Download PDF
Thromb Haemost 1997; 78(04): 1249-1254
DOI: 10.1055/s-0038-1657723
Rapid Communication
Schattauer GmbH Stuttgart

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
› Author Affiliations
Further Information

Publication History

Received 20 1996

Accepted after revision 30 May 1997

Publication Date:
12 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

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.

 

  • References

  • 1 Bachmann F. Fibrinolytic agents. Fibrinolysis 1995; 9 (Suppl. 01) 09-15
    PubMedGoogle Scholar
  • 2 Emeis JJ, Verheijen JH, Ronday HK, de Maat MPM, Brakman P. Progress in clinical fibrinolysis. Fibrinolysis & Proteolysis 1997; 11: 67-84
    PubMedGoogle Scholar
  • 3 Collen D. Fibrin-selective thrombolytic therapy for acute myocardial infarction. Circulation 1996; 93: 857-865
    CrossrefPubMedGoogle Scholar
  • 4 Spellman MW, Basa LJ, Leonard CK, Chakel JA, o’Connor JV, Wilson S, Van Halbeek H. Carbohydrate structures of human tissue-type plasminogen activator expressed in Chinese hamster ovary cells. J Biol Chem 1989; 264: 14100-14111
    PubMedGoogle Scholar
  • 5 Otter M, Kuiper J, Bos R, Rijken DC, van Berkel ThJC. Characterization of the interaction both in vitroand in vivo of tissue-type plasminogen activator (t-PA) with rat liver cells. Biochem J 1992; 284: 545-550
    CrossrefPubMedGoogle Scholar
  • 6 Narita M, Bu G, Herz J, Schwartz AL. Two receptor systems are involved in the plasma clearance of tissue-type plasminogen activator (t-PA) in vivo. J Clin Invest 1995; 96: 1164-1168
    CrossrefPubMedGoogle Scholar
  • 7 Biessen EAL, van Teijlingen M, Vietsch H, Barrett-Bergshoeff MM, Bijsterbosch MK, Rijken DC, van Berkel ThJC, Kuiper J. Antagonists of the mannose receptor and the LDL receptor-related protein dramatically delay the clearance of tissue-type plasminogen activator. Circulation 1997; 95: 46-52
    CrossrefPubMedGoogle Scholar
  • 8 Biessen EAL, Noorman F, van Teylingen M, Kuiper J, Barrett-Bergshoeff MM, Rijken DC, Bijsterbosch MK, van Berkel ThJC. Lysine-based cluster mannosides that inhibit ligand binding to the human mannose receptor at nanomolar concentration. J Biol Chem 1996; 271: 28024-28030
    CrossrefPubMedGoogle Scholar
  • 9 Sallusto F, Celia M, Danieli C, Lanzavecchia A. Dendritic cells use macro- pinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: Downregulation by cytokines and bacterial products. J Exp Med 1995; 182: 389-400
    CrossrefPubMedGoogle Scholar
  • 10 Åberg M, Hedner U, Bergentz SE. The antithrombotic effect of dextran. Scand J Haematol Suppl 1979; 334: 61-68
    PubMedGoogle Scholar
  • 11 Dubick MA, Wade CEA. Review of the efficacy and safety of 7.5% NaCl/6% Dextran 70 in experimental animals and in humans. J Trauma 1994; 36: 323-330
    CrossrefPubMedGoogle Scholar
  • 12 Schött U, Djöstrand U, Thorén T, Berséus O. Three per cent dextran 60 as a plasma substitute in blood component therapy. An alternative in surgical blood loss replacement. Acta Anaesthesiol Scand 1985; 29: 767-774
    CrossrefPubMedGoogle Scholar
  • 13 Ljungström KG. The antithrombotic efficacy of dextran. Acta Chir Scand Suppl 1988; 543: 26-30
    PubMedGoogle Scholar
  • 14 Clagett GP, Reisch JS. Prevention of venous thromboembolism in general surgical patients. Results of meta-analysis. Ann Surg 1988; 208: 227-240
    CrossrefPubMedGoogle Scholar
  • 15 Potyk DK, Tabbarah HJ. The pathogenesis and prevention of thromboembolic complications in patient undergoing total hip replacement. J Gener IntMed 1993; 8: 213-219
    PubMedGoogle Scholar
  • 16 Imperiale TF, Speroff TA. Meta analysis of methods to prevent venous thromboembolism following total hip replacement. JAMA 1994; 271: 1781-1785
    PubMedGoogle Scholar
  • 17 Eriksson M, Saldeen T. Effect of dextran on plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1) during surgery. Acta Anaestesiol Scand 1995; 39: 163-166
    CrossrefPubMedGoogle Scholar
  • 18 Noorman F, Braat EAM, Rijken DC. Degradation of tissue-type plasminogen activator (t-PA) by human monocyte derived macrophages is mediated by the mannose receptor and by the low density lipoprotein-related protein (LRP). Blood 1995; 86: 3421-3427
    PubMedGoogle Scholar
