KARDİYOVASKÜLER RİSK PANELİ
Faktör V GA (Leiden) Mutasyonu: Aktive protein C (APC), koagülasyon mekanizmasında faktör Va ve faktör VIIIa‘yı inaktive etmektedir. Faktör V mutasyonu varlığında bu inhibisyon gerçekleşmemekte, böylece trombin üretimi ve pıhtı oluşumu artmaktadır.
Heterozigot GA: Venöz tromboz riskini kat (1), hamilelik sürecinde VTE riskini 8 kat, gebelik kaybı, fetal büyüme gerilikleri ve preeklampsi riskini kat, plasental ablasyonu 5 kat arttırmaktadır (2).
Homozigot AA: Venöz tromboz riskini kat (1,3), gebeliğe bağlı gelişen VTE riskini kat arttırmaktadır (4).
Protrombin GA Mutasyonu: plazma protrombin düzeyini arttırmakta ve venöz tromboz eğilimine neden olmaktadır (5).
Protrombin mutasyonu; fetal kayıpları, plasental ablasyonu, ağır preeklampsi ve IUGR görülme riskini artırmaktadır (8).
Heterozigot GA: VTE rölatif riskini kat (6,9), gebeliğe bağlı gelişen VTE riskini 15 kat, tekrarlayan birinci trimester fetal kayıpların görülme riskini 3 kat (7), tekrarlamayan ikinci trimester gebelik kayıp riskini 9 kat (7), tüm trimesterlerde ise fetal kayıpların görülme riskini kat arttırmaktadır (2).
Homozigot AA: VTE riskini 10 kat (9), gebeliğe bağlı olarak gelişen VTE riskini ise 26 kat artırmaktadır (2).
Faktör V HR (FVR2) Mutasyonu: HR mutasyonunun (özellikle homozigot formu) APC rezistansına neden olduğu bildirilmiştir. APC rezistansının, tekrarlayan gebelik kayıplarında kalıtsal trombozun en sık nedeni olduğu gösterilmiştir. Heterozigot Faktör V Leiden; VTE riskini 7 kat artırırken, Faktör V HR mutasyonu ile birlikte görüldüğünde VTE riski ilaveten 3 kat daha artmaktadır (10). Heterozigot FVR2 varyantı, tekrarlayan gebelik kayıplarında kritik bir role sahip olup, risk faktörü olarak değerlendirilmesi önerilmektedir (11).
MTHFR CT Mutasyonu: MTHFR enzim aktivitesini azaltarak kardiyoserebrovasküler hastalıklar için önemli bir risk faktörü sayılan hiperhomosisteinemi ve homosisteinüri oluşumuna neden olmaktadır (12). Homosistein konsantrasyonundaki artış ise tromboembolizm, ateroskleroz, koroner arter hastalığı, preeklampsi, nöral tüp defektleri ve inmeye neden olabilmektedir.
Homozigot TT: Tromboz riskini kat arttırdığı bildirilmiş olup (9), tekrarlayan gebelik kayıplarında önemli rolü olduğu bildirilmiştir (11).
MTHFR AC Mutasyonu: Plazma homosistein konsantrasyonunda artışa neden olmaktadır.
Heterozigot AC ve heterozigot CT birlikte görülmesi durumunda veya homozigot TT bireylerde MTHFR aktivitesinin düştüğü ve homosistein düzeyinin yükseldiği gösterilmiştir (13,14).
APO-E Genotiplemesi: Apo E genotipinin hem lipid seviyeleri hem de KVH ile ilişkili olduğu gösterilmiştir.
ApoE ε2/ε2: Vasküler hastalık riskini arttırdığı (16), TGK için potansiyel risk faktörü olduğu bildirilmiştir (15).
ApoE ε3/ε3: Tekrarlayan gebelik kayıpları için koruyucu bir faktördür (15).
ApoE ε4/ε4: KVH’larda ölüm riskini %40 arttırdığı gösterilmiştir (17) ve TGK ile ilişkili olduğu bulunmuştur (15).
ApoB RQ (Apo B) Mutasyonu: ApoB RQ (Apo B) Mutasyonu: Apo B mutasyonu LDL’nin reseptöre bağlanmasını geciktirmekte ve LDL’nin ortamdan uzaklaştırılması azalmaktadır. Ateroskleroz ve KVH’lara yatkınlığı arttırmaktadır (16).
