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The Relationship Between Etiology and Genetic Polymorphism in Adults with Cerebral Venous Thrombosis

Year 2019, Volume: 21 Issue: 3, 166 - 171, 30.12.2019
https://doi.org/10.18678/dtfd.507400

Abstract

Aim: Cerebral venous thrombosis (CVT) is a rare cause of stroke, and there are many factors in its etiology. At least 1/4 of cases is based on thrombophilia. The most common risk factors for thromboembolism were methyl-tetra-hydro-folate reductase (MTHFR) C677T, factor V (FV) G1691A (Leiden), factor II (FII) GA20210 and their mutations. Its relationship with different genetic polymorphisms and high homocysteine levels were also investigated. In this study, it was aimed to investigate the existence of genetic polymorphism and the role of homocysteine levels in CVT etiology.

Material and Methods: Demographic characteristics, clinical, radiological and laboratory data of patients diagnosed with CVT between January 2010 and June 2018 were reviewed retrospectively. Etiologic risk factors for CVT and the role of genetic polymorphism in these risk factors were investigated.

Results: In this study, 92 (73 female and 19 male) patients and 52 (44 female and 8 male) control subjects were evaluated. The most frequent admission symptom was headache in patients with CVT. MTFHR, factor 13 (F13) V34L, plasminogen activator inhibitory (PAI) and β-fibrinogen mutations were higher in control group. No statistically significant difference was found between the two groups in terms of FV Leiden, FII, Glycoprotein 3a mutation and homocysteine level.

Conclusion: In this study, in addition to the results consistent with the literature, some different results were determined. MTHFR (C677T, A1289C), FV Leiden, FII G20210, β-fibrinogen 455 G-A, PAI-1 4G/5G polymorphisms do not pose a risk for CVT. F13 V34L polymorphism has a protective role against CVT.

