Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders

Marguerite Neerman-Arbez; Philippe de Moerloose; Alessandro Casini

doi:10.1055/s-0036-1571340

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2016; 42(04): 356-365
DOI: 10.1055/s-0036-1571340

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders

Authors

Marguerite Neerman-Arbez

¹Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
Philippe de Moerloose

²Division of Angiology and Haemostasis, Faculty of Medicine, University Hospitals of Geneva, Geneva, Switzerland
Alessandro Casini

²Division of Angiology and Haemostasis, Faculty of Medicine, University Hospitals of Geneva, Geneva, Switzerland

Abstract

Congenital fibrinogen disorders are classified into two types of plasma fibrinogen defects: type I (quantitative fibrinogen deficiencies), that is, hypofibrinogenemia or afibrinogenemia, in which there are low or absent plasma fibrinogen antigen levels, respectively, and type II (qualitative fibrinogen deficiencies), that is, dysfibrinogenemia or hypodysfibrinogenemia, in which there are normal or reduced antigen levels associated with disproportionately low functional activity. These disorders are caused by mutations in the three fibrinogen-encoding genes FGA, FGB, and FGG. Afibrinogenemia is associated with mild to severe bleeding, whereas hypofibrinogenemia is often asymptomatic. For these quantitative disorders, the majority of mutations prevent protein production. However, in some cases, missense or late-truncating nonsense mutations allow synthesis of the mutant fibrinogen chain, but intracellular fibrinogen assembly and/or secretion are impaired. Qualitative fibrinogen disorders are associated with bleeding, thrombosis, or both thrombosis and bleeding, but many dysfibrinogenemias are asymptomatic. The majority of cases are caused by heterozygous missense mutations. Here, we review the laboratory and genetic diagnosis of fibrinogen gene anomalies with an updated discussion of causative mutations identified.

Keywords

congenital fibrinogen disorders - mutations - afibrinogenemia - hypofibrinogenemia - dysfibrinogenemia - hypodysfibrinogenemia - bleeding - thrombosis