PAI 4G/5G Mutasyonu: PAI-1 konsantrasyonu yükselmesiyle fibrinolitik aktivite bozulmaktadır ve trombotik olaylara yatkınlık artmaktadır (18).
PAI 4G/4G: Tromboembolizm, fetal kayıp, IUGR, preeklampsi (19) ve MI riskini arttırmaktadır (20).
PAI 4G/5G: Özellikle protrombin gen mutasyonu ile birlikte görüldüğü durumlarda tromboz riskini arttırdığı (21) ve erken dönem gebelik kayıplarına neden olduğu bildirilmiştir (22).
PAI 5G/5G: Normal
ACE İnsersiyon/Delesyon Genotiplemesi: ACE geni; anjiotensin I'i anjiotensin II'ye dönüştürerek kan basıncı düzenlenmesi ve elektrolit dengesi üzerinde önemli bir rol oynayan ACE enzimini kodlamaktadır.
ACE I/D: Enzim seviyesi ara düzeydedir, trombotik olay riskini 5 kat arttırmaktadır (24) ve tekrarlayan gebelik kayıpları için bir risk faktörüdür (26).
ACE D/D: Trombotik olay riskini 11 kat arttırmakta (23,24), preeklampsi ve gebelikte hipertansiyon görülme riskini arttırmaktadır (25).
GPIIIa L33P (HPA-1) Mutasyonu: Trombosit agregasyonunda rol oynamaktadır (27).
Normal allel A1 (a) olarak ifade edilir.
Homozigot A2 (b) alleli; tromboza yatkınlık, erken yaşta akut koroner olaylara, MI, stroke’a yatkınlıkta rol oynadığı bilinmekte (28) ve ileri düzeyde İUGG ile ilişkilendirilmektedir (29).
Beta Fibrinojen G>A Mutasyonu: Fibrinojen seviyelerinde artışa neden olmakta ve miyokard enfarktüsü ile felç gibi arteryal hastalıklarla ilişkilendirilmektedir (30).
Homozigot A>A: Gebelik kaybı riskinin arttığı gözlemlenmiştir (31).
Faktör XIII V34L Mutasyonu: Faktör XIII, fibrin monomerleri arasında çapraz bağlar oluşturmakta ve pıhtıyı fibrinolizise karşı daha dirençli hale getirmektedir. FXIIIa’yı kodlayan gende görülen G-T değişimi en sık rastlanan mutasyondur. Bu mutasyon trombinin FXIII üzerinde proteolitik aktivite gösterdiği bölgeyi etkileyerek FXIII’ün aktive edilmesini engellemektedir (32). Miyokard enfarktüs (33), derin ven trombozu (34), pulmoner embolizme karşı koruyucu özellik göstermektedir.
Kaynaklar:
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3. EGAPP Recommendation Statement Genetics in Medicine () 13, 67–76; doi/GIM.0befbe46f
4. Martinelli I, Legnani C, Bucciarelli P, Grandone E, De Stefano V, Mannucci PM. Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia. Thromb Haemost. ;–3. [PubMed]
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6. Lijfering WM, Brouwer JL, Veeger NJ, Bank I, Coppens M, Middeldorp S, Hamulyák K, Prins MH, Büller HR, van der Meer J. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in relatives. Blood. ;–
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8. Roque H, Paidas M, Rebarber A, Khan S, Kuczynski E,Lockwood CJ. There is no association between maternal thrombophilia and recurrent first-trimester loss. Am J Obstet Gynecol ;S
9. M.G. Andreassi, N. Botto, S. Maffei, Factor V Leiden, prothrombin GA substitution and hormone therapy: indications for molecular screening, Clin Chem Lab Med 44 ()
Faioni EM, Franchi F, Bucciarelli P, Margaglione M, De Stefano V, Castaman G, Finazzi G, Mannucci PM. Coinheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thromboembolism to carriers of factor V RQ (Factor V Leiden) Blood. ;– [PubMed]
Oztürk Ozdemir, Gonca Imir Yenicesu, Fatma Silan, Binnur Köksal, Sinem Atik, Filiz Ozen, Mert Göl, and Ali Cetin. Genetic Testing and Molecular Biomarkers. April , 16(4): doi/gtmb Recurrent Pregnancy Loss and Its Relation to Combined Parental Thrombophilic Gene Mutations
