Download PDF
Thromb Haemost 1992; 68(05): 550-555
DOI: 10.1055/s-0038-1646316
Original Article
Schattauer GmbH Stuttgart

Influence of Heparin and a Low Molecular Weight Heparinoid on Specific Endogenous and Exogenous Fibrinolytic Factors during Rest and Exercise

A de Boer
1   The Centre for Human Drug Research, University Hospital Leiden, The Netherlands
,
C Kluft
2   The Gaubius Laboratory, IVVO-TNO, Leiden, The Netherlands
,
G Dooijewaard
2   The Gaubius Laboratory, IVVO-TNO, Leiden, The Netherlands
,
F J Kasper
1   The Centre for Human Drug Research, University Hospital Leiden, The Netherlands
,
J M Kroon
1   The Centre for Human Drug Research, University Hospital Leiden, The Netherlands
,
D D Breimer
3   The Center for Bio-Pharmaceutical Sciences, Division of Pharmacology, University of Leiden, The Netherlands
,
J C J Stiekema
4   The Organon International B.V., Oss, The Netherlands
,
A F Cohen
1   The Centre for Human Drug Research, University Hospital Leiden, The Netherlands
› Author Affiliations
Further Information

Publication History

Received 17 February 1992

Accepted after revision 15 June 1992

Publication Date:
04 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

The effects of heparin (5,000 IU i.v.) and the low molecular weight heparinoid Org 10172 (Orgaran®) (3,250 anti-Xa units i. v.) on components of the fibrinolytic system were studied in two double-blind, randomised, placebo-controlled, cross-over trials using healthy subjects. In study A (n = 6) the effects were studied during rest and standardized exercise and in study B (n = 6) during a low dose infusion of recombinant tissue-type plasminogen activator (rt-PA; 80 µg over 16 min). At rest, heparin and Org 10172 did not influence the plasma concentrations of endogenous t-PA antigen, and activity, urokinase-type PA (u-PA) antigen, plasmin activatable pro-urokinase (scu-PA), active urokinase (tcu-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen. Recombinant t-PA antigen and activity during rt-PA infusion were also not affected. During exercise, neither heparin nor Org 10172 influenced the area under the curve (AUC) of t-PA and u-PA antigen and t-PA activity when compared with placebo. Unexpectedly, after heparin the AUC of t-PA activity was 49% larger (range +19 to +245%) than after Org 10172 (p <0.05). The last difference was considered spurious. scu-PA, tcu-PA and PAI-1 antigen levels at 2 min after termination of exercise were unaffected by both compounds (p >0.05). Sulphated polysaccharides do not increase fibrinolytic activity of the plasma by changing the concentrations of the components of the fibrinolytic system.

 

