Semin Thromb Hemost 2009; 35(4): 382-389
DOI: 10.1055/s-0029-1225760
© Thieme Medical Publishers

Factor V Deficiency

Rosanna Asselta1 , Flora Peyvandi2
  • 1Department of Biology and Genetics for Medical Sciences, University of Milan, Milan, Italy
  • 2A. Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Medicine and Medical Specialties, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, University of Milan and Luigi Villa Foundation, Milan, Italy
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Publikationsverlauf

Publikationsdatum:
13. Juli 2009 (online)

ABSTRACT

Congenital factor V (FV) deficiency is a bleeding disorder associated with mild to severe hemorrhagic symptoms and a prevalence in the general population of 1 in 1,000,000 in the homozygous form. Patients with FV deficiency and clinically significant manifestations (mainly involving mucosal tracts) show very low or unmeasurable plasma FV levels and are usually homozygous or compound heterozygous for mutations located in the FV gene (F5). Heterozygous carriers have approximately half-normal levels of FV and are usually asymptomatic. Replacement therapy for FV-deficient patients can only rely on administration of fresh-frozen plasma because specific FV concentrates are unavailable and FV is not present in cryoprecipitate or prothrombin complex concentrates. A total of 56 mutations have been published to date as being responsible for severe or moderately severe FV deficiency; more than two thirds of these are null mutations (mainly decreasing FV expression), with the remaining being missense mutations (usually impairing FV secretion). This article will provide a concise description of the FV protein and gene and will review the molecular, clinical, and therapeutic aspects of FV deficiency.

