Thrombosis and Inflammation in Acute Coronary Syndromes

Rupture of atherosclerotic plaques is a major cause of cardiovascular events, including acute coronary syndromes, myocardial infarction and stroke. Identification of the vulnerable plaques is one of the most important steps leading to the treatment of patients with the disease. In spite of a considerable effort in identifying patients with vulnerable plaque, including the use of both circulatory and imaging biomarkers to delineate the molecular, cellular, and structural components and/or evolution of atherosclerosis and plaque vulnerability, it still lacks of such a specific biomarker for this disease. This review will focus on recent advances on discovery of circulating markers in atherosclerosis and hope that some of these markers might be of values to assess vulnerable atheromatous plaques. It is hoped that these biomarkers may be able to facilitate disease diagnosis and the development of new therapeutics to treat vulnerable plaque and its consequence of cardiovascular diseases.

This chapter describes the structure-function relationship of tissue factor (TF) also known as coagulation factor III, tissue thromboplastin, and CD142. Tissue factor is a procoagulant transmembrane glycoprotein and is essential to life. This single chain protein belongs to a Cytokine Receptor Superfamily (CRS) with a Fibronectin Type III topology. Proteins of the CRS group are transmembrane receptor proteins and fibronectins have been implicated in numerous functions such as blood clotting, wound healing, metastasis, cell signaling and embryogenesis. Tissue factor initiates the extrinsic pathway of blood coagulation leading to thrombin generation and clot formation. In addition to its primary role in coagulation, TF has also been an important player in many biological processes. Tissue factor is expressed by cells of arteriosclerotic lesions associated with plaque rupture in the vasculature. In addition, calcium- and phosphorylation-dependent regulation of TF makes it an important molecule in signal transduction and cell-to-cell interactions in the vasculature. In oncology, TF has been described as a marker of cancer development and a prometastatic molecule. The numerous functions of TF contribute to its importance in human biology. Although presently it is most prominently known for its role in coagulation, evolutionary sequence homologies and similar structural topologies with fibronectins of the CRS proteins place TF in a much wider spectrum of functions.

Hemostasis is the physiological process of clot formation in a delicate balance in the human body after a vessel injury. That process represents primary and secondary haemostasis that includes platelets, coagulation proteins and finally terminates with fibrinolysis to prevent widespread clot formation.Coagulation cascade, endotelium, fibrin, fibrinolysis, hemostasis, plasminogen, platelets, primary hemostasis, secondary hemostasis, subendothelial matrix, tissue factor, vonWillebrand factor.

Venous thromboembolism (VTE) is a common and preventable disorder which mostly manifests as deep-vein thrombosis of the legs. The incidence of VTE is 1 to 2 cases per 1000 persons in developed countries. After the first episode of VTE risk of recurrence increases in these patients, the cumulative rate of recurrence is about 25% and 30% at 5 years and 10 years respectively. Independent predictors of late recurrence include increasing patient age and body mass index, leg paresis, active cancer and other persistent VTE risk factors such as idiopathic VTE, antiphospholipid antibody syndrome, antithrombin, protein C or protein S deficiency, hyperhomocysteinemia and a persistently increased plasma fibrin D-dimer. The most important point during evaluation of VTE is not to forget that it is a multi-factorial status and can be caused by interaction between the systems which should be investigated carefully.

Antiplatelet therapy is the keystone in secondary prevention of the patients with cardiovascular diseases. The efficacy of aspirin, clopidogrel and novel oral antiplatelets like prasugrel and ticagrelor in atherotrombotic events has been shown in several landmark clinical trials and meta-analyses. Nevertheless, a significant number of patients experience recurrent events despite antiplatelet therapy. Increasing evidence indicates that there is considerable variability in response to antiplatelet therapy among patients and those who have higher levels of platelet reactivity are at increased risk for recurrent ischaemic events. These findings raised the possibility that decreased response, or ‘resistance’ to oral antiplatelet drugs may underlie many subsequent major cardiovascular events (MACE). The main problem with ‘resistance’ is the lack of a clear definition. In this chapter, aspirin, clopidogrel and glycoprotein IIb/IIIa receptor inhibitor resistance in patients with acute coronary syndromes will be discussed by the concept of residual platelet activity.

Acute coronary syndrome (ACS) is associated with significant morbidity, mortality and it is a major public health problem. The primary pathophysiological mechanism of the ACS is the response to vascular injury such as atherosclerotic plaque rupture or endothelial monolayer erosion that triggers platelet activation and aggregation leading to platelet-rich thrombi. These platelet-rich thrombi impair blood flow and result in ischemia. Inhibition of platelet aggregation by medical treatment prevents formation and progression of thrombotic process. Antiplatelet therapy is indispensible in the early and long-term management of patients with ACS. Current platelet inhibitors are thromboxane inhibitors (aspirin), P2Y12 inhibitors (ticlopidine, clopidogrel, prasugrel, ticagrelor, cangrelor and elinogrel) and protease-activated receptor antagonists (vorapaxar and atopaxar). The aim of this chapter is to discuss anti platelet therapy in ACS.

Chronic kidney disease (CKD) and acute kidney injury (AKI) after acute coronary syndrome (ACS) are strong predictors of morbidity and mortality in patients with ACS. Patients with concomitant kidney and cardiovascular disease constitute a population that is difficult to treat. There are limited data since patients with CKD are usually excluded from cardiovascular studies. Benefits of antiplatelet and antihrombotic therapy must be balanced with risk of adverse events. Kidney function should routinely be evaluated in patients with ACS when such therapies administered. Medications should be used with caution in patients with kidney dysfunction and estimated glomerular filtration rate should be the essential measure used for dosage adjustments. Although additional data are required for evaluation of aspirin's benefit-to-risk ratio in this special population due to inconsistent findings in clinical trials, aspirin is the usual practice and recommended without dose adjustment. Unfractionated heparin, generally do not warrant specific dose adjustment in face of kidney dysfunction. Factor Xa inhibitors, low-molecular-weight heparins and direct thrombin inhibitors except argatroban are predominantly cleared by the kidneys. Reduced doses and frequent monitoring of anticoagulation are indicated when these agents are used in patients with kidney dysfunction. Dose adjustment is usually not required for clopidogrel, prasugrel and ticagrelor in patients with renal impairment. In contrast to abciximab, both eptifibatide and tirofiban are largely eliminated via renal excretion thus, careful dose tailoring is warranted among patients with kidney disease.

Coronary artery disease is the cause of 20% of deaths worldwide, increasing up to 50% in developed countries. Atherosclerosis is a multifactorial disease that is strongly affected by inborn and acquired risk factors. It has predisposing factors such as hypercholesterolemia, hypertension, diabetes mellitus or smoking. The contribution of infection to atherosclerosis is still a challenge. Infectious agents can aggrevate plaque rupture, and cause acute myocardial infarction and death. Atherosclerosis is a chronic inflammatory process. Various bacterial and viral pathogens have been considered as a cause for inflammation of the vascular wall which leads to atherosclerosis. C. pneumoniae, H. pylori, influenza A virus, Hepatitis C virus, Cytomegalovirus, and human immunodeficiency virus (HIV) are related to atherosclerosis. This chapter is about the potential role of these infectious pathogens in acute atherosclerosis.