Inherited and Acquired Thrombophilic Factors in Young Patients with Acute Coronary Syndrome or Ischemic Stroke

Review Article

Austin J Clin Cardiolog. 2015; 2(1): 1036.

Inherited and Acquired Thrombophilic Factors in Young Patients with Acute Coronary Syndrome or Ischemic Stroke

Dragoni F*

Thrombosis Center, Department of Cellular Biotechnologies and Hematology, “Sapienza” University, Rome, Italy

*Corresponding author: Dragoni Francesco, Thrombosis Center, Department of Cellular Biotechnologies and Hematology, ”Sapienza” University, Rome, Italy

Received: May 18, 2015; Accepted: September 14, 2015; Published: September 30, 2015

Abstract

Cardiovascular disease is indisputably one of the most important health problems in the world. Cardiovascular disease is the number-one cause of disability and death in the United States. Despite important progress in diagnosis and prevention, cardiovascular diseases such as acute coronary syndrome, stroke, and peripheral vascular disease are responsible for disability and death at a stupefying rate. By 2030, researchers indicate that non-communicable diseases will account for more than three-quarters of deaths worldwide, and cardiovascular disease will be responsible for more deaths than infectious diseases, maternal and perinatal conditions, and nutritional disorders in low income countries. In order to reduce the morbidity and mortality related to cardiovascular disease, population-based strategies may be useful in patients with well established diseases but also for healthy subjects at high risk to developing cardiovascular disease. It has been recently hypothesized that individual polymorphisms may have less or no independent effect on venous or arterial thrombosis, but may act in synergy with other genetic or established factors predisposing to cardiovascular disease especially in young patients. The combination of inherited or acquired thrombophilic risk factors with the classical cardiovascular risk factors seems to increase significantly the risk to develop acute coronary syndrome or ischemic stroke in young patients. Therefore, a correct lifestyle decreasing the effect of classical cardiovascular risk factors could play a key role in reducing the incidence of cardiovascular disease and lowering the cost to cure million of patients every year in the world. In particular, a correct lifestyle is strongly recommended in young healthy subjects with inherited or acquired thrombophilic risk factors.

Keywords: Inherited thrombophilic factors; Acquired thrombophilic factors; Cardiovascular disease; Acute coronary syndrome; Ischemic stroke; Young patients; and Antiphospolipid antibodies

Abbreviations

ACS: Acute Coronary Syndrome; APA: Antiphospholipid Antibodies; ATF: Acquired Thrombophilic Factors; CRF: Cardiovascular Risk Factors; CVD: Cardiovascular Disease; ITF: Inherited Thrombophilic Factors; WHO: World Health Organization

Introduction

To date Cardiovascular Disease (CVD) is the most important single contributor to global mortality in the world and prospectively, it will continue to dominate mortality trends. By 2005, the total number of CVD deaths (acute coronary syndrome, stroke and rheumatic heart disease) showed an increment globally to 17.5 million from 14.4 million in 1990. Of these, 7.6 million were attributed to coronary heart disease and 5.7 million to stroke. More than 80 percent of the deaths occurred in low and middle income countries [1].

By 2030, prospective data indicate that non-communicable diseases will account for more than three-quarters of deaths worldwide and in particular CVD alone will be responsible for more deaths in low income countries than infectious diseases, maternal and perinatal conditions, and nutritional disorders combined [2,3].

Therefore, CVD may be considered the most important single contributor to mortality worldwide and it will remain still in dominance position in the future.

In order to reduce the morbidity and mortality related to cardiovascular disease, population-based strategies and cost-effective interventions accessible and affordable may be useful in patients with well established disease but also for healthy subjects at high risk to developing CVD.

A correct identification of Inherited Thrombophilic Factors (ITF) or Acquired Thrombophilic Factors (ATF) as risk factors for the developing of CVD especially in young patients, could allow to design effective strategies able to reduce significantly the cost to cure million of patients every year in the world.

Thrombophilia can be defined as an increased tendency towards thrombosis through enhanced coagulation and/or platelet aggregability. It comprises several rare inherited abnormalities, associated with thrombosis at a young age. Acute Coronary Syndromes (ACS) have intravascular thrombogenesis as their main pathogenetic mechanism, the latter being influenced by a complex interplay involving multiple genetic and environment factors related to atherosclerosis, thrombosis and their interaction [4]. The classical Cardiovascular Risk Factors (CRF) such as diabetes, hypercholesterolemia, hypertension, obesity, family history and smoking have been well characterized [5,6], while the role of thrombophilic conditions has been less well characterized [7].

It has been recently hypothesized that individual polymorphisms may have less or no independent effect on venous or arterial thrombosis, but they may act in synergy with other genetic or established factors predisposing to cardiovascular disease [8,9]. However, the synergistic effect of prothrombotic polymorphisms and traditional Cardiovascular Risk factors on the risk of CVD in young patients has so far been only partially investigated

Many studies provide conflicting data concerning the clinical importance of gene polymorphisms in the pathogenesis of arterial disease and myocardial infarction [10,11,12].

Inherited Thrombophilic Factors and Cardiovascular Disease

Among the single point genetic mutations evaluated, the main clinical manifestation of the F5 R506Q is deep venous thrombosis [13], while its role in arterial thrombosis has been only partially investigated. A study of 560 men under 70 years of age (mean age 56.2 years) with myocardial infarction, born in the Netherlands and living in the Leiden region, revealed a small increase in risk in carriers of F5 R506Q and F2 G20210A [10].

A single nucleotide change of glutamine to arginine was identified at position 20210 by Poort et al. in 1996 [14]. The presence of the abnormal gene is associated with increased circulating prothrombin levels. A preliminary study performed in 79 young women (18–44 years old) with myocardial infarction and 381 controls found an increased risk of myocardial infarction with this polymorphism (OR = 4.0; 95% CI = 1.1-15.1), especially in combination with other risk factors such as smoking [12].

More recent meta-analyses have confirmed a significant role of this prothrombin variant for coronary artery disease, particularly for ACS before 55 years of age with limited extent of coronary atherosclerosis at angiography [15]. Frost et al., in 1995, found a common C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene [16]. Increased levels of homocysteine have been linked with the TT homozygous genotype but have only been demonstrated when plasma folate values are low [17]. Some studies investigating a link between the MTHFR polymorphism and arterial thrombosis, in particular myocardial infarction, have shown an association [18,19], but other studies did not show a correlation [20,21]. Similarly, ischemic stroke did not seem to be linked with the MTHFR polymorphism, despite an association between the MTHFR variant and homocysteine levels [22,23].

The complex pathogenesis of thrombosis means that a single gene defect probably determines only a small effect; moreover, the impact of a given polymorphism will depend on gene–environment interactions that may be specific for a given cohort of patients.

A recent case-control study [24] was designed to evaluate the role of the most common ITF and ATF factors in the pathogenesis of ACS in young patients, and to evaluate whether the association with traditional cardiovascular risk factors could have an increased impact on the development of the disease. In this study the multivariate analysis confirmed a significant role of classical cardiovascular risk factors, such as smoking habit, hypertension, hypercholesterolemia and diabetes mellitus in the pathogenesis of ACS (Table 1). Moreover, pathological levels of homocysteine were a significant predictor of ACS in this group of young patients.