Influence on Platelet Function by Heparin in Men with Unstable Coronary Artery Disease

Summary

Ninetyseven men with unstable coronary artery disease (CAD), i.e. unstable angina or a non Q-wave myocardial infarction, entered a double-blind placebo-controlled study with heparin intravenously 30,000-40,000 U daily. Platelet function was evaluated as ex vivo aggregation toward collagen and ADP and as the platelet inhibitory effect of prostacyclin, before and after 5 days of treatment. Heparin increased aggregation induced by ADP 1 εM from 39.6 ± 3.1% to 52.1 ± 4.1% (p = 0.014) and reduced the inhibition of aggregation by prostacyclin 1.0 ng/ml from 59.6 ± 3.7% to 39.3 ± 5.6% (p <0.001). No changes occurred in the placebo group.

Thus, treatment with heparin enhances the platelet sensitivity to ADP and decreases the platelet inhibitory effect of prostacyclin in men with unstable CAD. Concomitant treatment with acetylsalicylic acid abolishes the increased reponse to ADP, but does not seem to influence the interaction between heparin and prostacyclin.

• References

• 1 Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 1985; 71: 699-708
• 2 Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med 1984; 310: 1137-40
• 3 Ambrose JA, Winters SL, Stern A. et al. Angiographic morphology and the pathogenesis of unstable angina pectoris. JACC 1985; 5: 609-16
• 4 Theroux P, Ouimet H, McCans J, Latour J-G, Joly P, Lévy G, Pelletier E, Juneau M, Stasiak J, de Guise P, Pelletier GB, Rinzler D, Waters DD. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988; 319: 1105-11
• 5 Telford AM, Wilson C. Trial of heparin versus atenolol in prevention of myocardial infarction in intermediate coronary syndrome. Lancet 1981; 1: 1225-8
• 6 Huber K. Resch I, Rosc D, Probst P, Kaindl F, Binder BR. Heparin-induced increase of T-PA antigen levels in patients with unstable angina: no evidence for clinical benefit of heparinization during the initial phase of treatment. Thromb Res 1989; 55: 779-84
• 7 Zwerner PL, Gore JM, Corrao JM, Mahan CG, Goldberg RJ, Weiner B, Dalen JE. Heparin in the treatment of unstable angina: 180.
• 8 The Risc group Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990; 336: 827-30
• 9 Saba HI, Saba SR, Morelli GA. Effect of heparin on platelet aggregation. Am J Hematol 1984; 17: 295-306
• 10 Saba SR, Saba HI, Morelli GA. Effect of collagen and citrate on heparin mediated platelet anti-aggregatory activity. Thromb Haemostas 1987; 58: 18 (Abstr)
• 11 Janson PA, Moake JL, Carpinito G. Aspirin prevents heparininduced platelet aggregation in vivo. Br J Haematol 1983; 53: 166-8
• 12 Salzman EW, Rosenberg RD, Smith MH, Lindon JN, Favreau L. Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest 1980; 65: 64-73
• 13 Cofrancesco E, Colombi M, Cristoforetti G, Pogliani EM. Selective PF4 release in vitro induced by heparin and related glycosaminoglycans (GAGs) – Correlation with β-TG release and platelet aggregation. Thromb Haemostas 1984; 51: 105-7
• 14 Greenbaum RA, Barradas MA, Mikhailidis DP, Jeremy JY, Evans TR, Dandona P. Effect of heparin and contrast medium on platelet function during routine cardiac catheterisation. Cardiovas Res 1987; 21: 878-85
• 15 Ljungberg B, Beving H, Egberg N, Johnsson H, Vesterqvist O. Immediate effects of heparin and LMW heparin on some platelet and endothelial factors. Thromb Res 1988; 51: 209-17
• 16 Westwick J, Scully MF, Poll C, Kakkar VV. Comparison of the effects of low molecular weight heparin and unfractionated heparin on activation of human platelets in vitro. Thromb Res 1986; 42: 435-47
• 17 Barradas MA, Mikhailidis DP, Epemolu O, Jeremy JY, Fonseca V, Dandona P. Comparison of the platelet pro-aggregatory effect of conventional unfractionated heparins and a low molecular weight heparin fraction (CY 222). Br J Haematol 1987; 67: 451-7
• 18 Brace LD, Fareed J. Heparin-induced platelet aggregation: dose/response relationships for a low molecular weight heparin derivative (PK 10169) and its subfractions. Thromb Res 1986; 42: 769-82
• 19 Mazurov AV, Sinitsyn VE, Repin VS. Potentiation of platelet interaction with collagen substrates by heparin is insensitive to aspirin. Thromb Res 1988; 52: 573-85
• 20 Ruggiero M, Fedi S, Bianchini P, Vannucchi S, Chiarugi V. Molecular events involved in the proaggregating effect of heparin on human platelets. Biochim Biophys Acta 1984; 802: 372-7
• 21 Swahn E, Aresklog M, Wallentin L. Early exercise testing after coronary care for suspected unstable coronary artery disease – safety and diagnostic value. Eur Heart J 1986; 7: 694-701
• 22 Gillum RF, Fortman SP, Prineas RJ, Kottke TE. International diagnostic criteria for acute myocardial infarction and stroke. Progr Cardiol 1984; 108: 150-7
• 23 Berglund U, van Schenck H, Wallentin L. Effects of ticlopidine on platelet function in men with stable angina pectoris. Thromb Haemostas 1985; 54: 808-12
• 24 Saba HI, Saba SR, Blackburn CA, Hartmann RC, Mason RG. Heparin neutralization of PGI2: Effects upon platelets. Science 1979; 205: 499-501
• 25 Bertele V, Roncaglioni MC, Donati MB, de Gaetano G. Heparin counteracts the antiaggregating effect of prostacyclin by potenting platelet aggregation. Thromb Haemostas 1983; 49: 81-3
• 26 Weber DR, Nichols WK, Mohammad SF. Effect of heparin on platelet aggregation inhibited by PGI2, trifluoperazine and verapamil. Thromb Res 1986; 42: 477-87
• 27 Saba SR, Saba HI. Heparin-mediated neutralization of platelet antiaggregatory activity of prostacyclin (PGI2): Studies on mechanism. Am J Hematol 1985; 20: 97-105
• 28 Wolf W, Wick G. Antibodies interacting with, and corresponding binding sites for, heparin on human thrombocytes. Lancet 1986; 2: 222-3
• 29 Horne MK, Chao ES. Heparin binding to resting and activated platelets. Blood 1989; 74: 238-43
• 30 Seid JM, Jones PBB, Russell RGG. The presence in normal plasma, serum and platelet of factors that stimulate the production of prostacyclin (PGI2) by cultured endothelial cells. Clin Sci 1983; 64: 387-94
• 31 Hasegawa N, Yamamoto M, Yamamoto K. Stimulation of cell growth and inhibition of prostacyclin production by heparin in human umbilical vein endothelial cells. J Cell Physiol 1988; 137: 603-7
• 32 Ouimet H, Theroux P, McCans J, Waters D. Rebound caused by withdrawal of heparin in the acute phase of unstable angina. Circulation 1989; 80 SII 266
• 33 Vacek JL, Bellinger RL, Phelix J. Heparin bolus therapy during cardiac catheterization. Am J Cardiol 1988; 62: 1314-7