A Comprehensive Overview of Coagulation Factor V and Congenital Factor V Deficiency

Abstract

Coagulation factor (F) V is a glycoprotein that plays an essential role in the formation of the prothrombinase complex, which is critical for progressing clot formation. FV deficiency is a rare bleeding disorder with an estimated incidence of one per 1 million in the general population. The disorder is manifested with a wide array of clinical bleeding events. The most common bleeding features of FV deficiency are mucosal bleedings. Life-threatening manifestations are rarely seen in this disorder. FV deficiency is diagnosed using routine coagulation tests and FV activity assay. A wide spectrum of mutations including missense, nonsense, and frameshift is observed throughout the F5 gene. Although fresh frozen plasma is the dominant therapeutic choice, a newly introduced plasma-derived FV concentrate was found effective in in vitro correction of prothrombin time, activated partial thromboplastin time, and thrombin generation parameters in severe FV deficiency and should provide more targeted treatment for patients with FV deficiency in the future.

Keywords

factor V deficiency - molecular basis - clinical manifestations

• References

• 1 Tabibian S, Dorgalaleh A, Camire RM. Congenital Factor V Deficiency. Congenital Bleeding Disorders. New York, NY: Springer; 2018: 201-218
• 2 Mann KG, Kalafatis M. Factor V: a combination of Dr Jekyll and Mr Hyde. Blood 2003; 101 (01) 20-30
• 3 Rosing J, Tans G, Govers-Riemslag JW, Zwaal RF, Hemker HC. The role of phospholipids and factor Va in the prothrombinase complex. J Biol Chem 1980; 255 (01) 274-283
• 4 Dorgalaleh A, Alavi SER, Tabibian S. , et al. Diagnosis, clinical manifestations and management of rare bleeding disorders in Iran. Hematology 2017; 22 (04) 224-230
• 5 Tabibian S, Kazemi A, Dorgalaleh A. Laboratory diagnosis of congenital factor V deficiency, routine, specific coagulation tests with molecular methods. J Cell Mol Anesth 2016; 1 (02) 87-90
• 6 Franchini M, Lippi G. Acquired factor V inhibitors: a systematic review. J Thromb Thrombolysis 2011; 31 (04) 449-457
• 7 Lawrie AS, Berbenni C, Menegatti M. , et al. In vitro characterizations of the first therapeutic factor V concentrate. Haemophilia 2014; 20: 25-26
• 8 Duga S, Asselta R, Tenchini ML. Coagulation factor V. Int J Biochem Cell Biol 2004; 36 (08) 1393-1399
• 9 Orfeo T, Brufatto N, Nesheim ME, Xu H, Butenas S, Mann KG. The factor V activation paradox. J Biol Chem 2004; 279 (19) 19580-19591
• 10 Segers K, Dahlbäck B, Nicolaes GA. Coagulation factor V and thrombophilia: background and mechanisms. Thromb Haemost 2007; 98 (03) 530-542
• 11 Hirbawi J, Vaughn JL, Bukys MA, Vos HL, Kalafatis M. Contribution of amino acid region 659-663 of factor Va heavy chain to the activity of factor Xa within prothrombinase. Biochemistry 2010; 49 (39) 8520-8534
• 12 Camire RM. A new look at blood coagulation factor V. Curr Opin Hematol 2011; 18 (05) 338-342
• 13 Cripe LD, Moore KD, Kane WH. Structure of the gene for human coagulation factor V. Biochemistry 1992; 31 (15) 3777-3785
• 14 Vadivel K, Kumar Y, Bunce MW, Camire RM, Bajaj MS, Bajaj SP. Interaction of factor V B-domain acidic region with its basic region and with TFPI/TFPI2: structural insights from molecular modeling studies. Int Biol Rev 2017 ;1(1)
• 15 Kim SW, Ortel TL, Quinn-Allen MA. , et al. Partial glycosylation at asparagine-2181 of the second C-type domain of human factor V modulates assembly of the prothrombinase complex. Biochemistry 1999; 38 (35) 11448-11454
