Fibrinogen, an abundant plasma glycoprotein, is involved in the final stage of blood coagulation. Decreased fibrinogen levels, which may be caused by mutations, are manifested mainly in bleeding and thrombotic disorders. Clinically relevant mutations of fibrinogen are listed in the Human Fibrinogen Database. For the αC-connector (amino acids Aα240-410, nascent chain numbering), we have extended this database, with detailed descriptions of the clinical manifestations among members of reported families. This includes the specification of bleeding and thrombotic events and results of coagulation assays. Where available, the impact of a mutation on clotting and fibrinolysis is reported. The collected data show that the Human Fibrinogen Database reports considerably fewer missense and synonymous mutations than the general COSMIC and dbSNP databases. Homozygous nonsense or frameshift mutations in the αC-connector are responsible for most clinically relevant symptoms, while heterozygous mutations are often asymptomatic. Symptomatic subjects suffer from bleeding and, less frequently, from thrombotic events. Miscarriages within the first trimester and prolonged wound healing were reported in a few subjects. All mutations inducing thrombotic phenotypes are located at the identical positions within the consensus sequence of the tandem repeats.

Department of Biochemistry Institute of Hematology and Blood Transfusion U Nemocnice 1 12800 Prague Czech Republic

Zobrazit více v PubMed

Chargaff E., Bendich A. On the coagulation of fibrinogen. J. Biol. Chem. 1943;149:93–110. doi: 10.1016/S0021-9258(18)72219-9. DOI

Davalos D., Akassoglou K. Fibrinogen as a key regulator of inflammation in disease. Semin. Immunopathol. 2011;34:43–62. doi: 10.1007/s00281-011-0290-8. PubMed DOI

Clark R.A., Lanigan J.M., Della Pelle P., Manseau E., Dvorak H.F., Colvin R.B. Fibronectin and fibrin provide a provisional matrix for epidermal cell migration during wound reepithelialization. J. Invest Dermatol. 1982;79:264–269. doi: 10.1111/1523-1747.ep12500075. PubMed DOI

Dvorak H.F. Tumors: Wounds That Do Not Heal. N. Engl. J. Med. 1986;315:1650–1659. doi: 10.1158/2326-6066.CIR-14-0209. PubMed DOI

Kollman J.M., Pandi L., Sawaya M.R., Riley M., Doolittle R.F. Crystal Structure of Human Fibrinogen. Biochemistry. 2009;48:3877–3886. doi: 10.1021/bi802205g. PubMed DOI

Kant J.A., Fornace A.J., Saxe D., Simon M.I., McBride O.W., Crabtree G.R. Evolution and organization of the fibrinogen locus on chromosome 4, gene duplication accompanied by transposition and inversion. Proc. Natl. Acad. Sci. USA. 1985;82:2344–2348. doi: 10.1073/pnas.82.8.2344. PubMed DOI PMC

Roy S.N., Mukhopadhyay G., Redman C.M. Regulation of fibrinogen assembly. Transfection of Hep G2 cells with B beta cDNA specifically enhances synthesis of the three component chains of fibrinogen. J. Biol. Chem. 1990;265:6389–6393. doi: 10.1016/S0021-9258(19)39338-X. PubMed DOI

Nickerson J.M., Fuller G.M. Modification of fibrinogen chains during synthesis: Glycosylation of Bβ and γ chains. Biochemistry. 1981;20:2818–2821. doi: 10.1021/bi00513a017. PubMed DOI

Doolittle R.F., McNamara K., Lin K. Correlating structure and function during the evolution of fibrinogen-related domains. Protein Sci. 2012;21:1808–1823. doi: 10.1002/pro.2177. PubMed DOI PMC

Yee V.C., Pratt K.P., Côté H.C., Le Trong I., Chung D.W., Davie E.W., Stenkamp R.E., Teller D.C. Crystal structure of a 30 kDa C-terminal fragment from the γ chain of human fibrinogen. Structure. 1997;5:125–138. doi: 10.1016/S0969-2126(97)00171-8. PubMed DOI

Medved L., Weisel J.W. Fibrinogen and factor xiii subcommittee of the scientific standardization committee of the international society on thrombosis and haemostasis. Recommendations for nomenclature on fibrinogen and fibrin. J. Thromb. Haemost. 2009;7:355–359. doi: 10.1111/j.1538-7836.2008.03242.x. PubMed DOI PMC