References

  • Coutinho JM, Zuurbier SM, Aramideh M, Stam J. The incidence of cerebral venous thrombosis: a cross-sectional study. Stroke. 2012;43(12):3375-7.
  • deVeber G, Andrew M, Adams C, Bjornson B, Booth F, Buckley DJ, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345(6):417-23.
  • Sassi SB, Touati N, Baccouche H, Drissi C, Romdhane NB, Hentati F. Cerebral venous thrombosis: a tunisian monocenter study on 160 patients. Clin Appl Thromb Hemost. 2017;23(8):1005-9.
  • Coutinho JM, Zuurbier SM, Stam J. Declining mortality in cerebral venous thrombosis: a systematic review. Stroke. 2014;45(5):1338-41.
  • Saadatnia M, Fatehi F, Basiri K, Mousavi SA, Mehr GK. Cerebral venous sinus thrombosis risk factors. Int J Stroke. 2009;4(2):111-23.
  • Alonso-Cánovas A, Masjuan J, González-Valcárcel J, Matute-Lozano MC, García-Caldentey J, Alonso-Arias MA, et al. Cerebral venous thrombosis: when etiology makes the difference. Neurologia. 2009;24(7):439-45.
  • Dordevic V, Rakicevic L, Spasic M, Mikovic D, Kovac M, Radojkovic D. Factor V Leiden, FII G20210A, MTHFR C677T mutations as risk factors for venous thrombosis during pregnancy and puerperium. Vojnosanit Pregl. 2005;62(3):201-5.
  • Lupi-Herrera E, Soto-López ME, Lugo-Dimas AJ, Núñez-Martínez ME, Gamboa R, Huesca-Gómez C, et al. Polymorphisms C677T and A1298C of MTHFR gene: Homocysteine levels and prothrombotic biomarkers in coronary and pulmonary thromboembolic disease. Clin Appl Thromb Hemost. 2019;25:1-8.
  • Catto AJ, Kohler HP, Coore J, Mansfield MW, Stickland MH, Grant PJ. Association of a common polymorphism in the factor XIII gene with venous thrombosis. Blood. 1999;93(3):906-8.
  • Wilhemsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311(8):501-5.
  • Roy SN, Mukhopadhyay G, Redman CM. Regulation of fibrinogen assembly. Transfection of Hep G2 cells with B beta cDNA specifically enhances synthesis of the three component chains of fibrinogen. J Biol Chem. 1990;265(11):6389-93.
  • Koster T, Rosendaal FR, Reitsma PH, van der Velden PA, Briët E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms--the Leiden Thrombophilia Study (LETS). Thromb Haemost. 1994;71(6):719-22.
  • Tsantes AE, Nikolopoulos GK, Bagos PG, Rapti E, Mantzios G, Kapsimali V, et al. Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis. A meta-analysis. Thromb Haemost. 2007;97(6):907-13.
  • Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, et al. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. New England J Med. 1996;334(17):1090-4.
  • Wagner KR, Giles WH, Johnson CJ, Ou CY, Bray PF, Goldschmidt-Clermont PJ, et al. Platelet glycoprotein receptor IIIa polymorphism P1A2 and ischemic stroke risk: The Stroke Prevention in Young Women Study. Stroke. 1998;29(3):581-5.
  • Mahale R, Mehta A, John AA, Buddaraju K, Shankar AK, Javali M, et al. Acute seizures in cerebral venous sinus thrombosis: what predicts it? Epilepsy Res. 2016;123:1-5.
  • Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F, ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35(3):664-70.
  • Bousser MG, Crassard I. Cerebral venous thrombosis, pregnancy and oral contraceptives. Thromb Res. 2012;130(Suppl 1):S19-22.
  • Lee DJ, Ahmadpour A, Binyamin T, Dahlin BC, Shahlaie K, Waldau B. Management and outcome of spontaneous cerebral venous sinus thrombosis in a 5-year consecutive single-institution cohort. J Neurointerv Surg. 2017;9(1):34-8.
  • Ben Salem-Berrabah O, Fekih-Mrissa N, Louati I, Layouni S, Zaouali J, N'siri B, et al. Cerebral venous thrombosis: Prospective etiological study of 26 Tunisian patients. Rev Neurol (Paris). 2011;167(2):141-9.
  • Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64(3):169-72.
  • Iorio A, Barnes C, Vedovati MC, Favaloro EJ. Thrombophilia and cerebral vein thrombosis. In: Caso V, Agnelli G, Paciaroni M, editors. Handbook on cerebral venous thrombosis. Basel: Karger; 2008. p.55-76.
  • Knekt P, Reunanen A, Alfthan G, Heliövaara M, Rissanen H, Marniemi J, et al. Hyperhomocystinemia: a risk factor or a consequence of coronary heart disease? Arch Intern Med. 2001;161(13):1589-94.
  • Maneoni AA, Jackson SH. Homocysteine and cardiovascular disease: current evidence and future prospects. Am J Med. 2002;112(7):556-65.
  • Iqbal MP, Fatima T, Parveen S, Yousuf FA, Shafiq M, Mehboobali N, et al. Lack of association of methylenetetrahyclrofolate reductase 677C>T mutation with coronary artery disease in Pakistani population. J Mol Gen Med. 2005;1(1):26-32.
  • Födinger M, Hörl WH, Sunder-Plassman G. Molecular biology of 5,10-methylenetetrahydrofolate reductase. J Nephrol. 2000;13(1):20-33.
  • Diaz-Arrastia R. Homocysteine and neurologic disease. Arch Neurol. 2000;57(10):1422-7.
  • Bezgin T, Kaymaz C, Akbal Ö, Yılmaz F, Tokgöz HC, Özdemir N. Thrombophilic gene mutations in relation to different manifestations of venous thromboembolism: A single tertiary center study. Clin Appl Thromb Hemost. 2018;24(1):100-6.
  • Liu F, Silva D, Malone MV, Seetharaman K. MTHFR A1298C and C677T polymorphisms are associated with increased risk of venous thromboembolism: A retrospective chart review study. Acta Haematol. 2017;138(4):208-15.
  • Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: A meta-analysis of published studies. Am Heart J. 2003;146(6):948-57.
  • Franchini M, Martinelli I, Mannucci PM. Uncertain thrombophilia markers. Thromb Haemost. 2016;115(1):25-30.
  • Rahimi Z, Mozafari H, Bigvand AH, Doulabi RM, Vaisi-Raygani A, Afshari D, et al. Cerebral venous and sinus thrombosis and thrombophilic mutations in Western Iran: Association with factor V Leiden. Clin Appl Thromb Hemost. 2010;16(4):430-4.
  • Voetsch B, Damasceno BP, Camargo EC, Massaro A, Bacheschi LA, Scaff M, et al. Inherited thrombophilia as a risk factor for the development of ischemic stroke in young adults. Thromb Haemost. 2000;83(2):229-33.
  • Kujovich JL. Factor V Leiden thrombophilia. Genet Med. 2011;13(1):1-16.
  • Kohler HP, Stickland MH, Ossei-Gerning N, Carter A, Mikkola H, Grant PJ. Association of a common polymorphism in the factor XIII gene with myocardial infarction. Thromb Haemost. 1998;79(1):8-13.
  • Muszbeck L, Adany R, Mikkola H. Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation, and function. Crit Rev Clin Lab Sci. 1996;33(5):357-421.
  • Heinrich J, Assmann G. Fibrinogen and cardiovascular risk. J Cardiovasc Risk. 1995;2(3):197-205.
  • 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.
  • Mottonen J, Strand A, Symersky J, Sweet RM, Danley DE, Geoghegan KF, et al. Structural basis of latency in plasminogen activator inhibitor-1. Nature. 1992;355(6357):270-3.
  • Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood. 1987;69(2):381-7.