• 16 Yang TL, Cui J, Rehumtulla A. , et al. The structure and function of murine factor V and its inactivation by protein C. Blood 1998; 91 (12) 4593-4599
• 17 Griffin JH, Zlokovic BV, Mosnier LO. Activated protein C: biased for translation. Blood 2015; 125 (19) 2898-2907
• 18 Steen M. Factor Va-factor Xa interactions: molecular sites involved in enzyme: cofactor assembly. Scand J Clin Lab Invest Suppl 2002; 237 (07) 5-11
• 19 Nakayama D, Ben Ammar Y, Miyata T, Takeda S. Structural basis of coagulation factor V recognition for cleavage by RVV-V. FEBS Lett 2011; 585 (19) 3020-3025
• 20 Hockin M, Kalafatis M, Cawthern K, Simoni P, Mann K. , eds. A novel cellular mechanism for factor Va inactivation. 40th Annual Meeting of the American Society of Hematology Blood, Miami Beach, FL, December 1998
• 21 Kalafatis M, Mann KG. The role of the membrane in the inactivation of factor Va by plasmin. Amino acid region 307-348 of factor V plays a critical role in factor Va cofactor function. J Biol Chem 2001; 276 (21) 18614-18623
• 22 Pellequer J-L, Gale AJ, Getzoff ED, Griffin JH. Three-dimensional model of coagulation factor Va bound to activated protein C. Thromb Haemost 2000; 84 (05) 849-857
• 23 Nicolaes GA, Dahlbäck B. Factor V and thrombotic disease: description of a janus-faced protein. Arterioscler Thromb Vasc Biol 2002; 22 (04) 530-538
• 24 Maas C, Meijers JC, Marquart JA. , et al. Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma. Proc Natl Acad Sci U S A 2010; 107 (20) 9083-9087
• 25 Thomassen MC, Castoldi E, Tans G. , et al. Endogenous factor V synthesis in megakaryocytes contributes negligibly to the platelet factor V pool. Haematologica 2003; 88 (10) 1150-1156
• 26 Gould WR, Silveira JR, Tracy PB. Unique in vivo modifications of coagulation factor V produce a physically and functionally distinct platelet-derived cofactor: characterization of purified platelet-derived factor V/Va. J Biol Chem 2004; 279 (04) 2383-2393
• 27 Camire RM, Kalafatis M, Cushman M, Tracy RP, Mann KG, Tracy PB. The mechanism of inactivation of human platelet factor Va from normal and activated protein C-resistant individuals. J Biol Chem 1995; 270 (35) 20794-20800
• 28 Diamandis M, Adam F, Kahr WH. , et al. Insights into abnormal hemostasis in the Quebec platelet disorder from analyses of clot lysis. J Thromb Haemost 2006; 4 (05) 1086-1094
• 29 Lippi G, Favaloro EJ, Montagnana M, Manzato F, Guidi GC, Franchini M. Inherited and acquired factor V deficiency. Blood Coagul Fibrinolysis 2011; 22 (03) 160-166
• 30 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 (09) 3615-3623
• 31 Thalji N, Camire RM. Parahemophilia: new insights into factor v deficiency. Semin Thromb Hemost 2013; 39 (06) 607-612
• 32 Murray JM, Rand MD, Egan JO, Murphy S, Kim HC, Mann KG. Factor VNew Brunswick: Ala221-to-Val substitution results in reduced cofactor activity. Blood 1995; 86 (05) 1820-1827
• 33 Naderi M, Tabibian S, Hosseini MS. , et al. Rare bleeding disorders: a narrative review of epidemiology, molecular and clinical presentations, diagnosis and treatment. J Pediatr Rev 2014; 2 (02) 31-46
• 34 Naderi M, Tabibian S, Alizadeh S. , et al. Congenital factor V deficiency: comparison of the severity of clinical presentations among patients with rare bleeding disorders. Acta Haematol 2015; 133 (02) 148-154
