Digestive Diseases and Sciences, Vol. 36, No. 8 (August 1991), pp. 1147-1150
REVIEW ARTICLE
Smoking, the Oral Contraceptive Pill, and Crohn's Disease A.J. WAKEFIELD, FRCS, A.M. SAWYERR, MRCP, M. HUDSON, MRCP, A.P. DHILLON, FRCPath, and R.E. POUNDER, FRCP
Both cigarette smoking and the oral contraceptive pill have been implicated as aggravating factors in Crohn's disease. Based upon the recent demonstration of multifocal gastrointestinal infarction in Crohn' s disease, a possible pathogenic mechanism for this condition, we propose how smoking and the oral contraceptive pill may potentiate a tendency f or focal thrombosis and hence exacerbate the activity of Crohn's disease. KEY WORDS: Crohn's disease; procoagulant activity; smoking; oral contraceptive.
There is a growing body of evidence that consistently links cigarette smoking to Crohn's disease (I-10). In particular, individuals with Crohn's disease who smoke have been reported to experience statistically significantly more relapses, hospital admissions, surgery, pain, diarrhea and changes in white cell count than nonsmokers with Crohn's disease, suggesting that smoking activates the disease (5). The evidence for a potentiating effect of the oral contraceptive pill on Crohn's disease, although less well defined than that for smoking, has been implicated in several studies (11-16). Moreover, discontinuation of the pill has led to a sustained improvement of disease activity in a number of patients (11-16). An understanding of the mechanism by which these two influences potentially exacerbate Crohn's disease may provide a further insight into the pathogenesis of this condition and may have important implications for the introduction of new therapeutic modalities in Crohn's disease. Manuscript received April 16, 1990; accepted May 24, 1990. From the Inflammatory Bowel Disease Study Group, Academic Departments of Medicine and Histopathology, Royal Free Hospital School of Medicine, London NW3 2QG, England. Address for reprint requests: Mr. A.J. Wakefield, FRCS, Academic Department of Medicine, Royal Free Hospital School of Medicine, Pond Street, London, NW3 2QG, England.
MULTIFOCAL GASTROINTESTINAL INFARCTION AND PROCOAGULANT ACTIVITY We have recently proposed a pathogenic mechanism for Crohn's disease, multifocal gastrointestinal infarction, which is mediated by a chronic mesenteric vasculitis (17). Focal vascular injury is confined to intramural vessels supplying segments of intestine affected by Crohn's disease, and it is characterised initially by fibrin deposition at the focus of monocyte adherence to endothelium. Advanced lesions consist of a chronic inflammatory cell infiltrate in the blood vessel wall with necrosis of the vessel wall and thrombosis of the affected vessel. It is likely that enhanced expression of both monocyte and vascular endothelial cell procoagulant activity (17, 18) is the initiating event in fibrin formation at the focus of this cellular interaction. Induction of procoagulant expression by these cells is a functional property of Interleukin-1 (ILl), levels of which are elevated in Crohn's disease (19, 20). IL-I, a monocyte/vascular endothelial cell-derived inflammatory cytokine, is capable of profoundly altering the antithrombotic properties of these cells. In addition to inducing the synthesis and expression of tissue factor procoagulant activity (21, 22), IL-I suppresses the anticoagulant
Digestive Diseases and Sciences, Vol. 36, No. 8 (August 1991)
0163-2116/91/0800-1147506.50/09 1991PlenumPublishingCorporation
1147
