Title
Inhibition of mannose receptor-mediated-clearance of tissue-type plasminogen activator (t-PA) by dextran: A new explanation for its antithrombotic effect
Author
Noorman, F.
Barrett-Bergshoeff, M.M.
Bekkers, M.
Emeis, J.J.
Rijken, D.C.
Gaubius Instituut TNO
Publication year
1997
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
Subject
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
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http://resolver.tudelft.nl/uuid:5841cf7e-9ae5-4a27-9c0e-9e14352053bf
DOI
https://doi.org/10.1055/s-0038-1657723
TNO identifier
234071
ISSN
0340-6245
Source
Thrombosis and Haemostasis, 78 (4), 1249-1254
Document type
article