• 35 Alavi SER, Jalalvand M, Assadollahi V, Tabibian S, Dorgalaleh A. Intracranial hemorrhage: a devastating outcome of congenital bleeding disorders-prevalence, diagnosis, and management, with a special focus on congenital factor XIII deficiency. Semin Thromb Hemost 2018; 44 (03) 267-275
• 36 Naderi M, Tabibian S, Shamsizadeh M, Dorgalaleh A. Miscarriage and recurrent miscarriage in patients with congenital factor V deficiency: a report of six cases in Iran. Int J Hematol 2016; 103 (06) 673-675
• 37 Tabibian S, Motlagh H, Naderi M, Dorgalaleh A. Intracranial hemorrhage in congenital bleeding disorders. Blood Coagul Fibrinolysis 2018; 29 (01) 1-11
• 38 Blavignac J, Bunimov N, Rivard GE, Hayward CP. Quebec platelet disorder: update on pathogenesis, diagnosis, and treatment. Semin Thromb Hemost 2011; 37 (06) 713-720
• 39 Hayward CP, Liang M, Tasneem S. , et al. The duplication mutation of Quebec platelet disorder dysregulates PLAU, but not C10orf55, selectively increasing production of normal PLAU transcripts by megakaryocytes but not granulocytes. PLoS One 2017; 12 (03) e0173991
• 40 Hayward CP, Rivard GE. Quebec platelet disorder. Expert Rev Hematol 2011; 4 (02) 137-141
• 41 Stormorken H. The discovery of factor V: a tricky clotting factor. J Thromb Haemost 2003; 1 (02) 206-213
• 42 Caudill JS, Sood R, Zehnder JL, Pruthi RK, Steensma DP. Severe coagulation factor V deficiency associated with an interstitial deletion of chromosome 1q. J Thromb Haemost 2007; 5 (03) 626-628
• 43 Guella I, Paraboschi EM, van Schalkwyk WA, Asselta R, Duga S. Identification of the first Alu-mediated large deletion involving the F5 gene in a compound heterozygous patient with severe factor V deficiency. Thromb Haemost 2011; 106 (02) 296-303
• 44 Nuzzo F, Bulato C, Nielsen BI. , et al. Characterization of an apparently synonymous F5 mutation causing aberrant splicing and factor V deficiency. Haemophilia 2015; 21 (02) 241-248
• 45 Frischmeyer PA, Dietz HC. Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet 1999; 8 (10) 1893-1900
• 46 Kalafatis M, Simioni P, Tormene D, Beck DO, Luni S, Girolami A. Isolation and characterization of an antifactor V antibody causing activated protein C resistance from a patient with severe thrombotic manifestations. Blood 2002; 99 (11) 3985-3992
• 47 Ang AL, Kuperan P, Ng CH, Ng HJ. Acquired factor V inhibitor. A problem-based systematic review. Thromb Haemost 2009; 101 (05) 852-859
• 48 Knöbl P, Lechner K. Acquired factor V inhibitors. Baillieres Clin Haematol 1998; 11 (02) 305-318
• 49 Miesbach W, Voigt J, Peetz D, Scharrer I. Massive bleeding symptoms in two patients with factor V inhibitor and antiphospholipid antibodies after treatment with ciprofloxacin [in German]. Med Klin (Munich) 2003; 98 (06) 339-343
• 50 Lucia JF, Aguilar C. A case of an asymptomatic idiopathic inhibitor to coagulation factor V. Haemophilia 2005; 11 (02) 178-180
• 51 Takahashi H, Fuse I, Abe T, Yoshino N, Aizawa Y. Acquired factor V inhibitor complicated by Hashimoto's thyroditis, primary biliary cirrhosis and membranous nephropathy. Blood Coagul Fibrinolysis 2003; 14 (01) 87-93
• 52 Emori Y, Sakugawa M, Niiya K. , et al. Life-threatening bleeding and acquired factor V deficiency associated with primary systemic amyloidosis. Blood Coagul Fibrinolysis 2002; 13 (06) 555-559
• 53 Koyama T, Saito T, Kusano T, Hirosawa S. Factor V inhibitor associated with Sjögren's syndrome. Br J Haematol 1995; 89 (04) 893-896
• 54 Wiwanitkit V. Spectrum of bleeding in acquired factor V inhibitor: a summary of 33 cases. Clin Appl Thromb Hemost 2006; 12 (04) 485-488
