Haplotypes encoding the factor VIII 1241Glu variation, factor VIII levels and the risk of venous thrombosis

Summary

Levels of factorVIII (FVIII) are associated with the risk of venous thrombosis.The FVIII variation D1241E has been reported to be associated with decreased levels of FVIII. Our objective was to study whether D1241E is associated with levels of FVIII and the risk of venous thrombosis and whether this association is caused by D1241E or another linked variation.We analyzed the association of three FVIII gene haplotypes encoding 1241E (further denoted as HT1, HT3, and HT5) with FVIII levels and thrombosis risk. This analysis was performed in the Leiden Thrombophilia Study (LETS). The control populations of two case-controls studies on arterial thrombosis in men and women, respectively, were used to confirm the effects observed on FVIII:C in the LETS.In men,HT1 was associated with a 6% reduction in FVIII:C and witha reduced risk of venous thrombosis [odds ratio 0.4 (CI95 0.2–0.8)]. Logistic regression showed that the risk reduction was only partially dependent of the reduction in FVIII levels. HT1 showed no effects in women on either FVIII:C or risk of thrombosis.The number of carriers of HT3 and HT5 was too low to make an accurate estimate of the risk of venous thrombosis. Neither HT3 nor HT5 showed effects on levels of FVIII:C.When we consider that all three haplotypes encoding 1241E show different effects on FVIII:C and thrombosis risk, it is possible that D1241E is not the functional variation. However, FVIII gene variations do contribute to both levels of FVIII and the risk of thrombosis.

Keywords

FVIII - haplotypes - levels - venous thrombosis - risk

• References

• 1 Koster T, Blann AD, Briet 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.
• 2 Lowe GD, Haverkate F, Thompson SG. et al. Prediction of deep vein thrombosis after elective hip replacement surgery by preoperative clinical and haemostatic variables: the ECAT DVT Study. European Concerted Action on Thrombosis. Thromb Haemost 1999; 81: 879-86.
• 3 Kraaijenhagen RA, in’t PSAnker, Koopman MM. et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5-9.
• 4 O’Donnell J, Mumford AD, Manning RA. et al. Elevation of FVIII: C in venous thromboembolism is persistent and independent of the acute phase response. Thromb Haemost 2000; 83: 10-3.
• 5 Kyrle PA, Minar E, Hirschl M. et al. High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-62.
• 6 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.
• 7 Tsai AW, Cushman M, Rosamond WD. et al. Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). Am J Med 2002; 113: 636-42.
• 8 Morelli VM, De Visser MC, Vos HL. et al. ABO blood group genotypes and the risk of venous thrombosis: effect of factor V Leiden. J Thromb Haemost 2005; 03: 183-5.
• 9 Kamphuisen PW, Eikenboom JC, Vos HL. et al. Increased levels of factor VIII and fibrinogen in patients with venous thrombosis are not caused by acute phase reactions. Thromb Haemost 1999; 81: 680-3.
• 10 Kawasaki T, Kaida T, Arnout J. et al. A new animal model of thrombophilia confirms that high plasma factor VIII levels are thrombogenic. Thromb Haemost 1999; 81: 306-11.
• 11 Kamphuisen PW, Houwing-Duistermaat JJ, van Houwelingen HC. et al. Familial clustering of factor VIII and von Willebrand factor levels. Thromb Haemost 1998; 79: 323-7.
• 12 Kamphuisen PW, Lensen R, Houwing-Duistermaat JJ. et al. Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia. Br J Haematol 2000; 109: 519-22.
• 13 Mansvelt EP, Laffan M, McVey JH. et al. Analysis of the F8 gene in individuals with high plasma factor VIII: C levels and associated venous thrombosis. Thromb Haemost 1998; 80: 561-5.
• 14 SeattleSNPs. SeattleSNPs. NHLBI Program for Genomic Applications, SeattleSNPs, Seattle, WA, USA 2004
• 15 Machiah D, Viel K, Almasy L. et al. A common SNP in the factor VIII (f-VIII) gene encodesa conservative aspartate to glutamate substitution (Asp1241Glu) in the B-domain that influences f-VIII activity levels. Blood. 2003 102. Abstract.
• 16 Scanavini D, Legnani C, Lunghi B. et al. The factor VIII D1241E polymorphism is associated with decreased factor VIII activity and not with activated protein C resistance levels. Thromb Haemost 2005; 93: 453-6.
• 17 Koster T, Rosendaal FR, de Ronde H. et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-6.
• 18 Doggen CJ, Kunz G, Rosendaal FR. et al. A mutation in the thrombomodulin gene, 127G to A coding for Ala25Thr, and the risk of myocardial infarction in men. Thromb Haemost 1998; 80: 743-8.
• 19 Tanis BC, Bloemenkamp DG, van den Bosch MA. et al. Prothrombotic coagulation defects and cardiovascular risk factors in young women with acute myocardial infarction. Br J Haematol 2003; 122: 471-8.
• 20 Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet 1955; 19: 251-3.
• 21 Toole JJ, Pittman DD, Orr EC. et al. A large region (approximately equal to 95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity. Proc Natl Acad Sci USA 1986; 83: 5939-42.
• 22 Miao HZ, Sirachainan N, Palmer L. et al. Bioengineering of coagulation factor VIII for improved secretion. Blood 2004; 103: 3412-9.
• 23 Lenting PJ, van Mourik JA, Mertens K. The life cycle of coagulation factor VIII in view of its structure and function. Blood 1998; 92: 3983-96.
• 24 Thompson AR. Structure and function of the factor VIII gene and protein. Semin Thromb Hemost 2003; 29: 11-22.
• 25 Dorner AJ, Bole DG, Kaufman RJ. The relationship of N-linked glycosylation and heavy chain-binding protein association with the secretion of glycoproteins. J Cell Biol 1987; 105: 2665-74.
• 26 Bovenschen N, Rijken DC, Havekes LM. et al. The B domain of coagulation factor VIII interacts with the asialoglycoprotein receptor. J Thromb Haemost 2005; 03: 1257-65.