Coagulation Factors and Recurrence of Ischemic and Bleeding Adverse Events in Patients with Acute Coronary Syndromes

Abstract

In the last years, management and prognosis of patients with acute coronary syndromes (ACS) are significantly improved. Nowadays antithrombotic (antiplatelet plus anticoagulant drugs) therapy represents the main treatment of ACS patients. Anticoagulant drugs are particularly helpful in the acute phase of ACS, whereas in the chronic phase are maintained only in selected cases. Many studies demonstrate that exists a significant variability in the coagulation factor levels between patients affected by ACS. This variation on coagulation factors levels is due to environmental (smoking, inflammation, sex, oral contraceptive, triglycerides, diabetes mellitus) and genetic determinants. Particularly several gene polymorphisms have been selected and clearly associated with significant variations in the coagulation factors values. The heightened levels of tissue factor, factor VII and fibrinogen are related with a “hypercoagulable status” and with a higher occurrence of ischemic complications after ACS and/or PCI. On the contrary, less data are available regarding the relationship between coagulation factors levels (or their gene polymorphisms) and bleeding complications. Recently, new anticoagulant drugs have been developed. They show less side effects and a better tolerability and, probably, their selected use in patients with a “hypercoagulable status” may improve the clinical outcome after ACS. In this review we analyze the current available data and we discuss how this finding may be useful for planning future studies to optimize the treatment of ACS patients.

Introduction

The burden of coronary heart disease (CHD) is projected to rise from around 47 million disability-adjusted life-years (DALYs) globally in 1990 to 82 million DALYs in 2020 [1]. Acute coronary syndromes (ACS), including myocardial infarction (MI) and unstable angina (UA), are severe clinical manifestations of CHD due to coronary artery lumen occlusion by a thrombus formed on the contact of a ruptured or eroded atherosclerotic plaque. Antithrombotic (antiplatelet plus anticoagulant drugs) therapy represents the main treatment of ACS patients.

In spite of recent improvements in treatment of ACS patients, a considerable number of them continue to experience both ischemic and bleeding complications [2]. To reduce ischemic complications, it is possible to use powerful antiplatelet treatment (e.g. glycoprotein IIb/IIIa inhibitor, double clopidogrel maintenance dose, prasugrel, ticagrelor), but this increases significantly bleeding occurrence. Otherwise it is plausible to optimize the outcome with a tailored approach of antiplatelet drugs based on platelet reactivity status. Unluckily, many studies showed conflicting results [3], [4], [5]. In the chronic phase anticoagulant drugs are used only in much selected cases. This is due to three main reasons: i) after stent implantation antiplatelet agents provide a better protection as compared to anticoagulant drugs, ii) old anticoagulant drugs (e.g. warfarin) showed several side effects, iii) the association between antiplatelet agents and old anticoagulant drugs increases significantly the bleeding complications. However the recent introduction of newer anticoagulant drugs (e.g. dabigatran, rivaroxaban, apixaban) may change this scenario. It is clearly reported the existence of patients with “hypercoagulable status”. This is due to different gene polymorphisms and higher coagulation factor levels. These patients showed a significant increase of adverse events after ACS. Actually it is unknown if a tailored approach with anticoagulant drugs for these patients may be helpful.

The aim of this review is to analyze and discuss all available data regarding the relationship between coagulation cascade factors plasmatic levels and the risk of MI and bleeding complications. Particularly, we are going to focus our attention on environmental and genetic determinants of coagulation factor plasmatic levels.

ACS is triggered by the exposition to blood of tissue factor (TF) that occurs during the rupture or ulceration of unstable atherosclerotic plaque. TF is a membrane protein expressed in a large variety of cells and it is able to activate the extrinsic pathway of coagulation cascade (Table 1, Fig. 1). Coagulation cascade may be activated also by the intrinsic pathway. Both pathways are able to induce the activation of the common pathway, acting on factor X (Table 1, Fig. 1). The final result is the generation of active thrombin that, in presence of calcium ions, cleaves fibrinogen (FI) in fibrin. The generation of insoluble fibrin is finally done by the activated factor XIII (Table 1, Fig. 1) [6].