• 55 Bowman LJ, Anderson CD, Chapman WC. Topical recombinant human thrombin in surgical hemostasis. Semin Thromb Hemost 2010; 36 (05) 477-484
• 56 Tilley D, Levit I, Samis JA. Measurement of factor v activity in human plasma using a microplate coagulation assay. J Vis Exp 2012; (67) 1-7
• 57 Tilley D, Levit I, Samis JA. Development of a microplate coagulation assay for Factor V in human plasma. Thromb J 2011; 9 (01) 11
• 58 Dacie JV. Dacie and Lewis Practical Haematology. Amsterdam: Elsevier Health Sciences; 2006
• 59 Favaloro EJ, Bonar R, Duncan E. , et al; RCPA QAP in Haematology Haemostasis Committee. Identification of factor inhibitors by diagnostic haemostasis laboratories: a large multi-centre evaluation. Thromb Haemost 2006; 96 (01) 73-78
• 60 Favaloro EJ, Bonar R, Duncan E. , et al. Mis-identification of factor inhibitors by diagnostic haemostasis laboratories: recognition of pitfalls and elucidation of strategies. A follow up to a large multicentre evaluation. Pathology 2007; 39 (05) 504-511
• 61 Kershaw G. Performance and interpretation of mixing tests in coagulation. Methods Mol Biol 2017; 1646: 85-90
• 62 Kadohira Y, Yamada S, Hayashi T, Morishita E, Asakura H, Ichinose A. A discrepancy between prothrombin time and Normotest (Hepaplastintest) results is useful for diagnosis of acquired factor V inhibitors. Int J Hematol 2018; 108 (02) 145-150
• 63 Kershaw G. Detection and measurement of factor inhibitors. Methods Mol Biol 2017; 1646: 295-304
• 64 Favaloro EJ, Posen J, Ramakrishna R. , et al. Factor V inhibitors: rare or not so uncommon? A multi-laboratory investigation. Blood Coagul Fibrinolysis 2004; 15 (08) 637-647
• 65 Peyvandi F, Menegatti M. Treatment of rare factor deficiencies in 2016. Hematology (Am Soc Hematol Educ Program) 2016; 2016 (01) 663-669
• 66 Delev D, Pavlova A, Heinz S, Seifried E, Oldenburg J. Factor 5 mutation profile in German patients with homozygous and heterozygous factor V deficiency. Haemophilia 2009; 15 (05) 1143-1153
• 67 Acharya SS, Coughlin A, Dimichele DM. ; 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 (02) 248-256
• 68 Mansouritorghabeh H, Manavifar L, Mobalegh A, Shirdel A. Haemorrhagic manifestations and prevalence of factor V deficiency in north-eastern Iran. Haemophilia 2010; 16 (02) 376-380
• 69 Lak M, Sharifian R, Peyvandi F, Mannucci PM. Symptoms of inherited factor V deficiency in 35 Iranian patients. Br J Haematol 1998; 103 (04) 1067-1069
• 70 Cutler JA, Patel R, Rangarajan S, Tait RC, Mitchell MJ. Molecular characterization of 11 novel mutations in patients with heterozygous and homozygous FV deficiency. Haemophilia 2010; 16 (06) 937-942
• 71 Park C-H, Yoo K, Lee K-O, Kim S-H, Sung K-W, Kim H-J. Genetic confirmation of congenital factor V deficiency in Korean patients. Ann Lab Med 2016; 36 (02) 182-184
• 72 Huang DD, Wang XF, Chen HY. , et al. Analysis of phenotype and genotype in four Chinese pedigrees with inherited coagulation factor V deficiency [in Chinese]. Zhonghua Xue Ye Xue Za Zhi 2010; 31 (03) 149-153
• 73 Cao L, Wang Z, Li H. , et al. Gene analysis and prenatal diagnosis for two families of congenital factor V deficiency. Haemophilia 2011; 17 (01) 65-69
• 74 Kanaji S, Kanaji T, Honda M. , et al. Identification of four novel mutations in F5 associated with congenital factor V deficiency. Int J Hematol 2009; 89 (01) 71-75
• 75 Chen T-Y, Lin T-M, Chen H-Y, Wu C-L, Tsao C-J. Gly392Cys missense mutation in the A2 domain of factor V causing severe factor V deficiency: molecular characterization by expression of the recombinant protein. Thromb Haemost 2005; 93 (03) 614-615
