Standard and Low Molecular Weight Heparin Have no Effect on Tissue Plasminogen Activator Induced Plasma Clot Lysis or Fibrinogenolysis

Summary

Although heparin is often given as an adjunct to tissue plasminogen activator (t-PA), the effect of heparin on t-PA induced fibrin(ogen)olysis is controversial. To address this controversy, we examined the effects of standard and low molecular weight heparin (enoxaparine) on both t-PA induced clot lysis and t-PA mediated fibrinogenolysis in a human plasma system. Accordingly, ₁₂₅I-labeled fibrin clots were incubated in t-PA containing citrated plasma in the presence or absence of these glycosaminoglycans, and the extent of thrombolysis was determined by measuring residual radioactivity of the clots, while Bβ1–42 levels were used as a specific index of fibrinogenolysis. Over a wide range of t-PA concentrations (0.1 to 1.6 μg/ml), neither heparin nor enoxaparine influences either t-PA induced clot lysis or t-PA mediated Bβ1–42 generation. These findings suggest that either agent could be used as an adjunct to t-PA without compromising either the thrombolytic potential of t-PA or its clotselectivity

• References

• 1 Andrade-Gordon P, Strickland S. Interaction of heparin with plasminogen activators and plasminogen. Effects on the activation of plasminogen. Biochemistry 1986 25. 4033-4040
• 2 Paques E-P, Stohr H-A, 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
• 3 Fears R. Kinetic studies on the effect of heparin and fibrin on plasminogen activators. Biochem J 1988; 246: 77-81
• 4 Fry ETA, Sobel BE. Lack of interference by heparin with thrombolysis or binding of tissue-type plasminogen activator to thrombi. Blood 1988; 71: 1347-1352
• 5 Lindahl LJ, Hook M. Glycosaminoglycans and their binding to biological macromolecules. Annu Rev Biochem 1978; 47: 385-417
• 6 Vairel EG, Bouty-Boye H, Toulemonde F, Doutremepuich C, Marsh 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
• 7 Agnelli G, Borm J, Cosmi B, Levi M, ten Cate WJ. Effects of standard heparin and a lower molecular weight heparin (Kabi 2165) on tibrinolysis. Thromb Haemostas 1988; 60: 311-313
• 8 Schulman S, Granquist S, Wiman B, Lockner D. Thrombolysis and fibrinolytic parameters during heparin treatment of deep vein thrombosis. Thromb Res 1985; 39: 605-612
• 9 Stassen JM, Juhan-Vague I, Alessi MC, DeCock R, Collen D. Potentiation by heparin fragments of thrombolysis induced with human tissue-type plasminogen activator or human single-chain urokinase-type plasminogen activator. Thromb Haemostas 1987; 58 947: 50
• 10 Mickelson JK, Simpson PJ, Lucchesi BR. Effects of heparin and intravenous plasminogen activator or streptokinase in a canine model of coronary artery thrombosis. Clin Res 1987 35. 305 (abstract)
• 11 Cercek B, Lew AS, Hod FI, Yano J, Reddy NKN, Ganz W. Enhancement of thrombolysis with tissue-type plasminogen activator by pretreatment with heparin. Circulation 1986; 74: 583-587
• 12 Agnelli G, Pascucci C, Cosmi B, Nenci GG. Failure of therapeutic doses of heparin to improve thrombolysis with tissue-type plasminogen activator in rabbits. Blood (in press)
• 13 Teien AN, Lie M, Abelgaard U. Assay of heparin in plasma using a chromogenic substrate for activated factor X. Thromb Res 1976; 8: 413-416
• 14 Béguin S, Mardiguian J, Lindhout I, Hemker HC. The mode of action of low molecular weight heparin preparation (PK10169) and two of its major components on thrombin generation in plasma. Thromb Haemostas 1989; 61: 30-34
• 15 Ikeno LC, Bowen BM, Der M. Commercial production of ₁₂₅I-fibrinogen injection. J Radioanal Chem 1981; 65: 179-188
• 16 McFarlane AS. Labeling of plasma proteins with radioactive iodine. Biochem J 1956; 62: 135-143
• 17 Hull RD, Raskob GE, Hirsh J, Jay RM, LeClerc JR, Geerts WH, Rosenbloom D, Sackett DL, Anderson C, Harrison L, Gent M. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis. N Engl J Med 1986; 315: 1109-1114
• 18 Hirsh J, van Arken WG, Gallus AS, Dollery CG, Cade JS, Young WG. Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation 1976; 53: 691-695
• 19 Weitz JI, Koehn JA, Canfield RE, Landman SL, Friedman R. Development of a radioimmunoassay for the fibrinogen-derived fragment Bβ1–42. Blood 1986; 67: 1014-1022
• 20 Ross AM, Hsia J, Hamilton W, Chaitman B, Roberts R, Kleiman NS. Heparin versus aspirin after recombinant tissue plasminogen activator therapy in myocardial infarction: a randomized trial. J Am Coll Cardiol 1990 13. 2 (abstract)
• 21 Bleich SD, Nichols T, Schumacher R, Cooke D, Tate D, Steiner C, Brinkman D. The role of heparin following coronary thrombolysis with tissue plasminogen activator. Circulation 1989 80. 113 (abstract)