Congenital Fibrinogen Deficiencies: Not So Rare

Abstract

Congenital fibrinogen deficiencies (CFDs), traditionally considered rare monogenic disorders, are now recognized as more prevalent and genetically complex than previously thought. Indeed, the symptoms manifested in CFD patients, such as bleeding and thrombosis, are likely to result from variation in several genes rather than solely driven by variants in one of the three fibrinogen genes, FGB, FGA, and FGG. This review highlights recent advances in understanding the genetic causes of CFD and their variability, facilitated by the growing use and availability of next-generation sequencing data. Using gnomAD v4.1.0. data, which includes more than 800,000 individuals, we provide updated global prevalence estimates for CFDs based on frequencies of predicted deleterious variants in FGB, FGA, and FGG. Recessively inherited fibrinogen deficiencies (homozygous genotypes) could be present in around 29 individuals per million, while dominantly inherited deficiencies (heterozygous genotypes) may be present in up to 15,000 per million. These increased estimates can be attributed to the inclusion of broader, more diverse genetic datasets in the new version of gnomAD, thus capturing a greater range of rare variants and homozygous cases.

Keywords

fibrinogen - fibrin - bleeding - prevalence

Publikationsverlauf

Eingereicht: 17. Oktober 2024

Angenommen: 03. Januar 2025

Artikel online veröffentlicht:
12. März 2025

• References

• 1 Ruggeri ZM, Mendolicchio GL. Platelet and von Willebrand factor interactions at the vessel wall. Hamostaseologie 2004; 24 (01) 1-11
• 2 Bennett JS. Platelet-fibrinogen interactions. Ann N Y Acad Sci 2001; 936: 340-354
• 3 Neerman-Arbez M, Casini A. Fifty years of fibrinogen structure and function. Semin Thromb Hemost 2024; 50 (01) 148-150
• 4 Weisel JW, Litvinov RI. Fibrin formation, structure and properties. Subcell Biochem 2017; 82: 405-456
• 5 Risman RA, Kirby NC, Bannish BE, Hudson NE, Tutwiler V. Fibrinolysis: an illustrated review. Res Pract Thromb Haemost 2023; 7 (02) 100081
• 6 Vu D, Di Sanza C, Caille D. et al. Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia. Hum Mol Genet 2005; 14 (21) 3271-3280
• 7 Wolberg AS. Fibrinogen and fibrin: synthesis, structure, and function in health and disease. J Thromb Haemost 2023; 21 (11) 3005-3015
• 8 Luyendyk JP, Schoenecker JG, Flick MJ. The multifaceted role of fibrinogen in tissue injury and inflammation. Blood 2019; 133 (06) 511-520
• 9 Vilar R, Fish RJ, Casini A, Neerman-Arbez M. Fibrin(ogen) in human disease: both friend and foe. Haematologica 2020; 105 (02) 284-296
• 10 Hamsten A, Iselius L, de Faire U, Blombäck M. Genetic and cultural inheritance of plasma fibrinogen concentration. Lancet 1987; 2 (8566) 988-991
• 11 de Lange M, Snieder H, Ariëns RAS, Spector TD, Grant PJ. The genetics of haemostasis: a twin study. Lancet 2001; 357 (9250) 101-105
• 12 Fort A, Fish RJ, Attanasio C, Dosch R, Visel A, Neerman-Arbez M. A liver enhancer in the fibrinogen gene cluster. Blood 2011; 117 (01) 276-282
• 13 Fish RJ, Neerman-Arbez M. A novel regulatory element between the human FGA and FGG genes. Thromb Haemost 2012; 108 (03) 427-434
• 14 Espitia Jaimes C. . Regulation of the human fibrinogen gene cluster through chromatin interactions. Ph.D. Dissertation. Université de Genève; 2018
