The ABO blood group genotype and factor VIII levels as independent risk factors for venous thromboembolism

Summary

Factor VIII (FVIII), von Willebrand factor (vWF) and the ABO blood groups have been associated with thrombosis. The ABO locus has functional effects on vWF and FVIII levels and is genetically correlated with FVIII, vWF and thrombosis. We carried out a case-control study to assess the role of FVIII, vWF and ABO types on thrombotic risk. We analyzed 250 patients with venous thrombosis and 250 unrelated controls. FVIII, vWF and other factors related to thrombophilia were measured, ABO groups were analyzed by genotyping. FVIII and vWF were higher in non-O individuals. Group O was more frequent in the controls (44.3% v 23.3%; difference 21.1%; 95% CI: 13.0–29.3%) and Group A in patients (59.2% v. 41.5%; difference 17.7%, 95% CI: 9.1–26.4%). Individuals carrying the A₁ allele had a higher risk of thrombosis (OR 2.6; 95% CI, 1.8–3.8). The risk attributed to vWF disappeared after adjusting for the ABO group. Patients with FVIII above the 90^th percentile had a high thrombotic risk (adjusted OR 3.7; 95%CI, 2.1–6.5), and a high risk of recurrence (OR 2.3; 95%CI: 1.3–4.1). In conclusion, high FVIII levels and non-O blood groups, likely those with the A₁ allele, are independent risk factors for venous thromboembolism and should be considered in evaluating of thrombophilia.

Keywords

Factor VIII - ABO genotypes - von Willebrand factor - venous thrombosis - thrombophilia