Veklich Y.I., Gorkun O.V., Medved L.V., Nieuwenhuizen W., Weisel J.W. Carboxyl-terminal portions of the alpha chains of fibrinogen and fibrin. Localization by electron microscopy and the effects of isolated alpha C fragments on polymerization. J. Biol. Chem. 1993;268:13577–13585. doi: 10.1016/S0021-9258(19)38688-0. PubMed DOI

Burton R.A., Tsurupa G., Medved L., Tjandra N. Identification of an ordered compact structure within the recombinant bovine fibrinogen αC-domain fragment by NMR. Biochemistry. 2006;45:2257–2266. doi: 10.1021/bi052380c. PubMed DOI PMC

Falvo M.R., Millard D., O’Brien I.I.I.E.T., Superfine R., Lord S.T. Length of tandem repeats in fibrin’s αC region correlates with fiber extensibility. Journal of thrombosis and haemostasis. JTH. 2008;6:1991. PubMed PMC

Tsurupa G., Tsonev L., Medved L. Structural organization of the fibrin (ogen) αC-domain. Biochemistry. 2002;41:6449–6459. doi: 10.1021/bi025584r. PubMed DOI

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;16:1887–1890. doi: 10.1111/jth.14216. PubMed DOI

Undas A., Casini A. Congenital structural and functional fibrinogen disorders: A primer for internists. Pol. Arch. Intern. Med. 2019;129:913–920. doi: 10.20452/pamw.15082. PubMed DOI

Casini A., von Mackensen S., Santoro C., Khayat C.D., Belhani M., Ross C., Dorgalaleh A., Naz A., Ünal E., Abdelwahab M., et al. Clinical phenotype, fibrinogen supplementation, and health-related quality of life in patients with afibrinogenemia. Blood. 2021;137:3127–3136. doi: 10.1182/blood.2020009472. PubMed DOI

van Meegeren M., de Rooy J., Schreuder H., Brons P. Bone cysts in patients with afibrinogenaemia: A literature review and two new cases. Haemophilia. 2014;20:244–248. doi: 10.1111/hae.12337. PubMed DOI

Arcagök B.C., Özdemir N., Tekin A., Özcan R., Eliçevik M., Şenyüz O.F., Çam H., Celkan T. Spontaneous splenic rupture in a patient with congenital afibrinogenemia. Turk. Arch. Pediatrics Türk Pediatri Arşivi. 2014;49:247. doi: 10.5152/tpa.2014.1070. PubMed DOI PMC

Peyvandi F., Haertel S., Knaub S., Mannucci P.M. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J. Thromb. Haemost. 2006;4:1634–1637. doi: 10.1111/j.1538-7836.2006.02014.x. PubMed DOI

Casini A., Blondon M., Lebreton A., Koegel J., Tintillier V., de Maistre E., Gautier P., Biron C., Neerman-Arbez M., de Moerloose P. Natural history of patients with congenital dysfibrinogenemia. Blood J. Am. Soc. Hematol. 2015;125:553–561. doi: 10.1182/blood-2014-06-582866. PubMed DOI PMC

Haverkate F., Samama M. Familial dysfibrinogenemia and thrombophilia. Thromb. Haemost. 1995;73:151–161. doi: 10.1055/s-0038-1653741. PubMed DOI

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;15:876–888. doi: 10.1111/jth.13655. PubMed DOI

Chapman J., Dogan A. Fibrinogen alpha amyloidosis: Insights from proteomics. Expert Rev. Proteom. 2019;16:783–793. doi: 10.1080/14789450.2019.1659137. PubMed DOI PMC

Hanss M., Biot F. A Database for Human Fibrinogen Variants. Ann. N. Y. Acad. Sci. 2006;936:89–90. doi: 10.1111/j.1749-6632.2001.tb03495.x. PubMed DOI

Asselta R., Robusto M., Platé M., Santoro C., Peyvandi F., Duga S. Molecular characterization of 7 patients affected by dys- or hypo-dysfibrinogenemia: Identification of a novel mutation in the fibrinogen Bbeta chain causing a gain of glycosylation. Thromb. Res. 2015;136:168–174. doi: 10.1016/j.thromres.2015.05.007. PubMed DOI

