© 1996 American Heart Association, Inc.
Articles |
Antithrombin and Atherosclerosis in the Rotterdam Study
the Departments of Epidemiology and Biostatistics (J.G. van der B., M.L.B., A.H., D.E.G.); Netherlands Institute for Health Sciences (J.G. van der B.); Hematology (Hemostasis and Thrombosis Research) (H.H.D.M. van V.); and Internal Medicine III (H.A.P.P.), Erasmus University Medical School, Rotterdam, Netherlands.
Correspondence to Professor D.E. Grobbee, Department of Epidemiology and Biostatistics, Erasmus University Medical School, PO Box 1738, 3000 DR Rotterdam, Netherlands.
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Abstract |
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Antithrombin is a potent inhibitor of thrombotic tendency. Whether atherosclerotic disease is associated with high or low antithrombin is unclear. Studies of the relation between antithrombin and presence of arterial disease have shown contrasting results. In the Rotterdam Study, a single-center, population-based cohort study of 7983 subjects aged 55 years and older, the association between atherosclerosis and antithrombin was evaluated. The ratio of ankle to arm blood pressure is a graded marker for atherosclerosis and provides the opportunity to investigate nonlinear associations. In the first 1427 participants of the Rotterdam Study who did not use anticoagulants, both antithrombin and the ratio of ankle to arm blood pressure were measured. In men the association between the two was quadratic: antithrombin activity was increased in men with moderate peripheral arterial atherosclerosis compared with those without, and in men with more severe atherosclerosis it was decreased. In women the association was linear: a decreased ratio of ankle to arm pressure was associated with increased antithrombin activity. These associations were independent of smoking, body mass index, serum lipids, fibrinogen, and factor VIIc. We propose that antithrombin activity rises in response to increased risk of cardiovascular disease and also in response to the presence of atherosclerosis, whereas antithrombin may decrease with increasing severity of the atherosclerotic process in men. This may explain the contrasting results found in previous studies. Changes in antithrombin over time might be useful in predicting the risk of cardiovascular disease and progression.
Key Words: hemostasis • cardiovascular disease • risk • coagulation
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Introduction |
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An increase in procoagulatory factors has been associated with cardiovascular disease.1 2 Antithrombin is a potent inhibitor of coagulation. Familial deficiency of antithrombin increases the risk of venous thrombosis3 4 5 and possibly of arterial thrombosis.6 7 However, studies of the relation between antithrombin and arterial thrombosis have shown contrasting results. Both low8 9 and high10 11 12 activity levels of antithrombin have been associated with ischemic heart disease and stroke, whereas in subjects with an increased risk of cardiovascular disease (diabetes mellitus, postmenopausal women, hypercholesterolemic subjects, smokers), antithrombin activity was increased.9 13 14 15 16 In a longitudinal study among healthy men, cardiac mortality was higher in both the low and high tertiles of the antithrombin distribution compared with the middle tertile.17 In a longitudinal study of men and women with preexisting coronary, cerebral, or peripheral arterial disease, occurrence of cardiovascular events tended to be reduced in the highest quintiles of the antithrombin distribution.18 We examined the nature of the association of antithrombin activity with atherosclerosis to explore some of the discrepant previous observations.
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Methods |
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Population
The Rotterdam Study is a cohort study of subjects aged 55 years and older. Between March 1990 and July 1993, all residents of a suburb of Rotterdam were invited to participate in the study, which was approved by the Medical Ethics Committee of Erasmus University.19 Written consent was obtained from all participants. The response rate was 78%, and 7983 men and women participated in the study. The rationale of the study has been described elsewhere. In short, the Rotterdam Study aims to clarify the determinants of chronic disabling disease in the aging population. For cardiovascular disease, the study focuses on the contribution of thrombogenic factors to atherosclerotic disease and on the presence and progression of atherosclerosis and its determinants.
