We are witnessing increasingly frequent cases of acute coronary syndrome in younger patients, or in patients who did not present the typical risk factors. Most studies define younger patients as persons under 45 years of age. Such patients are typically diagnosed with acute myocardial infarction (AMI) with normal coronary arteries, i.e. the coronary artery does not show intraluminal anomalies (strict definition) or with a smaller artery stenosis but hemodynamically insignificant (in most cases <30% stenosis). A recently published study (APPROACH) determined the prevalence of AMI with normal coronary arteries was 2.8% in patients who underwent coronary angiography for AMI. Differential diagnosis of such acute coronary events includes myocarditis, stress cardiomyopathy, and Takotsubo syndrome. There is no single explanation for the origin of AMI with normal coronary arteries, but a few possible mechanisms have been suggested: latent atherosclerosis, vasospasm, thrombosis and hypercoagulability, embolization, and inflammation. We differentiate between acquired and inherited thrombophilia syndrome. In this report, we will describe a link between hereditary forms of trombophilia (a mutation of factor V Leiden, prothrombin gene mutation, deficiency of protein C and protein S, antithrombin deficiency, and mutations in the gene for glycoprotein plasminogen activator inhibitor-1) and acute forms of cardiovascular disease.
During 2013, the Cardiology Department of the Čakovec County Hospital treated eight patients that had had acute coronary syndrome, but coronarography showed normal lumen of coronary arteries (myocardial infarction with angiographically normal coronary arteries – MINCA). Six patients were under 40 years of age, with no typical risk factors for cardiovascular diseases (smoking, hyperlipidemia, arterial hypertension) and no positive family history. Two female patients with MINCA older than 40 years of age suffered from rheumatoid arthritis. Due to technical issues and lack of cooperation from the patients, we were unable to perform a genetic analysis and cardiac magnetic resonance imaging (MRI) for all the patients with MINCA and acute coronary syndrome, and will only present fully processed patients here.
Two female patients aged 40 that had had acute coronary syndrome in the past, with normal coronary catheterization results but myocardial ischemia detected with MRI, we determined the patient was homozygous for PAI‐1 4G (plasminogen activator inhibitor-1 glycoprotein-1). We also found risk factors for thrombophilia in patients with other forms of acute coronary disease.
In a female patient aged 29, with no typical risk factors that had had an ST-segment elevation acute myocardial infarction and undergone percutaneous coronary intervention, we diagnosed single vessel coronary artery disease and preformed primary stent implantation in the right coronary artery, and found a prothrombin 20210 mutation.
In a female patient aged 40, who had had a transitory ischemic attack in the past, with newly diagnosed patent foramen ovale and small nodular ischemic brain lesions discovered with MRI, we implanted an Amplatzer Septal Occluder and found PAI–1 4G homozygosity.
We would like to note that all these patients had normal CRP, D-dimer, and homocysteine values as well as normal basic coagulation tests (APTV, PV, fibrinogen).
In modern cardiologic practice, we are witnessing an increase in cases of acute coronary syndrome (ACS) in younger patients, i.e. in patients with no typical risk factors, either variable (smoking, hypercholesterolemia, arterial hypertension, diabetes, a sedentary lifestyle) or fixed (age, sex, family history). (
The term myocardial infarction (MI) is used when there is evidence of myocardial necrosis in clinical conditions indicative of myocardial infarction. There are clearly defined criteria for establishing a diagnosis of acute myocardial infarction (AMI) in those conditions. MI classification recognizes five types of infarction depending on pathophysiological, clinical, and prognostic factors. (
Type 1 non-atherosclerotic causes of myocardial infarction |
Type 2 non-atherosclerotic causes of myocardial infarction |
Diseases with positive troponin and normal coronary arteries |
Angioproliferative disorders and coronary heart disease |
Many coagulation cascade disorders classified under thrombophilia are not hereditary but rather acquired (e.g. antiphospholipid syndrome, high concentrations of Factor VII, IX, acquired deficiency of antithrombin in disseminated intravascular coagulation (DIC), eclampisa and nephrotic syndrome), but the rest of this text will primarily discuss hereditary, genetically influenced thrombophilia. (
Beside the traditional immunological and functional tests examining the hereditary lack of antithrombin and protein C and S that still most commonly manifest in venous thromboembolism, today we can also apply genetic tests that verify mutations related to thrombogenesis in acute cardiovascular disease. (
Factor V Leiden mutation (a consequence of the mutation is a replacement of arginine by glutamine at the place 506 protein for factor V) leads to hereditary activated protein C resistance (APCR). It is an autosomal recessive disease with an increased thrombosis prevalence of 5-10% in heterozygous patients, and 50-100% in homozygous patients. The prevalence of the mutation in the general population is estimated at 5%.
