SUMMARYMOLECULAR ANALYSIS OF INHERITED THROMBOFILIAThe aim of this thesis was to investigate the role of factor V Leiden,prothrombin20210G>A, metylenetetrahydrofolate reductase (MTHFR) 677C>T, andMTHFR1298A>C mutations, in inherited thrombophilic disorders, deep veinthrombosis (DVT) and pregnancy complications. The frequencies of these mutationsamong the Turkey thrombophilia patients were calculated. Screening and identificationof unknown mutations using single strand confromation analysis (SSCA) and DNAsequencing was performed.In this study, a total number of 270 thrombophilic patients and 67 normal controls,which formed our major thromboembolia group, were analysed for all these mutationsusing polymerase chain reaction (PCR) based restriction enzyme analysis (REA). Theresults were interpreted in two subgroups, namely, the DVT group and pregnancycomplications group. 46 patients and 67 normal controls were analysed within the DVTgroup. On the other hand, 60 women suffered pregnancy complications were analysedwith 33 normal controls. In the major thromboembolia group, 7 patients were found tobe homozygous and 69 patients were heterozygous for factor V Leiden with a calculatedfrequency of 2.65 % and 25.5 %, 20 patients were found to be homozygous and 112patients were heterozygous for MTHFR677C>T with a calculated frequency of 7.5 %and 41.4 %, 24 patients were found to be homozygous and 146 patients wereheterozygous for MTHFR1298A>C mutations with a calculated frequency of 9 % and54 %, 3 patients were found to be homozygous and 20 patients were heterozygous forprothrombin 20210G>A with a calculated frequency of 1.2 % and 7.4 % respectively. Inthe DVT group, 2 patients were found to be homozygous and 17 patients wereheterozygous for factor V Leiden with a calculated frequency of 4.5 % and 36.9 %, 5patients were found to be homozygous and 18 patients were heterozygous forMTHFR677C>T with a calculated frequency of 11 % and 39 %, 8 patients were foundto be homozygous and 21 patients were heterozygous for MTHFR1298A>C mutationswith a calculated frequency of 17.5 % and 45.6 %, 4 patients were heterozygous forprothrombin 20210G>A with a calculated frequency of 9 % respectively. In thepregnancy complications group, only one patient were found to be homozygous and 12patients were heterozygous for factor V Leiden with a calculated frequency of 1.67 %and 20.0 %, 2 patients were found to be homozygous and 29 patients were heterozygousfor MTHFR677C>T with a calculated frequency of 3.4 % and 48.31 %, 5 patients werefound to be homozygous and 32 patients were heterozygous for MTHFR1298A>Cmutations with a calculated frequency of 8.4 % and 53.3 %, only one patient were foundto be homozygous and 2 patients were heterozygous for prothrombin 20210G>A with acalculated frequency of 1.7 % and 3.3 % respectively.In major thromboembolia, DVT and pregnancy complications patient groups, the highprevalence of the factor V Ledien mutation (% 28.15, 41.4, and 21.67) andprothrombin20210G>A (% 8.6, 9, and 5) was determined. On the other hand, the highprevalence of the MTHFR677C>T and MTHFR1298A>C mutations both in normalcontrols (% 37.3, 37.3, 36.4 and 62.7, 62.7, 63.6) and patients (% 48.89, 50, 51.71 and62.3, 63.1, 61.67) doesn't support a role of this mutation in Turkey major thrombophiliapatients group, DVT patient group and during pregnancy.

ÖZETKALITSAL TROMBOFİLİ'NİN MOLEKÜLER ANALİZİBu tez çalışmasında, faktör V Leiden, metilentetrahidrofolat redüktaz (MTHFR)677C>T, MTHFR1298A>C ve protrombin20210G>A mutasyonlarının, kalıtsaltrombofilik bozukluklar, derin ven trombozu (DVT) ve gebelik komplikasyonlarındakirollerinin incelenmesi amaçlandı. İlk olarak, Türkiye tromboemboli hastalarında bumutasyonların frekansları hesaplandı. Ayrıca tek zincir konformasyon analizi (SSCA)ve DNA dizi analizi teknikleri ile bilinmeyen mutasyonların taranması ve adlandırılmasıgerçekleştirildi.Çalışmada, genel tromboemboli grubu olarak adlandırılan toplam 270 trombofilik hastave 67 kontrol bireyde restriksiyon enzim analizine (REA) dayalı polimeraz zincirreaksiyonu (PCR) tekniği ile tüm mutasyonlar analiz edildi. Sonuçlar, geneltromboemboli grubundan oluşturulan DVT ve gebelik komplikasyonları alt gruplarındabağımsız olarak değerlendirildi. DVT grubunda, 46 hasta ve 67 kontrol bireyde, gebelikkomplikasyonları grubunda ise komplikasyonlu gebelikleri olan 60 kadın hasta ve 33sağlıklı kadında adı geçen mutasyonlar analiz edildi. Genel tromboemboli grubunda,faktör V Leiden mutasyonu için 7 hasta homozigot (% 2.65) ve 69 hasta heterozigot(% 25.5) mutant, MTHFR677C>T mutasyonu için 20 hasta homozigot (% 7.5) ve 112hasta heterozigot (% 41.4) mutant, MTHFR1298A>C mutasyonu için 24 hastahomozigot (% 9) ve 146 hasta heterozigot (% 54) mutant ve protrombin20210G>Amutasyonu için 3 hasta homozigot (% 1.2) ve 20 hasta heterozigot (% 7.4) mutantolarak belirlendi. DVT grubunda, faktör V Leiden mutasyonu için 2 hasta homozigot(% 4.5) ve 17 hasta heterozigot (% 36.9) mutant, MTHFR677C>T mutasyonu için 5hasta homozigot (% 11) ve 18 hasta heterozigot (% 39) mutant, MTHFR1298A>Cmutasyonu için 8 hasta homozigot (% 17.5) ve 21 hasta heterozigot (% 45.6) mutant veprotrombin20210G>A mutasyonu için 4 hasta heterozigot mutant (% 9) olarakbelirlendi. Gebelik komplikasyonları grubunda, faktör V Leiden mutasyonu için 1 hastahomozigot (% 1.67) ve 12 hasta heterozigot mutant (%20.0), MTHFR677C>Tmutasyonu için 2 hasta homozigot (% 3.4) ve 29 hasta heterozigot (% 48.31) mutant,MTHFR1298A>C mutasyonu için 5 hasta homozigot (% 8.4) ve 32 hasta heterozigot(% 53.3) mutant ve protrombin20210G>A mutasyonu için 1 hasta homozigot (% 1.7)ve 2 hasta heterozigot (% 3.3) mutant olarak belirlendi.Genel tromboemboli, DVT ve gebelik komplikasyonları hasta gruplarında, sırası ile,faktör V Leiden (% 28.15, 41.4 ve 21.67) ve protrombin20210G>A (% 8.6, 9 ve 5)mutasyonları kontrol gruba kıyas ile daha yüksek frekanslarda belirlendi.MTHFR677C>T ve MTHFR1298A>C mutasyonları tüm hasta (% 48.9, 50 ve 51.71 ve% 63, 63.1 ve 61.7) ve kontrol gruplarında (% 37.3, 37.3 ve 36.4 ve % 62.7, 62.7 ve63.6) istatistiksel olarak yakın sıklıkta görülmektedir. Adı geçen iki mutasyonunTürkiye populasyonunda tromboemboli hastalarında, DVT ve gebelik süresince etkiliolmadığı düşünülmektedir.