Abstract
Background: A specific point G-A transition at nucleotide position 1691 in the factor V (FV) gene, FV-Leiden, was associated with increased risk of venous thromboembolism (VTE). Insofar as the association of FV-Leiden with coronary artery disease (CAD) remains poorly defined, the aim of this study was to determine the prevalence of FV-Leiden in a sample of 68 VTE patients, 69 CAD patients, and 192 randomly selected healthy subjects.
Methods: Total genomic DNA was extracted from the peripheral blood of study subjects and was used for PCR analysis. The presence (or absence) of FV-Leiden was assessed by PCR using primers flanking the mutant site (nt 1691), followed by hybridization with wild-type (‘G’) and mutant (‘A’) biotinylated DNA probes; detection was by DNA enzyme immunoassay (DEIA).
Results: While the prevalence of FV-Leiden in CAD patients was not statistically different from that of healthy subjects (14.5%% vs. 15.1%%; P=0.890, odds ratio 0.95; 95%% confidence interval 0.43–2.06), a significant increase in FV-Leiden prevalence was seen in VTE patients (70.6%% in VTE patients; P<0.001, odds ratio 13.4, 95%% confidence interval 6.9–25.8). Of the 48 VTE patients who tested positive for FV-Leiden, 42 were heterozygotes (G/A), while 6 were homozygotes (A/A) (allele frequency 0.397). All 10 CAD patients positive for FV-Leiden were heterozygote carriers (allele frequency 0.072). While gender was not a factor in FV-Leiden expression, higher prevalence in FV-Leiden was seen in younger (≤45 years) VTE patients (38/51 vs. 10/17).
Conclusion: FV-Leiden is a major inherited risk factor for VTE, with a peak incidence in younger patients, but does not appear to play any role in CAD pathogenesis in the population studied.
Similar content being viewed by others
References
Kalafatis M, Rand MD, Mann KG. The mechanism of inactivation of human factor Va by activated protein C. J Biol Chem 1994;269:31,869–880.
Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64–67.
Kalafatis M, Bertina RM, Rand MD, Mann KG. Characterization of the molecular defect in factor V R506Q*. J Biol Chem 1995;270:4053–4057.
Dahlback B. Resistance to activated protein C as risk factor for thrombosis: Molecular mechanisms, laboratory investigation, and clinical management. Semin Hematol 1997;34:217–234.
Miletich JP, Prescott SM, White R, Majerus PW, Bovill EG. Inherited predisposition to thrombosis. Cell 1993;72:477–481.
Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995;346:1133–1134.
Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA 1997;277:1305–1307.
Irani-Hakime N, Tamim H, Kreidy R, Almawi WY. The prevalence of factor V R506Q mutation-Leiden among apparently healthy Lebanese. Am J Hematol 2000;65:45–49.
Abdulkadir J, Feleke Y, Berg JP, Falch JA, Odegaard OR. Absence of the factor V Leiden mutation in Ethiopians. Thromb Res 1997;86:181–182.
Kim TW, Kim WK, Lee JH, et al. Low prevalence of activated protein C resistance and coagulation factor V Arg506 to Gln mutation among Korean patients with deep venous thrombosis. J Korean Med Sci 1998;13:587–590.
Takamiya O, Ishida F, Kodaira H, Kitano K. APC-resistance and MnII genotype (Gln 506) of coagulation factor V are rare in Japanese population. Thromb Haemost 1995;74:996–1002.
Bertina RM. Molecular risk factors for thrombosis. Thromb Hemost 1999;82:601–609.
Rosen SB, Sturk A. Activated protein C resistance — a major risk factor for thrombosis. Eur J Clin Chem Clin Biochem 1997;35:501–516.
De Stefano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of factor V Leiden: clinical implications. Semin Thromb Hemost 1998;24:367–379.
Dahlback B. Are we ready for factor V Leiden screening? Lancet 1996;347:1346–1347.
Beauchamp NJ, Daly ME, Cooper PC, Makris M, Preston FE, Peake IR. Molecular basis of protein S deficiency in three families also showing independent inheritance of factor V Leiden. Blood 1996;88:1700–1707.
Ridker PM, Hennekens CH, Lindpainter K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1994;332:912–917.
Hirsch DR, Mikkola KM, Marks PW, et al. Pulmonary embolism and deep venous thrombosis during pregnancy or oral contraceptive use: prevalence of factor V Leiden. Am Heart J 1996;131:1145–1148.
