Monocyte Tissue Factor Expression Is Enhanced in Women who Smoke and Use Oral Contraceptives

Summary

The association between use of oral contraceptives (OCs) and increased risk of thromboembolic disease has been firmly established. This risk increases when use of OCs is combined with cigarette smoking. The cellular mechanism favoring an hypercoagulable state under these behaviours is not known. Circulating monocytes are potent activators of the coagulation cascade through their ability to synthesize procoagulant tissue factor (TF). In the present study we report that monocyte TF expression is increased in women who use OCs and smoke.

We studied monocyte TF expression in 4 groups of healthy pre-menopausal women (n = 15 each): (1) non-smoking OC non-users, (2) nonsmoking current OC users, (3) smoking OC non-users and (4) smoking OC users. TF expression was assessed on both mRNA and protein levels in unstimulated and LPS-stimulated cells. Transcriptional activation of the TF gene was assessed by analysis of the transcription factor NF-κB and its inhibitor molecule IκBα. Monocyte TF generation was significantly higher in OC users than in women who did not use OCs. Enhanced monocyte TF generation was also observed in smoking women when compared to non-smokers. Strongest monocyte TF expression occurred in women with combined smoking and use of OCs. The enhanced TF expression in monocytes from women using OCs or smoking was based on an increased TF gene transcription following activation of NF-κB. Experiments on cultured monocytes/macrophages demonstrated enhanced IκBα degradation in the presence of estradiol, suggesting that a direct hormone effect is responsible for the observed increase in monocyte TF expression.

This study demonstrates that use of OCs and smoking is associated with an increase in monocyte TF expression in pre-menopausal women. Aberrant TF expression by blood monocytes may favour intravascular clotting activation in women with OC therapy. The further enhancement of TF activity observed in women who smoke and use OCs may explain the synergistic effect of smoking on risk of thromboembolic events associated with contraceptive use.

