Platelet-vessel Wall Interactions with Third-generation Oral Contraceptives: No Evidence of Detrimental Effects

Summary

Because of the association of oral contraceptives (OC) and cigarette smoking with an increased thrombotic risk, we evaluated thromboxane (TX) and prostacyclin urinary (u) metabolites, as in vivo indices of platelet-vessel wall interactions, in women assigned to third generation OC. Twenty-eight women (15 smokers) underwent a 6-month trial of 30 μg ethinylestradiol plus 0.150 mg desogestrel. Cotinine plasma levels were elevated only in persons classified as smokers and serum TXB₂ determination confirmed the absence of cyclooxygenase inhibition throughout the study. u-TXB₂ and 11-dehydro-TXB₂ were higher in smokers than in non-smokers. OC decreased u-11-dehydro-TXB₂ both in smokers (from (pg/μmol creatinine) 35.1 ± 6.9 to 15.8 ± 2.8; P <0.025) and non-smokers (from 31.7 ± 9.8 to 20.6 ± 4.8, P = N.S.). u-6-keto-prostaglandin(PG)F_1α excretion, also higher in smokers compared to non-smokers, was also reduced after OC in smokers (from (pg/μmol creatinine) 24.3 ± 5.2 to 14.8 ± 2.3; P <0.05). Smokers also had a trend to higher u-2,3-dinor-6-keto-PGF_1α, marginally reduced by OC.

Thus, the OC regimen used here improves – if anything – platelet vessel wall interactions as assessed by prostanoid production in vivo. The prothrombotic tendency associated with the use of OC in smokers does not appear to be mediated by changes in platelet-vessel wall interactions.

Key words

Oral contraceptive - ethinylestradiol - desogestrel - platelets - thromboxane - prostacyclin - urinary prostanoids - platelet-vessel wall interactions

