Haemostatic and Inflammatory Markers in the Prediction of Cardiovascular Disease

Login or register to view PDF.
DOI
http://dx.doi.org/10.15420/ecr.2006.0.2.1s

Clinicians and pathologists have long recognised the role of the haemostatic system in acute coronary and cerebral thrombosis, and anti-platelet, anticoagulant and fibrinolytic therapies are well established in clinical practice. Pathologists have suggested for several decades that 'hypercoagulabilityÔÇÖ contributes to the development of atheroma,1 plaque formation and rupture.2,3 Pioneering epidemiological studies suggested that markers of haemostasis as well as inflammation, such as fibrinogen,4,5 white-cell count,6 viscosity7 and C-reactive protein (CRP)8 are associated with risk of cardiovascular disease (CVD), and may have a role in both pathogenesis, and in long-term risk prediction. Low-grade inflammation is present in arterial plaques and may play a role in plaque rupture.8

The risk of a cardiovascular event has also been linked to the 'acute-phase responseÔÇÖ, the acute inflammatory and immunological response to infection. In a large case-series, based in a national primary care database, a first myocardial infarction (MI) and stroke were each more common following recent respiratory or urinary tract infections (UTIs), (relative risks (RRs) 5.0 and 3.2 for MI and stroke, respectively). The risk was greatest within the first three days after diagnosis and fell during the following weeks.9 Hence, the roles of both acute, high-grade; and chronic, low-grade inflammation in the pathogenesis of CVD (which may be reduced by preventive or therapeutic interventions), and the evaluation of suitable haemostatic and inflammatory biomarkers, are growing research topics. Table 1 summarises meta-analyses of individual risk markers that have been examined in prospective epidemiological studies to date.10-17

Table 1 shows the odds of a coronary heart disease (CHD) event in a person with a value for each risk marker in the upper third of the population distribution compared with that of someone with a value in the lower third of the distribution. However, adjustment for classical risk factors and other confounders varies from publication to publication, and direct comparisons between the size of the association (odds ratio) cannot be made reliably between these studies.

Haemostatic Markers

Fibrinogen is the most studied haemostatic marker. A recent meta-analysis of individual participant data10 observed strong associations with risk of CHD, stroke and other cardiovascular death. However, large-scale studies of functional genetic variants that affect fibrinogen levels, suggest that these associations may not be directly causal.18 Furthermore, fibrinogen is also associated with risk of non-cardiovascular death, which suggests that its association with CVD is not specific.10

Fibrin D-dimer appears a clinically useful marker of coagulation activation. D-dimer assay is already widely used in clinical practice to rule out clinically suspected deep venous thrombosis and pulmonary embolism, since normal levels have a high negative predictive value for these conditions.19 Clinical and epidemiological studies have linked D-dimer levels with atrial fibrillation and the risk of CHD or stroke,14,20-22 and it has been suggested that D-dimer levels might be used in clinical practice to evaluate the need for oral anticoagulants in patients with atrial fibrillation.22 Two common genetic thrombophilias (the factor V Leiden and prothrombin G20120A mutations), which are associated with increased coagulation activation and with increased risk of venous thromboembolism (RR 2-4),23 have recently also been associated with risk of CHD (RR 1.2-1.4).17

A marker of fibrinolysis, tissue plasminogen activator, (t-PA) shows modest associations with risk of CHD, although the association is attenuated when adjustment is made for classical risk factors, e.g. lipids.13 Associations between von Willebrand factor (vWF) and CHD are also modest.11

The evidence that functional polymorphisms for t-PA, vWF, coagulation factor VII, or plasminogen activator inhibitor type-1 (PAI-1) either promote or reduce hypercoagulability is inconclusive.17,23 Rare genetic variants of homocysteine are closely associated with premature thrombotic disorders, and homocysteine has been reported as a possible modest independent risk factor for cardiovascular risk.16 A strong synergistic association between homocysteine and smoking habit has been reported.24

Inflammatory Markers

Numerous markers of either acute or chronic inflammation can be detected in blood. Haematological inflammatory markers that have been linked to the risk of CHD include white-cell count, erythrocyte sedimentation rate (ESR) and plasma viscosity : these are also correlated with each other and also with fibrinogen.25 Biochemical products of inflammation, such as CRP and low albumin, are produced as a result of the activity of pro-inflammatory cytokines, such as interleukin-6 and interleukin-18, which have each been linked with risk of CHD.26,27 Again, these markers are correlated with each other and with haematological markers of inflammation, and also with other unmeasured factors; hence the process of establishing primary causality for individual markers requires further basic scientific research.

Can Haemostatic/inflammatory Markers Improve Cardiovascular Risk Prediction in Clinical Practice?