Measurements
Information on current health status, medical history (including myocardial infarction and stroke), drug use, and smoking was obtained with a computerized questionnaire, which included the Dutch version of the Rose questionnaire for angina pectoris and intermittent claudication.20 Height and weight were measured, and body mass index (in kilograms per meter squared) was calculated. Sitting blood pressure was measured in the right upper arm with a random zero sphygmomanometer; the average of two measurements was used. Systolic blood pressure at the ankles (posterior tibial artery) was measured with the patient in a half-lying (±45°) position with the use of a regular cuff just above the malleoli and an 8-MHz Doppler transducer.21 The ankle-arm index (AAI) is the ratio of the ankle systolic blood pressure to the arm systolic blood pressure. Participants were categorized according to the lowest of the left or right AAI. Blood handling has been described previously.22 Antithrombin activity was determined by a chromogenic method as heparin cofactor (Coatest, Chromogenix). Factor VII activity was determined with Thromborel S (Hoechst-Behring) as reagent, a sensitive thromboplastin preparation from human placenta and factor VII-deficient plasma. Fibrinogen was measured as derived fibrinogen of the prothrombin time assay with Thromborel S as reagent on an Automated Coagulation Laboratory system (ACL 300, Instrumentation Laboratory).23 Serum total cholesterol was determined with an automated enzymatic procedure.24 HDL cholesterol concentration was derived similarly after precipitation according to the phosphotungstate method,25 with a minor modification as described by Grove.26
Data Analysis
The present study was based on information of the first 1656 subjects who visited the research center. Subjects in whom measurement of AAI was missing (n=140) and those using anticoagulant drugs (n=89) were excluded from the analysis. The number of people on whom final analyses were performed was 1427. The association of antithrombin with AAI and with each cardiovascular risk factor was evaluated with simple and multiple linear regression analyses. The quadratic association was evaluated by linear regression analysis of antithrombin in relation to AAI combined with AAI squared. ANCOVA was used to estimate mean antithrombin activity in groups with increasing AAI. When appropriate, adjustments were made for age and sex.
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Results |
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Baseline characteristics of the study population are presented in Table 1
. Antithrombin activity ranged from 49% to 161%, with a mean of 108% (SD, 16%). Antithrombin activity below 75% was found in 44 subjects (3.1%). Women had a higher mean level of antithrombin activity than men, at 110% (SE, 0.5) and 105% (SE, 0.7), respectively (P<.01). For men and women mean antithrombin activity decreased with age, at 4% (SE, 0.8; P<.01) and 3% (SE, 0.6; P<.01) per decade, respectively (Fig 1).
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Mean antithrombin activity levels (adjusted for age) in men and women across groups of AAI are shown in Fig 2. In men, the association between antithrombin and AAI was quadratic; regression coefficients for antithrombin (expressed as a percentage) in relation to AAI (per 0.1 increase) and AAI squared were 3.0 (SE, 1.5; P=.04) and -1.7 (SE, 0.7; P=.02), respectively. In women, a linear association between antithrombin and AAI was observed. A decrease in AAI of 0.1 was associated with an increase of antithrombin of 0.7% (SE, 0.3; P=.01). When the square of AAI was added to the model, regression coefficients for antithrombin (percentage) in relation to AAI (per 0.1 increase) and AAI2 were 0.7 (SE, 1.1; P=.53) and -0.8 (SE, 0.6; P=.19), respectively. In men and women, antithrombin was linearly associated with serum total cholesterol, factor VIIc, fibrinogen, and smoking (Table 2). Antithrombin was not related to HDL cholesterol, body mass index, or systolic or diastolic blood pressure. Additional adjustment for smoking, body mass index, serum lipids, fibrinogen, and factor VIIc did not substantially change the association between antithrombin and AAI. Subjects with a history of myocardial infarction (n=129) or stroke (n=67) and those free of symptomatic cardiovascular disease had similar antithrombin levels: 109% (SE, 1.4), 112% (SE, 2.0), and 108% (SE, 0.4), respectively.
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Discussion |
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We found a quadratic association between antithrombin and atherosclerosis in men. Antithrombin activity was higher in men with moderate peripheral arterial atherosclerosis, compared with those without. In men with more severe atherosclerosis, antithrombin activity showed no further increase and if anything, it is decreased. In women, antithrombin increased with decreasing AAI. The present study was based on a large population-based cohort of men and women aged 55 years and older. Response rates were high in the study, the subgroup on whom the present study was based consisted of the first subjects who visited the research center for whom AAI data were available. Laboratory analyses were performed in a blinded manner.