Serebral Venöz Trombozlu Erişkinlerde Etiyoloji ve Genetik Polimorfizm İlişkisi

Year 2019, Volume: 21 Issue: 3, 166 - 171, 30.12.2019
https://doi.org/10.18678/dtfd.507400

Abstract

Amaç: Serebral ven trombozu (SVT) nadir bir inme nedeni olup etiyolojisinde birçok faktör yer almaktadır. Olguların en az 1/4'ü trombofiliye bağlıdır. Tromboembolizm için en yaygın risk faktörleri metilen-tetra-hidro-folat redüktaz (MTHFR) C677T, faktör 5 (FV) G1691A (Leiden), faktör 2 (FII) GA20210 ve mutasyonlarıdır. Farklı genetik polimorfizmleri ve yüksek homosistein düzeyleri ile ilişkisi de araştırılmıştır. Bu çalışmada SVT’li olgularda genetik polimorfizm varlığı ve homosistein düzeylerinin SVT etiyolojisindeki rolünün araştırılması amaçlanmıştır.

Gereç ve Yöntemler: Ocak 2010-Haziran 2018 yılları arasında merkezimizde geliş tanısı SVT olan hastaların demografik özellikleri, klinik, radyolojik ve laboratuvar verileri geriye dönük olarak incelendi. SVT için etiyolojik risk faktörleri ve bu risk faktörleri içinde genetik polimorfizmin rolü araştırıldı.

Bulgular: Çalışmada 92 (73 kadın ve 19 erkek) hasta ve 52 (44 kadın ve 8 erkek) kontrol birey değerlendirildi. SVT’li hastalarda en sık başvuru semptomu baş ağrısı idi. MTHFR, Faktör 13 (F13) V34L, plazminojen aktivatör inhibitörü (PAI) ve β-fibrinojen mutasyonları kontrol grubunda daha yüksek idi. FV Leiden, FII, Glikoprotein 3a mutasyonu ve homosistein düzeyi açısından her iki grup arasında anlamlı istatistiksel fark tespit edilmedi.