Asselta R., Platè M., Robusto M., Borhany M., Guella I., Soldà G., Afrasiabi A., Menegatti M., Tahir S., Peyvandi F., et al. Clinical and molecular characterisation of 21 patients affected by quantitative fibrinogen deficiency. Thromb. Haemost. 2015;113:567–576. doi: 10.1160/TH14-07-0629. PubMed DOI

Bamford S., Dawson E., Forbes S., Clements J., Pettett R., Dogan A., Flanagan A., Teague J., A Futreal P., Stratton M.R., et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br. J. Cancer. 2004;91:355–358. doi: 10.1038/sj.bjc.6601894. PubMed DOI PMC

Forbes S.A., Beare D., Boutselakis H., Bamford S., Bindal N., Tate J., Cole C.G., Ward S., Dawson E., Ponting L., et al. COSMIC: Somatic cancer genetics at high-resolution. Nucleic Acids Res. 2017;45:D777–D783. doi: 10.1093/nar/gkw1121. PubMed DOI PMC

Sherry S.T., Ward M., Sirotkin K. dbSNP-database for single nucleotide polymorphisms and other classes of minor genetic variation. Genome Res. 1999;9:677–679. doi: 10.1101/gr.9.8.677. PubMed DOI

Hanss M.M.L., Ffrench P.O., Mornex J.F., Chabuet M., Biot F., De Mazancourt P., Dechavanne M. Two novel fibrinogen variants found in patients with pulmonary embolism and their families. J. Thromb. Haemost. 2003;1:1251–1257. doi: 10.1046/j.1538-7836.2003.00244.x. PubMed DOI

Arthur J.W., Cheung F.S., Reichardt J.K. Single Nucleotide Differences (SNDs) Continue to Contaminate the dbSNP Database With Consequences for Human Genomics and Health. Hum. Mutat. 2015;36:196–199. doi: 10.1002/humu.22735. PubMed DOI

Musumeci L., Arthur J.W., Cheung F.S.G., Hoque A., Lippman S., Reichardt J.K.V. Single nucleotide differences (SNDs) in the dbSNP database may lead to errors in genotyping and haplotyping studies. Hum. Mutat. 2010;31:67–73. doi: 10.1002/humu.21137. PubMed DOI PMC

Fiorini N., Lipman D.J., Lu Z. Cutting edge: Towards PubMed 2.0. eLife. 2017;6:e28801. doi: 10.7554/eLife.28801. PubMed DOI PMC

Den Dunnen J.T., Dalgleish R., Maglott D.R., Hart R.K., Greenblatt M.S., McGowan-Jordan J., Roux A.-F., Smith T., Antonarakis S.E., Taschner P.E.M. HGVS recommendations for the description of sequence variants: 2016 update. Hum. Mutat. 2016;37:564–569. doi: 10.1002/humu.22981. PubMed DOI

Wahab M.A., de Moerloose P., Fish R.J., Neerman-Arbez M. Identification and functional characterization of a novel nonsense mutation in FGA accounting for congenital afibrinogenemia in six Egyptian patients. Blood Coagul. Fibrinolysis. 2010;21:164–167. doi: 10.1097/MBC.0b013e32833678d5. PubMed DOI

Neerman-Arbez M., de Moerloose P. Mutations in the fibrinogen gene cluster accounting for congenital afibrinogenemia: An update and report of 10 novel mutations. Hum. Mutat. 2007;28:540–553. doi: 10.1002/humu.20483. PubMed DOI

Monaldini L., Asselta R., Duga S., Peyvandi F., Karimi M., Malcovati M., Tenchini M.L. Mutational screening of six afibrinogenemic patients: Identification and characterization of four novel molecular defects. Thromb. Haemost. 2007;97:546–551. doi: 10.1160/TH06-12-0743. PubMed DOI

Robert-Ebadi H., De Moerloose P., El Khorassani M., El Khattab M., Neerman-Arbez M. A novel frameshift mutation in FGA accounting for congenital afibrinogenemia predicted to encode an aberrant peptide terminating 158 amino acids downstream. Blood Coagul. Fibrinol. 2009;20:385–387. doi: 10.1097/MBC.0b013e328329f2a0. PubMed DOI

Sumitha E., Jayandharan G.R., Arora N., Abraham A., David S., Devi G.S., Shenbagapriya P., Nair S.C., George B., Mathews V. Molecular basis of quantitative fibrinogen disorders in 27 patients from I ndia. Haemophilia. 2013;19:611–618. doi: 10.1111/hae.12143. PubMed DOI

