The effect of genetic thrombophilia the severity of hemolytic-uremic syndrome in children


A.V. Popa, H.M. Emirova, N.L. Kozlovskaja, O.V. Zajceva, T.Ju. Abaseeva

1 St. Vladimir City Children's Hospital, Moscow; 2 MSMSU n.a. A.I. Evdokimov, Moscow; 3 Sechenov First Moscow State Medical University, Moscow; 4 SBHI of MA MRRCI n.a. M.F. Vladimirskiy, Department of Pediatric Dialysis and Hemocorrection of Division of Transplantology, Nephrology and Surgical Hemocorrection, Moscow
Objective: To investigate the effect of genetic thrombophilia on the severity of the hemolytic-uremic syndrome (HUS) in children.
Materials and methods: 47 patients with the typical form of HUS (mean age ‒ 19,3±2,1 months) were included in the study. PCR, mass spectroscopy, and PCR-restriction analysis were used to analyze genetic markers of thrombophilia: allelic polymorphism in genes of fibrinogen (FGB), prothrombin (PTG), methylenetetrahydrofolate reductase (MTHFR), plasminogen activator inhibitor (PAI-1), Factor V Leiden (F5), platelet fibrinogen receptor (ITGB3). Effects of polymorphism of the coagulation system genes on the clinical manifestations of HUS (duration of anuria, oliguria, uremia, anemia, dialysis therapy, the severity of thrombocytopenia, proteinuria during the acute stage and at discharge) were studied.
Results: Compared with the general population incidence of homozygous genotype MTHFR and ITGB genes in children with HUS was twice as high; incidence of heterozygotes of FGB and PAI-1 genes was significantly higher. Children with a mutant variant of MTHFR C677T gene polymorphism is a group with more severe HUS. Patients with «protrombogenic genotype» of FGB gene also showed prolonged anemia, anuria, uremia, dialysis therapy. The presence of heterozygous and homozygous genotypes of PAI-1 4G (675) 5G and ITGB3 S176T genes affected the duration of anuria, dialysis support and time of renal function recovery.
Conclusion: Severity of clinical manifestations of HUS determined by «protrombogenic genotype» of genes MTHFR, ITGB, FGB and PAI-1.

Literature


  1. Козловская Н.Л., Боброва Л.А. Генетическая тромбофилия и почки. Клиническая нефрология. 2009;3:23–34.
  2. Макацария А.Д., Бицадзе В.О. Антифосфолипидный синдром, генетические тромбофилии в патогенезе основных форм акушерской патологии. Русский Медицинский журнал (специальный выпуск). 2006;2:10.
  3. Khan S., Dickerman S.D. Hereditary thrombophilia. Thrombosis Jornal. 2006;4:15.
  4. Martiskainen M., Pohjasvaara T., Mikkelsson J. Fibrinogen gene promoter-455 A allele as a risk factor for lacunar stroke. Stroke. 2003;34(4):886–891.
  5. Jacques P.F., Bostom A.G., Williams R.R. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93 (l):7–9.
  6. Fodinger M., Wagner O.F., Horl W.H., Sunder-Plassmann G. Recent insights into the molecular genetics of the homocysteine metabolism. Kidney Int. 2001;59(78):238–42.
  7. Zou C., Tsukahara H., Hiraoka M. Methylenetetrahydrofolate reductase polymorphism in childhood primary focal segmental glomeru!osclerosis. Nephron. 2002;92(2):449–51.
  8. Jacques P.F., Bostom A.G., Williams R.R. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996;93(l):7–9.
  9. Sucker C., Kurschat C. Farokhzad F. The TT genotype of the polymorphism in the methylentetrahydrofolatereductase as a risk factor in thrombotic microangiopathies: resalt from a pilot study. Clin. Appl. Thromb. Hemost. 2009;15:283–8.
  10. Burzotta F., Di Castelnuovo A., Amore C. 4G/5G promoter PAI-1 gene polymorphism is associated with plasmatic PAI-1 activity in Italians: a model of gene-environment interaction. Thromb Haemost. 1998;79:354–8.
  11. Forastiero R., Martinuzzo M. Prothrombotic mechanisms based on the impairment of fibrinolysis in the antiphospholipid syndrome. Lupus. 2008;17:872–7.
  12. Lee A.J., Fowkes F.G.R., Lowe G.D.O., Rumley A. Determinantsof fibrin D-dimerin the Edinburgh Artery study. Arterioscler Thromb Vasc. Biol. 1995;15:1094–7.
  13. Paueksakon P., Revelo M.P, Ma L.J. Microangiopathic injury and augmented PAI-1 in human diabetic nephropathy. Kidney Intern. 2002;61:2142–8.
  14. Crandaliano G., Gesualdo L., Ranieri E. Tissue factor, plasminogen activaror ingibitor-1, and thrombin receptor expression in human crescentic glomerulonephritis. Am. J. Kidney Dis. 2000;35:726–38.
  15. Wang A.Y., Poon P., Lai F.M. Plasminogen activator inhibitor-1 gene polymorphism 4G/4G genotype and lupus nephritis in Chinese patients. Kidney Int. 2001;59:1520–8.
  16. Suzuki H., Sakuma Y., Kanesaki Y. Close relationship of plasminogen activator inhiditor-1 4G/5G polymorphism and progression of Ig-A nephropathy. CI. Nephrol. 2004;62(3):368–73.
  17. Капустин С.И. Молекулярно-генетические аспекты патогенеза венозного тромбоэмболизма. Дисс. док. биолог. наук. СПб., 2007.
  18. Sheereen S.J., Mammo L. The 4G/5G insertion/deletion polymorphism of the plasminogen activator inhibitor-1 gene is associated with venous thrombosis. J. Thromb Haemost. 2007;5(2):359.
  19. Undas A., Brummel K., Musial J. Pl(A2) polymorphism of beta-3 integrins is associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury. Circulation. 2001;104:2666–72.
  20. Cushman M. Epidemiology and Risk Factors for Venous Thrombosis. Semin Hematol. 2007;44(2):62–9.
  21. Pierangeli S. Antiphospholipid antibodies and the antiphospholipid syndrome: an update on treatment and pathogenic mechanisms. Current. Opinion in Hematology. 2006;13:366–75.
  22. Rosendaal F.R. Venous thrombosis: a multicausal disease. Lancet. 1999:353(9159):1167–73.
  23. Rosendaal F.R. Risk factors for venous thrombotic disease. Thromb Haemost. 1999;82:610–9.


About the Autors


Information about the authors:
Popa A.V. – Anesthesiologist Intensivist, SBIH « St. Vladimir City Children's Hospital of DHM», Center of Gravitational Blood Surgery and Hemodialysis.
E-mail: avpopa1@gmail.com
Emirova H.M. – MSMSU n.a. A.I. Evdokimov, Associate Professor of Pediatric Department, Ph.D.
Kozlovskaja N.L. – Sechenov First Moscow State Medical University, Prof. of Department of Nephrology and Hemodialysis of SPEP, Ph.D.
Zajceva O.V. – SBHI of MA MRRCI n.a. M.F. Vladimirskiy, Head of Pediatric Department, Prof., Ph.D.
Abaseeva T.Ju. – SBHI of MA MRRCI n.a. M.F. Vladimirskiy, Department of Pediatric Dialysis and Hemocorrection of Division of Transplantology, Nephrology and Surgical Hemocorrection, Senior Researcher, Ph.D.


Similar Articles


Бионика Медиа