No association between thrombosis and factor V gene polymorphisms in Chinese Han population

Summary

Activated protein C resistance (APCR) is the most common hereditary condition of thrombosis in Western countries. And it is significantly linked to a single nucleotide polymorphisms (SNPs) in the coagulation factor V gene that results in the mutations at R506, R306 and HR2 alleles. To determine the prevalence of APCR and its association with the factor V gene SNPs in Chinese Han thrombotic patients, we investigated a total of 346 Chinese thrombotic patients and 140 normal controls for APCR using the APTT-based assays, according to manufacturer’s instructions, APC ratio ≦2 indicated APC resistance. Mutations of factor V at R506, R306, HR2 allele were detected by PCRMnl/I, Bst/NI, Rsa/I digestion as described before respectively. The results showed that the incidence of APC resistance were 12.0% (12 of 100 cases) in acute cerebral thrombosis (ACT) patients (P <0.05), 13.5% (13 of 96 cases) in acute myocardial infarction (AMI) patients (P <0.05), 16.7% (10 of 60 cases) in deep venous thrombosis (DVT) patients (P <0.05), 15.6% (14 of 90 cases) in systemic lupus erythematosus (SLE) patients (P <0.05) and 5.0% (7 of 140 cases) in normal controls. APCR is associated with thrombotic events. But no factor V R506Q mutation (FV Leiden) was found in all 5 groups. Only one AMI patient and one DVT patient revealed heterozygous R306G mutation, which was confirmed by direct sequencing PCR products. Additionally, two SLE patients showed to be heterozygous HR2 allele for the first time in the Chinese Han population. We concluded that APC resistance in the Chinese Han population might not be associated with mutations of factor V at R506, R306 and HR2 polymorphisms. Some other factors might contribute to APC resistance in the Chinese Han population.

Keywords

Activated protein C resistance (APCR) - factor V - single nucleotide polymorphisms (SNPs) - thrombosis - Chinese Han population