Several well-established epidemiological studies have reported that the addition of haemostatic or inflammatory markers can improve risk prediction of CVD.28-30 Particular interest has focussed on CRP,11 but a range of markers has been proposed from other studies.29,30

A recent report in the US proposed that CRP should be an 'optionÔÇÖ in predicting CHD risk,31 but this proposal has been questioned both in the US32-35 and in Europe.23,36

Incorporation of CRP and other emerging risk factors into routine practice for prediction of cardiovascular risk may be premature, therefore, and criteria for the rigorous evaluation of such factors have been proposed.37 These criteria include: applicability to all relevant clinical cardiovascular events; ability to predict in short-, intermediate- and long-term follow-up; standardised measurements; examination of variability; the degree of correlation with established risk factors; and improvement in overall prediction, among other criteria.

Current investigation of determinants of inflammatory markers, which include physical activity,38 dietary factors,39 alcohol40 and weightloss41 as protective factors, and infections that promote periodontitis (a potentially treatable risk factor),42 encourage the detailed examination of these biomarkers in future research. Ôûá

References
  1. Duguid JB, Thrombosis as a factor in the pathogenesis of aortic atherosclerosis, J Pathol and Bacteriol (1948);60: pp. 57-61.
    Crossref | PubMed
  2. Davies MJ, Thomas A, Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death, N Engl J Med (1984);310: pp. 1137-1140.
    Crossref | PubMed
  3. Falk E, Unstable angina with fatal outcome: Dynamic coronary thrombosis leading to infarction and/or sudden death, Circulation (1985);71: pp. 699-708.
    Crossref | PubMed
  4. Meade TW, Chakrabarti R, Haines et al., Haemostatic function and cardiovascular death: early results of a prospective study, Lancet (1980);i: pp. 1050-1054.
    Crossref | PubMed
  5. Wilhelmsen L, Svardsudd K, Korsan-Bengsten K, et al., Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med (1984);311: pp. 501-505.
    Crossref | PubMed
  6. Sweetnam PM, Thomas HF, Yarnell JWG, et al., Total and differential leukocyte counts as predictors of ischemic heart disease: The Caerphilly and Speedwell Studies, Am J Epidemiol (1997);145: pp. 416-421.
    Crossref | PubMed
  7. Lowe GDO, Rumley A, Norrie J, et al., on behalf of the West of Scotland Coronary Prevention Group, Blood rheology, cardiovascular risk factors, and cardiovascular disease: the West of Scotland Coronary Prevention Study, Thrombosis and Haemostasis (2000);84: pp. 553-558.
  8. Libby P, Ridker PM, Maseri A, Inflammation and Atherosclerosis , Circulation (2002);105: pp. 1135-1143.
    Crossref | PubMed
  9. Smeeth L, Thomas SL, Hall AJ, et al., Risk of Myocardial Infarction and Stroke after Acute Infection or Vaccination, N Engl J Med (2004);351: pp. 2611-2618.
    Crossref | PubMed
  10. Fibrinogen Studies Collaboration, Plasma Fibrinogen Level and the Risk of Major Cardiovascular Diseases and Nonvascular Mortality: An Individual Participant Meta-analysis, JAMA (2005);294: pp. 1799-1809.
    Crossref | PubMed
  11. Danesh J, Wheeler JG, Hirschfield GM, et al., C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease, N Engl J Med (2004);350: pp. 1387-1397.
    Crossref | PubMed
  12. Danesh J, Collins R, Appleby P, Peto R, Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease. Meta-analyses of prospective studies, JAMA (1998);279: pp. 1477-1482.
    Crossref | PubMed
  13. Lowe GDO, Danesh J, Lewington S, et al., Tissue plasminogen activator antigen and coronary heart disease: prospective study and meta-analysis, European Heart Journal (2004);25: pp. 252-259.
    Crossref | PubMed
  14. Danesh J, Whincup P, Walker M, et al., Fibrin D-dimer and coronary heart disease: prospective study and metaanalysis, Circulation (2001);103: pp. 2323-2327.
    Crossref | PubMed
  15. Danesh J, Collins R, Peto R, Lowe GDO, Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease, European Heart Journal (2000);21: pp. 515-520.
    Crossref | PubMed
  16. Homocysteine Studies Collaboration, Homocysteine and risk of ischemic heart disease and stroke. A meta-analysis. JAMA (2002);288: pp. 2015-2022.
    Crossref | PubMed
  17. Ye Z, Liu EHC, Higgins JPT, et al., Seven haemostatic polymorphisms and coronary disease: a meta analysis comprising 66155 cases and 91307 controls, Lancet (2006);367: pp. 651-658.
    Crossref | PubMed
  18. Davey Smith G, Harbord R, Milton J, et al., Does elevated plasma fibrinogen increase the risk of coronary heart disease? Evidence from a meta-analyses of genetic association studies, Arteriosclerosis, Thrombosis and Vascular Biology (2005);25: pp. 2228-2233.
    Crossref