• 76 Kovács KB, Tisza B, Komáromi I, Muszbek L, Bereczky Z. Inherited factor V deficiency associated with a novel heterozygous missense mutation (p.G493R) in a patient with excessive surgical bleeding. Thromb Haemost 2009; 102 (04) 787-789
• 77 Xie F, Cheng F, Zhu X. Studies on hereditary deficiency of coagulation factor V [in Chinese]. Zhonghua Xue Ye Xue Za Zhi 2001; 22 (09) 453-456
• 78 van Wijk R, Nieuwenhuis K, van den Berg M. , et al. Five novel mutations in the gene for human blood coagulation factor V associated with type I factor V deficiency. Blood 2001; 98 (02) 358-367
• 79 Lunghi B, Scanavini D, Castoldi E. , et al. The factor V Glu1608Lys mutation is recurrent in familial thrombophilia. J Thromb Haemost 2005; 3 (09) 2032-2038
• 80 Brugge JM, Simioni P, Bernardi F. , et al. Expression of the normal factor V allele modulates the APC resistance phenotype in heterozygous carriers of the factor V Leiden mutation. J Thromb Haemost 2005; 3 (12) 2695-2702
• 81 Calzavarini S, Villoutreix BO, Lunghi B, Livaja R, Bernardi F, Dahlbäck B. Molecular basis of coagulation factor V deficiency caused by the R1698W inter-domain mutation. Thromb Haemost 2013; 110 (01) 31-38
• 82 Castoldi E, Simioni P, Kalafatis M. , et al. Combinations of 4 mutations (FV R506Q, FV H1299R, FV Y1702C, PT 20210G/A) affecting the prothrombinase complex in a thrombophilic family. Blood 2000; 96 (04) 1443-1448
• 83 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 (09) 3210-3216
• 84 Wang X, Tang N, Lu Y, Li D. Congenital factor V deficiency and decreased VWF in a Chinese male patient with hematuria. Haemophilia 2018; 24 (01) e16-e18
• 85 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 (05) 407-413
• 86 Fu WJ, Hou J, Wang DX, Yu RQ. Identification of a novel mutation of human blood coagulation FV gene associated with congenital FV deficiency [in Chinese]. Zhonghua Xue Ye Xue Za Zhi 2003; 24 (03) 119-121
• 87 Asselta R, Bossone A, Iannaccone L, Duga S, Brancaccio V, Margaglione M. Rescue of activated protein C-resistance phenotype by cis-acting factor V Gly2032Asp mutation. Haematologica 2004; 89 (06) 761-762
• 88 Asselta R, Tenchini ML, Holme R, Brosstad F, Stormorken H. The discovery of Mary's mutation. J Thromb Haemost 2003; 1 (02) 397-398
• 89 Duga S, Montefusco MC, Asselta R. , et al. Arg2074Cys missense mutation in the C2 domain of factor V causing moderately severe factor V deficiency: molecular characterization by expression of the recombinant protein. Blood 2003; 101 (01) 173-177
• 90 Bossone A, D'Angelo F, Santacroce R, De Lucia D, Margaglione M. Factor V Arg2074Cys: a novel missense mutation in the C2 domain of factor V. Thromb Haemost 2002; 87 (05) 923-924
• 91 Schrijver I, Houissa-Kastally R, Jones CD, Garcia KC, Zehnder JL. Novel factor V C2-domain mutation (R2074H) in two families with factor V deficiency and bleeding. Thromb Haemost 2002; 87 (02) 294-299
• 92 Jin P-P, Wang X-F, Ding Q-L. , et al. Ser234Leu missense mutation in the A1 domain of factor V causing moderate factor V deficiency in a Chinese family. Pathology 2009; 41 (06) 566-571
• 93 Liu H-C, Lin T-M, Eng H-L, Lin Y-T, Shen M-C. Functional characterization of a novel missense mutation, His147Arg, in A1 domain of FV protein causing type II deficiency. Thromb Res 2014; 134 (01) 153-159