WAKEFIELD ET AL activity of thrombomodulin (23), which is expressed normally by endothelial cells. Furthermore, IL-1 alters the fibrinolytic properties of endothelial cells by decreasing tissue-type plasminogen-activator activity, also reported to be reduced in Crohn's disease (24), and augmenting production of a tissue plasminogen activator inhibitor (25-27). In addition, IL-I increases the endothelial cell production of platelet-activating factor, a potent activator of platelets and leukocytes and a vasoconstrictor (28), levels of which have been reported to be raised in colitis (29). There is evidence to suggest that modulation of IL-1 synthesis, and consequently the maintenance of thromboresistance at the surface of quiescent endothelium, is a functional property of bioactive prostaglandins, derived from arachidonate metabolism via the cyclooxygenase pathway (30, 31). Prostacyclin, a principal arachidonate derivative, is synthesized by endothelial cells at a low rate under normal circumstances. However, perturbation of the endothelium, leading to IL-1 expression, increased procoagulant activity, and local thrombin formation, stimulates endothelial cell prostacyclin synthesis (27). This probably reflects an highly integrated feedback loop, operative at the level of the endothelial cell, that acts to restore the anticoagulant integrity of these cells (32). Prostacyclin is also a powerful inhibitor of platelet aggregation and a vasodilator (33), and thus exerts its effects at multiple levels in the inhibition of focal thrombosis and the maintenance of microvascular perfusion. Evidence for this pivotal role for prostaglandins in the control of intravascular hemostasis has received considerable support from studies in which therapeutic intervention with prostaglandin analogs has produced marked attenuation of procoagulant activity and improvement in clinical condition in diseases in which this pathway is thought to be a principal effector of tissue injury (34, 35). CIGARETTE SMOKING AND PROCOAGULANT ACTIVITY With knowledge that focal activation of intravascular coagulation is a principal feature in the pathogenesis of Crohn's disease, it is possible to propose how both cigarette smoking and the oral contraceptive pill may potentiate this mechanism. Cigarette smoking, a risk factor for atherosclerosis (36, 37), has been shown to induce morphological injury to
1148
endothelial cells. This injury was associated with formation of microthrombi, impaired endothelial cell prostacyclin synthesis, and an enhanced aggregatory capacity of platelets (38). Furthermore chronic infusion of nicotine into rats has been reported to inhibit aortic endothelial prostacyclin synthesis (35). These findings have been substantiated by reports of the inhibition of endothelial cell prostacyclin synthesis by nicotine (35, 39). Furthermore, elevated plasma fibrinogen levels and decreased levels of both plasminogen and tissue plasminogen activator activity have been reported in habitual smokers (40). These findings may explain, at least in part, the increased risk of thrombotic vascular disease in smokers. ORAL CONTRACEPTIVE AND PROCOAGULANT ACTIVITY Although an association between thromboembolic disease and the oral contraceptive pill remains controversial (41), these drugs are able to exert a number of influences upon substrates of coagulation that may enhance a tendency to focal thrombosis in conditions where prior activation of coagulation exists. Estrogens above a dosage level of 50 ~g of ethinylestradiol induce effects in both the coagulation and fibrinolytic enzyme systems (42, 43). There have been a number of reports of increased levels of fibrinogen (42, 43), factors II (prothrombin) (42, 44), VII (a direct substrate for tissue factor activity) (42, 44), VIII, and X (42). Reduced levels of antithrombin III, a circulating anticoagulant that inhibits thrombin activity at the endothelial cell surface, also have been described in users of the pill (42, 46), a finding that also has been reported in association with Crohn's disease (47). In addition, rapid fibrinolysis (42, 48) and decreased levels of vascular endothelial-tissue plasminogen activator (42, 49) have been reported during oral contraceptive use, possibly reflecting enhanced consumption in response to intravascular coagulation. Tissue plasminogen activator activity is reduced in active Crohn's disease (23), possibly as a result of the presence of a monocyte/vascular endothelial cell-derived tissue plasminogen activator inhibitor (26, 50), and this may contribute to a tendency for focal thrombosis in this condition. It is of interest that both changes in indices of coagulation and Crohn's disease activity may undergo sustained improvement following cessation of oral contraceptive therapy (6, 42). Digestive Diseases and Sciences, Vol. 36, No. 8 (August 1991)