• References

• 1 Coon WW, Park WW, Keller JB. Venous thromboembolism and other venous disease in the Tecumseh Community Health Study. Circulation 1973; 48: 839-46.
• 2 Nordstrom M, Lindblad B, Bergqvist D. et al. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992; 232: 155-60.
• 3 Anderson FA, Wheeler HB, Goldberg RJ. et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991; 151: 933-8.
• 4 Orstavik KH, Magnus P, Reisner H. et al. Factor VIII and factor IX in a twin population: evidence for a major effect of ABO locus on factor VIII level. Am J Hum Genet 1985; 37: 89-101.
• 5 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.
• 6 Gill JC, Endres-Brooks J, Bauer PJ. et al. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691-5.
• 7 Caekebeke-Peerlinck KMJ, Koster T, Briët E. Bleeding time, blood groups and von Willebrand factor. Br J Haematol 1989; 73: 217-20.
• 8 Souto JC, Almansy L, Muñiz-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. Arteriocler Thromb Vasc Biol 2000; 20: 2024-8.
• 9 Medalie JH, Levene C, Papier CH. et al. Blood groups, myocardial infarction and angina pectoris among 10000 adult males. N Engl J Med 1971; 285: 1348-53.
• 10 Meade TW, Cooper JA, Stirling Y. et al. Factor VIII, ABO blood group and the incidence of ischaemic heart disease. Br J Haematol 1994; 88: 601-7.
• 11 Kingsbury KJ. Relation of ABO groups to atherosclerosis. Lancet 1971; 1: 199-203.
• 12 Hall R, Bunch GA, Humpery CS. The frequencies of ABO blood group and secretors of ABH group substances in peripheral atherosclerosis. Atherosclerosis 1971; 14: 241-6.
• 13 O’Donell J, Tuddenham EGD, Manning R. et al. High prevalence of elevated factor VIII levels in patients referred for thrombophilia screening: role of increased synthesis and relationship to the acute phase reaction. Thromb Haemost 1997; 77: 825-8.
• 14 Wautrecht JC, Galle C, Motte S. et al. The role of ABO blood groups in the incidence of deep vein thrombosis. Thromb Haemost 1998; 79: 668-9.
• 15 Folsom AR, Wu KK, Rosamond WD. et al. Prospective study of hemostatic factors and incidence of coronary heart disease: The atherosclerosis risk in communities (ARIC) study. Circulation 1997; 96: 1102-8.
• 16 Wahlberg TB, Blomback M, Overmark I. Blood coagulation studies in 45 patients with ischemic cerebrovascular disease and 44 patients with venous thromboembolic disease. Acta Med Scand 1980; 207: 385-90.
• 17 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.
• 18 Oger E, Lacut K, van Dreden P. et al. High plasma concentration of factor VIII coagulant is also a risk factor for venous thromboembolism in the elderly. Haematologica 2003; 88: 465-9.
• 19 Kamphuisen PW, Eikenboom JCJ, 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.
• 20 O’Donell 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.
• 21 Souto JC, Almasy L, Borrell M. et al. Genetic susceptibility to thrombosis and its relationship to physiological risk factors: The GAIT study. Am J Hum Genet 2000; 67: 1452-9.
• 22 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.
• 23 Tirado I, Soria JM, Mateo J. et al. Association after linkage analysis indicates that the 46 C → T polymorphism in the F12 gene is a new genetic risk factor for venous thrombosis. Thromb Haemost 2004; 91: 899-904.
• 24 Souto JC, Almasy L, Borrell M. et al. Genetic determinants of hemostasis phenotypes in Spanish families. Circulation 2000; 101: 1546-51.
• 25 Hyland K, Bottiglieri T. Measurement of total plasma and cerebrospinal homocysteine by fluorescence following high-performance liquid chromatography and precolumn with opthaldialdehyde. J Chromatogr 1992; 79: 55-62.
• 26 Exner T, Rickard KA, Kronenberg H. A sensitive test demonstrating lupus anticoagulant and its behavioral patterns. Br J Haematol 1987; 40: 143-51.
• 27 Gharavi AE, Harris EN, Asherson RA. et al. Anticardiolipin antibodies: isotype distribution and phospholipid specificity. Ann Rheum Dis 1987; 46: 1-6.
• 28 Blanco-Vaca F, Arcelús R, González-Sastre F. et al. Comparison of the Abbott IMX® and a high-performance liquid chromatography method for measuring total plasma homocysteine. Clin Chem Lab Med 2000; 38: 327-9.
• 29 Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res 1988; 16: 1215
• 30 Soria JM, Almasy L, Souto JC. et al. A quantitativetrait locus in the human factor XII gene influences both plasma factor XII levels and susceptibility to thrombotic disease. Am J Hum Genet 2002; 70: 567-74.
• 31 Souto JC, Coll I, Llobet D. et al. The Prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population. Thromb Haemost 1998; 80: 366-9.
• 32 Muñiz-Díaz E, Martínez C, Arilla M. et al. ABO Genotyping and frequency of the O 2 allele in a Spanish population. Transfusion 1999; 39: 45S
• 33 Kyrle PA, Minar E, Hirschll M. et al. High plasma of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med 2000; 343: 457-62.
• 34 Kraaijenhagen RA, Anker PS, Koopman MM. et al. High plasma concentration of factor VIIIc is a major risk factor for venous thromboembolism. Thromb Haemost 2000; 83: 5-9.
• 35 Schambeck CM, Hinney K, Haubitz I. et al. Familial clustering of high factor VIII levels in patients with venous thromboembolism. Arterioscler Thromb Vas Biol 2001; 21: 289-92.
• 36 Kyrle PA, Minar E, Bialonczyk C. et al. The risk of recurrent venous thromboembolism in men and women. N Engl J Med 2004; 350: 2558-63.
• 37 Baglin T, Luddington R, Brown K. et al. High risk of recurrent venous thromboembolism in men. J Thromb Haemost 2004; 2: 2152-5.
• 38 O’Donell J, Boulton FE, Manning RA. et al. Amount of H antigen expressed on circulating von Willebrand factor is modified by ABO blood group genotype and is a major determinant of plasma von Willebrand factor antigen levels. Arterioscler Thromb Vasc Biol 2002; 22: 335-41.
• 39 Bowen DJ. An influence of ABO group on the rate of proteolysis of von Willebrand factor by ADAMTS13. J Thromb Haemost 2003; 1: 33-40.