Volltext

Referenzen

References
1 Neerman-Arbez M, de Moerloose P. Hereditary fibrinogen abnormalities. In: Kaushansky K, Lichtman M, Beutler E, et al, eds. Williams Hematology. 8th ed. New York, NY: McGraw-Hill; 2010: 1-33
2 Tennent GA, Brennan SO, Stangou AJ, O'Grady J, Hawkins PN, Pepys MB. Human plasma fibrinogen is synthesized in the liver. Blood 2007; 109 (5) 1971-1974
3 Medved L, Weisel JW ; Fibrinogen and Factor XIII Subcommittee of Scientific Standardization Committee of International Society on Thrombosis and Haemostasis. Recommendations for nomenclature on fibrinogen and fibrin. J Thromb Haemost 2009; 7 (2) 355-359
4 de Moerloose P, Casini A, Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Hemost 2013; 39 (6) 585-595
5 Palla R, Peyvandi F, Shapiro AD. Rare bleeding disorders: diagnosis and treatment. Blood 2015; 125 (13) 2052-2061
6 Peyvandi F, Menegatti M, Palla R. Rare bleeding disorders: worldwide efforts for classification, diagnosis, and management. Semin Thromb Hemost 2013; 39 (6) 579-584
7 Casini A, de Moerloose P, Neerman-Arbez M. Clinical features and management of congenital fibrinogen deficiencies. Semin Thromb Hemost 2016; 42 (4) 356-365
8 Cunningham MT, Brandt JT, Laposata M, Olson JD. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med 2002; 126 (4) 499-505
9 Mackie IJ, Kitchen S, Machin SJ, Lowe GD ; Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. Guidelines on fibrinogen assays. Br J Haematol 2003; 121 (3) 396-404
10 Casini A, Sokollik C, Lukowski SW , et al. Hypofibrinogenemia and liver disease: a new case of Aguadilla fibrinogen and review of the literature. Haemophilia 2015; 21 (6) 820-827
11 Casini A, Neerman-Arbez M, Ariëns RA, de Moerloose P. Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. J Thromb Haemost 2015; 13 (6) 909-919
12 Miesbach W, Schenk J, Alesci S, Lindhoff-Last E. Comparison of the fibrinogen Clauss assay and the fibrinogen PT derived method in patients with dysfibrinogenemia. Thromb Res 2010; 126 (6) e428-e433
13 Shapiro SE, Phillips E, Manning RA , et al. Clinical phenotype, laboratory features and genotype of 35 patients with heritable dysfibrinogenaemia. Br J Haematol 2013; 160 (2) 220-227
14 Llamas P, Santos AB, Outeiriño J, Soto C, Tomás JF. Diagnostic utility of comparing fibrinogen Clauss and prothrombin time derived method. Thromb Res 2004; 114 (1) 73-74
15 Lefkowitz JB, DeBoom T, Weller A, Clarke S, Lavrinets D. Fibrinogen Longmont: a dysfibrinogenemia that causes prolonged clot-based test results only when using an optical detection method. Am J Hematol 2000; 63 (3) 149-155
16 Jennings I, Peyvandi F, Kitchen S , et al. A failure to diagnosis dysfibrinogenaemia: data from multicentre studies amongst UK Nequas and proRBDD project laboratories. In: XXV Congress of the International Society on Thrombosis and Haemostasis, Abstract PO500. Toronto, Canada; June 2015
17 Casini A, Blondon M, Lebreton A , et al. Natural history of patients with congenital dysfibrinogenemia. Blood 2015; 125 (3) 553-561
18 Krammer B, Anders O, Nagel HR, Burstein C, Steiner M. Screening of dysfibrinogenaemia using the fibrinogen function versus antigen concentration ratio. Thromb Res 1994; 76 (6) 577-579
19 Peyvandi F. Results of an international, multicentre pharmacokinetic trial in congenital fibrinogen deficiency. Thromb Res 2009; 124 (Suppl. 02) S9-S11
20 de Moerloose P, Boehlen F, Neerman-Arbez M. Fibrinogen and the risk of thrombosis. Semin Thromb Hemost 2010; 36 (1) 7-17
21 Dupuy E, Soria C, Molho P , et al. Embolized ischemic lesions of toes in an afibrinogenemic patient: possible relevance to in vivo circulating thrombin. Thromb Res 2001; 102 (3) 211-219
22 Ariëns RA. Fibrin(ogen) and thrombotic disease. J Thromb Haemost 2013; 11 (Suppl. 01) 294-305
23 Sugo T, Endo H, Matsuda M , et al. A classification of the fibrin network structures formed from the hereditary dysfibrinogens. J Thromb Haemost 2006; 4 (8) 1738-1746
24 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 (8) 2462-2469
25 Westbury SK, Duval C, Philippou H , et al. Partial deletion of the αC-domain in the Fibrinogen Perth variant is associated with thrombosis, increased clot strength and delayed fibrinolysis. Thromb Haemost 2013; 110 (6) 1135-1144