• 15 Espitia Jaimes C, Fish RJ, Neerman-Arbez M. Local chromatin interactions contribute to expression of the fibrinogen gene cluster. J Thromb Haemost 2018; 16 (10) 2070-2082
• 16 Fish RJ, Neerman-Arbez M. Fibrinogen gene regulation. Thromb Haemost 2012; 108 (03) 419-426
• 17 Dobson DA, Fish RJ, de Vries PS, Morrison AC, Neerman-Arbez M, Wolberg AS. Regulation of fibrinogen synthesis. Thromb Res 2024; 242: 109134
• 18 Fu Y, Grieninger G. Fib420: a normal human variant of fibrinogen with two extended α chains. Proc Natl Acad Sci U S A 1994; 91 (07) 2625-2628
• 19 Grieninger G, Lu X, Cao Y. et al. Fib420, the novel fibrinogen subclass: newborn levels are higher than adult. Blood 1997; 90 (07) 2609-2614
• 20 Grieninger G. Contribution of the α EC domain to the structure and function of fibrinogen-420. Ann N Y Acad Sci 2001; 936 (01) 44-64
• 21 Freire C, Fish RJ, Vilar R. et al. A genetic modifier of venous thrombosis in zebrafish reveals a functional role for fibrinogen AαE in early hemostasis. Blood Adv 2020; 4 (21) 5480-5491
• 22 de Vries JJ, Visser C, van Ommen M. et al. Levels of fibrinogen variants are altered in severe COVID-19. TH Open 2023; 7 (03) e217-e225
• 23 Wolfenstein-Todel C, Mosesson MW. Carboxy-terminal amino acid sequence of a human fibrinogen γ-chain variant (γ′). Biochemistry 1981; 20 (21) 6146-6149
• 24 Chung DW, Davie EW. γ and γ′ chains of human fibrinogen are produced by alternative mRNA processing. Biochemistry 1984; 23 (18) 4232-4236
• 25 Wolfenstein-Todel C, Mosesson MW. Human plasma fibrinogen heterogeneity: evidence for an extended carboxyl-terminal sequence in a normal γ chain variant (γ′). Proc Natl Acad Sci U S A 1980; 77 (09) 5069-5073
• 26 Lovely RS, Kazmierczak SC, Massaro JM, D'Agostino Sr RB, O'Donnell CJ, Farrell DH. γ′ fibrinogen: evaluation of a new assay for study of associations with cardiovascular disease. Clin Chem 2010; 56 (05) 781-788
• 27 Macrae FL, Domingues MM, Casini A, Ariëns RAS. The (patho)physiology of fibrinogen γ′. Semin Thromb Hemost 2016; 42 (04) 344-355
• 28 Casini A, Moerloose P, Neerman-Arbez M. One hundred years of congenital fibrinogen disorders. Semin Thromb Hemost 2022; 48 (08) 880-888
• 29 Richard M, Celeny D, Neerman-Arbez M. Mutations accounting for congenital fibrinogen disorders: an update. Semin Thromb Hemost 2022; 48 (08) 889-903
• 30 Casini A, von Mackensen S, Santoro C. et al; QualyAfib Study Group. Clinical phenotype, fibrinogen supplementation, and health-related quality of life in patients with afibrinogenemia. Blood 2021; 137 (22) 3127-3136
• 31 Casini A, Blondon M, Tintillier V. et al. Mutational epidemiology of congenital fibrinogen disorders. Thromb Haemost 2018; 118 (11) 1867-1874
• 32 Neerman-Arbez M, de Moerloose P, Bridel C. et al. Mutations in the fibrinogen aalpha gene account for the majority of cases of congenital afibrinogenemia. Blood 2000; 96 (01) 149-152
• 33 Attanasio C, de Moerloose P, Antonarakis SE, Morris MA, Neerman-Arbez M. Activation of multiple cryptic donor splice sites by the common congenital afibrinogenemia mutation, FGA IVS4 + 1 G-->T. Blood 2001; 97 (06) 1879-1881
• 34 Neerman-Arbez M, Honsberger A, Antonarakis SE, Morris MA. Deletion of the fibrinogen [correction of fibrogen] alpha-chain gene (FGA) causes congenital afibrogenemia. J Clin Invest 1999; 103 (02) 215-218
