Ishemijski moždani udar u mlađem životnom dobu kod bolesnika sa novom F2 c.1824C>T genskom varijantom i PAI-1 4G/4G, MTHFR 677TT genotipom

  • Iva Pruner University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Belgrade, Serbia
  • Evica Dinčić University of Defence, Faculty of Medicine of the Military Medical Academy, Belgrade, Serbia; Military Medical Academy, Clinic for Neurology, Belgrade, Serbia
  • Maja Gvozdenov University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Belgrade, Serbia
  • Branko Tomić University of Belgrade, Institute of Molecular Genetics and Genetic Engineering, Belgrade, Serbia
  • Mirjana Kovač University of Belgrade, Faculty of Medicine, Belgrade, Serbia
  • Valentina Djordjević University of Belgrade, Faculty of Medicine, Belgrade, Serbia
DOI: https://doi.org/10.2298/VSP210323066P
Ključne reči: fibrin;, geni;, geni, varijacije;, genotip;, dna, analiza sekvenci;, moždani udar;, trombofilija.

Sažetak


Uvod. Ishemijski moždani udar (IMU) je heterogeni poremećaj koji može biti uzrokovan genetskim faktorima rizika i faktorima sredine. Poremećaji koagulacije mogu biti uzročnici u 1-4% slučajeva IMU, naročito kod bolesnika kod kojih se IMU dogodi u mlađem životnom dobu. Prikaz bolesnika. Prikazan je slučaj bolesnika koji je u mlađem životnom dobu razvio IMU nepoznatog uzroka. Urađeni su biohemijski, imunološki i testovi za trombofiliju kao i sekvenciranje DNK sa ciljem da se utvrdi molekularna patologija koja je mogla biti u osnovi moždanog udara kod tog bolesnika. Testovima za trombofiliju utvrđeno je da je bolesnik homozigotni nosilac mutacija PAI-1 4G/5G i MTHFR C677T. Dodatnom genetičkom analizom otkriveno je prisustvo nedavno opisane F2 c.1824C>T genske varijante, koja se nalazi u poslednjem egzonu gena za protrombin i za koju je prethodno pokazano da izaziva hiperprotrombinemiju, hipofibrinolizu i izmenjeni fenotip fibrinskog ugruška. Zaključak. Naši rezultati ukazuju na to da bi nova F2 c.1824C>T genska varijanta mogla imati sinergistički efekat sa PAI 4G/4G i MTHFR 677TT genotipom u nastanku fibrinskog ugruška sa izmenjenim fenotipom, koji se odlikuje tankim, gusto upakovanim fibrinskim vlaknima, što čini ugrušak manje podložnim fibrinolizi i povećava rizik od nastanka IMU u ranijem životnom dobu.

Reference

1.      Tuncer N, Tuglular S, Kiliç G, Sazci A, Us O, Kara I. Evaluation of the angiotensin-converting enzyme insertion/deletion polymorphism and the risk of ischaemic stroke. J Clin Neurosci 2006; 13(2): 224‒7.

2.      Szolnoki Z, Somogyvári F, Kondacs A, Szabó M, Fodor L. Evaluation of the interactions of common genetic mutations in stroke subtypes. J Neurol 2002; 249(10): 1391‒7.

3.      Hassan A, Markus HS. Genetics and ischaemic stroke. Brain 2000; 123(Pt 9): 1784‒812.

4.      Voetsch B, Loscalzo J. Genetic determinants of arterial thrombosis. Arterioscler Thromb Vasc Biol 2004; 24(2): 216‒29.

5.      Hankey GJ, Eikelboom JW, van Bockxmeer FM, Lofthouse E, Staples N, Baker RI. Inherited thrombophilia in ischemic stroke and its pathogenic subtypes. Stroke 2001; 32(8): 1793‒9.

6.      Ng KW, Loh PK, Sharma VK. Role of investigating thrombophilic disorders in young stroke. Stroke Res Treat 2011; 2011: 670138.

7.      Pezzini A, Grassi M, Del Zotto E, Archetti S, Spezi R, Vergani V, et al. Cumulative effect of predisposing genotypes and their interaction with modifiable factors on the risk of ischemic stroke in young adults. Stroke 2005; 36(3): 533‒9.

