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Genetic Thrombophilia

In Western countries the incidence of venous thromboembolism (VTE) is about 1 case/1000 patients per year. The term Thrombophilia describes the tendency to develop a thrombosis on the basis of inherited or acquired disorders of blood coagulation or fibrinolysis which lead to a prothrombotic state. The familial thrombophilia has been described for the first time in 1956 by Jordan and Nandorff on a clinical basis . The hereditary deficiency of antithrombin III (AT III), protein C (PC) and its cofactor, protein S (PS), were the first identified causes of thrombophilia. In recent years, two polymorphisms (SNPs) have been recognized as genetic causes additional hypercoagulability: the mutation G1691A of coagulation factor V (Leiden factor), responsible for a framework of resistance to anticoagulant action of activated protein C and the mutation G20210A of coagulation factor II (prothrombin), which is associated with an increase in the level of circulating prothrombin.

The average degree of hyperhomocysteinemia has also been identified as a risk factor for thrombophilia. Acquired factors (low food introduction of pyridoxine, cobalamin and folate) may cause an average hyperhomocysteinemia interacting with genetic factors, such as the C677T polymorphism in the gene of methylenetetrahydrofolate (MHTFR), which determines a reduction of the enzymatic activity and has been associated with increased concentrations of plasma homocysteine and to an altered metabolism of folate. A second polymorphism has been identified in the MTHFR gene, the variant A1298C, whose functional relevance in vivo is not well defined. It seems that the mutated variant of A1298C reduces in vitro the enzymatic function of MTHFR in a lesser degree than the C677T, and the subjects bearers are frequently characterized by normal serum concentrations of homocysteine as well as folate. Some findings suggest that individuals heterozygous for both the two mutations may have a clinical and laboratory findings similar to homozygous C677T. The venous thromboembolic disease is, therefore, considered to be a multifactorial disease, where the thrombotic event is the result of gene-gene and gene-environment (such as eating habits or occasional risk factors such as surgery, trauma, pregnancy the puerperium, the ‘use of oral contraceptives or estrogen-progestogen therapy).

Furthermore, the risk of developing a venous thrombosis, thromboembolism complicated or less, increases in the presence of defects combined. Thus, the simultaneous presence in heterozygosity, genetic variants (SNPs) of Factor V and Factor II coagulation above leads to an increased risk for VTE equal to about 20 folds, compared with non-carriers. This risk value is significantly higher than that related to the simple heterozygosity of only one of the two SNPs (5-8 folds of increased risk for the FV Leiden heterozygous and 3-4 folds increased for the bearers, always in the heterozygous, of variant 20210 Prothrombin). In most cases the clinical manifestations of genetic thrombophilia consist in deep venous thrombosis of the legs with or without pulmonary embolism, as well as in the superficial thrombophlebitis or in more severe splanchnic thrombosis or cerebral. Complications of pregnancy may be associated with genetic thrombophilia, in addition to the risk of thromboembolism in the puerperium, including pre-eclampsia, the miscarriage, fetal growth retardation and the placental abruption, complications, all linked to a poor placental perfusion. As regards the SNPs involved in the predisposition to arterial thrombosis, there is still no unanimous consent.

A part of the genetic variant of prothrombin, which has also been associated with an increased risk of arterial thrombotic, particularly in younger subjects, other candidate genes are those which encode for the PAI-1 and the GPIIIa. The PAI-1, a member of the serpin family, binds to tissue plasminogen activator (tPA) inhibiting the activation, resulting in decreased fibrinolysis. High levels of this inhibitor were associated with an increased risk of thrombosis is of type arterial (myocardial infarction and coronary artery disease) and venous (thromboembolism), especially in smokers and hypertensives. At the level of this promoter is a SNP of insertion (4G/5G) and the 4G allele was associated with a thrombotic risk aumentatato as related to an increase entries transcriptional activity of the gene. The complex GP IIb/IIIa is the most abundant receptor present on the platelet surface. The gene has a SNP (Leu33Pro) (HPA-1a/b), which appears to predispose to arterial thrombosis. The platelets of subjects wearing the b allele (PlA2), species in homozygosity, have a higher binding capacity with fibrinogen and increased aggregability. The b allele (PlA2) was then associated with an increased risk of myocardial infarction, especially at a young age and especially in smokers, as well as a greater resistance to antiplatelet activity of aspirin. To go to the pages of the individual SNPs click on the corresponding links.

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