Amri Y., Toumi N.E.H., Fredj S.H., de Moerloose P. Congenital afibrinogenemia: Identification and characterization of two novel homozygous fibrinogen Aα and Bβ chain mutations in two Tunisian families. Thromb. Res. 2016;143:11–16. doi: 10.1016/j.thromres.2016.04.016. PubMed DOI

Angles-Cano E., Mathonnet F., Dreyfus M., Claeyssens S., de Mazancourt P. A case of afibrinogenemia associated with A-alpha chain gene compound heterozygosity (HUMFIBRA c.[4110delA]+[3200+1G>T]) Blood Coagul. Fibrinolysis. 2007;18:73–75. doi: 10.1097/MBC.0b013e328010bd16. PubMed DOI

Ridgway H.J., Brennan S.O., Faed J.M., George P.M. Fibrinogen Otago: A major α chain truncation associated with severe hypofibrinogenaemia and recurrent miscarriage. Br. J. Haematol. 1997;98:632–639. doi: 10.1046/j.1365-2141.1997.2753090.x. PubMed DOI

Santacroce R., Cappucci F., Pisanelli D., Perricone F., Papa M.L., Santoro R., Grandone E., Margaglione M. Inherited abnormalities of fibrinogen: 10-year clinical experience of an Italian group. Blood Coagul. Fibrinolysis. 2006;17:235–240. doi: 10.1097/01.mbc.0000224841.48463.be. PubMed DOI

Rottenstreich A., Lask A., Schliamser L., Zivelin A., Seligsohn U., Kalish Y. Thromboembolic events in patients with severe inherited fibrinogen deficiency. J. Thromb. Thrombolysis. 2015;42:261–266. doi: 10.1007/s11239-015-1325-0. PubMed DOI

Neerman-Arbez M., de Moerloose P., Honsberger A., Parlier G., Arnuti B., Biron C., Borg J.-Y., Eber S., Meili E., Peter-Salonen K., et al. Molecular analysis of the fibrinogen gene cluster in 16 patients with congenital afibrinogenemia: Novel truncating mutations in the FGA and FGG genes. Qual. Life Res. 2001;108:237–240. doi: 10.1007/s004390100469. PubMed DOI

Asselta R., Spena S., Duga S., Peyvandi F., Malcovati M., Mannucci P.M. Tenchini, M.L. Analysis of Iranian patients allowed the identification of the first truncating mutation in the fibrinogen Bbeta-chain gene causing afibrinogenemia. Haematologica. 2002;87:855–859. PubMed

Štikarová J., Blatný J., Kotlín R., Suttnar J., Zapletal O., Pimková K., Májek P., Hrachovinová I., Dyr J.E. Novel homozygous fibrinogen Aα chain truncation causes severe afibrinogenemia with life threatening complications in a two-year-old boy. Thromb. Res. 2013;132:490–492. doi: 10.1016/j.thromres.2013.08.022. PubMed DOI

Xue F., Ge J., Gu D.-S., Du W.-T., Sui T., Zhao H.-F., Zhang L., Yang R.-C. Genetic analysis of an inherited afibrinogenemia family caused by a novel frameshift mutation in FGA. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009;17:1021–1025. PubMed

Neerman-Arbez M., De Moerloose P., Bridel C., Honsberger A., Schönbörner A., Rossier C., Peerlinck K., Claeyssens S., Michele D.D., d’Oiron R. Mutations in the fibrinogen Aα gene account for the majority of cases of congenital afibrinogenemia. Blood J. Am. Soc. Hematol. 2000;96:149–152. PubMed

Kotlín R., Suttnar J., Cápová I., Hrachovinová I., Urbánková M., Dyr J.E. Šumperk, F. II. Dysfibrinogenemia in an individual with two coding mutations. Am. J. Hematol. 2012;87:555–557. doi: 10.1002/ajh.23162. PubMed DOI

Saes J.L., Gorkom B.A.P.L., Coppens M., Schols S.E.M. Pregnancy outcome in afibrinogenemia: Are we giving enough fibrinogen concentrate? A case series. Res. Pract. Thromb. Haemost. 2020;4:343–346. doi: 10.1002/rth2.12300. PubMed DOI PMC