SMOKING, THE PILL, AND CROHN'S DISEASE ACTIVATION OF CROHN'S DISEASE We have observed microvascular changes in patients with Crohn's disease who neither smoke nor take oral contraceptives (17). However, it is tempting to suggest that when further prothrombotic stimuli such as oral contraceptives, which contain more than 50 p~g of ethinylestradiol, or cigarette smoking are superimposed upon Crohn's disease, exacerbation of disease activity is the likely outcome. In the case of cigarette smoking, this activation may be due to a direct endothelial cell injury, impaired prostacyclin production, and a decreased fibrinolytic capacity of these cells. With oral contraceptives containing more than 50 ~g of ethinylestradiol, potentiation of thrombosis may result from augmented levels of procoagulant substrates and associated decreases of both anticoagulant and fibrinolytic activity. It is of note that Lashner et al, have recently failed to find an association between oral contraceptives and Crohn's disease (51). However, this study did not gather information on the nature or strength of the oral contraceptive used. In light of the dose-dependent effects of ethinylestradiol on levels of procoagulant substrate and anticoagulant activity (42), this would seem to be crucial information, and thus lack of an association cannot be based on this study alone. Their findings may reflect, in part, the current trend towards prescribing oral contraceptives that contain lower levels of estrogen. CONCLUSION
We are presently investigating the role of the cellular procoagulant pathway in Crohn's disease and will be paying close attention to the activity of this pathway in both smokers and those taking an oral contraceptive. In the meantime, patients who suffer from Crohn's disease should be advised to abstain from smoking and female sufferers should seek expert guidance concerning the type of oral contraceptive they are using. ACKNOWLEDGMENTS We thank Miss Doris Elliott for her help in preparation of this manuscript, the Wellcome Trust for their continued support (Mr. A.J. Wakefield is a Wellcome Research Fellow), and the Crohn's in Childhood Research Appeal.
REFERENCES 1. Thornton JR, Emmett PM, Heaton KW: Smoking, sugar and inflammatory bowel disease. Br Med J 2190:1786-1787, 1985 Digestive Diseases and Sciences, Vol. 36, No. 8 (August 1991)
2. Calkins B: Smoking factors in ulcerative colitis and Crohn's disease in Baltimore. Am J Epidemiol 120:498-503, 1984 3. Beoni C, Nilsson A: Smoking habits in patients with inflammatory bowel disease. Scand J Gastroenterol 19:824-830, 1984 4. Somerville KW, Loban RFA, Edmond M, Langman MJS: Smoking and Crohn's disease. Br Med J 289:954-956, 1984 5. Holdstock G, Savage D, Harman M, Wright I: Should patients with inflammatory bowel disease smoke? Br Med J 288:362, 1984 6. Mendelhoff AI, Calkins BM: The epidemiology of idiopathic inflammatory bowel disease. In Inflammatory Bowel Disease. JB Kirsner, RG Shorter (eds). Philadelphia, Lea and Febiger, 1988, pp 3-34 7. Katschinski B, Logan RFA, Edmond M, Langman MJS: Smoking and sugar are separate but interactive risk factors in Crohn's disease. Gut 29:1202-1206, 1988 8. Lidberg E, Tysk C, Andersson K, Jarnerot G: Smoking and inflammatory bowel disease. A case control study. Gut 29:352-357, 1988 9. Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B: Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritiability and the influence of smoking. Gut 29:990-996, 1988 10. Vessey M, Jewell D, Smith A, Yeates D, MacPherson K: Chronic inflammatory bowel disease, cigarette smoking, and use of oral contraceptives: findings in a large cohort study of women of childbearing age. Br Med J 292: 1101-1103, 1986 11. Bonfils S, Hervoir P, Girodet J, Quintrec YL, Bader JP, Gastard J: Acute spontaneously recovering ulcerating colitis (ARUC). Am J Dig Dis 22:429-436, 1977 12. Bernadino ME, Lawson TL: Discrete colonic ulcers associated with oral contraceptives. Am J Dig Dis 21:503-506, 1976 13. Camilleri M, Schafler K, Chadwick VS, Hodgson HJ, Weinbren K: Periportal sinsusoidal dilatation, inflammatory bowel disease, and the contraceptive pill. Gastroenterology 80:810-815, 1981 14. Rhodes JM, Cockel R, Allan RN, Hawker PC: Colonic Crohn's disease and use of oral contraceptives. Br Med J 288:595-596, 1984 15. Lesko S: Oral contraceptive use and Crohn's disease. Am J Epidemiol 120:466-471, 1984 16. Tedesco FJ, Volpicelli NA, More FS: Oestrogen and progesterone-associated colitis: A disorder with clinical and endoscopic features mimicking Crohn's colitis. Gastrointest Endosc 28:247-251, 1982 17. Wakefield AJ, Sawyerr AM, Dhillon AP, Pittilo RM, Rowles PM, Lewis AAM, Pounder RE: Pathogenesis of Crohn's disease: Multifocal gastrointestinal infarction. Lancet 1:1057-1062, 1989 18. Edwards RL, Levine JB, Green R, Duffy M, Matthews E, Brande W, Rickles FR: Activation of blood coagulation in Crohn's disease. Gastroenterology 92:329-337, 1987 19. Suzuki Y, Tobin A, Quinn D, Whelan D, O'Morain C: Interleukin-1 in inflammatory bowel disease. Gastroenterology 96:A498, t989 20. Satsangi J, Walstencroft JC, Cason J, Ainley CC, Dumonde DC, Thompson RPH: Interleukin-1 in Crohn's disease. Clin Exp Immunol 67:594-605, 1987
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W A K E F I E L D ET AL 21. Bevilaqua MP, Pober JS, Majeau GR, Cotran R, Gimbrone MA: Interleukin-1 (IL-1) induces bisynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells. J Exp Med 160:618-623, 1984 22. Pober JS: Cytokine mediated activation of the vascular endothelium. Am J Pathol 133:426-433, 1988 23. Narworth PP, Handley CT, Esmon C, Stern D: Interleukin-I induces endothelial procoagulant activity while suppressing cell surface anticoagulant activity. Proc Natl Acad Sci USA 83:3460-3464, 1986 24. Bruin PAF, Crama-Bohbouth G, Verspaget HW, Verheigen JH, Dooijewaard G, Weterman IT, Lamers C: Plasminogen activators in the intestine of patients with inflammatory bowel disease. Thromb Haemost 60:262-266, 1988 25. Bevilaqua MP, Schleef RR, Gimbrone MA, Loskutoff DJ: Regulation of the fibronolytic system of cultured human vascular endothelium by Interleukin-1. J Clin Invest 78:587591, 1986 26. Nachman RL, Haj,jar KA, Silverstein RL, Dinaretlo CA: Interleukin-I induces endothelial cell synthesis of plasminogen activator inhibitor. J Exp Med 163:1595-1600, 1986 27. Emeis JJ, Kooistra T: Interleukin-1 and lipopolysaccaride induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells. J Exp Med 163:12601266, 1986 28. Bussolino F, Brevario F, Tetta C, Aglietta M, Mantovani A, Dejana E: Interleukin-I stimulates platelet-activating factor production in cultured human endothelial cells. J Clin Invest 77:2027-2033, 1986 29. Eliakim R, Karmeli F, Razin E, Rachmilewitz D: Role of platelet-activating factor in ulcerative colitis. Gastroenterology 95:1167-1172, 1988 30. Knusden PJ, Dinarello Ca, Strom TB: Prostaglandins posttranscriptionally inhibit monocyte expression of Interleukin-1 activity by increasing intracellular cyclic adenosine monophosphate. J Immunol 136:!86-192, 1986 31. Kunkle SC, Cheunsue SW, Phan SH: Prostaglandins as endogenous mediators of lnterleukin-1 production. J Immunol 136:186-192, 1986 32. Mantovani A, Dejana E: Cytokines as communication signals between leucocytes and endothelial cells, lmmunol Today 10:370-375, 1989 33. Simmet TH, Peskar BA: Prostaglandin E and arterial occlusive disease: Pharmacological considerations. Eur J Clin Invest 18:549-554, 1988 34. Abecassis M, Falk R, Makowka L, Dindzans V, Falk RE, Levy GA: 16-16-dimethyl prostaglandin E, prevents the development of fulminant hepatitis and blocks the induction of monocyte/macrophage procoagulant activity after murine hepatitis virus strain 3 infection. J Clin Invest 80:881-889, 1987 35. Sinclair S, Creig PD, Blendis LM, Abecassis M, Roberts EA, Phillips MJ, Cameron R, Levy GA: Biochemical and
