MOLECULAR BASIS OF THROMBOPHILIA

Summary Thrombophilia is a multifactorial disorder, involving both genetic and acquired risk factors that affect the balance between procoagulant and anticoagulant factors and lead to increased thrombotic tendency. The severe forms of thrombophilia are caused by a deficiency of natural anticoagulants: antithrombin, protein C and protein S. The advances in DNA technology played an important role in the identification of the exact nature of these deficiencies and opened up new possibilities in genetic research and molecular diagnostics of thrombophilia. The major breakthrough came with the discovery of activated protein C resistance and the Factor V Leiden gene mutation. Shortly afterwards, a variant in the 3' untranslated region of the Factor II gene (FII G20210A) associated with an increased concentration of Factor II in plasma was described. These two gene variants represent the most common thrombophilic genetic risk factors. Recently, a novel prothrombin mutation (c.1787G>T) was identified in a Japanese family with juvenile thrombosis. This mutation leads to impaired inhibition of mutant thrombin by antithrombin, proposing a new mechanism of thrombophilia named resistance to antithrombin. In the last decade, se veral prothrombotic genetic risk factors have been described, including gene variants associated with defects of natural coagulation inhibitors, increased levels of coagulation factors or their impaired inhibition and defects of the fibrinolytic system. However, most of them are not of diagnostic value, due to their minor or unknown impact on the thrombotic risk. Large-scale DNA analysis systems are now becoming available, opening a new era in the genetic studies of the molecular basis of thrombophilia. Keywords: thrombophilia, genetic risk factors, gene variants Kratak sadr`aj Trombofilija nastaje kao rezultat kompleksne interakcije izme|u negeneti~kih i geneti~kih faktora rizika koji hemostaznu ravnote`u pomeraju u smeru hiperkoagulacije i dovode do pojave tromboze. Veoma zna~ajan faktor rizika za nastanak trombofilije je deficijencija inhibitora koagulacije: antitrombina, proteina C ili proteina S. Veliki korak u razu mevanju geneti~ke osnove i molekularne dijagnostike trombofilije napravljen je otkri}em rezistencije na aktivirani protein C i faktor V Leiden mutacije. Ubrzo je otkrivena i varijanta u 3'-nekodiraju}em regionu gena za faktor II (FII G20210A), za koju je pokazano da dovodi do povi{ene koncentracije protrombina u plazmi. Ove dve genske varijante su naju~estaliji geneti~ki faktori rizika za nastanak trombofilije. Nedavno je opisana nova mutacija u genu za protrombin (c.1787G >T) za koju je pokazano da dovodi do rezistencije na anti trombin, odnosno do smanjene mogu}nosti inaktivacije mu tira nog trombina od strane antitrombina, {to predstavlja novi mehanizam za nastanak trombofilije. U toku poslednjih decenija, opisan je veliki broj geneti~kih faktora rizika za nastanak trombofilije, uklju~uju}i one koji dovode do: nedos tatka inhibitora koagulacije, pove}anog nivoa ili smanjene inaktivacije koagulacionih faktora ili defekata sistema za fibri nolizu. Me|utim, ve}ina njih nije od dijagnosti~ke va`nosti zbog njihovog malog ili jo{ uvek nepoznatog uticaja na etiologiju trombofilije. Primena novih tehnologija koje omo gu}avaju analizu velikog broja gena kod jednog pacijenta otvori}e mogu}nost individualnog utvr|ivanja geneti~kih faktora rizika, samim tim i adekvatan terapeutski pristup