Role of Thrombophilic Mutations in Childhood Cardiac and Great Vessel Thrombosis

Baris Malbora, Namik Ozbek, Zekai Avci, Hasibe Verdi, Bulent Alioglu, Birgul Varan, Fatma Belgin Atac
3.785 998

Abstract


Objective: This study was conducted to analyze the thrombophilic mutations of children with cardiac and great vessel thrombosis diagnosed in our hospital and investigate the risk factors.Methods: The clinical and laboratory findings of 41 children having cardiac and/or great vessel thrombosis between 1997 and 2009 were retrospectively analyzed. Results: All patients with cardiac thrombosis had an underlying associated clinical condition. The frequency of cardiac thrombosis was highest in children older than one year. Patients with congenital heart disease were the largest group (53.7%). Acquired risk factors were identified in 32 of the 41 patients. There was a significant relationship between right atrial thrombosis and wearing a central venous catheter, between right atrial thrombosis and systemic infection, between right ventricle thrombosis and angiographic procedure, and between right ventricle thrombosis and systemic infection. 33 of 41 patients (80.5%) who were examined had at least one thrombophilic mutation. Conclusion: Our study implies not only the underlying disorders   but the factor V Leiden and prothrombin G20210A mutations are the important predisposing molecular risk factors for cardiac thrombosis.  


Keywords


Children, congenital heart disease, cardiac thrombosis, great vessel thrombosis, thrombophilic mutations

Full Text:

E218


DOI: http://dx.doi.org/10.17334/jps.89654

References


Goldenberg NA, Pipe SW. Acquired disorders of hemostasis. In Nathan and Oski’s Hematology of Infancy and Childhood. 7th edition. Edited by Nathan DG, Orkin SH, Ginsburg D, Look AT. Pennsylvania: Saunders; 2009:1591-1620.

Nowak-Gottl U, Duering C, Kempf-Bielack B, Strater R. Thromboembolic diseases in neonates and children. Pathophysiol. Haemost Thromb 2004; 33(5-6):269-74.

Hanslik A, Thom K, Haumer M, Kitzmüller E, Albinni S, Wolfsberger M, Salzer-Muhar U, Male C. Incidence and diagnosis of thrombosis in children with short-term central venous lines of the upper venous system. Pediatrics 2008; 122(6):1284-91.

Tegeler CH, Downes TR. Thrombosis and the heart. Semin. Neurol. 1991; 11(4):339-52.

Brugnara C. Reference values in infancy and childhood. In Nathan and Oski’s Hematology of Infancy and Childhood. 7th edition. Edited by Nathan DG, Orkin SH, Ginsburg D, Look AT. Pennsylvania: Saunders; 2009:1769-96.

Altuntas N, Soylu K, Suskan E, Akar N. Homocysteine levels in Turkish children. Turk J Hematol 2004; 21: 79–

Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1998; 16(3):1215.

Ozbek N, Ataç FB, Verdi H, Cetintas S, Gürakan B, Haberal A. Relationship between small-for-gestational age births and maternal thrombophilic mutations. Thromb Res 2008; 122(2):175-8.

Kinik ST, Ozbek N, Yuce M, Yazici AC, Verdi H, Ataç FB. PAI-1 gene 4G/5G polymorphism, cytokine levels and their relations with metabolic parameters in obese children. Thromb Haemos 2008; 99(2):352-6.

Akar N, Akar E, Akcay R, Avcu F, Yalcin A, Cin S. Effect of methylenetetrahydrofolate reductase 677 C-T, 1298 A-C, and 1317 T-C on factor V 1691 mutation in Turkish deep vein thrombosis patients. Thromb Res 2000; 97(3):163-7.

De Stefano V, Zappacosta B, Persichilli S, Rossi E, Casorelli I, Paciaroni K, Chiusolo P, Leone AM, Giardina B, Leone G. Prevalence of mild hyperhomocysteinaemia and association with thrombophilic genotypes (factor V Leiden and prothrombin G20210A) in Italian patients with venous thromboembolic disease. Br J Haematol 1999;106(2):564-8.

Raffini L, Huang YS, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children's hospitals in the United States from 2001 to 2007. Pediatrics 2009; 124(4):1001-8.

Ozbek N, Atac FB, Yildirim SV, Verdi H, Yazici C, Yilmaz BT, Tokel NK. Analysis of prothrombotic mutations and polymorphisms in children who developed thrombosis in the perioperative period of congenital cardiac surgery. Cardiol Young 2005; 15(1):19-25.

Oren H, Devecioglu O, Ertem M, Vergin C, Kavakli K, Meral A, Canatan D, Toksoy H, Yildiz I, Kürekçi E, et al. Analysis of pediatric thrombotic patients in Turkey. Pediatr Hematol Oncol 2004; 21(7):573-83.

Atalay S, Akar N, Tutar HE, Yilmaz E. Factor V 1691 G-A mutation in children with intracardiac thrombosis: a prospective study. Acta Paediatr 2002; 91(2):168-71.

Gurgey A, Ozyurek E, Gumruk F, Celiker A, Ozkutlu S, Ozer S, Bilgiç A. Thrombosis in children with cardiac pathology: frequency of factor V Leiden and prothrombin G20210A mutations. Pediatr Cardiol 2003; 24(3):244-8.