1 15 0
clinical response of fulminant viral hepatitis to administration of prostaglandin E,. J Clin Invest 84:1368-1374, 1989 36. Murphy EA, Mustard JF: Tobacco and thrombosis. Am J Public Health 56:1061-1073, 1966 37. Spain DM, Bradess VA: Sudden death from coronary heart disease: Survival time, frequency of thrombi and cigarette smoking. Chest 58:107-110, 1970 38. Pittilo RM, Mackin IJ, Rowles PM, Machin SJ, Woolf N: Effects of cigarette smoking on the ultrastructure of the thoracic aorta and its ability to produce prostacyclin. Thromb Haemost 48:173-176, 1982 39. Bull HA, Pittilo M, Blow DJ, Blow CM, Rowles PM, Woolf N, Machin SJ: The effects of nicotine on PGI2 production by rat aortic endothelium. Thromb Haemost 54:472-474, 1985 40. Bull HA, Pittilo RM, Woolf N, Machin SJ: The effect of nicotine on human endothelial cell release of prostaglandins and ultrastructure. Br J Exp Pathol 69:413-421, 1988 41. Stadel BV: Oral contraceptives and cardiovascular disease. N Engl J Med 305:612-618, 672-677, 1981 42. Belch JJF, McArdle BM, Burns P, Lowe GDO, Forbes CD: The effect of acute smoking on platelet behavior, fibrinolysis and haemoreheology in habitual smokers. Thromb Haemost 52:6-8, 1984 43. Belier FK, Ehert C: Effects of oral contraceptives on blood coagulation. A review. Obstet Gynaecol Surv 40:425-436, 1988 44. Meade TW, Haines AP, North WRS: Haemostatic, lipid and blood pressure profiles of women on oral contraceptives containing 50 ~g or 30 Ixg oestrogen. Lancet 1:948-950, 1970 45. Poller L: Oral contraceptives, blood clotting and thrombosis. Br Med Bull 34:151-156, 1978 48. Peterson C, Kelly R, Minard B, Cawley LP: Antithrombin III: Comparison of functional and immunologic assays. Am J Clin Pathol 69:500-504, 1978 47. Koerigs KP, McPhedran P, Spiro HM: Thrombosis in inflammatory bowel disease. J Clin Gastroenterol 9:627-631, 1987 48. Gordon EM, Ratnoff OD, Saiato H, Donaldson VH, Pensky J, Jones P: Rapid fibrinolysis, augmented Hageman factor (factor XII), and decreased C1 esterase inhibitor titres in women taking oral contraceptives. J Lab Clin Med 96:762769, 1980 49. Astedt B: Low fibrinolytic activity of veins during treatment with ethinyl oestradiol. Acta Obstet Gynaecol Scand 50:279283, 1971 50. Vassalli JD, Dayer JM, Wohlend A, Belin D: Concomitant secretion of prourokinase and of a plasminogen activatorspecific inhibitor by cultured human monocytes-macrophages. J Exp Med 159:1653-1658, 1984 51. Lashner BA, Kane SV, Hanauer SB: Lack of association between oral contraceptive use and Crohn's disease: A community-based matched case-control study. Gastroenterology 97:1442-t447, 1989
Digestive Diseases and Sciences. Vol. 36, No. 8 (August 1991)
REVIEW ARTICLE
Smoking, the Oral Contraceptive Pill, and Crohn's Disease A.J. WAKEFIELD, FRCS, A.M. SAWYERR, MRCP, M. HUDSON, MRCP, A.P. DHILLON, FRCPath, and R.E. POUNDER, FRCP
Both cigarette smoking and the oral contraceptive pill have been implicated as aggravating factors in Crohn's disease. Based upon the recent demonstration of multifocal gastrointestinal infarction in Crohn' s disease, a possible pathogenic mechanism for this condition, we propose how smoking and the oral contraceptive pill may potentiate a tendency f or focal thrombosis and hence exacerbate the activity of Crohn's disease. KEY WORDS: Crohn's disease; procoagulant activity; smoking; oral contraceptive.