  • REFERENCES

  • 1 Mantovani M, Prino G. Inhibitory effect of Ateroid® on rat serum antiplasmin activity. Eur J Pharmacol 1970; 13: 108-112
    CrossrefPubMedGoogle Scholar
  • 2 Kudrjashov BA, Liapina LA, Uljanov AM. Complex fibrinogen-heparin (FH) and fibrinogen degradation products (FDP) in blood of rats after intravenous injection of thrombin. Thromb Res 1978; 13: 397-407
    CrossrefPubMedGoogle Scholar
  • 3 Rothschild Z, Batarra SP, Polizello ACM. Proteases of bovine plasma activated by sulfated polysaccharides. Thromb Res 1983; 31: 187-193
    CrossrefPubMedGoogle Scholar
  • 4 Pâques EP, Stöhr HA, Heimburger N. Study on the mechanism of action of heparin and related substances on the fibrinolytic system: relationship between plasminogen activators and heparin. Thromb Res 1986; 42: 797-807
    CrossrefPubMedGoogle Scholar
  • 5 Takada Y, Takada A. Influence of dextran sulfate and tranexamic acid on the activation of plasminogen by urokinase. Thromb Res 1979; 16: 865-869
    CrossrefPubMedGoogle Scholar
  • 6 Kumada T, Abiko Y. Fibrinolytic action of a new semi-synthetic polysaccharide sulphate, galactan polysulphate (DH 6322) in the rat. Thromb Res 1985; 39: 09-19
    CrossrefPubMedGoogle Scholar
  • 7 Kumar S, Panagakos F. Stimulation of plasminogen activator catalyzed plasminogenolysis by heparin and heparan sulphate. Fet Proc 1987; 46: 2271 (Abstr)
    PubMedGoogle Scholar
  • 8 Dosne AM, Benbetowicz AV, Kher A, Samama M. Marked potentiation of the plasminogenolytic activity of pro-urokinase by unfractionated heparin and a low molecular-weight heparin. Thromb Res 1988; 51: 627-630
    CrossrefPubMedGoogle Scholar
  • 9 Lijnen HR, Collen D. Stimulation by heparin of the plasmin-mediated conversion of single-chain to two-chain urokinase-type plasminogen activator. Thromb Res 1986; 43: 687-690
    CrossrefPubMedGoogle Scholar
  • 10 Doutremepuich C, Gestreau JL, Kuttler C, Fenelon L, Toulemonde F, Vairel EG, Quilichini R. Fibrinolytic activity of heparin and heparin fractions. Haemostasis 1984; 14: 119 (Abstr)
    PubMedGoogle Scholar
  • 11 Lackner H, Merskey C. Variation in fibrinolytic activity after acute myocardial infarction and after the administration of oral anticoagulant drugs and intravenous heparin. Br J Haematol 1960; 6: 402-413
    CrossrefPubMedGoogle Scholar
  • 12 Arnesen H, Engebretsen LF, Ugland OM, Seljeflot I, Kierulf P. Increased fibrinolytic activity after surgery induced by low dose heparin. Thromb Res 1987; 45: 553-559
    CrossrefPubMedGoogle Scholar
  • 13 Melissari E, Scully MF, Paes T, Kakkar VV. The influence of LMW heparin on the coagulation and fibrinolytic response to surgery. Thromb Res 1985; 37: 115-126
    CrossrefPubMedGoogle Scholar
  • 14 Klein P. Plasma levels of t-PA:Ag under standard heparin therapy. Thromb Res 1989; 56: 649-653
    CrossrefPubMedGoogle Scholar
  • 15 Vairel EG, Bouty-Boye H, Toulemonde F, Doutremepuich C, Marsch NA, Gaffney PJ. Heparin and a low molecular weight fraction enhances thrombolysis and by this pathway exercises a protective effect against thrombosis. Thromb Res 1983; 30: 219-224
    CrossrefPubMedGoogle Scholar
  • 16 Agnelli G, Borm J, Cosmi B, Levi M, Ten Cate JW. Effects of standard heparin and a low molecular weight heparin (Kabi 2165) on fibrinolysis. Thromb Haemostas 1988; 60: 311-313
    PubMedGoogle Scholar
  • 17 Fischer AM, Merton RE, Marsh NA, Williams S, Gaffney PJ, Barrowcliffe TW, Thomas DP. A comparison of pentosan polysulphate and heparin. II. Effects of subcutaneous injection. Thromb Haemostas 1982; 47: 109-113
    PubMedGoogle Scholar
  • 18 Marsh NA, Born GVR. In vivo and in vitro effects of low molecular weight heparan sulphate on the human fibrinolytic enzyme system. Blood Coagulation Fibrinolysis 1991; 2: 453-458
    CrossrefPubMedGoogle Scholar
  • 19 Vinazzer H, Stemberger A, Haas S, Blümel G. Influence of heparin; of different heparin fractions and of a low molecular weight heparin-like substance on the mechanism of fibrinolysis. Thromb Res 1982; 27: 341-352
    CrossrefPubMedGoogle Scholar
  • 20 Holemans R, Adamis D, Horace JF. Interaction of heparin with fibrinolysis. Thromb Diath Haemorrh 1963; 9: 447-458
    PubMedGoogle Scholar
  • 21 Bounameaux H, Lijnen HR, Hellemans H, Verstraete M. Effect of standard and low-molecular weight heparin fractions on fibrinolysis and platelet aggregation in patients undergoing hysterectomy. Thromb Haemostas 1986; 55: 298
    PubMedGoogle Scholar