REFERENCES

  • 1 Mann K G, Kalafatis M. Factor V: a combination of Dr Jekyll and Mr Hyde.  Blood. 2003;  101 20-30
  • 2 Stormorken H. The discovery of factor V: a tricky clotting factor.  J Thromb Haemost. 2003;  1 206-213
  • 3 Mannucci P M, Duga S, Peyvandi F. Recessively inherited coagulation disorders.  Blood. 2004;  104 1243-1252
  • 4 Lak M, Sharifian R, Peyvandi F, Mannucci P M. Symptoms of inherited factor V deficiency in 35 Iranian patients.  Br J Haematol. 1998;  103 1067-1069
  • 5 Acharya S S, Coughlin A, Dimichele D M. North American Rare Bleeding Disorder Study Group . Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias.  J Thromb Haemost. 2004;  2 248-256
  • 6 Zhang B, Spreafico M, Zheng C et al.. Genotype-phenotype correlation in combined deficiency of factor V and factor VIII.  Blood. 2008;  111 5592-5600
  • 7 Kent W J, Sugnet C W, Furey T S et al.. The human genome browser at UCSC.  Genome Res. 2002;  12 996-1006
  • 8 Chiu H C, Schick P K, Colman R W. Biosynthesis of factor V in isolated guinea pig megakaryocytes.  J Clin Invest. 1985;  75 339-346
  • 9 Gewirtz A M, Keefer M, Doshi K, Annamalai A E, Chiu H C, Colman R W. Biology of human megakaryocyte factor V.  Blood. 1986;  67 1639-1648
  • 10 Giampaolo A, Vulcano F, Macioce G et al.. Factor-V expression in platelets from human megakaryocytic culture.  Br J Haematol. 2005;  128 108-111
  • 11 Sun H, Yang T L, Yang A, Wang X, Ginsburg D. The murine platelet and plasma factor V pools are biosynthetically distinct and sufficient for minimal hemostasis.  Blood. 2003;  102 2856-2861
  • 12 Dall'Osso C, Guella I, Duga S et al.. Molecular characterization of three novel splicing mutations causing factor V deficiency and analysis of the F5 gene splicing pattern.  Haematologica. 2008;  93 1505-1513
  • 13 Frischmeyer P A, Dietz H C. Nonsense-mediated mRNA decay in health and disease.  Hum Mol Genet. 1999;  8 1893-1900
  • 14 Lejeune F, Maquat L E. Mechanistic links between nonsense-mediated mRNA decay and pre-mRNA splicing in mammalian cells.  Curr Opin Cell Biol. 2005;  17 309-315
  • 15 Jenny R J, Pittman D D, Toole J J et al.. Complete cDNA and derived amino acid sequence of human factor V.  Proc Natl Acad Sci U S A. 1987;  84 4846-4850
  • 16 Cripe L D, Moore K D, Kane W H. Structure of the gene for human coagulation factor V.  Biochemistry. 1992;  31 3777-3785
  • 17 Nicolaes G A, Dahlbäck B. Factor V and thrombotic disease: description of a janus-faced protein.  Arterioscler Thromb Vasc Biol. 2002;  22 530-538
  • 18 Xue J, Kalafatis M, Mann K G. Determination of the disulfide bridges in factor Va light chain.  Biochemistry. 1993;  32 5917-5923
  • 19 Xue J, Kalafatis M, Silveira J R, Kung C, Mann K G. Determination of the disulfide bridges in factor Va heavy chain.  Biochemistry. 1994;  33 13109-13116
  • 20 Kumar H PM, Besman M J, Lundblad R L, Jenny N S, Mann K G. Carbohydrate analysis of plasma factor V and factor VIII.  Thromb Haemost. 1999;  (Suppl 82) 102a
  • 21 Macedo-Ribeiro S, Bode W, Huber R et al.. Crystal structures of the membrane-binding C2 domain of human coagulation factor V.  Nature. 1999;  402 434-439
  • 22 Adams T E, Hockin M F, Mann K G, Everse S J. The crystal structure of activated protein C-inactivated bovine factor Va: implications for cofactor function.  Proc Natl Acad Sci U S A. 2004;  101 8918-8923
  • 23 Stoilova-McPhie S, Parmenter C D, Segers K, Villoutreix B O, Nicolaes G A. Defining the structure of membrane-bound human blood coagulation factor Va.  J Thromb Haemost. 2008;  6 76-82
  • 24 Lee C J, Lin P, Chandrasekaran V et al.. Proposed structural models of human factor Va and prothrombinase.  J Thromb Haemost. 2008;  6 83-89
  • 25 Asselta R, Tenchini M L, Duga S. Inherited defects of coagulation factor V: the hemorrhagic side.  J Thromb Haemost. 2006;  4 26-34
  • 26 Lunghi B, Scanavini D, Castoldi E et al.. The factor V Glu1608Lys mutation is recurrent in familial thrombophilia.  J Thromb Haemost. 2005;  3 2032-2038
  • 27 Schrijver I, Hong D W, Mandle L et al.. High frequency of premature termination mutations in the factor V gene: three factor V deficiency case reports and a mutation review.  Thromb Haemost. 2005;  93 610-611
  • 28 Asselta R, Dall'Osso C, Duga S, Spreafico M, Saxena R, Tenchini M L. Coagulation factor V gene analysis in five Indian patients: identification of three novel small deletions.  Haematologica. 2006;  91 1724-1726
  • 29 Kling S J, Griffee M, Flanders M M, Rodgers G M. Factor V deficiency caused by a novel missense mutation, Ile417Thr, in the A2 domain.  J Thromb Haemost. 2006;  4 481-483
  • 30 Traynis I, Jones C D, Gibb C B, Acharya S S, Zehnder J L. First molecular characterization of a patient with combined factor V and factor VII deficiency.  Thromb Haemost. 2006;  95 1031-1032
  • 31 Yamakage N, Ikejiri M, Okumura K et al.. A case of coagulation factor V deficiency caused by compound heterozygous mutations in the factor V gene.  Haemophilia. 2006;  12 172-178
  • 32 Zheng W D, Liu Y H, Liu H F, Chen Z H, Wang Y. [Identification of two novel mutations of human blood coagulation factor V gene in a Chinese family with congenital factor V deficiency].  Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2006;  23 515-518
  • 33 Cai X H, Wang X F, Ding Q L, Fu Q H, Wang H L. Factor V C1149G and 5609-10INSCGTGGTT causing factor V deficiency: molecular characterization by in-vitro expression.  Thromb Haemost. 2007;  98 683-685