There is a growing body of evidence that consistently links cigarette smoking to Crohn's disease (I-10). In particular, individuals with Crohn's disease who smoke have been reported to experience statistically significantly more relapses, hospital admissions, surgery, pain, diarrhea and changes in white cell count than nonsmokers with Crohn's disease, suggesting that smoking activates the disease (5). The evidence for a potentiating effect of the oral contraceptive pill on Crohn's disease, although less well defined than that for smoking, has been implicated in several studies (11-16). Moreover, discontinuation of the pill has led to a sustained improvement of disease activity in a number of patients (11-16). An understanding of the mechanism by which these two influences potentially exacerbate Crohn's disease may provide a further insight into the pathogenesis of this condition and may have important implications for the introduction of new therapeutic modalities in Crohn's disease. Manuscript received April 16, 1990; accepted May 24, 1990. From the Inflammatory Bowel Disease Study Group, Academic Departments of Medicine and Histopathology, Royal Free Hospital School of Medicine, London NW3 2QG, England. Address for reprint requests: Mr. A.J. Wakefield, FRCS, Academic Department of Medicine, Royal Free Hospital School of Medicine, Pond Street, London, NW3 2QG, England.
MULTIFOCAL GASTROINTESTINAL INFARCTION AND PROCOAGULANT ACTIVITY We have recently proposed a pathogenic mechanism for Crohn's disease, multifocal gastrointestinal infarction, which is mediated by a chronic mesenteric vasculitis (17). Focal vascular injury is confined to intramural vessels supplying segments of intestine affected by Crohn's disease, and it is characterised initially by fibrin deposition at the focus of monocyte adherence to endothelium. Advanced lesions consist of a chronic inflammatory cell infiltrate in the blood vessel wall with necrosis of the vessel wall and thrombosis of the affected vessel. It is likely that enhanced expression of both monocyte and vascular endothelial cell procoagulant activity (17, 18) is the initiating event in fibrin formation at the focus of this cellular interaction. Induction of procoagulant expression by these cells is a functional property of Interleukin-1 (ILl), levels of which are elevated in Crohn's disease (19, 20). IL-I, a monocyte/vascular endothelial cell-derived inflammatory cytokine, is capable of profoundly altering the antithrombotic properties of these cells. In addition to inducing the synthesis and expression of tissue factor procoagulant activity (21, 22), IL-I suppresses the anticoagulant
Digestive Diseases and Sciences, Vol. 36, No. 8 (August 1991)
0163-2116/91/0800-1147506.50/09 1991PlenumPublishingCorporation
1147
WAKEFIELD ET AL activity of thrombomodulin (23), which is expressed normally by endothelial cells. Furthermore, IL-1 alters the fibrinolytic properties of endothelial cells by decreasing tissue-type plasminogen-activator activity, also reported to be reduced in Crohn's disease (24), and augmenting production of a tissue plasminogen activator inhibitor (25-27). In addition, IL-I increases the endothelial cell production of platelet-activating factor, a potent activator of platelets and leukocytes and a vasoconstrictor (28), levels of which have been reported to be raised in colitis (29). There is evidence to suggest that modulation of IL-1 synthesis, and consequently the maintenance of thromboresistance at the surface of quiescent endothelium, is a functional property of bioactive prostaglandins, derived from arachidonate metabolism via the cyclooxygenase pathway (30, 31). Prostacyclin, a principal arachidonate derivative, is synthesized by endothelial cells at a low rate under normal circumstances. However, perturbation of the endothelium, leading to IL-1 expression, increased procoagulant activity, and local thrombin formation, stimulates endothelial cell prostacyclin synthesis (27). This probably reflects an highly integrated feedback loop, operative at the level of the endothelial cell, that acts to restore the anticoagulant integrity of these cells (32). Prostacyclin is also a powerful inhibitor of platelet aggregation and a vasodilator (33), and thus exerts its effects at multiple levels in the inhibition of focal thrombosis and the maintenance of microvascular perfusion. Evidence for this pivotal role for prostaglandins in the control of intravascular hemostasis has received considerable support from studies in which therapeutic intervention with prostaglandin analogs has produced marked attenuation of procoagulant activity and improvement in clinical condition in diseases in which this pathway is thought to be a principal effector of tissue injury (34, 35). CIGARETTE SMOKING AND PROCOAGULANT ACTIVITY With knowledge that focal activation of intravascular coagulation is a principal feature in the pathogenesis of Crohn's disease, it is possible to propose how both cigarette smoking and the oral contraceptive pill may potentiate this mechanism. Cigarette smoking, a risk factor for atherosclerosis (36, 37), has been shown to induce morphological injury to