• 35 Casini A, Undas A, Palla R, Thachil J, de Moerloose P. Subcommittee on Factor XIII and Fibrinogen. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (09) 1887-1890
• 36 Hanss M, Biot F. A database for human fibrinogen variants. In: Annals of the New York Academy of Sciences. Vol 936. John Wiley & Sons, Ltd; 2001: 89-90
• 37 Sheen CR, Low J, Joseph J, Kotlyar E, George PM, Brennan SO. Fibrinogen Darlinghurst: hypofibrinogenaemia caused by a W253G mutation in the gamma chain in a patient with both bleeding and thrombotic complications. Thromb Haemost 2006; 96 (05) 685-687
• 38 Casini A, de Moerloose P, Neerman-Arbez M. Clinical features and management of congenital fibrinogen deficiencies. Semin Thromb Hemost 2016; 42 (04) 366-374
• 39 Mohsenian S, Palla R, Menegatti M. et al. Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database. Blood Adv 2024; 8 (06) 1392-1404
• 40 Casini A, Duval C, Pan X, Tintillier V, Biron-Andreani C, Ariëns RAS. Fibrin clot structure in patients with congenital dysfibrinogenaemia. Thromb Res 2016; 137: 189-195
• 41 Koopman J, Haverkate F, Grimbergen J, Egbring R, Lord ST. Fibrinogen Marburg: a homozygous case of dysfibrinogenemia, lacking amino acids A α 461-610 (Lys 461 AAA-->stop TAA). Blood 1992; 80 (08) 1972-1979
• 42 Casini A, Blondon M, Lebreton A. et al. Natural history of patients with congenital dysfibrinogenemia. Blood 2015; 125 (03) 553-561
• 43 Mohsenian S, Seidizadeh O, Mirakhorli M, Jazebi M, Azarkeivan A. Clinical and molecular characterization of Iranian patients with congenital fibrinogen disorders. Transfus Apher Sci 2021; 60 (06) 103203
• 44 Casini A, de Moerloose P. Can the phenotype of inherited fibrinogen disorders be predicted?. Haemophilia 2016; 22 (05) 667-675
• 45 Koopman J, Haverkate F, Lord ST, Grimbergen J, Mannucci PM. Molecular basis of fibrinogen Naples associated with defective thrombin binding and thrombophilia. Homozygous substitution of B β 68 Ala----Thr. J Clin Invest 1992; 90 (01) 238-244
• 46 Engesser L, Koopman J, de Munk G. et al. Fibrinogen Nijmegen: congenital dysfibrinogenemia associated with impaired t-PA mediated plasminogen activation and decreased binding of t-PA. Thromb Haemost 1988; 60 (01) 113-120
• 47 Collet JP, Soria J, Mirshahi M. et al. Dusart syndrome: a new concept of the relationship between fibrin clot architecture and fibrin clot degradability: hypofibrinolysis related to an abnormal clot structure. Blood 1993; 82 (08) 2462-2469
• 48 Casini A, Brungs T, Lavenu-Bombled C, Vilar R, Neerman-Arbez M, de Moerloose P. Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation. J Thromb Haemost 2017; 15 (05) 876-888
• 49 Casini A, Moerloose P, Neerman-Arbez M. Clinical, laboratory, and molecular aspects of congenital fibrinogen disorders. Semin Thromb Hemost 2024; ; (published online ahead of print)
• 50 Zhou J, Ding Q, Chen Y. et al. Clinical features and molecular basis of 102 Chinese patients with congenital dysfibrinogenemia. Blood Cells Mol Dis 2015; 55 (04) 308-315
• 51 Peyvandi F, Palla R, Menegatti M. et al; European Network of Rare Bleeding Disorders Group. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost 2012; 10 (04) 615-621
• 52 De Marco L, Girolami A, Zimmerman TS, Ruggeri ZM. von Willebrand factor interaction with the glycoprotein IIb/IIa complex. Its role in platelet function as demonstrated in patients with congenital afibrinogenemia. J Clin Invest 1986; 77 (04) 1272-1277