Simsek I., de Mazancourt P., Horellou M., Erdem H., Pay S., Dinc A., Samama M.M. Afibrinogenemia resulting from homozygous nonsense mutation in A alpha chain gene associated with multiple thrombotic episodes. Blood Coagul. Fibrinol. 2008;19:247–253. doi: 10.1097/MBC.0b013e3282f564fd. PubMed DOI

Amri Y., Jouini H., Becheur M., Dabboubi R., Mahjoub B., Messaoud T., Sfar M.T., Casini A., de Moerloose P., Toumi N.E.H. Fibrinogen Mahdia: A congenitally abnormal fibrinogen characterized by defective fibrin polymerization. Haemophilia. 2017;23:e340–e347. doi: 10.1111/hae.13268. PubMed DOI

Lefebvre P., Velasco P.T., Dear A., Lounes K.C., Lord S.T., Brennan S.O., Green D., Lorand L. Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AαIVS4 1G> T mutation and an AαGln328 truncation (fibrinogen Keokuk) Blood. 2004;103:2571–2576. doi: 10.1182/blood-2003-07-2316. PubMed DOI

Park R., Doh H., An S.A., Choi J., Chung K., Song K. A novel fibrinogen variant (fibrinogen Seoul II; AαGln328Pro) characterized by impaired fibrin α-chain cross-linking. Blood. 2006;108:1919–1924. doi: 10.1182/blood-2005-11-007591. PubMed DOI

Castaman G., Rimoldi V., Giacomelli S.H., Duga S. Congenital hypofibrinogenemia associated with novel homozygous fibrinogen Aα and heterozygous Bβ chain mutations. Thromb. Res. 2015;136:144–147. doi: 10.1016/j.thromres.2015.04.025. PubMed DOI

Brennan S.O., Laurie A.D., Mo A., Grigg A. Novel fibrinogen mutations (Aα17Gly→Cys and Aα381Ser→Phe) occurring with a 312Thr→ Ala polymorphism: Allelic phase assigned by direct mass measurement. Blood Coagul. Fibrinol. 2015;26:882–886. doi: 10.1097/MBC.0000000000000316. PubMed DOI

Remijn J.A., van Wijk R., Nieuwenhuis H.K., de Groot P.G., van Solinge W.W. Molecular Basis of Congenital Afibrinogenaemia in a Dutch Family. Blood Coagul. Fibrinolysis Int. J. Haemost. Thromb. 2003;14:299–302. doi: 10.1097/01.mbc.0000061285.28953.be. PubMed DOI

Neerman-Arbez M., Honsberger A., Antonarakis S.E., Morris M.A. Deletion of the fibrogen alpha-chain gene (FGA) causes congenital afibrogenemia. J. Clin. Investig. 1999;103:215–218. doi: 10.1172/JCI5471. PubMed DOI PMC

Neerman-Arbez M., Antonarakis S.E., Honsberger A., Morris M.A. The 11 kb FGA deletion responsible for congenital afibrinogenaemia is mediated by a short direct repeat in the fibrinogen gene cluster. Eur. J. Hum. Genet. 1999;7:897–902. doi: 10.1038/sj.ejhg.5200395. PubMed DOI

Polack B., Pouzol P., De Mazancourt P., Gay V., Hanss M. Is primary prophylaxis required in afibrinogenemia? Transfusion. 2010;50:1401–1403. doi: 10.1111/j.1537-2995.2010.02612.x. PubMed DOI

Berens C., Rühl H., Ivaškevicius V., Oldenburg J., Hertfelder H., Pötzsch B. Recurrent VTE in a heterozygote of the fibrinogen Aα IVS4 1G> T and Aα p. Arg168Ter mutation. Thromb. Haemost. 2016;116:1073–1075. PubMed

Nathoo N., Rydz N., Poon M.-C., Metz L.M. Ischemic Strokes in a Man with Congenital Afibrinogenemia. Can. J. Neurol. Sci. J. Can. Sci. Neurol. 2018;45:590–592. doi: 10.1017/cjn.2018.57. PubMed DOI

Le Quellec S., Desjonqueres A., Rugeri L., Clavel H.D., Farhat F., Mechtouff L., Dargaud Y. Combined life-threatening thromboses and hemorrhages in a patient with afibrinogenemia and antithrombin deficiency. Thromb. J. 2018;16:6. doi: 10.1186/s12959-018-0162-8. PubMed DOI PMC