  • 19 Kluft C, Van Wezel AL, Van der VeldenCAM, Emeis JJ, Verheijen JH, Wijngaards G. Large scale production of extrinsic (tissue-type) plasminogen activator from human melanoma cells. In: Advances in biotechnological processes, vol 2. Mizrahi A, Van Wezel AL. eds. Alan R. Liss Inc; New York USA: 1983. pp 097-110
    Google Scholar
  • 20 Herz J, Goldstein JL, Strickland DK, Ho YK, Brown MS. 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/α2-macroglobulin receptor. J Biol Chem 1991; 266: 21232-21238
    PubMedGoogle Scholar
  • 21 Otter M, Barrett-Bergshoeff MM, Rijken DC. Binding of tissue-type plasminogen activator by the mannose receptor. J Biol Chem 1991; 266: 13931-13935
    PubMedGoogle Scholar
  • 22 Otter M, Zockova P, Kuiper J, van Berkel ThJC, Barrett-Bergshoeff MM, Rijken DC. Isolation and characterization of the mannose receptor from human liver potentially involved in the plasma clearance of tissue-type plasminogen activator. Hepatology 1992; 16: 54-59
    CrossrefPubMedGoogle Scholar
  • 23 Emeis JJ, Hoekzema R, Vos AF. Inhibiting interleukin-1 and tumor necrosis factor-α does not reduce induction of plasminogen activator inhibitor type-1 by endotoxin in rats in vivo. Blood 1995; 85: 115-120
    PubMedGoogle Scholar
  • 24 Bos R, Hoegee-de Nobel E, Laterveer R, Meyer P, Nieuwenhuizen W. A one- step enzyme immunoassay for the determination of total tissue-type plasminogen activator (t-PA) antigen in plasma. Blood Coagul Fibrinol 1992; 3: 303-307
    CrossrefPubMedGoogle Scholar
  • 25 Rijken DC, Emeis JJ. Clearance of the heavy and light polypeptide chains of human tissue-type plasminogen activator in rats. Biochem J 1986; 238: 643-646
    CrossrefPubMedGoogle Scholar
  • 26 Bergqvist D. Dextran and haemostasis. Acta Chir Scand 1982; 148: 633-640
    PubMedGoogle Scholar
  • 27 Carr ME, Alving BM. Effect of fibrin structure on plasmin-mediated dissolution of plasma clots. Blood Coagul Fibrinol 1995; 6: 567-573
    CrossrefPubMedGoogle Scholar
  • 28 Flordal PA, Svensson J, Ljungström KG. Effects of desmopressin and dextran on coagulation and fibrinolysis in healthy volunteers. Thromb Res 1991; 62: 355-364
    CrossrefPubMedGoogle Scholar
  • 29 Lethagen S, Rugam P, Åberg M, Nilsson IM. Effects of desmopressin acetate (DDAVP) and dextran on hemostatic and thromboprophylactic mechanisms. Acta Chir Scand 1990; 156: 597-602
    PubMedGoogle Scholar
  • 30 Battle J, del Rio F, López Fernandez MF, Martin R, López Borrasca A. Effect of dextran on factor Vlll/von Willebrand factor structure and function. Thromb Haemost 1985; 54: 697-699
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Eriksson BI, Eriksson E, Gyzander E, Teger-Nilsson AC, Risberg B. Thrombosis after hip replacement. Relationship to the fibrinolytic system. Acta Orthop Scand 1989; 60: 159-163
    CrossrefPubMedGoogle Scholar
  • 32 Lucore CL, Fry ET A, Nachowiak DA, Sobel BE. Biochemical determinants of clearance of tissue-type plasminogen activator from the circulation. Circulation 1988; 77: 906-914
    CrossrefPubMedGoogle Scholar
  • 33 Matthiasson SE, Lindblad B, Matzach T, Holst J, Bergqvist D. Effect of low molecular weight heparin, dextran and their combinations on experimental venous thrombosis in rabbits. Thromb Haemost 1994; 71: 363-5
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Matthiasson SE, Lindblad B, Bergqvist D. Prevention of experimental venous thrombosis in rabbits with low molecular weight heparin, dextran and their combinations, administered before or during induction of venous endothelial trauma. Thromb Res 1994; 6: 655-663
    PubMedGoogle Scholar
  • 35 Brommer EJP. The level of extrinsic plasminogen activator (t-PA) during clotting as a determinant of the rate of fibrinolysis: inefficiency of activators added afterwards. Thromb Res 1984; 34: 109-115
    CrossrefPubMedGoogle Scholar
  • 36 Zamarron C, Lijnen HR, Collen D. Influence of exogenous and endogenous tissue-type plasminogen activator on the lysability of clots in a plasma milieu in vitro. Thromb Res 1984; 35: 335-345
    CrossrefPubMedGoogle Scholar
  • 37 Emeis JJ, Bekkers M. Low-dose infusion of tissue-type plasminogen activator (t-PA) prevents arterial thrombosis in a rat thrombosis model: t-PA as antithrombotic agent. Fibrinolysis 1996; 10 (Suppl. 03) 128
    PubMedGoogle Scholar