Evolving Concepts in the Triad of Atherosclerosis, Inflammation and Thrombosis

Abstract

Recent developments into antherothrombosis, the leading cause of morbidity and mortality in Western Society, may help to change our treatment strategy to a more casual approach. The composition of the atherosclerotic plaque, rather than the percent stenosis, appears to be a critical predictor for both risk of plaque rupture and subsequent thrombogenicity. A large lipid core, rich in tissue factor (TF) and inflammatory cells including macrophages, and a thin fibrous cap with compromise of its structural integrity by matrix degrading enzymes, such as metalloproteinases (MMPs), render a lesion susceptible to rupture and subsequent acute thrombosis. Thrombosis may lead to a complete occlusion or, in the case of mural thrombus or intraplaque hemorrhage, to plaque progression. Disruption of a vulnerable or unstable plaque (type IV and Va lesions of the AHA classification) with a subsequent change in plaque geometry and thrombosis may result in an acute coronary syndrome. The high-risk plaque tend to be relatively small, but soft or vulnerable to "passive" disruption because of high lipid content. Inflammatory processes are important components of all stages of atherosclerotic development, including plaque initiation and disruption. As such the early steps in atherosclerotic lesion formation are the over expression of endothelial adhesive protein (i.e. selectins, VCAM and ICAM), chemotactic factors (MCP-1), growth factors (M-CSF), and cytokines (IL-2) that will facilitate the recruitment, internalization and survival of blood-borne inflammatory cells into the vascular wall. Macrophages, following what appears to be a defense mission by protecting the vessel wall from excess lipid accumulation, may eventually undergo apoptosis with release of MMPs and TF. Specific cell recruitment in the vessel wall and build-up of the extracellular matrix are coordinated by a wide variety of stimulators and inhibitors. Active interaction of immune competent cells within the atherosclerotic lesions appears to play a pivotal role in the control of atherosclerotic plaque evolution and, therefore, deserves particular attention from the research community with the ultimate goal of improving preventive and therapeutic medical approaches. Inflammation, thrombosis and atherosclerosis are interdependent and define a triad within the complex pathogenic process of atherothrombosis.

Thrombin induced connective tissue growth factor expression in rat vascular smooth muscle cells via the PAR-1/JNK/AP-1 pathway

“…Plaque disruption may result in mural thrombi. Such thrombi may be the main contributor of progression of atherosclerosis [28] . In our present study, we found that thrombin could induce CTGF expression in VSMCs.…”

Thrombophilia and Arteriovenous Fistula Survival in ESRD

“…The clinical consequences are also rather similar: insufficient maturation or a need for intervention or access abandonment. In fact, thrombosis, atherosclerosis, and inflammation form a pathogenic continuum in cardiovascular disease (15,16). Inflammatory mechanisms upregulate procoagulants, downregulate anticoagulants, and inhibit fibrinolysis, resulting in prothrombotic states (15)(16)(17).…”

“…In fact, thrombosis, atherosclerosis, and inflammation form a pathogenic continuum in cardiovascular disease (15,16). Inflammatory mechanisms upregulate procoagulants, downregulate anticoagulants, and inhibit fibrinolysis, resulting in prothrombotic states (15)(16)(17). Furthermore, acquired coagulation abnormalities (i.e., elevated factor VIII:C level, short thrombin time, and high fibrinogen and D-dimer levels) were frequent in our patients with ESRD (Table 3) and failed to differentiate problems in access thrombosis or stenosis.…”

Collagens in the progression and complications of atherosclerosis

“…Plaque rupture is thought to be responsible for the majority of acute coronary syndromes, which in turn are the major causes of morbidity and mortality in coronary artery disease. 87,88 MMPs secreted by macrophages and SMCs in the shoulder regions of the plaque degrade collagens in the fibrous cap rendering the plaque vulnerable to rupture. [89][90][91][92] Fibrillar collagen monomers are cleaved into fragments that are ¼ and ¾ of the length of the native full-length molecules following cleavage at a bond between glycine and isoleucine by the collagenases (MMPs 1, 8, and 13).…”