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
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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