Smith N., Bornikova L., Noetzli L., Guglielmone H., Minoldo S., Backos D., Ms L.J., Thornburg C.D., Escobar M., White-Adams T.C., et al. Identification and characterization of novel mutations implicated in congenital fibrinogen disorders. Res. Pract. Thromb. Haemost. 2018;2:800–811. doi: 10.1002/rth2.12127. PubMed DOI PMC

Kotlín R., Zichová K., Suttnar J., Reicheltová Z., Salaj P. Congenital dysfibrinogenemia Aa Gly13Glu associated with bleeding during pregnancy. Thromb. Res. 2011;127:277–278. doi: 10.1016/j.thromres.2010.11.003. PubMed DOI

Pietrys D., Balwierz W., Iwaniec T., Vorjohann S., Neerman-Arbez M., Undas A. Two different fibrinogen gene mutations associated with bleeding in the same family (AαGly13Glu and γGly16Ser) and their impact on fibrin clot properties: Fibrinogen Krakow II and Krakow III. Thromb. Haemost. 2011;106:558–560. doi: 10.1160/TH11-02-0102. PubMed DOI

Rosenfeld M.A., Vasilyeva A.D., Yurina L.V., Bychkova A.V. Oxidation of proteins: Is it a programmed process? Free Radic. Res. 2018;52:14–38. doi: 10.1080/10715762.2017.1402305. PubMed DOI

Sovová Ž., Štikarová J., Kaufmanová J., Májek P., Suttnar J., Šácha P., Malý M., Dyr J.E. Impact of posttranslational modifications on atomistic structure of fibrinogen. PLoS ONE. 2020;15:e0227543. doi: 10.1371/journal.pone.0227543. PubMed DOI PMC

Stikarová J., Kotlín R., Riedel T., Suttnar J., Pimková K., Chrastinová L., Dyr J.E. The Effect of Reagents Mimicking Oxidative Stress on Fibrinogen Function. Sci. World J. 2013;2013:359621. doi: 10.1155/2013/359621. PubMed DOI PMC

Becatti M., Marcucci R., Bruschi G., Taddei N., Bani D., Gori A.M., Giusti B., Gensini G.F., Abbate R., Fiorillo C. Oxidative Modification of Fibrinogen Is Associated With Altered Function and Structure in the Subacute Phase of Myocardial Infarction. Arter. Thromb. Vasc. Biol. 2014;34:1355–1361. doi: 10.1161/ATVBAHA.114.303785. PubMed DOI

Pederson E.N., Interlandi G. Oxidation-induced destabilization of the fibrinogen α; C-domain dimer investigated by molecular dynamics simulations. Proteins Struct. Funct. Bioinform. 2019;87:826–836. doi: 10.1002/prot.25746. PubMed DOI PMC

Becatti M., Mannucci A., Argento F.R., Gitto S., Vizzutti F., Marra F., Taddei N., Fiorillo C., Laffi G. Super-Resolution Microscopy Reveals an Altered Fibrin Network in Cirrhosis: The Key Role of Oxidative Stress in Fibrinogen Structural Modifications. Antioxidants. 2020;9:737. doi: 10.3390/antiox9080737. PubMed DOI PMC

Sies H., Berndt C., Jones D.P. Oxidative stress. Annu. Rev. Biochem. 2017;86:715–748. doi: 10.1146/annurev-biochem-061516-045037. PubMed DOI

Kaiser C., Seydewitz H., Witt I. Studies on the primary structure of the Aα-chain of human fibrinogen: Clarification of hitherto uncertain amino acid residues. Thromb. Res. 1984;33:543–548. doi: 10.1016/0049-3848(84)90020-3. PubMed DOI

Baumann R.E., Henschen A.H. Human fibrinogen polymorphic site analysis by restriction endonuclease digestion and allele-specific polymerase chain reaction amplification: Identification of polymorphisms at positions a alpha 312 and B beta 448. Blood. 1993;2:2117–2124. doi: 10.1182/blood.V82.7.2117.2117. PubMed DOI

Clarke L., Zheng-Bradley X., Smith R., Kulesha E., Xiao C., Toneva I., Vaughan B., Preuss D., Leinonen R., Shumway M., et al. The 1000 Genomes Project: Data management and community access. Nat. Methods. 2012;9:459–462. doi: 10.1038/nmeth.1974. PubMed DOI PMC