26 Pieters M, Undas A, Marchi R, De Maat MP, Weisel J, Ariëns RA ; Factor XIII And Fibrinogen Subcommittee Of The Scientific Standardisation Committee Of The International Society For Thrombosis And Haemostasis. An international study on the standardization of fibrin clot permeability measurement: methodological considerations and implications for healthy control values. J Thromb Haemost 2012; 10 (10) 2179-2181
27 Sugo T, Nakamikawa C, Yoshida N , et al. End-linked homodimers in fibrinogen Osaka VI with a B beta-chain extension lead to fragile clot structure. Blood 2000; 96 (12) 3779-3785
28 Undas A, Pastuszczak M, Iwaniec T, Kapelak K, Neerman-Arbez M. Functional characterisation of plasma fibrin clots in Polish carriers of fibrinogen gammaArg275His mutation (fibrinogen Zabrze). Thromb Haemost 2010; 104 (2) 415-417
29 Galanakis DK, Neerman-Arbez M, Brennan S , et al. Thromboelastographic phenotypes of fibrinogen and its variants: clinical and non-clinical implications. Thromb Res 2014; 133 (6) 1115-1123
30 Kant JA, Fornace Jr AJ, Saxe D, Simon MI, McBride OW, Crabtree GR. Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion. Proc Natl Acad Sci U S A 1985; 82 (8) 2344-2348
31 de Maat MP, Verschuur M. Fibrinogen heterogeneity: inherited and noninherited. Curr Opin Hematol 2005; 12 (5) 377-383
32 Blombäck M, Blombäck B, Mammen EF, Prasad AS. Fibrinogen Detroit—a molecular defect in the N-terminal disulphide knot of human fibrinogen?. Nature 1968; 218 (5137) 134-137
33 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 (2) 215-218
34 Roberts HR, Stinchcombe TE, Gabriel DA. The dysfibrinogenaemias. Br J Haematol 2001; 114 (2) 249-257
35 Galanakis D. Afibrinogenemias and dysfibrinogenemias. In: Marder V, White GC, Aird WC, eds. Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012: 693-708
36 Vu D, Neerman-Arbez M. Molecular mechanisms accounting for fibrinogen deficiency: from large deletions to intracellular retention of misfolded proteins. J Thromb Haemost 2007; 5 (Suppl. 01) 125-131
37 Ebert RF. Index of Variant Human Fibrinogens. Boca Raton, Ann Arbor, Boston: CRC Press; 1994
38 Galanakis DK, Neerman-Arbez M, Kudryk B, Henschen A. Decreased plasmin resistance by clots of a homophenotypic Aalpha R 16H fibrinogen (Kingsport, slower fibrinopeptide A than fibrinopeptide B release). Blood Coagul Fibrinolysis 2010; 21 (2) 135-139
39 Monaldini L, Asselta R, Duga S , et al. Mutational screening of six afibrinogenemic patients: identification and characterization of four novel molecular defects. Thromb Haemost 2007; 97 (4) 546-551
40 Neerman-Arbez M, Antonarakis SE, Honsberger A, Morris MA. 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 (8) 897-902
41 Neerman-Arbez M, de Moerloose P, Honsberger A , et al. Molecular analysis of the fibrinogen gene cluster in 16 patients with congenital afibrinogenemia: novel truncating mutations in the FGA and FGG genes. Hum Genet 2001; 108 (3) 237-240
42 Watanabe K, Shibuya A, Ishii E , et al. Identification of simultaneous mutation of fibrinogen alpha chain and protein C genes in a Japanese kindred. Br J Haematol 2003; 120 (1) 101-108
43 Spena S, Duga S, Asselta R , et al. Congenital afibrinogenaemia caused by uniparental isodisomy of chromosome 4 containing a novel 15-kb deletion involving fibrinogen Aalpha-chain gene. Eur J Hum Genet 2004; 12 (11) 891-898
44 Brennan SO, Maghzal G, Shneider BL, Gordon R, Magid MS, George PM. Novel fibrinogen gamma375 Arg—>Trp mutation (fibrinogen aguadilla) causes hepatic endoplasmic reticulum storage and hypofibrinogenemia. Hepatology 2002; 36 (3) 652-658
45 Brennan SO, Wyatt J, Medicina D, Callea F, George PM. Fibrinogen brescia: hepatic endoplasmic reticulum storage and hypofibrinogenemia because of a gamma284 Gly—>Arg mutation. Am J Pathol 2000; 157 (1) 189-196
46 Asselta R, Robusto M, Braidotti P , et al. Hepatic fibrinogen storage disease: identification of two novel mutations (p.Asp316Asn, fibrinogen Pisa and p.Gly366Ser, fibrinogen Beograd) impacting on the fibrinogen γ-module. J Thromb Haemost 2015; 13 (8) 1459-1467
47 Dib N, Quelin F, Ternisien C , et al. Fibrinogen angers with a new deletion (gamma GVYYQ 346-350) causes hypofibrinogenemia with hepatic storage. J Thromb Haemost 2007; 5 (10) 1999-2005
48 Brennan SO, Davis RL, Conard K, Savo A, Furuya KN. Novel fibrinogen mutation γ314Thr→Pro (fibrinogen AI duPont) associated with hepatic fibrinogen storage disease and hypofibrinogenaemia. Liver Int 2010; 30 (10) 1541-1547