• References

• 1 Vessey M, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 1968; 2: 199-205.
• 2 Vessey M, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease: a further report. Br Med J 1969; 2: 651-7.
• 3 Inman W, Vessey M, Westerholm B, Engelund A. Thromboembolic disease and the steroidal content of oral contraceptives: a report to the Committee on Safety of Drugs. Br Med J 1970; 2: 203-9.
• 4 Lidegaard O. Oral contraception and risk of a cerebral thromboembolic attack: result of a case-control study. BMJ 1993; 306: 956-63.
• 5 Thorogood M. Oral contraceptive and cardiovascular disease: an epidemiological overview. Pharmacoepidemiol Drug Saf 1993; 2: 21-31.
• 6 Schwingl P, Shelton J. Modeled estimates of myocardial infarction and venous thromboembolic disease in users of second and third generation oral contraceptives. Contraception 1997; 55: 125-9.
• 7 Mann J, Inman W, Thorogood M. Oral contraceptive use and fatal myocardial infarction. Br Med J 1975; 2: 445-7.
• 8 Salonen J. Oral contraceptives, smoking and risk of myocardial infarction in young women. Acta Med Scand 1982; 212: 141-4.
• 9 Croft P, Hannaford P. Risk factors for acute myocardial infarction in women: Evidence from the Royal College of General Practitioners’ Oral Contraception Study. Br Med J 1989; 298: 165-8.
• 10 Stampfer M, Willett W, Colditz G. et al. A prospective study of past use of oral contraceptive agents and risk of cardiovascular diseases. N Engl J Med 1988; 319: 1313-9.
• 11 Meade T. Oral contraceptives, clotting factors and thrombosis. Am J Obstet Gynecol 1982; 142: 758-61.
• 12 Melis G, Fruzzetti F, Paoletti A, Carmassi F, Fioretti P. Fibrinopeptide A plasma levels during low-dose oral contraceptive treatment. Contraception 1984; 30: 575-83.
• 13 Gram J, Munkvad S, Jespersen J. Enhanced generation and resolution of fibrin in women above the age of 30 years using oral contraceptives low in estrogen. Am J Obstet Gynecol 1990; 163: 438-42.
• 14 Levine A, Teppa J, McGough B, Cowchock S. Evaluation of the prethrom-botic state in pregnancy and in women using oral contraceptives. Contraception 1996; 53: 255-7.
• 15 Notelovitz M, Kitchens C, Khan F. Changes in coagulation and anticoagulation in women taking low-dose oral contraceptives: A controlled comparative 12-month clinical trial. Am J Obstet Gynecol 1992; 167: 1255-61.
• 16 Norris L, Bonnar J. The effect of oestrogen dose and progestogen type on haemostatic changes in women taking low dose oral contraceptives. Br J Obstet Gynaecol 1996; 103: 261-7.
• 17 Kloosterboer H, van Wayjen R, van den Ende A. Effects of three low-dose oral contraceptive combinations on sex-hormone binding globulin, corti-costeroid-binding globulin and antithrombin III activity in healthy women: two monophasic desogestrel-containing combinations (containing 0.020 or 0.030 mg ethinylestradiol) and one triphasic levonorgestrel combination. Acta Obstet Gynecol Scand 1987; (Suppl) 144: 41-4.
• 18 Daly L, Bonnar J. Comparative studies of 30 μg ethinyl estradiol combined with gestodene and desogestrel on blood coagulation, fibrinolysis and platelets. Am J Obstet Gynecol 1990; 163: 430-7.
• 19 Abbate R, Pinto S, Rostagno C, Bruni V, Rosati D. GM Effects of long-term gestodene-containing oral contraceptive administration on hemostasis. Am J Obstet Gynecol 1990; 163: 424-9.
• 20 Campbell S, Mackie I, Robinson G, Machin S. Contact factor-mediated fibrinolysis is increased by the combined oral contraceptive pill. Br J Obstet Gynaecol 1993; 100: 79-84.
• 21 Fruzzetti F, Ricci C, Fioretti P. Haemostasis profile in smoking and nonsmoking women taking low-dose oral contraceptives. Contraception 1994; 49: 579-92.
• 22 Jespersen J, Gram J. Increased fibrin formation in blood in women above the age of 30 who are both oral contraceptive users and smokers. Fibrinolysis 1996; 10: 9-13.
• 23 Fuster V, Badimon L, Badimon J. The pathophysiology of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242-50.
• 24 Falk E, Shah P, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657-70.
• 25 Lewis M, Heinemann L, Spitzer W, MacRae K, Bruppacher R. for the Transnational Reseach Group on Oral Contraceptives and the Health of Young Women. The use of oral contraceptives and the occurrence of acute myocardial infarction in young women. Contraception 1997; 56: 129-40.
• 26 Engel H, Engel E, Lichtlen P. Coronary atherosclerosis and myocardial infarction in young women – role of oral contraceptives. Eur Heart J 1983; 4: 1-9.