• References

• 1 Hoyer LW, Wyshock EG, Colman RW. Coagulation confactors: factors V and VIII. Colman RW, Hirsh J, Marder VJ, Salzman EW IB, eds. Philadelphia: Lippincott Company 1994; 109-33.
• 2 Don D.Monkovic, Paula B.Tracy. Activation of Human factor V by factor Xa and thrombin. Blood 1998; 91: 4-6.
• 3 Kalafatis M, Rand MD, Mann KG. The mechanism of inactivation of human factor V and human factor Va by activated protein C. J Biol Chem 1994; 269 (50) 31869-80.
• 4 Nicolaes GAF, Tans G, Thomassen MCLGD. et al. Peptide bond cleavages and loss of functional activity during inactivation of factor Va and factor Va R506Q by activated protein C. J Biol Chem 1995; 270: 21158-66.
• 5 Heeb MJ, Kojima Y, Greengard J, Griffin JH. Activated protein C resistance: Molecular mechanisms based on studies using purified Gln506-factor V. Blood 1995; 85: 3405-11.
• 6 Rosing J, Hoekema L, Nicolaes GAF. et al Effects of protein S and factor Xa on peptide bond cleavages during inactivation of factor Va and factor Va R506Q by activated protein C. J Biol Chem 1995; 270: 27852-8.
• 7 Ferrer-Antunes C, Palmeiro A, Green F. et al Polymorphisms of fibrinogen, factor VII and factor V genes. Comparison of allele frequencies in different ethnic groups. Thromb Haemost 1995; 73: 1379.
• 8 Zivelin A, Gitel S, Griffin JH. et al Extensive venous and arterial thrombosis associated with an inhibitor to activated protein C. Blood 1999; 94: 895-901.
• 9 Dahlback B. Resistance to activated protein C caused by the factor V R506Q mutation is a common risk factor for venous thrombosis. Thromb Haemost 1997; 8: 483-8.
• 10 Griffin JH, Evatt B, Wideman C, Fernandez JA. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82: 1889-993.
• 11 Koster T, Rosendaal FR, de Ronde H. et al Venous thrombosis due to poor anticoagulation to activated protein C: Leiden thrombophilia study. Lancet 1993; 342: 1503-7.
• 12 Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-21.
• 13 Bertina RM, Koeleman BPC, Koster F. et al Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
• 14 Zoller B, Svensson P, He X. et al Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994; 94: 252-4.
• 15 Williamson D, Brown K, Luddington R. et al Factor V Cambridge: a new mutation (Arg306 to Thr) associated with resistance to activated proein C. Blood 1998; 91: 1140-4.
• 16 Egan JO, Kalafatis M, Mann KG. The effect of Arg306-Ale and Arg506-Gln substitutions in the inactivation of recombinant human factor Va by activated protein C and protein S. J Prot Sci 1997; 6: 2016
• 17 Franco RF, Maffei FH, Lourenco D. et al FV Arg306-Thr (FV Cambridge) and FV Arg 306-Gly mutations in venous thrombotic disease. Br J Haemotol 1998; 103: 888-90.
• 18 Can WP, Lee CK, Kwone YL. et al A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood 1998; 91 (04) 1135-9.
• 19 Lunghi B, Iacovello L, Gemmati D. et al Detection of new polymorphic markers in the factor V gene: association with factor V levels in plasma. Thromb Haemost 1996; 75: 45-8.
• 20 Bernardi F, Faioni EM, Castoldi E, Lunghi B. et al A factor V genetic component differing from factor V R506Q contributes to the activated protein C resistance phenotype. Blood 1997; 90: 1552-7.
• 21 Alhenc-Gelas M, Nicaud V, Gandrille S. et al The factor V gene A4070G mutation and the risk of venous thrombosis. Thromb Haemost 1999; 81: 193-7.
• 22 Luddington R, Jackson A, Pannerselvam S. et al The factor V R2 allele: Risk of venous thromboembolism, factor V levels and resistance to activated protein C. Thromb Haemost 2000; 83: 204-8.
• 23 Sambrook J, Frotsch EF, Maniatis T. Molecular cloning. Ford N, Nolan C, Ferguson M. Cold Spring Harbor Laboratory Press, NY; New York: 1989. 9 16-9. 19
• 24 Bokarewa MI, Bolmback M. Heterogeneity of the APC phenomenon. Thromb Res 1994; 75: 395-400.
• 25 Henkens CM, Bom VJ, Seinen AJ. et al Sensitivity to activated protein C: influence of oral contraceptives and sex. Thromb Haemost 1995; 73: 402-4.
• 26 Svensson PJ, Zoller B, Dahlback B. et al Evaluation of original and modified APC resistance tests in unselected outpatients with clinically suspected thrombosis and in healthy controls. Thromb Haemost 1997; 77: 332-5.
• 27 Rees DC, Cox M, Clegg JB. et al World distribution of factor V Leiden. Lancet 1995; 346: 1133-4.
• 28 Guglielmina Pepe, Rickards O, Vagegas OC. et al Prevalence of factor V Leiden mutation in non-European populations. Thromb Haemost 1997; 77 (02) 329-31.
• 29 Philip WM. Bad blood by mutation. Nature 1994; 369: 14.
• 30 Ozawa T, Niiya k, Sakuragawa N. et al Absence of factor V. Leiden in the Japanese. Thromb Res 1996; 5: 595-6.
• 31 Lee CK, Chen WP, Liang R. et al Absence of factor V gene mutation in Hong Kong. Chinese patients with deep vein thrombosis. Blood 1995; 86 (Suppl) 919
• 32 Luo Jiabin, Guan Yue, Ma Hongxin. et al Distribution of coagulation factor V gene mutation 1691A in populations of different races. Clin J Med Genet 1996; 13: 4
• 33 Hong Mei, Wei Wenning, Song Shanjun. et al Study of activated protein C resistance (APC-R) and FV Leiden in healthy blood donors and patients with thrombosis. (Chinese) Clin J Hematol 1998; 19: 9
• 34 Triplett DA. Lupus anticoagulants: diagnostic dilemma and clinical challenge. Clin Lab Sci 1997; 10 (04) 225-7.
• 35 Marcucci R, Abbate R, Fedi S. et al Acquired activated protein C resistance in postmenopausl women is dependent on factor VIII: C levels. Am J Clin Pathol 1999; 111 (06) 769-72.
• 36 Tsakiris DA, Yasikoff ML, Wolf F. et al Anticardiolipin antibodies do not seem to be associated with APC resistance in vivo or in vitro. Ann Hematol 1995; 71: 195-8.
• 37 Simantov R, Lo SK, Salmon JE. et al Factor V Leiden increases the risk of thrombosis in patients with antiphospholipid antibodies. Thromb Res 1996; 84: 361-5.