Inhibition of mannose receptor-mediated-clearance of tissue-type plasminogen activator (t-PA) by dextran : A new explanation for its antithrombotic effect
article
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
Topics
Anticoagulant agentDextranDextran 40Dextran 70Low density lipoprotein receptorMannose receptorTissue plasminogen activatorAnimal experimentBolus injectionControlled studyDeep vein thrombosisDrug infusionDrug mechanismHumanHuman cellMacrophageMaleMonocyteNonhumanPlasma clearancePriority journalProtein blood levelRatThrombogenesisAcetylgalactosamineAnimalsCells, CulturedDepression, ChemicalDextransFibrinolytic AgentsGlucoseHumansLectins, C-TypeMacrophagesMaleMannoseMannose-Binding LectinsMetabolic Clearance RateProtein BindingRatsRats, WistarReceptors, Cell SurfaceReceptors, LDLRecombinant ProteinsTissue Plasminogen Activator
TNO Identifier
234071
ISSN
03406245
Source
Thrombosis and Haemostasis, 78(4), pp. 1249-1254.
Pages
1249-1254
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