Sonuç: Bu çalışmada literatür ile uyumlu olan sonuçlar yanında bazı farklı sonuçlarda tespit edilmiştir. MTHFR (C677T, A1289C), FV Leiden, FII G20210, β-fibrinojen 455 G-A, PAI-1 4G/5G polimorfizmleri SVT için risk oluşturmamaktadır. F13 V34L polimorfizminin SVT'ye karşı koruyucu rolü vardır.

References

  • Coutinho JM, Zuurbier SM, Aramideh M, Stam J. The incidence of cerebral venous thrombosis: a cross-sectional study. Stroke. 2012;43(12):3375-7.
  • deVeber G, Andrew M, Adams C, Bjornson B, Booth F, Buckley DJ, et al. Cerebral sinovenous thrombosis in children. N Engl J Med. 2001;345(6):417-23.
  • Sassi SB, Touati N, Baccouche H, Drissi C, Romdhane NB, Hentati F. Cerebral venous thrombosis: a tunisian monocenter study on 160 patients. Clin Appl Thromb Hemost. 2017;23(8):1005-9.
  • Coutinho JM, Zuurbier SM, Stam J. Declining mortality in cerebral venous thrombosis: a systematic review. Stroke. 2014;45(5):1338-41.
  • Saadatnia M, Fatehi F, Basiri K, Mousavi SA, Mehr GK. Cerebral venous sinus thrombosis risk factors. Int J Stroke. 2009;4(2):111-23.
  • Alonso-Cánovas A, Masjuan J, González-Valcárcel J, Matute-Lozano MC, García-Caldentey J, Alonso-Arias MA, et al. Cerebral venous thrombosis: when etiology makes the difference. Neurologia. 2009;24(7):439-45.
  • Dordevic V, Rakicevic L, Spasic M, Mikovic D, Kovac M, Radojkovic D. Factor V Leiden, FII G20210A, MTHFR C677T mutations as risk factors for venous thrombosis during pregnancy and puerperium. Vojnosanit Pregl. 2005;62(3):201-5.
  • Lupi-Herrera E, Soto-López ME, Lugo-Dimas AJ, Núñez-Martínez ME, Gamboa R, Huesca-Gómez C, et al. Polymorphisms C677T and A1298C of MTHFR gene: Homocysteine levels and prothrombotic biomarkers in coronary and pulmonary thromboembolic disease. Clin Appl Thromb Hemost. 2019;25:1-8.
  • Catto AJ, Kohler HP, Coore J, Mansfield MW, Stickland MH, Grant PJ. Association of a common polymorphism in the factor XIII gene with venous thrombosis. Blood. 1999;93(3):906-8.
  • Wilhemsen L, Svärdsudd K, Korsan-Bengtsen K, Larsson B, Welin L, Tibblin G. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med. 1984;311(8):501-5.
  • Roy SN, Mukhopadhyay G, Redman CM. Regulation of fibrinogen assembly. Transfection of Hep G2 cells with B beta cDNA specifically enhances synthesis of the three component chains of fibrinogen. J Biol Chem. 1990;265(11):6389-93.
  • Koster T, Rosendaal FR, Reitsma PH, van der Velden PA, Briët E, Vandenbroucke JP. Factor VII and fibrinogen levels as risk factors for venous thrombosis. A case-control study of plasma levels and DNA polymorphisms--the Leiden Thrombophilia Study (LETS). Thromb Haemost. 1994;71(6):719-22.
  • Tsantes AE, Nikolopoulos GK, Bagos PG, Rapti E, Mantzios G, Kapsimali V, et al. Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and venous thrombosis. A meta-analysis. Thromb Haemost. 2007;97(6):907-13.
  • Weiss EJ, Bray PF, Tayback M, Schulman SP, Kickler TS, Becker LC, et al. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. New England J Med. 1996;334(17):1090-4.
  • Wagner KR, Giles WH, Johnson CJ, Ou CY, Bray PF, Goldschmidt-Clermont PJ, et al. Platelet glycoprotein receptor IIIa polymorphism P1A2 and ischemic stroke risk: The Stroke Prevention in Young Women Study. Stroke. 1998;29(3):581-5.
  • Mahale R, Mehta A, John AA, Buddaraju K, Shankar AK, Javali M, et al. Acute seizures in cerebral venous sinus thrombosis: what predicts it? Epilepsy Res. 2016;123:1-5.
  • Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F, ISCVT Investigators. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35(3):664-70.
  • Bousser MG, Crassard I. Cerebral venous thrombosis, pregnancy and oral contraceptives. Thromb Res. 2012;130(Suppl 1):S19-22.