The AAI is a reliable measure of the presence and severity of atherosclerosis, and a low AAI is strongly related to atherosclerotic abnormalities in other vascular beds.27 Moreover, a low AAI is a strong predictor of cardiovascular disease and all-cause mortality,28 29 and shows an inverse dose-response relation with risk factors for cardiovascular disease.30 The AAI provides a graded marker for arterial lesions, which enables investigation of nonlinear associations.
We found no difference in antithrombin activity between those with a history of myocardial infarction or stroke and those without such a history. Earlier findings on the association between antithrombin and cardiovascular disease are conflicting: low31 and high32 levels of antithrombin activity have been associated with its presence. To compare subjects with cardiovascular disease with subjects free of symptomatic disease may indeed give conflicting results if the association under study is not linear. We therefore used AAI as a marker for atherosclerosis rather than focusing on the presence or absence of a positive history of cardiovascular disease.
Our findings on the association between antithrombin activity and AAI may explain discrepant results reported from other studies. In the Northwick Park Heart Study, a population of men initially free of clinically manifest ischemic heart disease, higher ischemic heart disease mortality in the highest and lowest tertiles of antithrombin was observed.16 17 This suggests that in asymptomatic subjects both high and low levels of antithrombin activity indicate an increased risk of cardiovascular events. In the Progreto Lombardi Aterotrombosi (PLAT) Study population, 953 subjects with preexisting coronary, cerebral, or peripheral ischemic disease, a higher although not significant incidence of cardiovascular events in the lowest fifths of antithrombin activity was found.18 Furthermore, the mean level of antithrombin activity was lower in those with peripheral arterial disease who subsequently developed atherothrombotic events.33 The PLAT findings suggest that in patients with symptomatic cardiovascular disease a low level of antithrombin activity reflects an increased risk of subsequent cardiovascular thrombotic events. When we combine results from the PLAT Study, the Northwick Park Heart Study, and our study, a possible explanation is that subjects with active atherosclerosis have increased levels of antithrombin as a result of a protective mechanism against procoagulatory influences. In contrast, in cases of severe atherosclerosis the capacity of the defense mechanism is limited and antithrombin is not increased further. Rather, a decrease may follow increased consumption of antithrombin in subclinical thrombotic processes. The increased consumption of antithrombin might lower circulating antithrombin despite its increased production, as has been recognized in other conditions.34 Consequently, increased as well as decreased levels of antithrombin may indicate increased risk and vascular damage. Except for our findings at AAI levels below 0.6 women showed a similar pattern for the association between AAI and antithrombin (Fig 2
). Nevertheless, in linear regression analyses the association between the two is linear, which may support the theory that the association between antithrombin and peripheral atherosclerosis is modified by sex. Further studies are needed to clarify this possible difference.
Antithrombin activity was influenced by age and sex. Men had lower values than women, and in both men and women antithrombin decreased with age. Previous investigations have not agreed on the correlation of antithrombin with age and sex. Several previous studies did not demonstrate age- or sex-related differences,35 but others did.36 In the Atherosclerosis Risk in Communities (ARIC) Study, antithrombin also decreased with age in men but, in contrast to our findings, increased with age in women.16 The women included in the ARIC Study were aged 45 to 65 years, and this age difference could explain why antithrombin rose with age in the ARIC Study and fell in the women in our study.
In conclusion, our findings suggest that increased cardiovascular disease risk is associated with increased levels of antithrombin. Likewise, antithrombin increases in response to the atherosclerotic process but with increasing severity of the disease antithrombin tends to decrease. Such changes may reflect a protective mechanism in response to atherosclerosis combined with an increased consumption in proportion to its severity. Changes in antithrombin over time might be useful in predicting the risk of cardiovascular disease and the progression of atherosclerosis.
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Acknowledgments |
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The present study was supported by grant 92.398 from the Netherlands Heart Foundation. The Rotterdam Study is supported in part by the NESTOR program for geriatric research (Ministry of Health and Ministry of Education), the Netherlands Heart Foundation, the Netherlands Organization for Scientific Research (NWO), the Rotterdam Medical Research Foundation (ROMERES), and the Municipality of Rotterdam. We are grateful to the participants of the Rotterdam Study. We thank all field workers and laboratory technicians in the Ommoord Research center for their enthusiasm and skillful contributions to the data collection. The comments on the manuscript by Drs Stephen Lock and Jan Jaques Michiels are highly appreciated.
