Factor V Leiden, prothrombin G20210A and MTHFR C677T mutations in Romanian patients with deep venous thrombosis

Introduction Deep venous thrombosis (DVT), with an incidence of about 1 case/year/1000 adults, is a multifactorial disease, result of the interaction between genetic and acquired risk factors. Although considered idiopathic in majority of the cases, an underlying cause could be detected in up to 80% of the patients with DVT, as shown in the literature (Whitlatch 2008). Genetic factors contribute also to the increased tendency towards coagulationthrombophilia. The most common inherited thrombophilic factors in Caucasians are factor V Leiden (with a prevalence of 1-15% in healthy population, respective 15-65% in venous thromboembolism) and factor II (prothrombin) G20210A polymorphisms (found in 1-8% of healthy subjects, respective 3-17% in venous thromboembolism) according to Jadaon (2011a). Their frequencies vary according to geographical and ethnic factors. Factor V Leiden is the result of the substitution of adenine to guanine at nucleotide position 1691 of exon 10 of FV gene, leading to procoagulation effects by the elimination of one of the cleavage sites for Activated Protein C (also called resistance to APC); most homozygotes for factor V Leiden experience at least one thrombotic episode in their life time, presenting 80fold higher risk for DVT whereas heterozygotes, found in 1520% of cases with venous thromboembolism, have 3to 5-fold increased risk of thrombosis, according to Franchini (2012). Prothrombin G20210A polymorphism represents the substitution of adenine to guanine at the position 20210 in the regulatory 3’end of the prothrombin gene, leading to an increased efficiency of the 3′ end cleavage signal and a more effective poly(A) site, as shown in literature (Bosler et al 2006). The prevalence in Europe is of 1.7-3% amongst healthy individuals, with the highest in European Caucasians, and increases in DVT at 6.2%, respective 18% in the presence of a positive family history; the relative risk of DVT is 2-4fold higher in carriers of this mutation and increases at 16fold in patients presenting both factor V Leiden and factor II G20210A polymorphisms, as Jadaon has shown (2011b). Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, the result of the alanine to valine substitution at codon 222, is associated with decreased activity of the enzyme 5,10 MTHFR and hyperhomocysteinemia, according to literature (Fay 2012). Although some studies showed the association of MTHFR C677T with DVT (Shmeleva et al 2003; Kupeli et al 2011), the current knowledge does not consider it as a significant risk factor, as it was shown by Spiroski et al (2008), Bezemer et al (2007), Naess et al (2009). While numerous studies worldwide showed the prevalence and the thrombotic risk of these genetic factors, as far as we know, few Romanian data were previously reported, regarding only the pregnancy-associated thrombophilia (Trifa et al 2009; Popp et al 2012). We aimed to assess the frequency of factor V Leiden, prothrombin G20210A and MTHFR C677T polymorphisms in a group of Romanian patients with DVT and the associated risk. Abstract. Objective: to determine the frequency of factor V Leiden, prothrombin G20210A and MTHFR C677T polymorphisms in idiopathic deep venous thrombosis (DVT) and the associated risk. Materials and methods: an observational, case-control study was designed and 144 subjects were enrolled: 72 with confirmed idiopathic DVT of the lower limbs and 72 sexand agematched healthy controls. Results: the presence of at least one genetic mutation, found in 61.11% patients with DVT versus 44.44% controls was associated with almost double risk of DVT (OR=1.964, p= 0.045, 95% CI: 1.011-3.814). Only factor V Leiden, detected in 13.88% patients with DVT and 2.77% of controls, showed a significant association with DVT (p= 0.015, OR= 5.645, 95% CI: 1.19026.762). Prothrombin G20210A polymorphism was equally distributed in DVT and controls, 2.77%. MTHFR C677T polymorphism presented the highest prevalence, 58.97% in DVT and 44% in controls, but without significant difference (p= 0.498, OR= 1.257, 95% CI: 0.647-2.441). Among the mutant genotypes, only heterozygosity for factor V Leiden was associated with 8.875fold increased risk of thrombosis (p= 0.015, 95% CI: 1.080-72.923). Conclusions: this study may be considered the first attempt offering some data regarding the frequency of genetic factors in Romanian patients with DVT and confirms the association of factor V Leiden with DVT in this population.