  • Lee DJ, Ahmadpour A, Binyamin T, Dahlin BC, Shahlaie K, Waldau B. Management and outcome of spontaneous cerebral venous sinus thrombosis in a 5-year consecutive single-institution cohort. J Neurointerv Surg. 2017;9(1):34-8.
  • Ben Salem-Berrabah O, Fekih-Mrissa N, Louati I, Layouni S, Zaouali J, N'siri B, et al. Cerebral venous thrombosis: Prospective etiological study of 26 Tunisian patients. Rev Neurol (Paris). 2011;167(2):141-9.
  • Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998;64(3):169-72.
  • Iorio A, Barnes C, Vedovati MC, Favaloro EJ. Thrombophilia and cerebral vein thrombosis. In: Caso V, Agnelli G, Paciaroni M, editors. Handbook on cerebral venous thrombosis. Basel: Karger; 2008. p.55-76.
  • Knekt P, Reunanen A, Alfthan G, Heliövaara M, Rissanen H, Marniemi J, et al. Hyperhomocystinemia: a risk factor or a consequence of coronary heart disease? Arch Intern Med. 2001;161(13):1589-94.
  • Maneoni AA, Jackson SH. Homocysteine and cardiovascular disease: current evidence and future prospects. Am J Med. 2002;112(7):556-65.
  • Iqbal MP, Fatima T, Parveen S, Yousuf FA, Shafiq M, Mehboobali N, et al. Lack of association of methylenetetrahyclrofolate reductase 677C>T mutation with coronary artery disease in Pakistani population. J Mol Gen Med. 2005;1(1):26-32.
  • Födinger M, Hörl WH, Sunder-Plassman G. Molecular biology of 5,10-methylenetetrahydrofolate reductase. J Nephrol. 2000;13(1):20-33.
  • Diaz-Arrastia R. Homocysteine and neurologic disease. Arch Neurol. 2000;57(10):1422-7.
  • Bezgin T, Kaymaz C, Akbal Ö, Yılmaz F, Tokgöz HC, Özdemir N. Thrombophilic gene mutations in relation to different manifestations of venous thromboembolism: A single tertiary center study. Clin Appl Thromb Hemost. 2018;24(1):100-6.
  • Liu F, Silva D, Malone MV, Seetharaman K. MTHFR A1298C and C677T polymorphisms are associated with increased risk of venous thromboembolism: A retrospective chart review study. Acta Haematol. 2017;138(4):208-15.
  • Kim RJ, Becker RC. Association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system: A meta-analysis of published studies. Am Heart J. 2003;146(6):948-57.
  • Franchini M, Martinelli I, Mannucci PM. Uncertain thrombophilia markers. Thromb Haemost. 2016;115(1):25-30.
  • Rahimi Z, Mozafari H, Bigvand AH, Doulabi RM, Vaisi-Raygani A, Afshari D, et al. Cerebral venous and sinus thrombosis and thrombophilic mutations in Western Iran: Association with factor V Leiden. Clin Appl Thromb Hemost. 2010;16(4):430-4.
  • Voetsch B, Damasceno BP, Camargo EC, Massaro A, Bacheschi LA, Scaff M, et al. Inherited thrombophilia as a risk factor for the development of ischemic stroke in young adults. Thromb Haemost. 2000;83(2):229-33.
  • Kujovich JL. Factor V Leiden thrombophilia. Genet Med. 2011;13(1):1-16.
  • Kohler HP, Stickland MH, Ossei-Gerning N, Carter A, Mikkola H, Grant PJ. Association of a common polymorphism in the factor XIII gene with myocardial infarction. Thromb Haemost. 1998;79(1):8-13.
  • Muszbeck L, Adany R, Mikkola H. Novel aspects of blood coagulation factor XIII. I. Structure, distribution, activation, and function. Crit Rev Clin Lab Sci. 1996;33(5):357-421.
  • Heinrich J, Assmann G. Fibrinogen and cardiovascular risk. J Cardiovasc Risk. 1995;2(3):197-205.
  • 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.
  • Mottonen J, Strand A, Symersky J, Sweet RM, Danley DE, Geoghegan KF, et al. Structural basis of latency in plasminogen activator inhibitor-1. Nature. 1992;355(6357):270-3.
  • Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood. 1987;69(2):381-7.
There are 40 citations in total.