Stern LL, Bagley PJ, Rosenberg IH, et al. unimpaired in folate- adequate persons homozygous for the CT mutation in the methylenetetrahydrofolate reductase gene. J Nutr, ;
N.M. van der Put, F. Gabreels, E.M. Stevens, J.A. Smeitink, F.J. Trijbels, T.K. Eskes, L.P. van den Heuvel, H.J. Blom, A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?, American journal of human genetics 62 ()
I. Weisberg, P. Tran, B. Christensen, S. Sibani, R. Rozen, A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity, Molecular genetics and metabolism 64 ()
Li J1, Chen Y, Wu H, Li L. Apolipoprotein E (Apo E) gene polymorphisms and recurrent pregnancy loss: a meta-analysis. J Assist Reprod Genet. Feb;31(2) doi: /s Epub Nov
S. D. Gepdiremen. Apolipoprotein E ve hastalıklara yatkınlık. AİBÜ İzzet Baysal Tıp Dergisi Cilt: 4 Sayı: 2 /
Jari H. Stengard, MD; Kim E. Zerba, PhD; Juha Pekkanen, MD; Christian Ehnholm, MD; Aulikki Nissinen, MD; Charles F. Sing, PhD. Apolipoprotein E Polymorphism Predicts Death From Coronary Heart Disease in a Longitudinal Study of Elderly Finnish seafoodplus.infoation. ;
seafoodplus.info Tekrarlayan gebelik kayıpları sonrası oluşan gebeliklerin seyri. T.C. Sağlık Bakanlığı Süleymaniye Kadın Hastalıkları ve Doğum Eğitim ve Araştırma Hastanesi. Uzmanlık Tezi. İstanbul,
Glueck CJ, Phillips H, Cameron D, Wang P, Fontaine RN,Moore SK, et al. The 4G/4G polymorphism of the hypofibrinolytic plasminogen activator inhibitor type 1 gene: An independent risk factorfor serious pregnancy complications. Metabolism ;–
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E. Yılmaz, E. Akar, N. Akar. Effect of plasminogen activator inhibitor-1 4G/5G polymorphism in Turkish deep vein thromboembolic patients with and without prothrombin G-A. Turk J Haematol ;21(2):
Dossenbach-Glaninger A1, van Trotsenburg M, Dossenbach M, Oberkanins C, Moritz A, Krugluger W, Huber J, Hopmeier P. Plasminogen activator inhibitor 1 4G/5G polymorphism and coagulation factor XIII Val34Leu polymorphism: impaired fibrinolysis and early pregnancy loss.
Fatini C, Gensini F, Sticchi E, Battaglini B, Prisco D, Fedi S, Brunelli T, Marcucci R, Conti AA, Gensini GF, Abbate R: ACE DD genotype: an independent predisposition factor to venous thromboembolism. Eur J Clin Invest ; –
Philipp CS, Dilley A, Saidi P, et al. Deletion polymorphism in the angiotensin-converting enzyme gene as a thrombophilic risk factor after hip arthroplasty. Thromb Haemost ;
C. Mandò, P. Antonazzo, S. Tabano et al., “Angiotensin-converting enzyme and adducin-1 polymorphisms in women with preeclampsia and gestational hypertension,” Reproductive Sciences, vol. 16, no. 9, pp. –, View at Scopus
Fatini C, Gensini F, Battaglini B, Prisco D, Cellai AP, Fedi S, Marcucci R, Brunelli T, Mello G, Parretti E, Pepe G, Abbate R: Angiotensin-converting enzyme DD genotype, angiotensin type 1 receptor CC genotype, and hyperhomocysteinemia increase firsttrimester fetal-loss susceptibility. Blood CoagulFibrinolysis ; –
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Wayne W. Grody, John H. Griffin, Annette K. Taylor, Bruce R. Korf, John A. Heit. American College of Medical Genetics Consensus Statement on Factor V Leiden Mutation Testing. American College of Medical Genetics and Genomics Practice Guidelines. Genet Med
Andrea Gerhardt, Nadja Howe, Jan Steffen Kru¨ssel , Ruediger Eberhard Scharf , Rainer Bernd Zotz Elevated lipoprotein(a) levels and homozygous human platelet antigen 1b (HPA-1b) genotype are risk factors for intrauterine growth restriction (IUGR)
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