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Inhibition of mannose receptor-mediated-clearance of tissue-type plasminogen activator (t-PA) by dextran : A new explanation for its antithrombotic effect

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Author: Noorman, F. · Barrett-Bergshoeff, M.M. · Bekkers, M. · Emeis, J.J. · Rijken, D.C.
Type:article
Date:1997
Institution: Gaubius Instituut TNO
Source:Thrombosis and Haemostasis, 4, 78, 1249-1254
Identifier: 234071
doi: doi:10.1055/s-0038-1657723
Keywords: Biology · Anticoagulant agent · Dextran · Dextran 40 · Dextran 70 · Low density lipoprotein receptor · Mannose receptor · Tissue plasminogen activator · Animal experiment · Bolus injection · Controlled study · Deep vein thrombosis · Drug infusion · Drug mechanism · Human · Human cell · Macrophage · Male · Monocyte · Nonhuman · Plasma clearance · Priority journal · Protein blood level · Rat · Thrombogenesis · Acetylgalactosamine · Animals · Cells, Cultured · Depression, Chemical · Dextrans · Fibrinolytic Agents · Glucose · Humans · Lectins, C-Type · Macrophages · Male · Mannose · Mannose-Binding Lectins · Metabolic Clearance Rate · Protein Binding · Rats · Rats, Wistar · Receptors, Cell Surface · Receptors, LDL · Recombinant Proteins · Tissue Plasminogen Activator

Abstract

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 (IC50 14 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 2mg/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 tPA 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. Copyright © Schattauer Verlag