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Footnotes |
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Phone: +31-10-4087489, fax 31-10-4365933
Received June 14, 1995;
revision received February 5, 1996;
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References |
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1. Meade TW, Broznovic M, Chakrabarti RR, Haines AP, Imeson JD, Mellow S, Miller GJ, North WRS, Stirling Y, Thompson SG. Haemostatic function and ischemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986;2:533-537.[Medline] [Order article via Infotrieve]
2. Wilhelmsen L, Svardsudd K, Korsan-Bengsten K, Larsson B, Welin L, Libblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311:501-505.[Abstract]
3. Michiels JJ, van Vliet HHDM. Hereditary antithrombin III deficiency and venous thrombosis. Neth J Med. 1984;27:226-232.[Medline] [Order article via Infotrieve]
4. Lane DA, Olds RJ, Boisclair M, Chowdhury V, Thein SL, Cooper DN, Blajchman M, Perry D, Emmerich J, Aiach M. Antithrombin III mutation database: first update. Thromb Haemost. 1993;70:361-369.[Medline] [Order article via Infotrieve]
5. Perry DJ. Antithrombin and its inherited deficiencies. Blood Rev.. 1994;8:37-55.[Medline] [Order article via Infotrieve]
6. Johnson EJ, Prentice CR, Paoapia LA. Premature arterial disease associated with familial antithrombin III deficiency. Thromb Haemost. 1990;63:13-15.[Medline] [Order article via Infotrieve]
7.
Hart RG, Kanter MC. Hematologic disorders and ischemic stroke: a selective review. Stroke. 1990;21:1111-1121.
8. Banerjee R, Sahni A, Kumar V, Arya M. Antithrombin III deficiency in maturity onset diabetes mellitus and atherosclerosis. Thromb Diath Haemorrhag. 1974;31:339-345.
9.
ECAT Angina Pectoris Study Group. ECAT Angina Pectoris Study: baseline associations of hemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography. Eur Heart J. 1993;14:8-17.
10. Yue R, Gertler M, Starr T, Koutrouby R. Alterations of plasma antithrombin III levels in ischemic heart disease. Thromb Haemost. 1976;35:598-606.[Medline] [Order article via Infotrieve]
11. Wu KK, Folsom AR, Heiss G, Davies CE, Conlan MG, Barnes R, for the ARIC Investigators. Association of coagulation factors and inhibitors with carotid artery atherosclerosis: early results of the Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol. 1992;2:471-480.[Medline] [Order article via Infotrieve]
12. Meade TW. The epidemiology of atheroma, thrombosis and ischemic heart disease. In: Bloom AL, Forbes CD, Thomas DP, Tuddenham EGD, eds. Haemostasis and Thrombosis. Edinburgh, UK: Churchill Livingstone; 1994:1199-1227.
13. Meilahn EN, Lewis HK, Kuller LH, Matthews KA, Kiss JE. Hemostatic factors according to menopausal status and use of hormone replacement therapy. Ann Epidemiol. 1992;2:445-455.[Medline] [Order article via Infotrieve]
14. Fuller JH, Keen H, Jarret RJ. Hemostatic variables associated with diabetes and its complications. BMJ. 1979;2:964-966.
15. Cortellaro M, Boschetti C, Cofrancesco E, Zanussi C, Catalano M, de Gaetano G, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, Della Volpe A, Polli E, and the PLAT Study Group. The PLAT Study: a multidisciplinary study of hemostatic function and conventional risk factors in vascular disease patients. Atherosclerosis. 1991;90:109-118.[Medline] [Order article via Infotrieve]
16. Conlan MG, Folsom AR, Finch A, Davis CE, Marcucci G, Sorli P, Wu KK. Antithrombin III: associations with age, race, sex and cardiovascular risk factors. Thromb Haemost. 1994;72:551-556.
17. Meade TW, Cooper J, Miller GJ, Howarth DJ, Stirling Y. Antithrombin III and arterial disease. Lancet. 1991:338:850-851.