  • 22 Eriksson E, Wollter IM, Christenson B, Stigendal L, Risberg B. Heparin and fibrinolysis - comparison of subcutaneous administration of unfractionated and low molecular weight heparin. Thromb Haemostas 1988; 59: 284-288
    PubMedGoogle Scholar
  • 23 Neerstrand H, Ostergard P, Bergqvist D, Mätzsch T, Hedner U. tPA inhibitor, tPA:Ag, plasminogen, and α2-antiplasmin after low molecular weight heparin or standard heparin. Fibrinolysis. 1987; 1: 39-43
    PubMedGoogle Scholar
  • 24 Marsch N. Does heparin stimulate fibrinolysis? Br J Haematol. 1990; 76: 163-167
    PubMedGoogle Scholar
  • 25 Martin M. The fibrinolytic effect of euglobulin fraction for human plasma before and after addition of an acid polysaccharide (SP 54). In: Synthetic Fibrinolytic and Thrombolytic Agents. Von Kaulla KN, Davidson JF, Charles CT. (eds) Springfield, IL.: 1975. pp 276-283
    Google Scholar
  • 26 Prino G, Mantovani M. The in vitro effect of Ateroid® on the fibrinolytic activity of rat euglobulins. Eur J Pharmacol 1969; 6: 190-192
    CrossrefPubMedGoogle Scholar
  • 27 Astrup T, Rosa AT. A plasminogen pro-activator system in human blood effective in absence of Hageman factor. Thromb Res 1974; 4: 609-613
    CrossrefPubMedGoogle Scholar
  • 28 Marsch N, Gaffney P. Some observations on the release of extrinsic and intrinsic plasminogen activators during exercise in man. Haemostasis 1980; 9: 238-247
    PubMedGoogle Scholar
  • 29 Fortuin NJ. Exercise stress testing. Circulation 1977; 56: 699-712
    CrossrefPubMedGoogle Scholar
  • 30 Manual Biopool Imulyse™ 5 t-PA Kit for determination of human tissue plasminogen activator antigen in plasma and biological fluids.
    PubMedGoogle Scholar
  • 31 Binnema DJ, Iersel JJL, Dooijewaard G. Quantitation of urokinase antigen in plasma and cultured media by use of an ELISA. Thromb Res 1986; 43: 569-577
    CrossrefPubMedGoogle Scholar
  • 32 Manual Biopool TintElize™PAI-l Enzyme immunoassay for determination of human plasminogen activator inhibitor 1.
    PubMedGoogle Scholar
  • 33 Verheijen JH, Mullart E, Chang GTG, Kluft C, Wijngaards G. A simple, sensitive spectrophotometric assay for extrinsic (tissue-type) plasminogen activator applicable to measurement in plasma. Thromb Haemostas 1982; 48: 266-269
    PubMedGoogle Scholar
  • 34 Gaffney PJ, Curtis AD. A collaborative study of a proposed International Standard for tissue plasminogen activator (t-PA). Thromb Haemostas 1985; 53: 134-136
    PubMedGoogle Scholar
  • 35 Dooijewaard G, De Boer A, Turion PNC, Cohen AF, Breimer DD, Kluft C. Physical exercise induces enhancement of urokinase-type plasminogen activator (u-PA) levels in plasma. Thromb Haemostas 1991; 65: 82-86
    PubMedGoogle Scholar
  • 36 Teien AN, Lie M. Evaluation of an amidolytic heparin assay method: increased sensitivity by adding purified antithrombin-III. Thromb Res 1978; 10: 399-410
    PubMedGoogle Scholar
  • 37 Larsen ML, Abildgaard U, Teien AN, Gjesdal K. Assay of plasma heparin using thrombin and the chromogenics substrate H-D-Phe-Pip-Arg-pNA (S-2238). Thromb Res 1978; 13: 285-288
    CrossrefPubMedGoogle Scholar
  • 38 Marder VJ. A simple technique for the measurement of plasma heparin concentration during anticoagulant therapy. Thromb Diath Haemorrh 1970; 24: 230-239
    PubMedGoogle Scholar
  • 39 Biggs R. Human Blood Coagulation, Haemostasis and Thrombosis. 2nd ed. Blackwell Scientific Publications, Oxford: 1972
    Google Scholar
  • 40 Andreotti F, Davies GJ, Hackett DR, Khan MI, De Bart ACW, Dooijewaard G, Maseri A, Kluft C. Circadian variation of fibrinolytic factors in normal human plasma. Fibrinolysis 1988; 2: 90-92
    PubMedGoogle Scholar
  • 41 Vinazzer H, Woler M. A new low molecular weight heparin fragment (PK 10169): in vitro and in vivo studies. Thromb Res 1985; 40: 135-146
    CrossrefPubMedGoogle Scholar
  • 42 Agnelli G, Levi M, Cosmi B, Ten Cate JW, Nenci GG. Additive effect of dDAVP and standard heparin in increasing plasma t-PA. Thromb Haemostas 1989; 61: 507-510
    PubMedGoogle Scholar
  • 43 De Boer A, Kluft C, Kasper FJ, Kroon JM, Schoemaker HC, Breimer DD, Soons PA, Emeis JJ, Pruis J, Cohen AF. The clearance of recombinant human tissue-type plasminogen activator is dependent on liver blood flow. Thromb Haemostas 1992; 67: 83-87
    PubMedGoogle Scholar
  • 44 De Boer A, Kluft C, Cohen AF. Life style and blood fibrinolytic activity: a comment of clearance of plasminogen activators. Fibrinolysis 1990; 4: 61-63
    PubMedGoogle Scholar