Fattori genetici di rischio trombotico e loro ruolo in patologia clinica.
Di Micco, Pierpaolo (2008) Fattori genetici di rischio trombotico e loro ruolo in patologia clinica. [Tesi di dottorato] (Inedito)
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Thrombosis is a multifactorial disease that may appear as arterial thrombosis and\or venous thrombosis. Several inherited and acquired risk factors are involved in the pathogenesis of a thrombotic event. Arterial acquired thrombotic risk factors are known since Framingham Study was developed and are mainly represented by aging, smoking, diabetes, dyslipidemia, hypertension. However, also familial history of arterial thrombosis was underlined as risk factor for arterial thrombotic events. On the other hand, venous thrombosis may be triggered by inherited or acquired thrombotic risk factors. Acquired thrombotic risk factors for venous thrombosis are represented by recent surgery, prolonged bed rest, cancer and its therapies, oral contraceptives use, pregnancy\puerperium and aging. However, also for venous thrombosis the presence of familial history of venous thrombosis is a well recognised thrombotic risk factor. In the last years, a number of prothrombotic inherited risk factors have been described, as the deficiency of clotting inhibitors (i.e., antithrombin III, Protein C, Protein S), the resistance to inhibitors (i.e., Factor V Leiden), the reduced activity of fibrinolytic proteins or, finally, the increased activity of some procoagulant factors (i.e., A20210G variant of Factor II, etc.). Although it is well known the association between inherited thrombophilia and some thrombotic diseases as deep venous thrombosis and pulmonary embolism, controversial data are present on the association between inherited thrombophilia and other thrombotic diseases as the early onset acute coronary syndrome, benign intracranial hypertension, deep venous thrombosis of upper limb and thromboangioiitis obliterans. The aim of our study was to select a large group of subjects bearing such thrombotic diseases, well characterised from the clinical and instrumental point of view and to analyze the possible role of a large panel of prothrombotic factors (i.e., AT III, PC, PS, FV Leiden, A20210G variant of FII, hyperhomocysteine and MTHFR mutations, etc.), as risk factors for such diseases. In particular, our data revealed that: i) Buerger’s disease is associated to hyperhomocysteinemia (frequently due to MTHFR gene variants); ii) juvenile myocardial infarction is associated to a higher occurrence of FVHR variant; iii) upper limb deep venous thrombosis is frequently associated to FV Leiden and hyperhomocysteinemia; iv) benign intracranial hypertension is also associated to a higher occurrence of FV Leiden and MTHFR gene variants. In addition, during our study, we identified six patients bearing the rare genotype of homozygosity for the A20210G variant of FII (about 60 patients described so far in the world); our study revealed that only four of the six cases developed thrombotic diseases while two did not experienced such diseases; we suggested that liver insufficiency (present in such two cases) may be a protective factor toward thrombotic diseases in patients bearing inherited thrombophilia. These data may have a clinical impact, because: i) it is possible to use specific thromboprophylaxis to prevent thrombotic diseases in well defined groups of high risk patients; ii) once identified a patient at risk for inherited prothrombotic conditions, the genetic counselling to the family permits to extend the analysis (and prophilaxis in the case) to other consanguineous that bear the same prothrombotic predisposition.
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