The factor VIII D1241E polymorphism is associated with decreased factor VIII activity and not with activated protein C resistance levels

Daniela Scanavini; Cristina Legnani; Barbara Lunghi; Federico Mingozzi; Gualtiero Palareti; Francesco Bernardi

doi:10.1160/TH04-09-0629

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2005; 93(03): 453-456
DOI: 10.1160/TH04-09-0629

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

The factor VIII D1241E polymorphism is associated with decreased factor VIII activity and not with activated protein C resistance levels

Daniela Scanavini

¹Department of Biochemistry and Molecular Biology, Ferrara University, Italy

,

Cristina Legnani

²Department of Angiology, Unità Ricerca Clinica sulla Trombofilia “Marino Golinelli“, University Hospital S. Orsola-Malpighi, Bologna, Italy

,

Barbara Lunghi

¹Department of Biochemistry and Molecular Biology, Ferrara University, Italy

,

Federico Mingozzi

¹Department of Biochemistry and Molecular Biology, Ferrara University, Italy

³Department of Pediatrics, Children's Hospital of Philadelphia and University of Pennsylvania Medical Center, Philadelphia, USA

,

Gualtiero Palareti

²Department of Angiology, Unità Ricerca Clinica sulla Trombofilia “Marino Golinelli“, University Hospital S. Orsola-Malpighi, Bologna, Italy

,

Francesco Bernardi

¹Department of Biochemistry and Molecular Biology, Ferrara University, Italy

› Institutsangaben

Abstract

Summary

Elevated factor VIII (FVIII) levels are a recognized risk factor for venous thrombosis. Recently, family studies suggested that the G allele of the 3951C/G (D1241E) FVIII polymorphism is associated to lower FVIII activity. We investigated in case-control studies both biological effects (FVIII levels and activated protein C sensitivity ratio) and clinical associations (venous thromboembolism) of the D1241E change. Among 145 healthy and 150 thrombotic women, not carriers of known thrombophilic defects, the 1241E allele was associated with 11% reduced (t-test, P< 0.05) FVIII levels. The effect on activated protein C sensitivity ratio was not statistically significant. Carriership of the 1241E allele, potentially conferring protection from thrombosis, was found in 22.8% of controls and in 15.3% of cases. In an additional cohort of factor V Leiden carriers (n=283), carriership of the 1241E allele was 25.2% among 143 asymptomatic subjects and 17.1% among 140 thrombotic patients. Our data do not indicate a specific interaction with factor V Leiden. These genotype distributions suggest a mild protective effect from venous thrombosis conferred by 1241E FVIII, masked by other genetic and/or environmental components, and detectable only in very large population studies. Our findings point toward the presence of genetic determinant of coagulation factor levels with a biologically significant role, but with a poor predictive value to estimate thrombotic risk beyond established risk factors.

Keywords

FVIII levels - FVIII polymorphisms - thrombosis - APC resistance

Volltext

Referenzen

References
1 Kamphuisen PW, Eikenboom JC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol 2001; 21: 731-8.
2 Koster T, Blann AD, Briët E. et al. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis. Lancet 1995; 345: 152-5.
3 Kyrle PA. et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-62.
4 Legnani C, Cosmi B, Cini M. et al. High plasma levels of factor VIII and risk of recurrence of venous thromboembolism. Br J Haematol 2004; 124: 504-10.
5 Henkens CM, Bom VJ, van der Meer J. Lowered APC-sensitivity ratio related to increased factor VIII-clotting activity. Thromb Haemost 1995; 74: 1198-9.
6 Laffan MA, Manning R. The influence of factor VIII on measurement of activated protein C resistance. Blood Coagul Fibrinolysis 1996; 7: 761-5.
7 de Visser MCH, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93: 1271-6.
8 Souto JC, Almasy L, Muniz-Diaz E. et al. Functional effects of the ABO locus polymorphism on plasma levels of von Willebrand factor, factor VIII, and activated partial thromboplastin time. Arterioscler Thromb Vasc Biol 2000; 20: 2024-8.
9 Conlan MG, Folsom AR, Finch A. et al. Associations of factor VIII and von Willebrand factor with age, race, sex, and risk factors for atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study. Thromb Haemost 1993; 70: 380-5.
10 Souto JC, Almasy L, Borrell M. et al. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 2000; 101: 1546-51.
11 Mansvelt EP, Laffan M, Mc Vey JH. et al. Analysis of the F8 gene in individuals with high plasma factor VIII:C levels and associated venuos thrombosis. Thromb Haemost 1998; 80: 561-5.
12 Kamphuisen PW, Eikenboom JC, Rosendaal FR. et al. High factor VIII antigen levels increase the risk of venous thrombosis but are not associated with polymorphisms in the von Willebrand factor and factor VIII gene. Br J Haematol 2001; 115: 156-8.
13 Keigthley AM, Lam YM, Brady JN. et al. Variation at the von Willebrand factor (vWF) gene locus is associated with plasma vWF:Ag levels: identification of three novel single nucleotide polymorphisms in the vWF gene promoter. Blood 1999; 93: 4277-83.
14 De Visser MC, Sandkuijl LA, Lensen RP. et al. Linkage analysis of factor VIII and von Willebrand factor loci as quantitative trait loci. J Thromb Haemost 2003; 1: 1771-6.
15 Soria JM, Almasy L, Souto JC. et al. A new locus on chromosome 18 that influences normal variation in activated protein C resistance phenotype and factor VIII activity and its relation to thrombosis susceptibility. Blood 2003; 101: 163-7.
16 Machiah DK, Viel K, Almasy L. et al. A common SNP in the factor VIII (FVIII) gene encodes a conservative aspartate to glutamate substitution (Asp1241Glu) in the B-domain that influences FVIII activity levels. Blood 2003; 102 (11) Abstract 181
17 Becker J, Schwaab R, Moller-Taube A. et al. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: family studies indicate a mutation type-dependent sex ratio of mutation frequencies. Am J Hum Genet 1996; 58: 657-70.
18 Scanavini D. et al. Modulation of factor V levels in plasma by polymorphisms in the C2 domain. Arterioscler Thromb Vasc Biol 2004; 24: 200-6.
19 de Ronde H, Bertina RM. Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost 1994; 72: 880-6.