Platelet Focus with Paul Gurbel, MD: Inflammation, Platelets, and Thrombosis
The complex interplay between platelet function, coagulation, and inflammation strongly influences the development of atherothrombosis. The progression of a stable plaque to a vulnerable plaque—leading to occlusive thrombus generation—is a discontinuous and unpredictable process. Transition from the asymptomatic disease state to the sudden occurrence of MI may be preceded by increased inflammation and the development of blood vulnerability, characterized by measurements of heightened platelet function and hypercoagulability. A major goal in the prevention of acute thrombotic complications is pinpointing the mechanisms responsible for the transition from an asymptomatic disease state to an unstable disease state, thus enabling the identification of the "thrombogenic" phenotype.1 Research has identified one such culprit: systemic and local inflammation have been strongly implicated in the initiation, progression, and vulnerability of an atherosclerotic plaque.
CRP: A Marker and Active Participant in Inflammation
Various prospective studies have established that C-reactive protein (CRP) is an important systemic inflammation marker predictive of future MI and stroke. Elevated CRP has been associated with CAD risk in a generally healthy population with an odds ratio of 1.45, and data from 25 prospective cohort studies in subjects with and without documented heart disease have indicated that high sensitivity (hs)-CRP concentrations are independently associated with the future risk of CV events.2,3
In addition to being a marker, CRP has been identified as an active participant in the development of atherothrombosis. Results from in vitro studies suggest a direct influence of CRP on endothelial and platelet function, and it has been reported that CRP enhances procoagulant activity by stimulating tissue factor release and reducing fibrinolysis.1 In autopsy studies, atherosclerotic, but not normal, arteries demonstrated CRP immune reactivity.4,5 Levels of CRP in fibrous tissue and atheroma of atherectomy specimens were also higher in patients with unstable angina and MI, compared to those with stable angina.6
CRP is an important regulator of endothelial cell activation; it up-regulates the surface expression of pro-inflammatory adhesion molecules, such as intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin, in addition to tissue factor (TF) on endothelial cells, vascular smooth muscle cells, and monocytes. By inducing the adhesion of platelets and monocytes to endothelial cells, and monocyte chemoattractant protein-1 from monocytes, CRP also promotes atherothrombotic processes. Finally, inhibition of nitric oxide, prostaglandin, and plasminogen activator inhibitor type release may also contribute to the prothrombotic actions of CRP.
Two important mechanisms for these prothombotic effects have been attributed to the binding of monomeric CRP, which results from the conformational rearrangement of native CRP to FcRg receptors and complement protein.7 Hypercoagulability is strongly associated with CRP, as determined by high thrombin-induced platelet-fibrin clot strength measured at different stages of CAD. CRP has also been shown to play a supporting role in plaque instability and subsequent thrombotic complications.1
Other Measures of Inflammation and Thrombotic Risk CRP is a major player in inflammation, but other markers, like elevated CD40 ligand (CD40L), selected interleukins (ILs), tumor necrosis factors (TNFs), and adhesion molecules, have also been associated with ischemic event occurrences.
The CD40L expressed on activated platelets has been shown to activate endothelial cells and promote the release of IL-6, IL-8, and TF—all of which play different roles in atherothrombosis generation. IL-6 is an important procoagulant cytokine, whereas IL-8 is a pivotal molecule influencing leukocyte recruitment. IL-6 has been shown not only to increase platelet reactivity but is also associated with elevated plasma concentrations of fibrinogen and CRP.
In patients undergoing stenting, the highest quartile of thrombin-induced platelet-fibrin clot strength was associated with greater levels of adenosine diphosphate (ADP)-induced platelet aggregation, CRP, epidermal growth factor, vascular endothelial growth factor, and IL-8. As expected, highest-quartile patients also had significantly greater 2-year ischemic event occurrence than patients in the lowest quartile of thrombin-induced platelet-fibrin clot strength. These data suggest a link between inflammation and heightened thrombogenicity identified pre-procedurally; post-stenting, patients with heightened thrombogenicity are at a significantly higher risk for recurrent ischemic events.8
In a study of symptomatic CAD patients undergoing PCI, a correlation was observed between plasma levels of inflammation markers (IL-6, RANTES, and CRP) and ADP- and arachidonic acid (AA)-induced aggregation. High baseline CRP and high on-treatment platelet reactivity were independent predictors for combined major events and stent thrombosis after multivariate adjustment.9 Furthermore, a significant association between IL-10, IF-g, IL-4, and AA- and ADP-induced platelet aggregation in acute coronary syndrome patients undergoing PCI on dual antiplatelet therapy was demonstrated after adjustment for age, sex, CV risk factors, ejection fraction, body mass index, von Willebrand factor (vWF), and CRP.10
The Role of Inflammation in the Progression of CAD
More rapid progression of CAD has been associated with elevated levels of matrix metalloproteinase (MMP)-9, whereas other studies have demonstrated that MMP-2 and MMP-9 are involved in various acute complications of CVD. Other MMPs are associated with plaque destabilization, as well as vascular remodeling, by collagen metabolism in the fibrous cap. Moreover, patients undergoing elective PCI for stable angina exhibit a specific biomarker fingerprint, characterized by elevated levels of MMPs that differ significantly from patients with long-term quiescent disease. In addition to increased MMP levels, increased tissue inhibitor of metalloproteinase (TIMP)-1 and α2-macroglobulin levels were also found in symptomatic patients compared to asymptomatic patients, suggesting the presence of an active counterbalancing mechanism in patients undergoing stenting.11
Hypercoagulability—characterized by elevated levels of fibrinogen, D-dimer, vWF, and tissue plasminogen activator inhibitor—have also been linked to CAD progression. Research has suggested a distinct stepwise increment in hypercoagulability (determined by thrombin-induced platelet-fibrin clot strength) among levels of CAD progression. A strong correlation between thrombin-induced platelet-fibrin clot strength and other prothrombotic markers, inflammation markers, and CRP has also been demonstrated at different levels of CAD acuity.
The demonstration of significant correlations between markers of inflammation, platelet function, and hypercoagulability strengthens the hypothesis that crosstalk among these processes plays an important role in the development of progressive and unstable CAD.1 These observations may provide a foundation for future larger investigations to identify high-risk patients based on a specific biomarker profile, which could include the assessment of platelet reactivity, coagulation, and inflammation. Serial implementation of such a combination biomarker analysis may facilitate early intervention with a personalized therapeutic strategy.
1. Tantry US, et al. Platelets. 2010;21:360-7.
2. Ridker PM. J Am Coll Cardiol. 2007;49:2129-38.
3. Ridker PM. Clin Chem. 2008;54:234-7.
4. Kreutz RP et al. J Thromb Haemost. 2005 ;3:2108-9.
5. Kreutz RP, et al. Blood Coagul Fibrinolysis. 2007;18:713-8.
6. Norja S et al. J Clin Pathol. 2007;60:545–548.
7. Gurbel PA et al. CRP and its role in coronary heart disease: New research developments. In: C-Reactive Protein. Satoshi Nagasawa. (editor), Nova Science Publications Inc., Hauppauge, New York, pp. 39-41, 2009.
8. Gurbel PA et al. Platelets. 2009;20:97-104.
9. Müller K et al. Atherosclerosis. 2010;213:256-62.
10. Gori AM et al. Atherosclerosis. 2009;202:255-62.
11. Gurbel PA et al. Am Heart J. 2008;155:56-61.
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