  • 34 Caudill J S, Sood R, Zehnder J L, Pruthi R K, Steensma D P. Severe coagulation factor V deficiency associated with an interstitial deletion of chromosome 1q.  J Thromb Haemost. 2007;  5 626-628
  • 35 Jones C D, Yeung C, Negro F, Zehnder J L. Molecular characterization and subcellular localization of Tyr478del: a pathogenic in-frame deletion in coagulation factor V.  J Thromb Haemost. 2007;  5 431-433
  • 36 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. 2007;  86 407-413
  • 37 Lunghi B, Pinotti M, Maestri I, Batorova A, Bernardi F. Evaluation of factor V mRNA to define the residual factor V expression levels in severe factor V deficiency.  Haematologica. 2008;  93 477-478
  • 38 Song J, Guella I, Kwon K Y et al.. A novel in-frame deletion in the factor V C1 domain associated with severe coagulation factor V deficiency in a Korean family.  Blood Coagul Fibrinolysis. 2009;  20 150-156
  • 39 Vos H L. An online database of mutations and polymorphisms in and around the coagulation factor V gene.  J Thromb Haemost. 2007;  5 185-188
  • 40 Castoldi E, Lunghi B, Mingozzi F et al.. A missense mutation (Y1702C) in the coagulation factor V gene is a frequent cause of factor V deficiency in the Italian population.  Haematologica. 2001;  86 629-633
  • 41 Scanavini D, Girelli D, Lunghi B et al.. Modulation of factor V levels in plasma by polymorphisms in the C2 domain.  Arterioscler Thromb Vasc Biol. 2004;  24 200-206
  • 42 Vos H L. Inherited defects of coagulation factor V: the thrombotic side.  J Thromb Haemost. 2006;  4 35-40
  • 43 Yamazaki T, Nicolaes G A, Sørensen K W, Dahlbäck B. Molecular basis of quantitative factor V deficiency associated with factor V R2 haplotype.  Blood. 2002;  100 2515-2521
  • 44 Murray J M, Rand M D, Egan J O, Murphy S, Kim H C, Mann K G. Factor V New Brunswick: Ala221-to-Val substitution results in reduced cofactor activity.  Blood. 1995;  86 1820-1827
  • 45 Steen M, Miteva M, Villoutreix B O, Yamazaki T, Dahlbäck B, Factor V. Factor V New Brunswick: Ala221Val associated with FV deficiency reproduced in vitro and functionally characterized.  Blood. 2003;  102 1316-1322
  • 46 Monaldini L, Asselta R, Malcovati M, Tenchini M L, Duga S. The DNA-pooling technique allowed for the identification of three novel mutations responsible for afibrinogenemia.  J Thromb Haemost. 2005;  3 2591-2593
  • 47 Duckers C, Simioni P, Spiezia L et al.. Low plasma levels of tissue factor pathway inhibitor in patients with congenital factor V deficiency.  Blood. 2008;  112 3615-3623
  • 48 Adcock D M, Hoefner D M, Kottke-Marchant K, Marlar R A, Szamosi D I, Warunek D J. Collection, Transport, and Processing of Blood Specimens for Testing Plasma-Based Coagulation Assays and Molecular Hemostasis Assays: Approved Guideline, Fifth Edition. Wayne, PA; Clinical Laboratory Standards Institute 2008 CLSI document H21–A5
  • 49 Zürcher M, Sulzer I, Barizzi G, Lämmle B, Alberio L. Stability of coagulation assays performed in plasma from citrated whole blood transported at ambient temperature.  Thromb Haemost. 2008;  99 416-426
  • 50 Di Paola J, Nugent D, Young G. Current therapy for rare factor deficiencies.  Haemophilia. 2001;  7(Suppl 1) 16-22
  • 51 Bolton-Maggs P H, Perry D J, Chalmers E A et al.. The rare coagulation disorders—review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation.  Haemophilia. 2004;  10 593-628
  • 52 Peyvandi F, Duga S, Akhavan S, Mannucci P M. Rare coagulation deficiencies.  Haemophilia. 2002;  8 308-321
  • 53 Salooja N, Martin P, Khair K, Liesner R, Hann I. Severe factor V deficiency and neonatal intracranial haemorrhage: a case report.  Haemophilia. 2000;  6 44-46
  • 54 Tarantino M D, Ross M P, Daniels T M, Nichols W L. Modulation of an acquired coagulation factor V inhibitor with intravenous immune globulin.  J Pediatr Hematol Oncol. 1997;  19 226-231
  • 55 Chediak J, Ashenhurst J B, Garlick I, Desser R K. Successful management of bleeding in a patient with factor V inhibitor by platelet transfusions.  Blood. 1980;  56 835-841
  • 56 Salooja N, Martin P, Khair K, Liesner R, Hann I. Severe factor V deficiency and neonatal intracranial haemorrhage: a case report.  Haemophilia. 2000;  6 44-46
  • 57 Altisent C, Lozano M, Sol E et al.. Dental extraction using rFVIIa in a patient with severe FV deficiency.  Haemophilia. 2000;  6 408
  • 58 Divanon F, Hecquard C, Borel-Derlon A. Experience with use of recombinant activated factor VII.  J Clin Pharm Ther. 2002;  27 133-138
  • 59 González-Boullosa R, Ocampo-Martínez R, Alarcón-Martín M J, Suárez-Rodríguez M, Domínguez-Viguera L, González-Fajo G. The use of activated recombinant coagulation factor VII during haemarthroses and synovectomy in a patient with congenital severe factor V deficiency.  Haemophilia. 2005;  11 167-170
  • 60 Lee C A, Chi C, Pavord S R UK Haemophilia Centre Doctors' Organization et al. The obstetric and gynaecological management of women with inherited bleeding disorders—review with guidelines produced by a taskforce of UK Haemophilia Centre Doctors' Organization.  Haemophilia. 2006;  12 301-336

Dr. Rosanna AsseltaPh.D. 

Department of Biology and Genetics for Medical Sciences, University of Milan

Via Viotti 3/5 - 20133 Milan, Italy

eMail: rosanna.asselta@unimi.it