The coagulation factor V variant is a single point mutation, described as a transition of G (guanine) to A (adenine) in 1601 nucleotide position in exon 10, causes changes in the protein chain; the substitution of arginine for glutamine (R506Q) [10, 11]. This pathogenic variant leads to the resistance of coagulation factor V to proteolytic inactivation by the activated protein C (APC), which is consequently related to a predisposition to thrombosis. Factor V Leiden is a poor risk factor of VTE when we compared it with the impact of natural anticoagulants deficiency, but it may be present in around 20% of patients with venous thrombosis [12]. The legitimacy of conducting a molecular test of Leiden mutation in patients without a personal or familial history of VTE is constantly discussed. Apart from the Leiden mutation study, the evaluation of the pathogenic variant in the prothrombin gene is equally important. Despite the fact that the G20210A mutation in the FII gene increases the risk of deep venous thrombosis to a lesser extent than the Leiden mutation, it occurs even in 6.2% of patients with venous thrombosis and about 2.3% of healthy patients. These two pathogenic variants in the FV and FII genes are together considered as a common cause of hereditary thrombophilia. The clinical utility of molecular testing of c.1601G>A and 20210G>A variants for hereditary thrombophilia may have predictive value for future thromboembolic events, both in patients with and without prior thromboembolic disease. It is corroborated by published cohort studies in which patients both with and without mutation are observed for the development of thromboembolism [13]. Genetic tests for thrombophilia and their clinical utility are included in medical practice in the context of the general risk of thromboembolism and possible risk as well as the benefits of treatment, mainly with anticoagulants. The decision regarding their implementation is related, among other things , to the general low incidence of thromboembolism in the general population, taking into account the interaction of environmental and genetic factors that determine the appearance of the disease. A relatively increased risk of thromboembolism occurs in people with familial hereditary thrombophilia [14]. The importance of genetic variants in connection with the increased risk of VTE in the FII and FV genes has been described in the introduction. Heterozygosity of c.1601G>A and 20210G>A variants is a strong risk factor for occurrence of the first clot and increases this risk by up to 20 times [15]. In our study population we showed that the GA genotypes, separately for both variants, were observed in 5.1% (FII) and 14.3% (FV) of cases. The simultaneous mutations of Leiden and in the prothrombin gene was found in only 4 subjects (0.64%).The pathogenic allele in FV (A) gene were observed in our analyzed group of people to the value of 7%. The previously published data in the Polish population by Alder et al showed the incidence value of the variant c.1601G> A of the FV gene at 2.0% (0.02) [16]. The difference in the frequency of the examined allele between our result and the Alder study may have multiple causes. The selection of the test group, exclusion criteria, geographical conditions or ultimately the choice of test method may significantly influence difference in results. Notwithstanding the aggregation of their data with the current data (in our study n=633 and in Alder study n=1588- total n=2221) indicates a frequency value for Poland of 4,5% [16]. The distribution of the A allele of the FV gene shown in our study places Poland, according to the study by Clark et al. in the group of European countries with a frequency above 3% , regardless of whether we add our result to the one previously published by Alder [16,17]. These include Northern European countries such as Sweden (4. 5%), Norway (4. 2%), Denmark (3. 9%), U. K. (3. 7%) [17-20], and Central European countries like Germany (3. 8%), The Czech Republic (5. 1%), Italy (4%), Greece (3. 2%), Hungary (3. 8%) Austria (2. 8%) [17]. The Romanian value (8. 3%) was found to be significantly higher than in all European countries [21]. However, in Slavic countries a lower frequency of this allele was observed (<3%)[a]. In countries such as Slovenia, Croatia, Bosnia and Herzegovina, Serbia and Montenegro, the distribution of c. 1601A ranged from 1. 5 to 2. 5% [22]. Also in the countries of the Eastern European bloc - Finland, Russia, Ukraine and Belarus the frequency of this variant is low (0. 6-2.4%) [22,23]. Interestingly, in Western European countries such as France, Spain and Portugal, the frequency of the A allele is very similar to that of Slavic countries (2%, 0. 9%, 1. 2% respectively) [17]. The result of the frequency of the A allele FV gene differentiates our country in this respect from the group of Slavic countries to which Poland belongs. The number of individuals in groups and geographical conditions can influences the results obtained. In our study for variant 20210G>A in the FII gene, we observed a frequency of prevalence with the value 0.03. By way of comparison, in the Bosnian population, the A variant of the FII gene occurred at a frequency of 6%, 1% in the Saudi population and 5.4% in the Italian population [24-26]. No data on the distribution of this allele in other populations is available.
It should be emphasized that individuals who carry either or both variants of the C.1601G> A gene FV and 20210G> A of the FII gene may never develop the VTE symptoms due to the multifactorial nature of this disease. Only a combination of various risk factors along with genetic factors such as surgery, hospitalization with prolonged immobilization or estrogen therapy can lead to the provoking of a clinical manifestation of thrombophilia. Up to a certain age the carriers of pathogenic variants remain asymptomatic because the risk of VTE increases with age [27]. The question arises whether it is worthwhile conducting a study for inherited thrombophilia in healthy subjects ? Considering the fact that thrombosis is the cause of significant morbidity and mortality in the world and the main reason for VTE, the answer should be “yes”, but in a selected group of patients. The American College of Medical Genetics (ACMG) published a standards guide for laboratory testing for factor V Leiden and factor II c.*97G>A [28]. All recommendations are presented in table 3.
Tab. 3. Recommendation of ACMG (American College of Medical Genetics and Genomics).
Main recommendation in patients:
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1. before the age of 50 with first unprovoked VTE or with recurrent VTE
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2. with VTE when the results of it may influence the treatment and clinical decisions
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3. with at least two VTE in the family or VTE cases which occurred in relatives of the first generation at an early age
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May be considered in several circumstances:
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1. like smoking females under the age of 50 with a history of acute myocardial infarction
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2. in siblings of individuals known to be homozygous for factor V Leiden or factor II c.*97G>A
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3. in an asymptomatic pregnant woman or a woman considering pregnancy, with first degree relatives with unprovoked VTE or VTE caused by pregnancy or by use of contraception can be considered to undergo this test
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4. in a pregnant woman’s family and a woman planning to conceive, the first degree relative who is the carrier of mutation Leiden and / or factor II c.* 97G> A and a history of VTE
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5. in women who plan to start taking contraceptives or have hormone replacement therapy
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The ACMG does not recommend routine testing for patients with a personal or family history of coronary artery disease or ischemic stroke
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