Inhibition of mannose receptor-mediated clearance of tissue-type plasminogen activator (t-PA) by dextran: a new explanation for its antithrombotic effect.
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 2 mg/ml, respectively). The alpha2-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.
Noorman
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Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands.
Barrett-Bergshoeff
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Bekkers
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Emeis
J J
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Rijken
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D000116:Acetylgalactosamine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003864:Depression, Chemical; D003911:Dextrans / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D037181:Lectins, C-Type; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008358:Mannose / Q000494:pharmacology; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008657:Metabolic Clearance Rate / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism* / Q000493:pharmacokinetics
D003911:Dextrans; D005343:Fibrinolytic Agents; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D005947:Glucose; D000116:Acetylgalactosamine; D008358:Mannose