Key Words

Tissue factor - monocytes - oral contraception - smoking

• References

• 1 Vessey MP, Doll R. Investigation of relation between use of oral contraceptives and thromboembolic disease. Br Med J 1968; 2: 199-205.
• 2 Mammen EF. Oral contraceptives and blood coagulation: a critical review. Am J Obstet Gynecol 1982; 142: 781-90.
• 3 Stadel BV. Oral contraceptives and cardiovascular disease (first of two parts). N Engl J Med 1981; 305: 612-8.
• 4 Stadel BV. Oral contraceptives and cardiovascular disease (second of two parts). N Engl J Med 1981; 305: 672-7.
• 5 The Health Consequences of Smoking for Women: A Report of the Surgeon General. Rockville, MD: Office on Smoking and Health; 1980
• 6 Petitti DB, Wingerd J. Use of oral contraceptives, cigarette smoking, and risk of subarachnoid haemorrhage. Lancet 1978; 2: 234-6.
• 7 Rosenberg L, Kaufman DW, Helmrich SP, Miller DR, Stolley PD, Shapiro S. Myocardial infarction and cigarette smoking in women younger than 50 years of age. JAMA 1985; 253: 2965-9.
• 8 Jespersen J, Petersen K, Skouby S. Effects of newer oral contraceptives on the inhibition of coagulation and fibrinolysis in relation to dosage and type of steroid. Am J Obstet Gynecol 1990; 163: 396-403.
• 9 Daly L, Bonnar J. Comparative studies of 30 mg ethinyl estradiol combined with gestodene and desogestrel on blood coagulation, fibrinolysis, and platelets. Am J Obstet Gynecol 1990; 163: 430-7.
• 10 David JL, Gaspard UJ, Gillain D, Raskinet R, Lepot MR. Hemostasis profile in women taking low-dose oral contraceptives. Am J Obstet Gynecol 1990; 163: 420-3.
• 11 Gevers Leuven JA, Kluft C, Bertina RM, Hessel LW. Effects of low-dose oral contraceptives on circulating components of the coagulation and fibrinolytic systems. Lab Clin Med 1987; 109: 631-6.
• 12 Inauen W, Baumgartner HR, Haeberli A, Straub PW. Excessive deposition of fibrin, platelets and platelet thrombin on vascular subendothelium during contraceptive drug treatment. Thromb Haemost 1987; 57: 306-9.
• 13 Østerud B, Flaestad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: Related to an unfavorable prognosis. Thromb Haemost 1983; 49: 5-7.
• 14 Nemerson Y. Tissue factor and hemostasis. Blood 1988; 71: 71-8.
• 15 Rao LVM. Tissue factor as a tumor procoagulant. Cancer Metastasis Rev 1992; 11: 249-66.
• 16 Jude B, Agraou B, McFadden EP, Susen S, Bauters C, Lepelley P, Vanhaesbroucke C, Devos P, Cosson A, Asseman P. Evidence for time-dependent activation of monocytes in the systemic circulation in unstable angina but not in acute myocardial infarction or in stable angina. Circulation 1994; 90: 1662-8.
• 17 Marmur JD, Thiruvikraman SV, Fyfe BS, Guha A, Sharma SK, Ambrose JA, Fallon JT, Nemerson Y, Taubman MB. Identification of active tissue factor in human coronary atheroma. Circulation 1996; 94: 1226-32.
• 18 Boyum A. Isolation of mononuclear cells and granulocytes from human blood: isolation of mononuclear cells by one centrifugation and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest 1963; 21 (Suppl. 97) 77-89.
• 19 Altieri DC, Mannucci PM, Capitanio M. Binding of fibrinogen to human monocytes. J Clin Invest 1986; 159: 1042-57.
• 20 Hölschermann H, Kohl O, Maus U, Dürfeld F, Bierhaus A, Nawroth PP, Lohmeyer J, Tillmanns H, Haberbosch W. Cyclosporine inhibits monocyte tissue factor activation in cardiac transplant recipients. Circulation 1997; 96: 4232-8.
• 21 Hölschermann H, Dürfeld F, Maus U, Bierhaus A, Heidinger K, Lohmeyer J, Nawroth PP, Tillmanns H, Haberbosch W. Cyclosporine A inhibits tissue factor expression in monocytes/macrophages. Blood 1996; 88: 3837-45.
• 22 Chomczynski P, Sacchi N. Single step method of RNA-isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156-9.
• 23 Scarpati EM, Wen D, Broze G, Miletich JP, Flandermayer RR, Siegel NR, Sadler E. Human Tissue Factor: cDNA-sequence and chromosome localization of the gene. Biochemistry 1987; 26: 5234-8.
• 24 Maus U, Rosseau S, Knies U, Seeger W, Lohmeyer J. Expression of pro-inflammatory cytokines by flow-sorted alveolar macrophages in severe pneumonia. Eur Respir J 1998; 11: 534-41.
• 25 Bierhaus A, Zhang Y, Deng Y, Mackman N, Quehenberger P, Haase M, Luther T, Müller M, Böhrer H, Greten J, Eike M, Bauerle P, Waldherr R, Kisiel W, Ziegler R, Stern DM, Nawroth PP. Mechanism of the TNFα mediated induction of endothelial tissue factor. J Biol Chem 1995; 270: 26419-32.
• 26 Mackman N. Regulation of the tissue factor gene. FASEB J 1995; 9: 883-9.
• 27 Brown K, Gerstberger S, Carlson L, Franzoso G, Siebenlist U. Control of IκBα proteolysis by site-specific, signal-induced phosphorylation. Science 1995; 267: 1485-91.
• 28 Böttiger LE, Bomann G, Eklund G, Westerholm B. Oral contraceptives and thromboembolic disease: effects of lowering oestrogen content. Lancet 1980; 1: 1097-101.
• 29 Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995; 346: 1589-93.
• 30 World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolism. Lancet 1995; 346: 1582-8.
• 31 Taylor FBJ, Chang A, Ruf W, Morrissey JH, Hinshaw L, Catlett R, Blick K, Edgington TS. Lethal E. coli septic shock is prevented by blocking tissue factor with monoclonal antibody. Circ Shock 1991; 33: 127-34.
• 32 Carlsen E, Flatmark A, Prydz H. Cytokine-induced procoagulant activity in monocytes and endothelial cells. Further enhancement by cyclosporine. Transplantation 1988; 46: 575-80.
• 33 Drake TA, Ruf W, Morrissey JH, Edgington TS. Functional tissue factor activity is entirely cell surface expressed on lipopolysaccharide-stimulated human blood monocytes and a constitutively tissue factor-producing cell line. J Cell Biol 1989; 109: 389-95.
• 34 Gregory SA, Kornbluth RS, Helin H, Remold HG, Edgington TS. Monocyte pro-coagulant inducing factor: a lymphokine involved in the T-cell instructed monocyte pro-coagulant response to antigen. J Immunol 1986; 141: 3231-9.
• 35 Omsjø IH, Øian P, Østerud B. Thromboplastin activity in blood monocytes from oral contraceptive users. Gynecol obstet Invest 1986; 22: 194-7.
• 36 Crutchley DJ, Que BG. Copper-induced tissue factor expression in human monocytic TPH-1 cells and its inhibition by antioxidants. Circulation 1995; 92: 238-43.
• 37 Heitzer T, Just H, Münzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers. Circulation 1996; 94: 6-9.
• 38 Church DF, Pryor WA. Free radical chemistry of cigarette smoke and its toxicologic implications. Environ Health Perspect 1985; 64: 111-26.
• 39 Weber C, Erl W, Peitsch A, Strobel M, Ziegler-Heitbrock HWL, Weber PC. Antioxidants inhibit monocyte adhesion by suppressing nuclear factor-κB mobilization and induction of vascular cell adhesion molecule-1 in endothelial cells stimulated to generate radicals. Arterioscler Thromb 1994; 14: 1665-73.
• 40 Marui N, Offermann MK, Swerlick R, Kunsch C, Rosen CA, Ahmad M, Alexander RW, Medford RM. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest 1993; 92: 1866-74.
• 41 Eugui EM, DeLustro B, Rouhafza S, Ilnicka M, Lee SW, Wilhelm R, Allison AC. Some antioxidants inhibit, in a co-ordinate fashion, the production of tumor necrosis factor-α, IL-β and IL-6 by human peripheral blood mononuclear cells. Int Immunol 1994; 6: 409-22.
• 42 Schreck R, Rieber P, Bauerle PA. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-κB transcription factor and HIV-1. EMBO J 1991; 10: 2247-58.