Tempe DK, Virmani S. Coagulation abnormalities in patients with cyanotic congenital heart disease. J Cardiothorac Vasc Anesth 2002;16(6):752-65.

Nowak-Gottl U, Kotthoff S, Hagemeyer E, Junker R, Kehl HG, Vielhaber H, Kececioglu D. Interaction of fibrinolysis and prothrombotic risk factors in neonates, infants and children with and without thromboembolism and underlying cardiac disease: a prospective study. Thromb Res 2001; 103(2):93-101.

Massicotte MP, Dix D, Monagle P, Adams M, Andrew M. Central venous catheter related thrombosis in children: analysis of the Canadian Registry of Venous Thromboembolic Complications. J Pediatr 1998; 133(6):770-6.

Male C, Chait P, Andrew M, Hanna K, Julian J, Mitchell L. PARKAA Investigators Central venous linerelated thrombosis in children: association with central venous line location and insertion technique. Blood 2003; 101(11):4273-8.

Beck C, Dubois J, Grignon A, Lacroix J, David M. Incidence and risk factors of catheterrelated deep vein thrombosis in a pediatric intensive care unit: a prospective study. J Pediatr 1998; 133(2):237-41.

Hentschel R, Wiescholek U, von Lengerke J, Harms E, Jorch G. Coagulation-associated complications of indwelling arterial and central venous catheters during heparin prophylaxis-a prospective study. Eur J Pediatr 1999; 158 Suppl 3:126-9.

Andrew M, Marzinotto V, Pencharz P, Zlotkin S, Burrows P, Ingram J, Adams M, Filler R. A crosssectional study of catheter-related thrombosis in children receiving total parenteral nutrition at home. J Pediatr 1995; 126(3):358-63.

Nowak-Gottl U, Dubbers A, Kececioglu D, Koch HG, Kotthoff S, Runde J, Vielhaber H. Factor V Leiden, protein C, and lipoprotein (a) in catheter-related thrombosis in childhood: a prospective study. J Pediatr 1997; 131(4):608-12.

Mirro J Jr, Rao BN, Stokes DC, Austin BA, Kumar M, Dahl GV, Colten M, Balas L, Rafferty M, Hancock M, et al. A prospective study of Hickman/Broviac catheters and implantable ports in pediatric oncology patients. J Clin Oncol 1989; 7(2):214-22.

Male C, Julian JA, Massicotte P, Gent M, Mitchell L, PROTEKT Study Group: Significant association with location of central venous line placement and risk of venous thrombosis in children. Thromb Haemos 2005; 94(3):516-21.

Salonvaara M, Riikonen P, Kekomaki R, Heinonen K. Clinically symptomatic central venous catheter-related deep venous thrombosis in newborns. Acta Paediatr 1999; 88(6):642-6.

Goutail-Flaud MF, Sfez M, Berg A, Laguenie G, Couturier C, Barbotin-Larrieu F, Saint- Maurice C. Central venous catheter-related complications in newborns and infants: a 587-casesurvey. J Pediatr Surg 1991; 26(6):645

Randolph AG, Cook DJ, Gonzales CA, Brun-Buisson C. Tunneling short-term central venous catheters to prevent catheter-related infection: a meta-analysis of randomized, controlled trials. Crit Care Med 1998; 26(8):1452-7.

Randolph AG, Cook DJ, Gonzales CA, Andrew M. Benefit of heparin in peripheral venous and arterial catheters: systematic review and meta-analysis of randomized controlled trials. BMJ 1998; 316(7136):969

Akar N. Factor V 1691 G-A mutation distribution in a healthy Turkish population. Turk J Hematol 2009; 26:9

Gurgey A. Clinical manifestations in thrombotic children with factor V Leiden mutation. Pediatr Hematol Oncol 1999; 16(3):233-7.

Gurgey A, Mesci L. The prevalence of Factor V Leiden (1691 G-->A) mutation in Turkey. Turk J Pediatr 1997; 39(3):313-5.

Akar N, Akar E, Dalgin G, Sozuoz A, Omurlu K, Cin S. Frequency of Factor V (1691 G -->A) mutation in Turkish population. Thromb Haemost 1997;78(6):1527-8. Akar N, Misirlioglu M, Akar E, Avcu F, Yalcin A, Sozuoz A. Prothrombin gene 20210 G-A mutation in the Turkish population. Am J Hematol 1998; 58(3):249.

Gurgey A, Hicsonmez G, Parlak H, Balta G, Celiker A. Prothrombin gene 20210 G-A mutation in Turkish patients with thrombosis. Am J Hematol 1998; 59(2):179-80.

Kluijtmans LA, van den Heuvel LP, Boers GH, Frosst P, Stevens EM, van Oost BA, den Heijer M, Trijbels FJ, Rozen R, Blom HJ. Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996;58:35-41.

Akar N, Akar E, Ozel D, Deda G, Sipahi T. Common mutations at the homocysteine metabolism pathway and pediatric stroke. Thromb Res 2001;102:115-20.