• 94 Janicki PK, Vaida S, Al-Mondhiry HA. Targeted next-generation resequencing of f5 gene identifies novel multiple variants pattern in severe hereditary factor v deficiency. Case Rep Genet 2013; 2013: 941684
• 95 Mumford AD, McVey JH, Morse CV. , et al. Factor V I359T: a novel mutation associated with thrombosis and resistance to activated protein C. Br J Haematol 2003; 123 (03) 496-501
• 96 Lunghi B, Castoldi E, Mingozzi F, Bernardi F, Castaman G. A novel factor V null mutation detected in a thrombophilic patient with pseudo-homozygous APC resistance and in an asymptomatic unrelated subject. Blood 1998; 92 (04) 1463-1464
• 97 Vellinga S, Steel E, Vangenechten I, Gadisseur A. Successful pregnancy in a patient with factor V deficiency: case report and review of the literature. Thromb Haemost 2006; 95 (05) 896-897
• 98 Schrijver I, Hong DW, 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 (03) 610-611
• 99 van Wijk R, Montefusco MC, Duga S. , et al. Coexistence of a novel homozygous nonsense mutation in exon 13 of the factor V gene with the homozygous Leiden mutation in two unrelated patients with severe factor V deficiency. Br J Haematol 2001; 114 (04) 871-874
• 100 Traynis I, Jones CD, Gibb CB, Acharya SS, Zehnder JL. First molecular characterization of a patient with combined factor V and factor VII deficiency. Thromb Haemost 2006; 95 (06) 1031-1032
• 101 Hou LH, Xie F, Liu XE. , et al. A novel mutation causes congenital factor V deficiency [in Chinese]. Zhonghua Xue Ye Xue Za Zhi 2003; 24 (09) 455-459
• 102 Nuzzo F, Paraboschi EM, Straniero L, Pavlova A, Duga S, Castoldi E. Identification of a novel large deletion in a patient with severe factor V deficiency using an in-house F5 MLPA assay. Haemophilia 2015; 21 (01) 140-147
• 103 Asselta R, Dall'Osso C, Duga S, Spreafico M, Saxena R, Tenchini ML. Coagulation factor V gene analysis in five Indian patients: identification of three novel small deletions. Haematologica 2006; 91 (12) 1724-1726
• 104 Montefusco MC, Duga S, Asselta R. , et al. A novel two base pair deletion in the factor V gene associated with severe factor V deficiency. Br J Haematol 2000; 111 (04) 1240-1246
• 105 Zehnder JL, Hiraki DD, Jones CD, Gross N, Grumet FC. Familial coagulation factor V deficiency caused by a novel 4 base pair insertion in the factor V gene: factor V Stanford. Thromb Haemost 1999; 82 (03) 1097-1099
• 106 Montefusco MC, Asselta R, van Wijk R, Duga S, Tenchini ML. Concerns about the mutations identified in a case of familial coagulation factor V deficiency: factor V Stanford. Thromb Haemost 2000; 84 (06) 1131-1132
• 107 Castoldi E, Kalafatis M, Lunghi B. , et al. Molecular bases of pseudo-homozygous APC resistance: the compound heterozygosity for FV R506Q and a FV null mutation results in the exclusive presence of FV Leiden molecules in plasma. Thromb Haemost 1998; 80 (03) 403-406
• 108 Guasch JF, Cannegieter S, Reitsma PH, van't Veer-Korthof ET, Bertina RM. Severe coagulation factor V deficiency caused by a 4 bp deletion in the factor V gene. Br J Haematol 1998; 101 (01) 32-39
• 109 Dargaud Y, Trzeciak MC, Meunier S. , et al. Two novel factor V null mutations associated with activated protein C resistance phenotype/genotype discrepancy. Br J Haematol 2003; 123 (02) 342-345
• 110 Ajzner E E, Balogh I, Szabó T, Marosi A, Haramura G, Muszbek L. Severe coagulation factor V deficiency caused by 2 novel frameshift mutations: 2952delT in exon 13 and 5493insG in exon 16 of factor 5 gene. Blood 2002; 99 (02) 702-705