1148
endothelial cells. This injury was associated with formation of microthrombi, impaired endothelial cell prostacyclin synthesis, and an enhanced aggregatory capacity of platelets (38). Furthermore chronic infusion of nicotine into rats has been reported to inhibit aortic endothelial prostacyclin synthesis (35). These findings have been substantiated by reports of the inhibition of endothelial cell prostacyclin synthesis by nicotine (35, 39). Furthermore, elevated plasma fibrinogen levels and decreased levels of both plasminogen and tissue plasminogen activator activity have been reported in habitual smokers (40). These findings may explain, at least in part, the increased risk of thrombotic vascular disease in smokers. ORAL CONTRACEPTIVE AND PROCOAGULANT ACTIVITY Although an association between thromboembolic disease and the oral contraceptive pill remains controversial (41), these drugs are able to exert a number of influences upon substrates of coagulation that may enhance a tendency to focal thrombosis in conditions where prior activation of coagulation exists. Estrogens above a dosage level of 50 ~g of ethinylestradiol induce effects in both the coagulation and fibrinolytic enzyme systems (42, 43). There have been a number of reports of increased levels of fibrinogen (42, 43), factors II (prothrombin) (42, 44), VII (a direct substrate for tissue factor activity) (42, 44), VIII, and X (42). Reduced levels of antithrombin III, a circulating anticoagulant that inhibits thrombin activity at the endothelial cell surface, also have been described in users of the pill (42, 46), a finding that also has been reported in association with Crohn's disease (47). In addition, rapid fibrinolysis (42, 48) and decreased levels of vascular endothelial-tissue plasminogen activator (42, 49) have been reported during oral contraceptive use, possibly reflecting enhanced consumption in response to intravascular coagulation. Tissue plasminogen activator activity is reduced in active Crohn's disease (23), possibly as a result of the presence of a monocyte/vascular endothelial cell-derived tissue plasminogen activator inhibitor (26, 50), and this may contribute to a tendency for focal thrombosis in this condition. It is of interest that both changes in indices of coagulation and Crohn's disease activity may undergo sustained improvement following cessation of oral contraceptive therapy (6, 42). Digestive Diseases and Sciences, Vol. 36, No. 8 (August 1991)
SMOKING, THE PILL, AND CROHN'S DISEASE ACTIVATION OF CROHN'S DISEASE We have observed microvascular changes in patients with Crohn's disease who neither smoke nor take oral contraceptives (17). However, it is tempting to suggest that when further prothrombotic stimuli such as oral contraceptives, which contain more than 50 p~g of ethinylestradiol, or cigarette smoking are superimposed upon Crohn's disease, exacerbation of disease activity is the likely outcome. In the case of cigarette smoking, this activation may be due to a direct endothelial cell injury, impaired prostacyclin production, and a decreased fibrinolytic capacity of these cells. With oral contraceptives containing more than 50 ~g of ethinylestradiol, potentiation of thrombosis may result from augmented levels of procoagulant substrates and associated decreases of both anticoagulant and fibrinolytic activity. It is of note that Lashner et al, have recently failed to find an association between oral contraceptives and Crohn's disease (51). However, this study did not gather information on the nature or strength of the oral contraceptive used. In light of the dose-dependent effects of ethinylestradiol on levels of procoagulant substrate and anticoagulant activity (42), this would seem to be crucial information, and thus lack of an association cannot be based on this study alone. Their findings may reflect, in part, the current trend towards prescribing oral contraceptives that contain lower levels of estrogen. CONCLUSION
We are presently investigating the role of the cellular procoagulant pathway in Crohn's disease and will be paying close attention to the activity of this pathway in both smokers and those taking an oral contraceptive. In the meantime, patients who suffer from Crohn's disease should be advised to abstain from smoking and female sufferers should seek expert guidance concerning the type of oral contraceptive they are using. ACKNOWLEDGMENTS We thank Miss Doris Elliott for her help in preparation of this manuscript, the Wellcome Trust for their continued support (Mr. A.J. Wakefield is a Wellcome Research Fellow), and the Crohn's in Childhood Research Appeal.
