Co-inheritance of Factor V Leiden in Cases with Inherited Hemophilia A in North India
Keywords:
Hemophilia A, Factor V Leiden, Co-inheritance, Prevalence, North India
Abstract
Background: Considerable variation has been noted in the age at onset and bleeding pattern in Cases with Hemophilia A (CWH) of severe type. Mechanisms seem multifactorial with co-inheritance of Factor V Leiden mutation (FVL) with severe Hemophilia A (HA) being one of them. There is evidence that carrier ship of FVL mutation in CWH might confer an evolutionary selective advantage leading to a milder clinical phenotype. The authors hypothesized that FVL mutation may be more prevalent in CWH. The present study was undertaken to determine the prevalence of FVL mutation in CWH and evaluate the phenotypic effect of this co-inheritance on clinical severity of hemophilia.Methods: A total of 100 CWH were recruited for this study. Detailed clinical history regarding the age at onset, type, frequency and site of bleeding was taken. Coagulation work up including Factor VIII (FVIII) assay and von willebrand factor antigen (VWFAg) were done. FVL mutation and intron 22 inversion mutation were studied.Result: Fifty six CWH had FVIII <1% categorizing them into severe category. FVL mutation was present in 3 cases. All the three cases had FVIII levels <1% with Intron 22 inversion, were heterozygous for FVL and were clinically severe. Out of these three patients, two were siblings and the third sibling who is also a severe hemophilia patient, did not carry FVL mutation.Conclusion: The results suggest that prevalence of FVL mutation in CWH is similar to that in non-hemophilic population and this mutation has no definite influence on the clinical severity in CWH.References
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23. Rossetti LC, Radic CP, Candela M, et al. Sixteen novel hemophilia A causative mutations in the first Argentinian series of severe molecular defects. Haematologica 2007;92:842-845.
24. Brummel-Zeidins K, Orfeo T,Jenny NS, et al. Blood coagulation and fibrinolysis. In: Greer JP, Foerster J, Lukens JN, Rodgers GM, Paraskevas F, Glader B, eds. Wintrobe’s Clinical Hematology Vol. 1, 11th edn. Philadelphia: Lippincott Williams & Wilkins 2004:677-774.
25. Lee DH, Walker IR, Teitel J, et al. Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A. Thromb Haemost 2000; 83:387–389.
26. Kurnik K, KreuzW, Homeff S, et al. Effects of the factor V G1691A mutation and the factor IIG20210A variant on the clinical expression of severe hemophilia A in children–results of a multicenter studys. Haematologica 2007;92:982–985.
27. Tizzano EF, Soria JM, Coll I, et al. The prothrombin 20210A allele influences clinical manifestations of hemophilia A in patients with intron 22 inversion and without inhibitors. Haematologica 2002;87: 279–285.
28. Vianello F, Belvini D, Dal Bello F, et al. Mild bleeding diathesis in a boy with combined severe haemophilia B (C10400→T) and heterozygous factor V Leiden. Haemophilia 2001;7:511–514.
29. Arbini AA, Mannucci 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.
30. Beltran-Miranda CP, Khan A, Jaloma-Cruz AR, et al. Thrombin generation and phenotypic correlation in haemophilia. Haemophilia 2005;11:326–334.
31. Petkova R, Chakarov S, Horvath A, et al. Coexistence of a common prothrombotic risk factor and hemophilia in the Bulgarian hemophilic population: genotype/phenotype correlations. Balk J Med Genet 2001;4:37–40.
32. Araújo F, Fraga M, Henriques I, Monteiro F, Meireles E, Pereira C, et al. The clinical phenotype modulation of haemophilia by prothrombotic gene mutations. Haemophilia 2003;9:235–236.
33. Foka ZJ, Lambropoulos AF, Makris PE,et al. High frequency of factor V Leiden and prothrombin G20210A mutations in Greek hemophiliacs. J Thromb Haemost 2003;1:1116–1117.
2. Tizzano EF, Cornet M, Dome`nech M, et al. Modifier genes in haemophilia: their expansion in the human genome. Haemophilia. 2002;8:250–254
3. van den Berg HM, De Groot PH, Fischer K. Phenotypic heterogeneity in severe hemophilia. J Thromb Haemost. 2007;5:151–156
4. Ar MC, Baykara O, Buyru AN, et al. The impact of prothrombotic mutations on factor consumption in adult patients with severe hemophilia. Clin Appl Thromb Hemost. 2009;15:660-665
5. Grunewald M, Grunewald A, Griesshammer M.Paradoxical hyperfibrinolysis is associated with a more intensely haemorrhagic phenotype in severe congenital haemophilia. Haemophilia. 2002;8: 768-775.
6. Siegemund T, Petros S, Siegemund A, et al. Thrombin generation in severe haemophilia A and B: the endogenous thrombin potential in platelet-rich plasma. Thromb Haemost. 2003;90: 781-786.
7. Shetty S, Ghosh K. Reduced clinical severity in a mutationally well characterized cohort of severe hemophilia with associated thrombophilia. Am J Clin Pathol. 2008;130: 84-87.
8. Escuriola Ettingshausen C, Halimeh S, Kurnik K, et al. Symptomatic onset of severe Hemophilia A in childhood is dependent on the presence of prothrombotic risk factors. Thromb Haemost. 2001; 85:218-220.
