Abstract
We identified 3 mutations in the factor V (FV) gene(F5) associated with FV deficiency in 3 unrelated Japanese patients. Patient 1 had severe bleeding symptoms (plasma FV activity, <1%; FV antigen, 9%) and was a compound heterozygote for a novel 5-bp deletion in exon 22 and the V1813M mutation. Patient 2 had moderate bleeding symptoms (plasma FV activity, <1%; FV antigen, 4%) and was homozygous for the V1813M mutation. Patient 3 had very mild symptoms (plasma FV activity, 1%; FV antigen, 5%) and was homozygous for the novel R2174L mutation. A study of recombinant protein expression revealed that the FV coagulant-specific activities in conditioned media for the FV-R2174L and FV-V1813M mutants were reduced to approximately 40% and 28% of wild-type FV, respectively. The amounts of FV-R2174L protein and messenger RNA in the platelets of patient 3 were similar to those of healthy subjects; however, the amount of FV-V1813M protein in patient 2 was decreased. Our data suggest that the severity of the bleeding tendency in patients with FV deficiency is correlated not only with plasma FV activity but also with the amount of FV protein in the platelets.
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Milstone JH. Thrombokinase as a prime activator of prothrombin: historical perspectives and present status.Fed Proc. 1964;23:742–748.
Rosing J, Tans G. Coagulation factor V: an old star shines again.Thromb Haemost. 1997;78:427–433.
Dahlbäck B. Blood coagulation.Lancet. 2000;355:1627–1632.
Mann KG, Kalafatis M. Factor V: a combination of Dr Jekyll and Mr Hyde.Blood. 2003;101:20–30.
Suzuki K, Dahlbäck B, Stenflo J. Thrombin-catalyzed activation of human coagulation factor V.J Biol Chem. 1982;257:6556–6564.
Nesheim ME, Foster WB, Hewick R, Mann KG. Characterization of factor V activation intermediates.J Biol Chem. 1984;259:3187–3196.
Mann KG, Nesheim ME, Tracy PB. Molecular weight of undegraded plasma factor V.Biochemistry. 1981;20:28–33.
Kane WH, Majerus PW. Purification and characterization of human coagulation factor V.J Biol Chem. 1981;256:1002–1007.
Cripe LD, Moore KD, Kane WH. Structure of the gene for human coagulation factor V.Biochemistry. 1992;31:3777–3785.
Tracy PB, Eide LL, Bowie EJ, Mann KG. Radioimmunoassay of factor V in human plasma and platelets.Blood. 1982;60:59–63.
Hayward CP, Fuller N, Zheng S, et al. Human platelets contain forms of factor V in disulfide-linkage with multimerin.Thromb Haemost. 2004;92:1349–1357.
Kane WH, Ichinose A, Hagen FS, Davie EW. Cloning of cDNAs coding for the heavy chain region and connecting region of human factor V, a blood coagulation factor with four types of internal repeats.Biochemistry. 1987;26:6508–6514.
Jenny RJ, Pittman DD,Toole JJ, et al. Complete cDNA and derived amino acid sequence of human Factor V.Proc Natl Acad Sci USA. 1987;84:4846–4850.
Foster WB, Nesheim ME, Mann KG. The factor Xa-catalyzed activation of factor V.J Biol Chem. 1983;258:13970–13977.
Wilson DB, Salem HH, Mruk JS, Maruyama I, Majerus PW. Biosynthesis of coagulation factor V by a human hepatocellular carcinoma cell line.J Clin Invest. 1984;73:654–658.
Owren PA. The coagulation of blood: investigations on a new clotting factor.Acta Med Scand. 1947;194(Suppl):1–7.
Peyvandi F, Mannucci PM. Rare coagulation disorders.Thromb Haemost. 1999;82:1207–1214.
Nagaizumi K, Inaba H, Suzuki T, et al. Two double heterozygous mutations in theF7 gene show different manifestations.Br J Haematol. 2002;119:1052–1058.
Shinozawa K. Congenital factor V deficiency and a mutation.Jpn J Thromb Hemost. 2005;16:281–296.
Hentze MW, Kulozik AE. A perfect message: RNA surveillance and nonsense-mediated decay.Cell. 1999;96:307–310.
Culbertson MR. RNA surveillance: unforeseen consequences for gene expression, inherited genetic disorders and cancer.Trends Genet. 1999;15:74–80.
Montefusco MC, Duga S, Asselta R, et al. Clinical and molecular characterization of 6 patients affected by severe deficiency of coagulation factor V: broadening of the mutational spectrum of factor V gene and in vitro analysis of the newly identified missense mutations.Blood. 2003;102:3210–3216.
Adams TE, Hockin MF, Mann KG, Everse SJ. The crystal structure of activated protein C-inactivated bovine factor Va: implications for cofactor function.Proc Natl Acad Sci USA. 2004;101:8918–8923.
Cui J, O’Shea KS, Purkayastha A, Saunders TL, Ginsburg D. Fatal hemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V.Nature. 1996;384:66–68.
Yang TL, Cui J, Taylor JM, Yang A, Gruber SB, Ginsburg D. Rescue of fatal neonatal hemorrhage in factor V deficient mice by low transgene expression.Thromb Haemost. 2000;83:70–77.
Shi Q, Wilcox DA, Fahs SA, et al. Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies. JClin Invest. 2006;116:1974–1982.
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Shinozawa, K., Amano, K., Suzuki, T. et al. Molecular characterization of 3 factor V mutations, R2174L, V1813M, and a 5-bp deletion, that cause factor V deficiency. Int J Hematol 86, 407–413 (2007). https://doi.org/10.1007/BF02983997
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DOI: https://doi.org/10.1007/BF02983997