Clinical and genetic study of thrombophilia in pregnancy

Abstract

Introduction. Thrombophilia is defined as an abnormal coagulation state of blood that increases the risk of thrombosis. Pregnancy represents a physiological hypercoagulation state. But, women with acquired and hereditary thrombophilia are at increased risk of developingvenous thromboembolism and other associated gestational vascular complications like Recurrent Pregnancy Loss (RPL), preeclampsia, intrauterine growth restriction, and placental abruption during pregnancy. These complications are a major cause of maternal and fetal morbidity and mortality.Aim of the study. This study focuses on the women who reported RPL, without any positive pregnancy and the identification of genetic factors that lead to the formation of thrombosis (F2 G20210A, F5 G1691A, MTHFR C677T, MTHFR A1289C, MTR A2756G, MTRR A66G), involved in fibrinolysis (PAI-1 4G/5G) and their association with primary female infertility. Materials and methods. Research design was constructed as case-control type. The case group was represented by 44 patients with RPL, without any positive pregnancy, with normal karyotype, and lack of other causes (intrauterine infections, uterine pathology) responsible for the RPL. The control group included 57 patients with 2 positive pregnancies who did not receive anticoagulant treatment. The Odds Ratio (OR) was calculated for the case group and control group, at a 95% confidence interval, and p values <0,005 were considered statistically significant. OR>1 demonstrate a strong association between mutation and RPL, OR<1 show a weak association. Results. We found that G1691A mutation in F5 gene encoding factor V (Leiden) (for heterozygous genotype OR=8,84; 95% CI; 1,02-76,42; p<0,05) and mutation G20210A in gene F2 encoding factor II (prothrombin), (for heterozygous genotype OR=7,18; 95% CI; 0,81- 63,87; p<0,05), are major risk factors for RPL and primary female infertility. Carriers of the homozygous genotype after mutant allele were not determined in either group. The 4G/5G polymorphism of the PAI-1 gene, in this study was not associated with RPL and primary female infertility. Analysis of genes involved in folate cycle as MTHFR C677T mutation (OR=3,33; 95% CI; 1,37-8,09; p<0,05 for the heterozygous genotype and OR=3,73; 95% CI; 0,99-14,05; p<0,05 for the homozygous genotype after the mutant allele), MTR mutation A2756G (for the heterozygous genotype OR=2,91; 95%CI; 1,19-7,08; p<0,05 and for the homozygous genotype after the mutant allele OR=6,30; 95%CI; 1,17-34,03; p<0,05), MTRR mutation A66G (for the heterozygous genotype OR=2,40; 95%CI; 1,02-5,62; p<0,05 and for the homozygous genotype after the mutant allele OR=5,77; 95%CI; 0,99-33,68; p<0,05),demonstrated that these polymorphisms are major risk factors of RPL and primary female infertility. A1289C mutation of the MTHFR gene was not associated with RPL and primary female infertility. Conclusion. According to the results of the study, it is recommended the genetic diagnosis of all patients with RPL, without organic or infectious causes, for detection of the genetic factors involved in hereditary thrombophilia.