Details

Primary Language Turkish
Subjects Clinical Sciences
Journal Section Research Article
Authors

Fatma Şimşek 0000-0003-1662-5534

Mustafa Ceylan 0000-0002-9916-0156

Nuray Bilge 0000-0002-9328-1678

Publication Date December 30, 2019
Submission Date January 3, 2019
Published in Issue Year 2019 Volume: 21 Issue: 3

Cite

APA Şimşek, F., Ceylan, M., & Bilge, N. (2019). Serebral Venöz Trombozlu Erişkinlerde Etiyoloji ve Genetik Polimorfizm İlişkisi. Duzce Medical Journal, 21(3), 166-171. https://doi.org/10.18678/dtfd.507400
AMA Şimşek F, Ceylan M, Bilge N. Serebral Venöz Trombozlu Erişkinlerde Etiyoloji ve Genetik Polimorfizm İlişkisi. Duzce Med J. December 2019;21(3):166-171. doi:10.18678/dtfd.507400
Chicago Şimşek, Fatma, Mustafa Ceylan, and Nuray Bilge. “Serebral Venöz Trombozlu Erişkinlerde Etiyoloji Ve Genetik Polimorfizm İlişkisi”. Duzce Medical Journal 21, no. 3 (December 2019): 166-71. https://doi.org/10.18678/dtfd.507400.
EndNote Şimşek F, Ceylan M, Bilge N (December 1, 2019) Serebral Venöz Trombozlu Erişkinlerde Etiyoloji ve Genetik Polimorfizm İlişkisi. Duzce Medical Journal 21 3 166–171.
IEEE F. Şimşek, M. Ceylan, and N. Bilge, “Serebral Venöz Trombozlu Erişkinlerde Etiyoloji ve Genetik Polimorfizm İlişkisi”, Duzce Med J, vol. 21, no. 3, pp. 166–171, 2019, doi: 10.18678/dtfd.507400.
ISNAD Şimşek, Fatma et al. “Serebral Venöz Trombozlu Erişkinlerde Etiyoloji Ve Genetik Polimorfizm İlişkisi”. Duzce Medical Journal 21/3 (December 2019), 166-171. https://doi.org/10.18678/dtfd.507400.
JAMA Şimşek F, Ceylan M, Bilge N. Serebral Venöz Trombozlu Erişkinlerde Etiyoloji ve Genetik Polimorfizm İlişkisi. Duzce Med J. 2019;21:166–171.
MLA Şimşek, Fatma et al. “Serebral Venöz Trombozlu Erişkinlerde Etiyoloji Ve Genetik Polimorfizm İlişkisi”. Duzce Medical Journal, vol. 21, no. 3, 2019, pp. 166-71, doi:10.18678/dtfd.507400.
Vancouver Şimşek F, Ceylan M, Bilge N. Serebral Venöz Trombozlu Erişkinlerde Etiyoloji ve Genetik Polimorfizm İlişkisi. Duzce Med J. 2019;21(3):166-71.