D C Rijken

doi:10.1055/s-0038-1657723

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1997; 78(04): 1249-1254
DOI: 10.1055/s-0038-1657723

Rapid Communication

Schattauer GmbH Stuttgart

Inhibition of Mannose Receptor-mediated Clearance of Tissue-type Plasminogen Activator (t-PA) by Dextran: a New Explanation for Its Antithrombotic Effect

F Noorman

The Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands

,

M M Barrett-Bergshoeff

The Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands

,

M Bekkers

The Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands

,

J J Emeis

The Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands

,

D C Rijken

The Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands

› Author Affiliations

Abstract

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Summary

Dextran is used during surgery as a prophylactic agent to prevent deep venous thrombosis. Recently it has been shown that dextran increases t-PA plasma concentrations in patients. As dextran is a potential ligand for the mannose receptor, we studied whether this glucose-polymer would be able to inhibit mannose receptor-mediated clearance of t-PA.

In this report we show that dextran 40 and dextran 70 were able to inhibit t-PA binding to the isolated human mannose receptor (IC₅₀14 and 4 mg/ml, respectively). Both glucose-polymers inhibited mannose receptor-mediated t-PA degradation by human monocyte-derived macrophages in vitro (IC₅₀ 7 and 2 mg/ml, respectively). The α₂-macroglobulin receptor/low density lipoprotein receptor-related protein (LRP)-mediated t-PA degradation by the macrophages was not affected by dextran. During and after a 45 min infusion of dextran 70 (Macrodex) in rats, in plasma endogenous t-PA concentrations increased to 162 ± 33% and 122 ± 35% respectively. The plasma clearance of a bolus injection of exogenous t-PA was decreased by 33 ± 9% in the same rats.

We conclude that dextran inhibits mannose receptor-mediated t-PA clearance. The inhibition of t-PA clearance during dextran infusion results in increased endogenous t-PA plasma concentrations. Increased t-PA concentrations present during thrombus formation are known to increase thrombus lysability. Thus the inhibition of t-PA clearance can contribute to the antithrombotic effect of dextran.

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References

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