9. Nichols WC, Amano K, Cacheris PM, et al. Moderation of hemophilia A phenotype by the factor V R506Q mutation. Blood. 1996;88: 1183–1187
10. Arruda VR, Annichino-Bizzacchi JM, Antunes SV, et al. Association of severe hemophilia A and Factor V Leiden: report of three cases. Hemophilia. 1996;2: 51-53.
11. Schulman S, Eelde A, Holmstrom M, et al.Validation of a composite score for clinical severity of Hemophilia. J Thromb Hemost 2008;6 :1113-1121
12. Rees DC, Cox M, Clegg JB. World distribution of Factor V Leiden. Lancet 1995;346:1133-1134.
13. Koshy A, Jeyakumari M. Factor V Leiden is not commonly associated with idiopathic portal vein thrombosis in southern India. Indian J Gastroenterol 2006;25:140-142.
14. Garewal G, Das R, Varma S, et al. Heterogenous distribution of Factor V Leiden in patients from North India with venous thromboembolism. J Thromb Haemost. 2003;1:1329-1330.
15. Sharma S, Kumar IS, Poddar U, et al. Factor V Leiden and Prothrombin gene G20210 mutations are uncommon in portal vein thrombosis in India. Indian J Gastroenterol. 2006;25:236-239.
16. Ghosh K, Shetty S, Madkaikar M, et al. Venous thromboembolism in young patients from western India: a study. Clin Appl Thromb Hemost.2001;7: 158–165.
17. Franchini M, Lippi G. Factor V Leiden and hemophilia. Thromb Res 2010;125:119-123.
18. Shetty S, Vora S, Kulkarni B, et al. Contribution of natural anticoagulant and fibrinolytic factors in modulating the clinical severity of hemophilia patients. Br J Haematol. 2007;138:541-544.
19. Ghosh K, Shetty S, Mohanty D. Milder clinical presentation of Hemophilia A with severe deficiency of factor VIII as measured by one-stage assay. Hemophilia 2001;7:9-12.
20. Ahmed R, Kannan M, Choudhry VP, et al. Does the MTHFR 677 T allele alter the clinical phenotype in severe haemophilia A? Thromb Res 2003; 109:71–72.
21. Friedman KD,Rodgers GM. Inherited coagulation disorders. In: Greer JP, Foerster J, Lukens JN, Rodgers GM, Paraskevas F, Glader B, eds. Wintrobe’s Clinical Hematology Vol. 1, 11th edn. Philadelphia: Lippincott Williams & Wilkins 2004:677-774.
22. Konkle BA, Josephson NC, Nakaya Fletcher SM,et al. Hemophilia A. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K, eds. Gene ReviewsTM [Internet] Seattle (WA): University of Washington, Seattle; 1993-2013.
23. Rossetti LC, Radic CP, Candela M, et al. Sixteen novel hemophilia A causative mutations in the first Argentinian series of severe molecular defects. Haematologica 2007;92:842-845.
24. Brummel-Zeidins K, Orfeo T,Jenny NS, et al. Blood coagulation and fibrinolysis. In: Greer JP, Foerster J, Lukens JN, Rodgers GM, Paraskevas F, Glader B, eds. Wintrobe’s Clinical Hematology Vol. 1, 11th edn. Philadelphia: Lippincott Williams & Wilkins 2004:677-774.
25. Lee DH, Walker IR, Teitel J, et al. Effect of the factor V Leiden mutation on the clinical expression of severe hemophilia A. Thromb Haemost 2000; 83:387–389.
26. Kurnik K, KreuzW, Homeff S, et al. Effects of the factor V G1691A mutation and the factor IIG20210A variant on the clinical expression of severe hemophilia A in children–results of a multicenter studys. Haematologica 2007;92:982–985.
27. Tizzano EF, Soria JM, Coll I, et al. The prothrombin 20210A allele influences clinical manifestations of hemophilia A in patients with intron 22 inversion and without inhibitors. Haematologica 2002;87: 279–285.
28. Vianello F, Belvini D, Dal Bello F, et al. Mild bleeding diathesis in a boy with combined severe haemophilia B (C10400→T) and heterozygous factor V Leiden. Haemophilia 2001;7:511–514.
29. Arbini AA, Mannucci 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.
30. Beltran-Miranda CP, Khan A, Jaloma-Cruz AR, et al. Thrombin generation and phenotypic correlation in haemophilia. Haemophilia 2005;11:326–334.
31. Petkova R, Chakarov S, Horvath A, et al. Coexistence of a common prothrombotic risk factor and hemophilia in the Bulgarian hemophilic population: genotype/phenotype correlations. Balk J Med Genet 2001;4:37–40.
32. Araújo F, Fraga M, Henriques I, Monteiro F, Meireles E, Pereira C, et al. The clinical phenotype modulation of haemophilia by prothrombotic gene mutations. Haemophilia 2003;9:235–236.
33. Foka ZJ, Lambropoulos AF, Makris PE,et al. High frequency of factor V Leiden and prothrombin G20210A mutations in Greek hemophiliacs. J Thromb Haemost 2003;1:1116–1117.
Published
2015-10-08
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