• 27 Ylikorrala O, Puolakka J, Viinikka L. The effect of oral contraceptives on antiaggregatory prostacyclin and proaggregatory thromboxane A₂ in humans. Am J Obstet Gynecol 1982; 142: 573-6.
• 28 Bruni V, Rosati D, Bucciantini S, Verni A. Platelet and coagulation functions during triphasic oestrogen-progestogen treatment. Contraception 1986; 33: 39-46.
• 29 Mileikowsky GN, Nadler JL, Huey F, Francis R, Roy S. Evidence that smoking alters prostacyclin formation and platelet aggregation in women who use oral contraceptives. Am J Obstet Gynecol 1988; 159: 1547-52.
• 30 Norris L, Bonnar J. The in vitro effect of aspirin on increased whole blood platelet aggregation in oral contraceptive users. Thromb Res 1994; 74: 309-15.
• 31 Schift A, Grandjean P, Donnez J, Lavenne E. Large increase in plasmatic 11-dehydro-TXB₂ levels due to oral contraceptives. Contraception 1995; 51: 53-8.
• 32 Nowak J, Murray J, Oates J, FitzGerald G. Biochemical evidence of a chronic abnormality in platelet and vascular function in healthy individuals who smoke cigarettes. Circulation 1987; 76: 6-14.
• 33 Rångemark C, Benthin G, Granström E, Persson L, Winell S, Wennmalm A. Tobacco use and urinary excretion of thromboxane A₂ and prostacyclin metabolites in women stratified by age. Circulation 1992; 86: 1495-500.
• 34 FitzGerald G, Smith B, Pedersen A, Brash A. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med 1984; 310: 1065-8.
• 35 Alessandrini P, McRae J, Feman S, FitzGerald G. Thromboxane biosynthesis and platelet function in type I diabetes mellitus. N Engl J Med 1988; 319: 208-12.
• 36 Davì G, Averna M, Catalano I, Barbagallo C, Ganci A, Notarbartolo A, Ciabattoni G, Patrono C. Increased thromboxane biosynthesis in type IIa hypercholesterolemia. Circulation 1992; 85: 1792-8.
• 37 Davì G, Gresele P, Violi F, Basili S, Catalano M, Giammarresi C, Volpato R, Nenci G, Ciabattoni G, Patrono C. Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease. Circulation 1997; 96: 69-75.
• 38 Davì G, Catalano I, Averna M, Notarbartolo A, Strano A, Ciabattoni G, Patrono C. Thromboxane biosynthesis and platelet function in type II diabetes mellitus. N Engl J Med 1990; 322: 1769-74.
• 39 Fitzgerald D, Roy L, Catella F, FitzGerald G. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315: 983-9.
• 40 Landolfi R, Ciabattoni G, Patrignani P, Castellana M, Pogliani E, Bizzi B, Patrono C. Increased thromboxane biosynthesis in patients with polycythemia vera: evidence for aspirin-suppressible platelet activation in vivo . Blood 1992; 80: 1965-71.
• 41 FitzGerald G, Pedersen A, Patrono C. Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease. Circulation 1983; 67: 1174-6.
• 42 Patrono C. Biosynthesis and pharmacological modulation of thromboxane in humans. Circulation 1990; 81 (Suppl. 01) I12-5.
• 43 Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994; 330: 1287-94.
• 44 Davis R. The determination of nicotine and cotinine in plasma. J Chroma-togr Sci 1986; 24: 134-41.
• 45 Feyerabend C, Russell M. A rapid gas-liquid chromatographic method for the determination of cotinine and nicotine in biological fluids. J Pharm Pharmacol 1990; 42: 450-2.
• 46 Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69: 1366-72.
• 47 Giannessi D, De Caterina R, Gazzetti P, Bernini W, Masini S, Zucchelli G. Methodological assessment and applications of a radioimmunoassay for thromboxane (TX) B₂ to measurement of TXB₂ release by platelets. J Nucl Med All Sci 1982; 26: 25-33.
• 48 Giannessi D, Lazzerini G, Filipponi P, Mannarelli C, Vaiani G, Grossi E, De Caterina R. Effects of nabumetone, a new non-steroidal anti-inflammatory drug, on urinary prostaglandin excretion in man. Pharmacol Res 1993; 28: 229-41.
• 49 De Caterina R, Giannessi D, Boem A, Bernini W, Battaglia D, Michelassi C, Dell’Amico F, L’Abbate A, Patrignani P, Patrono C. Equal antiplatelet effects of aspirin 50 or 324 mg/day in patients after acute myocardial infarction. Thromb Haemost 1985; 54: 528-32.
• 50 Marcus A. Stratton lecture 1989. Thrombosis and inflammation as multicellular processes: pathophysiologic significance of transcellular metabolism. Blood 1990; 76: 1903-7.
• 51 Ylikorkala O, Kuusi T, Tikkanen M, Viinikka L. Desogestrel- and levonor-gestrel-containing oral contraceptives have different effects on urinary excretion of prostacyclin metabolites and serum high density lipoproteins. J Clin Endocrin Metab 1987; 65: 1238-42.