C-Reactive Protein, Fibrin D-Dimer, and Incident Ischemic Heart Disease in the Speedwell Study

Abstract

Abstract-Plasma levels of C-reactive protein (CRP, a marker of the reactant plasma protein component of the inflammatory response) and of fibrin D-dimer (a marker of cross-linked fibrin turnover) have each been associated in recent studies with the risk of future ischemic heart disease (IHD). Previous experimental studies have shown that fibrin degradation products, including D-dimer, have effects on inflammatory processes and acute-phase protein responses. In the Speedwell Prospective Study, we therefore measured CRP and D-dimer levels in stored plasma samples from 1690 men aged 49 to 67 years who were followed-up for incident IHD for an average of 75Ϯ4 months (meanϮSD) and studied their associations with each other, with baseline and incident IHD, and with IHD risk factors. CRP and D-dimer levels were each associated with age, plasma fibrinogen, smoking habit, and baseline evidence of IHD. Key Words: C-reactive protein Ⅲ fibrin D-dimer Ⅲ ischemic heart disease C -reactive protein (CRP), a marker of the reactant plasma protein component of the inflammatory response, has been associated with the risk of future ischemic heart disease (IHD), not only among patients with stable and unstable angina 1,2 and high-risk subjects 3 but also among population samples of apparently healthy middle-aged men 4,5 and elderly men and women. 6 A recent meta-analysis 7 of these prospective studies found a combined risk ratio for IHD of 1.7 (95% confidence interval [CI], 1.4 to 2.1) for subjects in the top third of the distribution of CRP compared with the bottom third. There was no evidence of heterogeneity between these studies.Fibrin D-dimer, a marker of cross-linked fibrin turnover, has also been shown in recent studies to be associated with the risk of future IHD in persons with and without baseline evidence of vascular disease. 8 -16 Local fibrin formation and lysis are part of the inflammatory response, and fibrin degradation products, including D-dimer, have been shown to have diverse effects on inflammatory processes and acutephase responses, including neutrophil and monocyte activation; secretion of cytokines, including interleukin-6 and interleukin-1; and hepatic synthesis of acute-phase proteins, including fibrinogen and CRP. [17][18][19][20] We therefore hypothesized that (1) plasma levels of CRP and D-dimer and their associations with incident IHD in the general population might be linked; (2) linkage might result from focal, vessel wall-related fibrin formation and lysis and an inflammatory response associated with unstable atherosclerotic plaque activity 21,22 ; and (3) CRP and D-dimer might be related to IHD risk factors associated with thrombogenesis and inflammation, particularly cigarette smoking. We are unaware of previously published studies of CRP and D-dimer considered jointly. We tested these hypotheses by studying the mutual relationships of CRP, D-dimer, incident IHD, and risk factors (especially smoking habit) in the middle-aged men of the Speedwell population cohort. Methods Study PopulationThe Speedwe...

Cell‐derived microparticles in synovial fluid from inflamed arthritic joints support coagulation exclusively via a factor VII–dependent mechanism

“…Platelet-derived microparticles transport arachidonic acid to endothelial cells and induce the expression of cyclooxygenase 2 and the increased production of prostacyclin (43), enhance the interaction between monocytes and endothelial cells (44), and enhance leukocyte aggregation and their accumulation on the endothelium (45). Furthermore, thrombin, factor Xa, and fibrin degradation products are all potent inducers of the inflammatory response (46)(47)(48)(49)(50). Hence, the presence of microparticles in synovial fluid may facilitate not only coagulation, but also inflammation via direct and indirect mechanisms.…”

C-Reactive Protein, Fibrin D-Dimer, and Risk of Ischemic Heart Disease

“…9 -11 We recently hypothesized that plasma levels of CRP and D-dimer and their associations with incident IHD in the general population might be linked, possibly caused by vessel wallrelated fibrin turnover producing D-dimer and other fibrin degradation products, which stimulate an inflammatory response including CRP. 6 In an analysis of stored plasma samples from 1690 men in the Speedwell Study of IHD risk, we observed that CRP was associated with D-dimer; both were associated with incident IHD after follow-up for 75Ϯ4 months; and that each blood measure reduced the strength of the association of the other blood measure with incident IHD. 6 We suggested that further larger studies were required to assess their relative predictive value.…”

“…6 In an analysis of stored plasma samples from 1690 men in the Speedwell Study of IHD risk, we observed that CRP was associated with D-dimer; both were associated with incident IHD after follow-up for 75Ϯ4 months; and that each blood measure reduced the strength of the association of the other blood measure with incident IHD. 6 We suggested that further larger studies were required to assess their relative predictive value. We therefore assayed CRP in stored plasma samples from the Caerphilly Study of IHD 12 (which shares a common protocol with the neighboring Speedwell Study) and report a combined analysis of CRP, D-dimer, and incident IHD in an extended follow-up (averaging 90 months) of the combined Caerphilly-Speedwell cohort, comprising 4453 men, of whom 473 had major IHD events.…”

“…Chronic infections (eg, Helicobacter pylori, Chlamydia pneumoniae) or plasma homocysteine concentrations are not strongly associated with circulating CRP levels. 1 Cigarette smoking and obesity [1][2][3][4][5][6] are associated with increased CRP levels, 1 whereas long-term treatment with pravastatin reduces CRP levels. 7 Fibrin D-dimer, a marker of cross-linked fibrin turnover, has also been associated with the risk of future IHD; a recent meta-analysis found a combined risk ratio for IHD by tertiles (after adjustment for other risk factors) of 1.8 (95% CI, 1.4 to 2.4).…”

Leukocyte myeloperoxidase activity and serum CRP levels as predictive markers of inflammatory disorders amongst Passive smokers

“…On the contrary, Helmersson et al have reported that although smoking status correlated with a significant elevation in levels of IL-6 and serum amyloid protein A, another acute phase protein, the increase in CRP levels observed in smokers was not found to be statistically significant 29 . A dose dependent correlation between CRP and smoking habits was demonstrated in the 'Speedwell' survey of British men with respect to CRP levels which increased proportionately with the increase in number of cigarettes smoked 30 .…”