Hakan ÖZSOY, Bülent ALİOĞLU, Beray SELVER, Esra TAPCİ, Esra YAZARLI, Gökhan KOCA

YÜKSEK VONWİLLEBRAND FAKTÖR DÜZEYLERİ ÇOCUKLUK ÇAĞI AĞIR HEMOFİLİ A HASTALARINDA KORUYUCU MUDUR?: ANKARA HASTANESİ DENEYİMİ

Bu çalışmada çocukluk çağı hemofili A (HA) tanısı alan çocuklarda protrombotik risk faktörlerin ilk semptom ile ilişkisinin incelenmesi amaçlandı. Ağır hemofili A tanısı alan 44 çocuk hasta ve cinsiyet ve yaş açısından benzer 40 sağlıklı çocuk alındı. Hastaların ilk kanama atağı yaşı ortalaması 13,4 ay idi. Hastalığın ağırlık derecesi ile klinik prezentasyonu ve ilk kanama yaşı arasında istatistiksel olarak anlamlı fark bulunmadı. Hemofili A hastaları ve kontrol grubu arasında prokoagülan ve antikoagülan proteinler açısından anlamlı fark bulunmadı. Buna karşın ilk kanama atağı yaşı ile yüksek vWF düzeyleri arasında belirgin bir ilişki saptandı. Çalışmamızda protrombotik risk faktörleri ile ağır hemofili A hastalarındaki ilk kanama atağı arasında bir ilişki saptanmadı. Buna karşın yüksek vWF düzeylerinin ilk semptomatik kanama atağı üzerine etkisinin incelendiği geniş çağlı araştırmalara gereksinim vardır.

IS ELEVATED VON WILLEBRAND FACTOR LEVELS PROTECTIVE FROM BLEEDING IN CHILDREN WITH SEVERE HEMOPHILIA A? ANKARA HOSPITAL EXPERIENCE

The present study was conducted to unravel the role of prothrombotic risk factors co-inherited with severe hemophilia A (HA) with respect to the first symptomatic onset of the disease in pediatric hemophiliacs. Forty-four pediatric patients with severe HA and 40 age and sex matched healthy control subjects were enrolled in this study. Mean age at first bleed was 13.4 months. Statistical difference was not detected between patients with severe HA and clinical presentation at onset and age of first bleed. Statistical difference was not detected between patients with HA and healthy controls with respect to the presence of procoagulant and anticoagulant proteins. However, significant relation was determined between age of first bleed and elevated vWF levels. Our data demonstrate that the first symptomatic bleeding onset leading in children with severe hemophilia to diagnosis of the disease is not associated with in hemophilic subjects additionally carrying prothrombotic risk factors than in non-carriers. Future large studies are needed to investigate the effects of elevated vWF levels on first symptomatic bleeding in patients with severe HA.

PDF

___

1)Hoyer LW. Hemophilia A. N Engl J Med 1994; 330: 38-47.
2)Walsh PN, Rainsford SG, Biggs R. Platelet coagulant activities and clinical severity in hemophilia. Thromb Diath Haemorrh 1973; 29: 722-729.
3)Lane DA, Mannucci PM, Bertina RM, Bochkov NP, Bouljenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia: Part 1. Thromb Haemost 1996; 76: 651-662.
4)Oldenburg J, Schröder J, Schmitt C, Brackmann HH, Schwab R. Small deletion/insertion mutations within poly-A runs of the factor VIII gene mitigate the severe hemophilia A phenotype. Thromb Haemost 1998; 79: 452-453.
5)Lakich D, Kazazian HH, Antonarakis SE, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nature Genet 1993; 5: 236-241.
6)Nichols WC, Amano K, Cacheris PM, Figueiredo MS, Michaelides K, Schwaab R, Hoyer L, Kaufman RJ, Ginsburg D. Moderation of hemophilia A phenotype by the factor V R506Q mutation. Blood 1996; 88: 1183-1187.
7)Hacker MR, Funk SM, Manco-Johnson MJ. The Colorado Haemophilia Paediatric Joint Physical Examination Scale: normal values and interrater reliability. Haemophilia 2007; 13: 71-78.
8)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: 163-167.
9)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 Aug;106(2):564-568.
10)Lee DH, Walker IR, Teitel J, Poon MC, Ritchie B, Akabutu J, Sinclair GD, Pai M, Wu JWY, Reddy S, Carter C, Growe G, Lillicrap D, Lam M, Blajchman MA. Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A. Thromb Haemost 2000; 83: 387-389.
11)Ettingshausen CE, Halimeh S, Kurnik K et al. Symptomatic onset of severe hemophilia A in childhood is dependant on the presence of prothrombotic risk factors. Thromb Haemost 2001; 85: 218–220.
12)Tizzano EF, Cornet M, Domenech M, Baiget M. Modifier genes in haemophilia: their expansion in the human genome. Haemophilia 2002; 8: 250–254.
13)Kurnik K, Kreuz W, Horneff S, Düring C, Schobess R, Bidlingmaier C, Ettingshausen CE, Krümpel A, Bogdanova N, Nowak-Göttl U. Effects of the factor V G1691A mutation and the factor II G20210A variant on the clinical expression of severe hemophilia A in children--results of a multicenter studys. Haematologica 2007; 92: 982-985.
14)Ahmed R, Kannan M, Choudhry VP, et al. Does the MTHFR 677CT allele alter the clinical phenotype in severe hemophilia A. Thromb Res 2003; 109: 71-72.
15)Nowak-Gottl U, Escuriola C,Kurnik K, et al. Haemophilia and thrombophilia. What do we learn about combined inheritance of both genetic variations? Hamostaseologie 2003; 23: 36-40.
16)Ghosh K, Shetty S, Mohanty D. Milder clinical presentation of hemophilia A with severe deficiency of factor VIII as measured by one-stage assay. Haemophilia 2001; 7: 9–12.
17)Grünewald M, Grunwald A, Gireshammer M. Paradoxycal hyperfibrinolysis is associated with a more intensely haemorrhagic phemotype in severe congenital haemophilia. Hamostaseologie 2003; 23: 36-40.
18)Gurgey A, Mesci L. The prevalence of factor V Leiden (1691 G-->A) mutation in Turkey. Turk J Pediatr 1997; 39: 313-315.
19)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: 1527-1528.
20)Chan J, Weinmann AF, Thompson AR. Factor V Arg/ Gln 506 has no dominant influence on the severity of hemophilia when inherited concurrently. Thromb Haemost 1995; 73: 1368.
21)Arbini AA, Manucci PM, Bauer KA. Low prevalence of the factor V Leiden mutation among severe hemophiliacs with a milder bleeding diathesis. Thromb Haemost 1995; 74: 1255–1258.
22)Arruda VR, Annichino-Bizzachi JM, Antunes SV et al. Association of severe hemophilia A and factor V Leiden: report of three cases. Haemophilia 1996; 2: 51–53.
23)Ar MC, Baykara O, Buyru AN, Baslar Z. The impact of prothrombotic mutations on factor consumption in adult patients with severe hemophilia. Clin Appl Thromb Hemost. 2009 Dec;15(6):660-5. Epub 2008 Jul 3.38-41.
24)Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med. 1995 Mar 9;332(10):635-41.
25)Jastrzebska M, Torbus-Lisiecka B, Honczarenko K, Foltynska A, Chełstowski K, Naruszewicz M. Von Willebrand factor, fibrinogen and other risk factors of thrombosis in patients with a history of cerebrovascular ischemic stroke and their children. Nutr Metab Cardiovasc Dis. 2002 Jun;12(3):132-40.