Marz W, Seydewitz H, Winkelmann B, Chen M, Nauck M, Wit I. Mutation in coagulation factor V associated with resistance to activated protein C in patients with coronary artery disease. Lancet 1995;345:526–527.
Holm J, Zoller B, Berntorp E, Erhardt L, Dahlback B. Prevalence of factor V gene mutation amongst myocardial infarction patients and healthy controls is higher in Sweden than in other countries. J Intern Med 1996;239:221–226.
Rosendaal FR, Siscovick DS, Schwartz SM, et al. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997;89:2817–2821.
van der Bom JG, Bots ML, Haverkate F, Slagboom E, Grobbee DE, Kluft C. Reduced response to activated protein C is associated with increased risk for cerebrovascular disease. Ann Intern Med 1996;125:265–269.
Redondo M, Watzke HH, Stucki B, et al. Coagulation factors II, V, VII, and X, prothrombin gene 20210G → A transition, and factor V Leiden in coronary artery disease. Arterioscler Thromb Vasc Biol 1999;19:1020–1025.
Samani NJ, Lodwick D, Martin D, Kimber P. Resistance to activated protein C and the risk of premature myocardial infarction. Lancet 1994;344:1709–1710.
Feinberg WM, Pearce LA, Hart RG, et al. Markers of thrombin and platelet activity in patients with atrial fibrillation. Correlation with stroke among 1531 participants in the stroke prevention in atrial fibrillation III study. Stroke 1999;30:2547–2553.
Irani-Hakime N, Tamim H, Elias G, Finan RR, Daccache JL, Almawi WY. High prevalence of factor V mutation-Leiden in the eastern Mediterranean. Clin Chem 2000;46:134–136.
Svensson PJ, Zoller B, Mattiasson I, Dahlback B. The factor V R506Q mutation causing APC resistance is highly prevalent amongst unselected outpatients with clinically suspected deep venous thrombosis. J Intern Med 1997;241:379–385.
Ludemann P, Nabavi DG, Junker R, et al. Factor V Leiden mutation is a risk factor for cerebral venous thrombosis. A case-control study of 55 patients. Stroke 1998;29:2507–2510.
Simioni P, Prandoni P, Lensing AW, et al. The risk of recurrent venous thromboembolism in patients with an Arg506 → Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997;336:399–403.
De Stefano V, Martinelli I, Mannuccio P, et al. The risk of recurrent deep venous thrombosis among heterzygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 1999;341:801–806.
Eichinger S, Pabinger I, Stumpflen A, et al. The risk of recurrent venous thrombo-embolism in patients with and without factor V Leiden. Thromb Haemost 1997;77:624–628.
Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of anticoagulation. Thromb Haemost 1999;81:684–689.
Gardemann A, Arsic T, Katz N, Tillmanns H, Hehrlein FW, Haberbosch W. The factor II G20210A and factor V G1691A gene transitions and coronary heart disease. Thromb Haemost 1999;81:208–213.
Vargas M, Soto I, Pinto CR, et al. The prothrombin 20210A allele and factor V Leiden are associated with venous thrombosis but not with early coronary artery disease. Blood Coagul Fibrinolysis 1999;10:39–41.
Prohaska W, Schmidt M, Mannebach H, Gleichmann U, Kellsiek K. The prevalence of the prothrombin 20210 G → A mutation is not increased in angiographically confirmed coronary artery disease. Thromb Haemost 1999;81:161–162.
Margaglione M, D'Andrea G, Colaizzo D, et al. Coexistence of factor V Leiden and factor II A20210 mutations and recurrent venous thromboembolism. Thromb Haemost 1999;82:1583–1587.
Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999;353:1167–1173.
Grandone E, Margaglione M, Colaizzo D, et al. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 1997;77:822–824.
Helmerhorst FM, Bloemenkamp KW, Rosendaal FR, Vandenbroucke JP. Oral contraceptives and thrombotic disease: risk of venous thromboembolism. Thromb Haemost 1997;78:327–333.
Walker ID. Factor V Leiden: should all women be screened prior to commencing the contraceptive pill? Blood Rev 1999;13:8–13.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Irani-Hakime, N., Tamim, H., Elias, G. et al. Factor V R506Q Mutation-Leiden: An Independent Risk Factor for Venous Thrombosis but not Coronary Artery Disease. J Thromb Thrombolysis 11, 111–116 (2001). https://doi.org/10.1023/A:1011268531377
Issue Date:
DOI: https://doi.org/10.1023/A:1011268531377