• 53 Neerman-Arbez M, de Moerloose P, Casini A. Laboratory and genetic investigation of mutations accounting for congenital fibrinogen disorders. Semin Thromb Hemost 2016; 42 (04) 356-365
• 54 Mohsenian S, Seidizadeh O, Palla R. et al. Diagnostic utility of bleeding assessment tools in congenital fibrinogen deficiencies. Haemophilia 2023; 29 (03) 827-835
• 55 Couzens A, Lebreton A, Masclaux F. et al. Hemizygous FGG p.Ala108Gly in a hypofibrinogenemic patient with a heterozygous 14.8 Mb deletion encompassing the entire fibrinogen gene cluster. Haemophilia 2022; 28 (05) e132-e135
• 56 Bertina RM, Koeleman BPC, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369 (6475) 64-67
• 57 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88 (10) 3698-3703
• 58 Nichols WC, Amano K, Cacheris PM. et al. Moderation of hemophilia A phenotype by the factor V R506Q mutation. Blood 1996; 88 (04) 1183-1187
• 59 van 't Veer C, Golden NJ, Kalafatis M, Simioni P, Bertina RM, Mann KG. An in vitro analysis of the combination of hemophilia A and factor V(LEIDEN). Blood 1997; 90 (08) 3067-3072
• 60 Gill JC, Endres-Brooks J, Bauer PJ, Marks Jr WJ, Montgomery RR. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69 (06) 1691-1695
• 61 Ward SE, O'Sullivan JM, O'Donnell JS. The relationship between ABO blood group, von Willebrand factor, and primary hemostasis. Blood 2020; 136 (25) 2864-2874
• 62 Sayers EW, Beck J, Bolton EE. et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 2021; 49 (D1): D10-D17
• 63 Abecasis GR, Altshuler D, Auton A. et al; 1000 Genomes Project Consortium. A map of human genome variation from population-scale sequencing. Nature 2010; 467 (7319) 1061-1073
• 64 Gudmundsson S, Singer-Berk M, Watts NA. et al; Genome Aggregation Database Consortium. Variant interpretation using population databases: lessons from gnomAD. Hum Mutat 2022; 43 (08) 1012-1030
• 65 Halldorsson BV, Eggertsson HP, Moore KHS. et al; DBDS Genetic Consortium. The sequences of 150,119 genomes in the UK Biobank. Nature 2022; 607 (7920) 732-740
• 66 Skuladottir AT, Tragante V, Sveinbjornsson G. et al. Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease. NPJ Parkinsons Dis 2024; 10 (01) 140
• 67 Wright CF, West B, Tuke M. et al. Assessing the pathogenicity, penetrance, and expressivity of putative disease-causing variants in a population setting. Am J Hum Genet 2019; 104 (02) 275-286
• 68 Baxter S, Singer-Berk M, Russell K. et al. P138: Evaluating the impact of gnomAD v4 on genetic prevalence estimates*. Genet Med Open 2024; 2: 101035
• 69 Bycroft C, Freeman C, Petkova D. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 2018; 562 (7726) 203-209
• 70 Akbari P, Gilani A, Sosina O. et al; Regeneron Genetics Center, DiscovEHR Collaboration. Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science 2021; 373 (6550) x
• 71 Ryu J, Rämö JT, Jurgens SJ. et al. Thrombosis risk in single- and double-heterozygous carriers of factor V Leiden and prothrombin G20210A in FinnGen and the UK Biobank. Blood 2024; 143 (23) 2425-2432
• 72 Karczewski KJ, Francioli LC, Tiao G. et al; Genome Aggregation Database Consortium. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 2020; 581 (7809) 434-443
• 73 Mannucci PM, Duga S, Peyvandi F. Recessively inherited coagulation disorders. Blood 2004; 104 (05) 1243-1252
• 74 Asselta R, Paraboschi EM, Rimoldi V. et al. Exploring the global landscape of genetic variation in coagulation factor XI deficiency. Blood 2017; 130 (04) e1-e6