REFERENCES 1. Thornton JR, Emmett PM, Heaton KW: Smoking, sugar and inflammatory bowel disease. Br Med J 2190:1786-1787, 1985 Digestive Diseases and Sciences, Vol. 36, No. 8 (August 1991)
2. Calkins B: Smoking factors in ulcerative colitis and Crohn's disease in Baltimore. Am J Epidemiol 120:498-503, 1984 3. Beoni C, Nilsson A: Smoking habits in patients with inflammatory bowel disease. Scand J Gastroenterol 19:824-830, 1984 4. Somerville KW, Loban RFA, Edmond M, Langman MJS: Smoking and Crohn's disease. Br Med J 289:954-956, 1984 5. Holdstock G, Savage D, Harman M, Wright I: Should patients with inflammatory bowel disease smoke? Br Med J 288:362, 1984 6. Mendelhoff AI, Calkins BM: The epidemiology of idiopathic inflammatory bowel disease. In Inflammatory Bowel Disease. JB Kirsner, RG Shorter (eds). Philadelphia, Lea and Febiger, 1988, pp 3-34 7. Katschinski B, Logan RFA, Edmond M, Langman MJS: Smoking and sugar are separate but interactive risk factors in Crohn's disease. Gut 29:1202-1206, 1988 8. Lidberg E, Tysk C, Andersson K, Jarnerot G: Smoking and inflammatory bowel disease. A case control study. Gut 29:352-357, 1988 9. Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B: Ulcerative colitis and Crohn's disease in an unselected population of monozygotic and dizygotic twins. A study of heritiability and the influence of smoking. Gut 29:990-996, 1988 10. Vessey M, Jewell D, Smith A, Yeates D, MacPherson K: Chronic inflammatory bowel disease, cigarette smoking, and use of oral contraceptives: findings in a large cohort study of women of childbearing age. Br Med J 292: 1101-1103, 1986 11. Bonfils S, Hervoir P, Girodet J, Quintrec YL, Bader JP, Gastard J: Acute spontaneously recovering ulcerating colitis (ARUC). Am J Dig Dis 22:429-436, 1977 12. Bernadino ME, Lawson TL: Discrete colonic ulcers associated with oral contraceptives. Am J Dig Dis 21:503-506, 1976 13. Camilleri M, Schafler K, Chadwick VS, Hodgson HJ, Weinbren K: Periportal sinsusoidal dilatation, inflammatory bowel disease, and the contraceptive pill. Gastroenterology 80:810-815, 1981 14. Rhodes JM, Cockel R, Allan RN, Hawker PC: Colonic Crohn's disease and use of oral contraceptives. Br Med J 288:595-596, 1984 15. Lesko S: Oral contraceptive use and Crohn's disease. Am J Epidemiol 120:466-471, 1984 16. Tedesco FJ, Volpicelli NA, More FS: Oestrogen and progesterone-associated colitis: A disorder with clinical and endoscopic features mimicking Crohn's colitis. Gastrointest Endosc 28:247-251, 1982 17. Wakefield AJ, Sawyerr AM, Dhillon AP, Pittilo RM, Rowles PM, Lewis AAM, Pounder RE: Pathogenesis of Crohn's disease: Multifocal gastrointestinal infarction. Lancet 1:1057-1062, 1989 18. Edwards RL, Levine JB, Green R, Duffy M, Matthews E, Brande W, Rickles FR: Activation of blood coagulation in Crohn's disease. Gastroenterology 92:329-337, 1987 19. Suzuki Y, Tobin A, Quinn D, Whelan D, O'Morain C: Interleukin-1 in inflammatory bowel disease. Gastroenterology 96:A498, t989 20. Satsangi J, Walstencroft JC, Cason J, Ainley CC, Dumonde DC, Thompson RPH: Interleukin-1 in Crohn's disease. Clin Exp Immunol 67:594-605, 1987
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Digestive Diseases and Sciences. Vol. 36, No. 8 (August 1991)