The prothrombin 20210 mutation (replacement of guanine with adenine at nucleotide G20210A), also called Factor II mutation, results in increased gene expression and consequently higher levels of prothrombin, i.e. a procoagulant state. The prevalence is estimated at 2-3%; heterozygous patients have levels of prothrombin increased by 30%, and homozygous patients are rare.
When testing for PAI-1 polymorphism (plasminogen activator inhibitor-1 gene mutation that regulates the fibrinolytic system, primarily by inhibiting the tissue- and urokinase-type plasminogen activator (tPA and uPA)), the 4G/4G genotype represents an additional risk factor for myocardial infarction in younger patients and in patients with MINCA. The existence of a specific 4G/5G polymorphism has been established in the PAI-1 promoter region that which influences PAI-1 expression. Studies have shown that homozygous 4G/4G patients have 25% higher PAI-1 plasma concentration than 5G/5G homozygous patients, and consequently also a higher risk of thrombosis due to stronger inhibition of the fibrinolytic system. Patients with 4G/5G heterozygosity also have increased PAI-1 plasma levels, but the risk of thrombosis is significantly lower and varies from case to case. It is worth noting that PAI-1 is also secreted by adipocytes as well as endothelial cells – a thrombogenesis factor in obese patients, i.e. patients with metabolic syndrome, and that during pregnancy PAI-2 is secreted from the placenta. According to recent studies, not only do increased PAI-1 levels cause hypofibrinolysis, they also reduce the activity of matrix metalloproteinase (MMP) and cell adhesion.
Methylene tetrahydrofolate reductase (MTHFR) gene mutation (the most significant polymorphism being 677 TT) codes the MTHFR enzyme that participates in the generation of substrates for remethylation of homocysteine into methionine. Homozygosity (genotype 677 TT) leads to a thermolabile enzyme that ultimately causes the metabolism to produce homocysteines that speed up the atherosclerotic process. Patients with 677 CT heterozygosity have only slightly increased risk of thrombosis since the normal allele results in an adequately thermostable enzyme. (
Regarding acquired thrombophilia, we will touch upon antiphospholipid syndrome (it can be a isolated, primary, or secondary disease as part of other autoimmune disease or carcinoma). In addition to arterial and vein thrombosis, antiphospholipid syndrome is characterized by spontaneous abortions and thrombocytopenia. Antiphospholipid antibodies include antibodies that cause false-positive results in some tests, for instance the Veneral Disease Research Laboratory test (VDRL), Lupus Anti Coagulant test (LAC; represents prolonged APTV which does not improve when the patient’s plasma is diluted with normal plasma), anticardiolipin antibody tests, and anti-beta(2)-glycoprotein I antibody tests. (
Since thrombophilia is hereditary, genetic testing can benefit not only the person with a particular polymorphism but also other close members of the family. Being aware of a genetic predisposition can prevent exposure to factors that can facilitate thrombogenesis. Thus, genetic analysis must be performed in younger patients that had cardiovascular, cerebrovascular, and peripheral thromboembolic events but have no typical risk factors. The importance of proving the existence of genetic markers for thrombophilia is in the resulting proper treatment and awareness of risk that the patient must carry for the rest of their lives. This in turn necessitates an expansion of the concept of conventional risk factors. That topic is well beyond the scope of this article, since we have not yet even addressed the question of thromboembolic diseases that are a significant cause of morbidity and mortality. The future of medicine is in correct identification of hereditary risk factors which will, together with genetic testing and consultation, allow even better cooperation between patients and physicians and lead to most effective treatment.