18. Cortellaro M. Antithrombin III and arterial disease. Lancet. 1991;338:1525-1526.[Medline] [Order article via Infotrieve]
19. Hofman A, Grobbee DE, DeJong PTVM, Vanden Ouweland FA. Determinants of disease and disability in the elderly: the Rotterdam Study. Eur J Epidemiol. 1991;7:403-422.[Medline] [Order article via Infotrieve]
20. Rose GA, Blackburn H, Gillum RF, Prineas RJ. Cardiovascular Survey Methods. Geneva, Switzerland: World Health Organization; 1982.
21. Bots ML, van Swieten JC, Breteler MM, de Jong PTVM, van Gijn J, Hofman A, Grobbee DE. Cerebral white matter lesions and atherosclerosis in the Rotterdam Study. Lancet. 1993;341:1232-1237.[Medline] [Order article via Infotrieve]
22. van der Bom JG, Bots ML, de Bruijn AM, Hofman A, Grobbee DE. Measurement of ß-thromboglobulin in the elderly: findings from the Rotterdam Study. Fibrinolysis. 1994;8(suppl 2):157-159.
23. Rossi E, Mondonico P, Lombardi A, Preda L. Method for the determination of functional (clottable) fibrinogen by the new family of ACL coagulameters. Thromb Res. 1988;52:453-468.[Medline] [Order article via Infotrieve]
24. Vangent CM, Vandervoort HA, De Bruijn AM. Cholesterol determinations: a comparative study of methods with special reference to enzymatic procedures. Clin Chem Acta. 1977;75:243-251.[Medline] [Order article via Infotrieve]
25. Bernstein M, Scholnick HR, Morfin R. Rapid method for the isolation of lipoproteins from human serum by precipitation with polyanions. J Lipid Res. 1970;11:583-595.[Abstract]
26. Grove TH. Effect of reagent pH on determination of high-density lipoprotein cholesterol by precipitation with sodium phosphotungstate-magnesium. Clin Chim Acta. 1979;25:560-564.
27.
Newman AB, Siscovick DS, Manolio TA, Polak J, Fried LP, Borhani NO, Wolfson SK. Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Circulation. 1993;88:837-845.
28. Criqui MH, Langer RD, Fronek A, Feigelson HS, Klauber MR, McCann TJ, Browner D. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. 1992;326:381-386.[Abstract]
29. Banerjee AK, Pearsons J, Gilliland EL, Goss D, Lewis JD, Stirling Y, Meade TW. A six year prospective study of fibrinogen and other risk factors associated with mortality in stable claudicants. Thromb Haemost. 1992;68:261-263.[Medline] [Order article via Infotrieve]
30.
Fowkes FGR. The measurement of atherosclerotic peripheral arterial disease in epidemiologic surveys. Int J Epidemiol. 1988;17:248-254.
31. Innerfield I, Goldfischer JD, Reicher Reiss H, Greenberg J. Serum antithrombin in coronary artery disease. Am J Clin Pathol. 1976;64:64-68.
32.
Folsom A, Wu KK, Shahar E, Davies CE for the Atherosclerosis Risk in Communities (ARIC) Study Investigators. Association of hemostatic variables with prevalent cardiovascular disease and asymptomatic carotid artery atherosclerosis. Arterioscler Thromb. 1993;13:1829-1836.
33.
Cortellaro M, Boschetti C, Cofrancesco E, Zanussi C, Catalano M, de Gaetano G, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, della Volpe A, Polli E, and the PLAT Study Group. The PLAT Study: hemostatic function in relation to atherothrombotic ischemic events in vascular disease patients: principal results. Arterioscler Thromb. 1992;12:1063-1070.
34. Buller HR, ten Cate JW. Acquired antithrombin III deficiency: laboratory diagnosis, incidence, clinical implications, and treatment with antithrombin III concentrate. Am J Med. 1989;87(suppl 3B):44S-48S.
35.
Meade TW, North WRS, Chakrabarti R, Haines AP, Stirling Y. Population based distribution of haemostatic variables. Br Med Bull. 1977;33:283-288.
36. Tait RC, Walker ID, Islam SIAM, McCall F, Conkie JA, Mitchell R, Davidson JF. Influence of demographic factors on antithrombin III activity in a healthy population. Br J Haematol. 1993;84:476-480.[Medline] [Order article via Infotrieve]
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