8.      Danckwardt S, Gehring NH, Neu-Yilik G, Hundsdoerfer P, Pforsich M, Frede U, et al. The prothrombin 3'end formation signal reveals a unique architecture that is sensitive to thrombophilic gain-of-function mutations. Blood 2004; 104(2): 428‒35.

9.      Miljic P, Gvozdenov M, Takagi Y, Takagi A, Pruner I, Dragojevic M, et al. Clinical and biochemical characterization of the prothrombin Belgrade mutation in a large Serbian pedigree: new insights into the antithrombin resistance mechanism. J Thromb Haemost 2017; 15(4): 670‒7.

10.   Pruner I, Farm M, Tomic B, Gvozdenov M, Kovac M, Miljic P, et al. The Silence Speaks, but We Do Not Listen: Synonymous c.1824C>T Gene Variant in the Last Exon of the Prothrombin Gene as a New Prothrombotic Risk Factor. Clin Chem 2020; 66(2): 379‒89.

11.   Rooth E, Wallen NH, Blombäck M, He S. Decreased fibrin network permeability and impaired fibrinolysis in the acute and convalescent phase of ischemic stroke. Thromb Res 2011; 127(1): 51‒6.

12.   Cesari M, Pahor M, Incalzi RA. Plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions. Cardiovasc Ther 2010; 28(5): e72‒91.

13.   Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268(15): 10739‒45.

14.   Aso Y. Plasminogen activator inhibitor (PAI)-1 in vascular inflammation and thrombosis. Front Biosci 2007; 12: 2957‒66.

15.   Attia J, Thakkinstian A, Wang Y, Lincz L, Parsons M, Sturm J, et al. The PAI-1 4G/5G gene polymorphism and ischemic stroke: an association study and meta-analysis. J Stroke Cerebrovasc Dis 2007; 16(4): 173‒9.

16.   Sauls DL, Wolberg AS, Hoffman M. Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability: implications for the mechanism of thrombosis in hyperhomocysteinemia. J Thromb Haemost 2003; 1(2): 300‒6.

17.   Panigrahi I, Chatterjee T, Biswas A, Behari M, Choudhry PV, Saxena R. Role of MTHFR C677T polymorphism in ischemic stroke. Neurol India 2006; 54(1): 48‒50; discussion 51‒2.

18.   Undas A, Williams EB, Butenas S, Orfeo T, Mann KG. Homocysteine inhibits inactivation of factor Va by activated protein C. J Biol Chem 2001; 276(6): 4389‒97.

19.   Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88(10): 3698‒703.

20.   Ceelie H, Bertina RM, van Hylckama Vlieg A, Rosendaal FR, Vos HL. Polymorphisms in the prothrombin gene and their association with plasma prothrombin levels. Thromb Haemost 2001; 85(6): 1066‒70.

21.   De Stefano V, Chiusolo P, Paciaroni K, Casorelli I, Rossi E, Molinari M, et al. Prothrombin G20210A mutant genotype is a risk factor for cerebrovascular ischemic disease in young patients. Blood 1998; 91(10): 3562‒5.

22.   Undas A, Slowik A, Wolkow P, Szczudlik A, Tracz W. Fibrin clot properties in acute ischemic stroke: relation to neurological deficit. Thromb Res 2010; 125(4): 357‒61.

23.   Wolberg AS, Campbell RA. Thrombin generation, fibrin clot formation and hemostasis. Transfus Apher Sci 2008; 38(1): 15‒23.

24.   Pera J, Undas A, Topor-Madry R, Jagiella J, Klimkowicz-Mrowiec A, Slowik A. Fibrin clot properties in acute stroke: what differs cerebral hemorrhage from cerebral ischemia? Stroke 2012; 43(5): 1412‒4.

25.   Dikmen M, Ozbabalik D, Gunes HV, Degirmenci I, Bal C, Ozdemir G, et al. Acute stroke in relation to homocysteine and methylenetetrahydrofolate reductase gene polymorphisms. Acta Neurol Scand 2006; 113(5): 307‒14.

26.   Simmonds RE, Hermida J, Rezende SM, Lane DA. Haemostatic genetic risk factors in arterial thrombosis. Thromb Haemost 2001; 86(1): 374‒85.

Objavljeno
2022/12/02
Broj časopisa
Vol. 79 Br. 10 (2022): Vojnosanitetski pregled
Rubrika
Prikaz bolesnika