• 111 DesPain AW, Kshetrapal A, Kousa YA. , et al. Management of intracranial hemorrhage in severe factor V deficiency and definitive treatment with liver transplantation. Pediatr Transplant 2018; 22 (01) e13102
• 112 Nuzzo F, Beshlawi I, Wali Y, Castoldi E. High incidence of intracranial bleeding in factor V-deficient patients with homozygous F5 splicing mutations. Br J Haematol 2017; 179 (01) 163-166
• 113 Fu QH, Zhou RF, Liu LG. , et al. Identification of three F5 gene mutations associated with inherited coagulation factor V deficiency in two Chinese pedigrees. Haemophilia 2004; 10 (03) 264-270
• 114 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 (10) 1505-1513
• 115 Castoldi E, Duckers C, Radu C. , et al. Homozygous F5 deep-intronic splicing mutation resulting in severe factor V deficiency and undetectable thrombin generation in platelet-rich plasma. J Thromb Haemost 2011; 9 (05) 959-968
• 116 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 (03) 477-478
• 117 Schrijver I, Koerper MA, Jones CD, Zehnder JL. Homozygous factor V splice site mutation associated with severe factor V deficiency. Blood 2002; 99 (08) 3063-3065
• 118 Asselta R, Montefusco MC, Duga S. , et al. Severe factor V deficiency: exon skipping in the factor V gene causing a partial deletion of the C1 domain. J Thromb Haemost 2003; 1 (06) 1237-1244
• 119 Jones CD, Yeung C, Negro F, Zehnder JL. Molecular characterization and subcellular localization of Tyr478del: a pathogenic in-frame deletion in coagulation factor V. J Thromb Haemost 2007; 5 (02) 431-433
• 120 Paraboschi EM, Kayiran SM, Özbek N. , et al. Functional characterization of a novel missense mutation identified in a Turkish patient affected by severe coagulation factor V deficiency. Haemophilia 2012; 18 (02) 205-210
• 121 Kling SJ, Griffee M, Flanders MM, Rodgers GM. Factor V deficiency caused by a novel missense mutation, Ile417Thr, in the A2 domain. J Thromb Haemost 2006; 4 (02) 481-483
• 122 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 (02) 172-178
• 123 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 (03) 683-685
• 124 Fu Q, Wu W, Ding Q. , et al. Type I coagulation factor V deficiency caused by compound heterozygous mutation of F5 gene. Haemophilia 2003; 9 (05) 646-649
• 125 Zheng W, Liu Y, Luo Y. , et al. Molecular characterisation of Tyr530Ser and IVS16-1G>T mutations causing severe factor V deficiency. Thromb Haemost 2010; 104 (03) 536-543
• 126 Wang Y, Zhu L, Ye L, Xie Y, Pan J, Wang M. Factor V deficiency caused by a novel nonsense mutation (Gln2031stop) in a Chinese patient. Blood Coagul Fibrinolysis 2014; 25 (03) 283-285
• 127 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 (02) 150-156
• 128 Coppola A, Maruotti GM, Feola G. , et al. Management of patients with factor V deficiency: open issues from the challenging history of a woman with anaphylactic transfusion reactions. Haemophilia 2010; 16 (03) 560-563
• 129 Bafunno V, Favuzzi G, Fierro T. , et al. Coinheritance of three novel FV gene mutations in a patient with a severe FV deficiency. Haemophilia 2012; 18 (02) e51-e53
• 130 Borhany M, Ranc A, Fretigny M, Moulis G, Abid M, Shamsi T. , et al. Molecular analysis of eight severe FV-deficient patients in Pakistan: A large series of homozygous for frameshift mutations. Haemophilia 2019 . doi: 10.1111/hae.13741. [Epub ahead of print]
• 131 Paraboschi EM, Menegatti M, Peyvandi F, Duga S, Asselta R. Understanding the Impact of Aberrant Splicing in Coagulation Factor V Deficiency. Int J Mol Sci 2019; 20 (04) 910