  19. Palareti G, de Moerloose P (eds), Fibrin D-dimer testing for venous and arterial thrombotic disease, Seminars in Vascular Medicine (2005);5: pp. 309-398.
  20. Lip GYH, Zafiris J, Watson RDS, et al., Fibrin D-dimer and (-thromboglobulin as markers of thrombogenesis and platelet activation in atrial fibrillation. Effects of introducing ultra-low-dose warfarin and aspirin, Circulation (1996);94: pp. 425-431.
    Crossref | PubMed
  21. Lowe GDO, Fibrin D-dimer and cardiovascular risk, Seminars in Vascular Medicine (2005);5: pp. 387-398.
    Crossref | PubMed
  22. Lip GYH, Lowe GDO, Rumley A, Dunn FG, Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment, Br Heart J (1995);73: pp. 527-533.
    Crossref | PubMed
  23. Lowe GDO, Can haematological tests predict cardiovascular risk? The 2005 Kettle Lecture, Br J Haematol (2006); 133: pp. 232-250.
    Crossref | PubMed
  24. O'Callaghan P, Meleady R, Fitzgerald T, Graham I and the European COMAC group, Smoking and plasma homocysteine, Eur Heart J (2002);23: pp. 1580-1586.
    Crossref | PubMed
  25. GDO Lowe, Blood rheology, haemostasis and vascular disease , In: AL Bloom, CD Forbes, DP Thomas & EGD Tuddenham (eds), Haemostasis and Thrombosis, 3rd edition (1994), Edinburgh: Churchill Livingstone: pp. 1169-1188.
  26. Ridker PM, Rifai N, Stampfer MJ, Hennekens CH, Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men, Circulation (2000);101: pp. 1767-1772.
    Crossref | PubMed
  27. Blankenberg S, Luc G, Ducimetière P, Evans AE, et al., on behalf of the PRIME Study Group, Interleukin-18 and the risk of coronary heart disease in European men (PRIME), Circulation (2003);108: pp. 2453-2459.
    Crossref | PubMed
  28. Ridker PM, Rifai N, Rose L, et al., Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events, N Engl J Med (2002);347: pp. 1557-1565.
    Crossref | PubMed
  29. St-Pierre AC, Cantin B, Bergeron J, et al., Inflammatory markers and long-term risk of ischemic heart disease in men. A 13-year follow-up of the Quebec Cardiovascular Study, Atherosclerosis (2005);182: pp. 315-321.
    Crossref | PubMed
  30. Smith A, Patterson C, Yarnell J, Rumley A, Ben-Shlomo Y, Lowe G, Which hemostatic markers add to the predictive value of conventional risk factors for coronary heart disease and ischemic stroke? The Caerphilly Study , Circulation (2005);112: pp. 3080-3087.
    Crossref | PubMed
  31. Pearson TA, Mensah GA, Alexander RW, et al., Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association, Circulation (2003);197: pp. 499-551.
    Crossref | PubMed
  32. Kushner I, Sehgal AR, Is high-sensitivity C-reactive protein an effective screening test for cardiovascular risk? , Arch Intern Med (2002);162: pp. 867-869.
    Crossref | PubMed
  33. Hackam DG, Anand SS, Emerging risk factors for atherosclerotic vascular disease. A critical review of the evidence. JAMA (2003);290: pp. 932-940.
    Crossref | PubMed
  34. Lloyd-Jones DM, Tian L, Predicting cardiovascular risk: so what do we do now? , Arch Intern Med (2006);166: pp. 1342-1344.
    Crossref | PubMed
  35. Folsom AR, Chambless LE, Ballantyne CM, et al., An assessment of incremental coronary risk prediction using Creactive protein and other novel risk markers: the Atherosclerosis Risk in Communities Study, Arch Intern Med (2006);166: pp. 1368-1373.
    Crossref | PubMed
  36. Lowe GDO, Circulating inflammatory markers and risks of cardiovascular and noncardiovascular disease, Journal of Thrombosis and Haemostasis (2005);3: pp. 1618-1627.
    Crossref | PubMed
  37. Wilson PWF, CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: Ability of Inflammatory Markers to Predict Disease in Asymptomatic Patients: A Background Paper, Circulation (2004);110: pp. 568-571.
    Crossref | PubMed
  38. Panagiotakos DB, Pitsavos C, Chrysohoou C, et al., The associations between leisure-time physical activity and inflammatory and coagulation markers related to cardiovascular disease: the ATTICA Study, Preventive Medicine (2005);40: pp. 432-437.
    Crossref | PubMed
  39. Pischon T, Hankinson SE, Hotamisligil GS, et al., Habitual dietary intake of n-3 and n-6 fatty acids in relation to inflammatory markers among US men and women, Circulation (2003);108: pp. 155-160.
    Crossref | PubMed
  40. Volpato S, Pahor M, Ferrucci L, et al., Relationship of alcohol intake with inflammatory markers and plasminogen activator inhibitor-1 in well-functioning older adults. The Health, Aging, and Body Composition Study, Circulation (2004);109: pp. 607-612.
    Crossref | PubMed
  41. Clifton PM, Keogh JB, Foster PR, Noakes M, Effect of weight loss on inflammatory and endothelial markers and FMD using two low-fat diets, Int J Obes (London) (2005);29: pp. 1445-1451.
    Crossref | PubMed
  42. Lowe GDO, Dental disease, coronary heart disease and stroke, and inflammatory markers: What are the associations and what do they mean?, Circulation (2004);109: pp. 1076-1078.
    Crossref | PubMed