Koch L. Exploring human genomic diversity with gnomAD. Nat. Rev. Genet. 2020;21:448. doi: 10.1038/s41576-020-0255-7. PubMed DOI

Standeven K.F., Grant P.J., Carter A.M., Scheiner T., Weisel J.W., Ariëns R.A. Functional analysis of the fibrinogen Aα Thr312Ala polymorphism: Effects on fibrin structure and function. Circulation. 2003;107:2326–2330. doi: 10.1161/01.CIR.0000066690.89407.CE. PubMed DOI

Lim B.C., Ariens R., Carter A.M., Weisel J.W., Grant P.J. Genetic regulation of fibrin structure and function: Complex gene-environment interactions may modulate vascular risk. Lancet. 2003;361:1424–1431. doi: 10.1016/S0140-6736(03)13135-2. PubMed DOI

Rasmussen-Torvik L., Cushman M., Tsai M., Zhang Y., Heckbert S.R., Rosamond W.D., Folsom A.R. The association of α-fibrinogen Thr312Ala polymorphism and venous thromboembolism in the LITE study. Thromb. Res. 2007;121:1–7. doi: 10.1016/j.thromres.2007.02.008. PubMed DOI PMC

Li J.-F., Lin Y., Yang Y.-H., Gan H.-L., Liang Y., Liu J., Yang S.-Q., Zhang W.-J., Cui N., Zhao L., et al. Fibrinogen Aα Thr312Ala Polymorphism Specifically Contributes to Chronic Thromboembolic Pulmonary Hypertension by Increasing Fibrin Resistance. PLoS ONE. 2013;8:e69635. doi: 10.1371/journal.pone.0069635. PubMed DOI PMC

Reiner A.P., Carty C.L., Carlson C.S., Wan J.Y., Rieder M.J., Smith J.D., Rice K., Fornage M., Jaquish C.E., Williams O.D., et al. Association between patterns of nucleotide variation across the three fibrinogen genes and plasma fibrinogen levels: The Coronary Artery Risk Development in Young Adults (CARDIA) study. J. Thromb. Haemost. 2006;4:1279–1287. doi: 10.1111/j.1538-7836.2006.01907.x. PubMed DOI

Kamimoto Y., Wada H., Ikejiri M., Nakatani K., Sugiyama T., Osato K., Murabayashi N., Habe K., Mizutani H., Matsumoto T., et al. Hypofibrinogenemia and the α-Fibrinogen Thr312Ala Polymorphism may be Risk Factors for Early Pregnancy Loss. Clin. Appl. Thromb. 2016;23:52–57. doi: 10.1177/1076029615594003. PubMed DOI

Carter A.M., Catto A.J., Grant P.J. Association of the α-fibrinogen Thr312Ala polymorphism with poststroke mortality in subjects with atrial fibrillation. Circulation. 1999;99:2423–2426. doi: 10.1161/01.CIR.99.18.2423. PubMed DOI

Carter A.M., Catto A.J., Kohler H.P., Ariens R.A., Stickland M.H., Grant P.J. α-Fibrinogen Thr312Ala polymorphism and venous thromboembolism. Blood J. Am. Soc. Hematol. 2000;96:1177–1179. PubMed

Suntharalingam J., Goldsmith K., van Marion V., Long L., Treacy C.M., Dudbridge F., Toshner M.R., Pepke-Zaba J., Eikenboom J.C.J., Morrell N.W. Fibrinogen Aα Thr312Ala polymorphism is associated with chronic thromboembolic pulmonary hypertension. Eur. Respir. J. 2008;31:736–741. doi: 10.1183/09031936.00055107. PubMed DOI

Le Gal G., Delahousse B., Lacut K., Malaviolle V., Regina S., Blouch M., Couturauda F., Mottiera D., Ogere E., Gruel Y. Fibrinogen Aα-Thr312Ala and factor XIII-A Val34Leu polymorphisms in idiopathic venous thromboembolism. Thromb. Res. 2007;121:333–338. doi: 10.1016/j.thromres.2007.05.003. PubMed DOI

Siegerink B., Rosendaal F.R., Algra A. Genetic variation in fibrinogen; its relationship to fibrinogen levels and the risk of myocardial infarction and ischemic stroke. J. Thromb. Haemost. 2009;7:385–390. doi: 10.1111/j.1538-7836.2008.03266.x. PubMed DOI