• 75 Paraboschi EM, Duga S, Asselta R. Fibrinogen as a pleiotropic protein causing human diseases: the mutational burden of Aα, Bβ, and γ chains. Int J Mol Sci 2017; 18 (12) 2711
• 76 Seidizadeh O, Cairo A, Baronciani L, Valenti L, Peyvandi F. Population-based prevalence and mutational landscape of von Willebrand disease using large-scale genetic databases. NPJ Genom Med 2023; 8 (01) 31
• 77 Seidizadeh O, Cairo A, Mancini I, George JN, Peyvandi F. Global prevalence of hereditary thrombotic thrombocytopenic purpura determined by genetic analysis. Blood Adv 2024; 8 (16) 4386-4396
• 78 McLaren W, Gil L, Hunt SE. et al. The Ensembl variant effect predictor. Genome Biol 2016; 17 (01) 122
• 79 Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF. et al. Predicting splicing from primary sequence with deep learning. Cell 2019; 176 (03) 535-548.e24
• 80 Rentzsch P, Witten D, Cooper GM, Shendure J, Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res 2019; 47 (D1): D886-D894
• 81 Landrum MJ, Lee JM, Benson M. et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 2018; 46 (D1): D1062-D1067
• 82 Cheng J, Novati G, Pan J. et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 2023; 381 (6664) eadg7492
• 83 Ng PC, Henikoff S. Predicting deleterious amino acid substitutions. Genome Res 2001; 11 (05) 863-874
• 84 Adzhubei IA, Schmidt S, Peshkin L. et al. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7 (04) 248-249
• 85 Brennan SO, Fellowes AP, Faed JM, George PM. Hypofibrinogenemia in an individual with 2 coding (γ82 A-->G and Bbeta235 P-->L) and 2 noncoding mutations. Blood 2000; 95 (05) 1709-1713
• 86 Zdziarska J, Undas A, Basa J. et al. Severe bleeding and miscarriages in a hypofibrinogenemic woman heterozygous for the γ Ala82Gly mutation. Blood Coagul Fibrinolysis 2009; 20 (05) 374-376
• 87 Wypasek E, Klukowska A, Zdziarska J. et al. Genetic and clinical characterization of congenital fibrinogen disorders in Polish patients: Identification of three novel fibrinogen gamma chain mutations. Thromb Res 2019; 182: 133-140
• 88 de Vries PS, Chasman DI, Sabater-Lleal M. et al. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration. Hum Mol Genet 2016; 25 (02) 358-370
• 89 Huffman JE, de Vries PS, Morrison AC. et al. Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. Blood 2015; 126 (11) e19-e29
• 90 Pankratz N, Wei P, Brody JA. et al. Whole-exome sequencing of 14 389 individuals from the ESP and CHARGE consortia identifies novel rare variation associated with hemostatic factors. Hum Mol Genet 2022; 31 (18) 3120-3132
• 91 Huffman JE, Nicholas J, Hahn J. et al. Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles. Blood 2024; 144 (21) 2248-2265
• 92 Ivaskevicius V, Jusciute E, Steffens M. et al. gammaAla82Gly represents a common fibrinogen γ-chain variant in Caucasians. Blood Coagul Fibrinolysis 2005; 16 (03) 205-208
• 93 Lek M, Karczewski KJ, Minikel EV. et al; Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016; 536 (7616) 285-291
• 94 Goodrich JK, Singer-Berk M, Son R. et al; AMP-T2D-GENES Consortia. Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. Nat Commun 2021; 12 (01) 3505
• 95 Gillmore JD, Lachmann HJ, Rowczenio D. et al. Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A α-chain amyloidosis. J Am Soc Nephrol 2009; 20 (02) 444-451