49 Asselta R, Platè M, Robusto M , et al. Clinical and molecular characterisation of 21 patients affected by quantitative fibrinogen deficiency. Thromb Haemost 2015; 113 (3) 567-576
50 Sumitha E, Jayandharan GR, Arora N , et al. Molecular basis of quantitative fibrinogen disorders in 27 patients from India. Haemophilia 2013; 19 (4) 611-618
51 Chapin J, DeSancho M. Pulmonary embolism in a patient with congenital afibrinogenemia. Haemophilia 2013; 19 (6) e380-e382
52 Kulkarni BP, Nair SB, Vijapurkar M , et al. Molecular pathology of rare bleeding disorders (RBDs) in India: a systematic review. PLoS ONE 2014; 9 (9) e108683
53 Stikarová J, Blatný J, Kotlín R , et al. Novel homozygous fibrinogen Aα chain truncation causes severe afibrinogenemia with life threatening complications in a two-year-old boy. Thromb Res 2013; 132 (4) 490-492
54 Zhang J, Zhao X, Wang Z , et al. A novel fibrinogen B beta chain frameshift mutation causes congenital afibrinogenaemia. Thromb Haemost 2013; 110 (1) 76-82
55 Casini A, Lukowski S, Quintard VL , et al. FGB mutations leading to congenital quantitative fibrinogen deficiencies: an update and report of four novel mutations. Thromb Res 2014; 133 (5) 868-874
56 Castaman G, Rimoldi V, Giacomelli SH, Duga S. Congenital hypofibrinogenemia associated with novel homozygous fibrinogen Aα and heterozygous Bβ chain mutations. Thromb Res 2015; 136 (1) 144-147
57 Marchi R, Brennan S, Meyer M , et al. A novel mutation in the FGB: c.1105C>T turns the codon for amino acid Bβ Q339 into a stop codon causing hypofibrinogenemia. Blood Cells Mol Dis 2013; 50 (3) 177-181
58 Riedelová-Reicheltová Z, Riedel T, Májek P , et al. Abnormal fibrinogen Zlín (γThr21Ile) with missense mutation causing hypofibrinogenemia. Acta Haematol 2014; 132 (2) 140-143
59 Soya K, Takezawa Y, Okumura N, Terasawa F. Nonsense-mediated mRNA decay was demonstrated in two hypofibrinogenemias caused by heterozygous nonsense mutations of FGG, Shizuoka III and Kanazawa II. Thromb Res 2013; 132 (4) 465-470
60 Brennan SO, Mangos H, Faed JM. Benign FGB (148Lys→Asn, and 448Arg→Lys), and novel causative γ211Tyr→His mutation distinguished by time of flight mass spectrometry in a family with hypofibrinogenaemia. Thromb Haemost 2014; 111 (4) 679-684
61 Kotlín R, Pastva O, Stikarová J , et al. Two novel mutations in the fibrinogen γ nodule. Thromb Res 2014; 134 (4) 901-908
62 Zhu L, Wang Y, Zhao M , et al. Novel mutations (γTrp208Leu and γLys232Thr) leading to congenital hypofibrinogenemia in two unrelated Chinese families. Blood Coagul Fibrinolysis 2014; 25 (8) 894-897
63 Zhu L, Wang M, Xie H, Jin Y, Yang L, Xu P. A novel fibrinogen mutation (γ Thr277Arg) causes hereditary hypofibrinogenemia in a Chinese family. Blood Coagul Fibrinolysis 2013; 24 (6) 642-644
64 Wang Y, Zhu L, Hao X, Xie Y, Jin Y, Wang M. Unique de-novo mutation of fibrinogen gene in a Chinese girl with hypofibrinogenemia. Blood Coagul Fibrinolysis 2014; 25 (7) 780-782
65 Vorjohann S, Fish RJ, Biron-Andréani C , et al. Hypodysfibrinogenaemia due to production of mutant fibrinogen alpha-chains lacking fibrinopeptide A and polymerisation knob ‘A’. Thromb Haemost 2010; 104 (5) 990-997
66 Brennan SO, Davis RL, Lowen R, Ruskova A. Deletion of five residues from the coiled coil of fibrinogen (Bbeta Asn167_Glu171del) associated with bleeding and hypodysfibrinogenemia. Haematologica 2009; 94 (4) 585-588
67 Brennan SO, Roncolato F. Novel fibrinogen (B β401Gly→Val) presents as dys- or hypodysfibrinogenaemia due to alterations in sialic acid content. Thromb Haemost 2011; 106 (3) 551-553
68 Jayo A, Arnold E, González-Manchón C, Green D, Lord ST. Hypodysfibrinogenemia causing mild bleeding and thrombotic complications in a compound heterozygote of AalphaIVS4+1G>T mutation and Aalpha4841delC truncation (Aalpha(Perth)). Thromb Haemost 2009; 101 (4) 770-772
69 Ding Q, Ouyang Q, Xi X, Wang X, Shen Y, Wang H. Maternal chromosome 4 heterodisomy/isodisomy and Bβ chain Trp323X mutation resulting in severe hypodysfibrinogenaemia. Thromb Haemost 2012; 108 (4) 654-661
70 Brennan SO, Davis RL, Chitlur M. New fibrinogen substitution (gammaSer313Arg) causes diminished gamma chain expression and hypodysfibrinogenaemia. Thromb Haemost 2010; 103 (2) 478-479
71 Cheah CY, Brennan SO, Kennedy H, Januszewicz EH, Maxwell E, Burbury K. Fibrinogen Melbourne: a novel congenital hypodysfibrinogenemia caused by γ326Cys-Phe in the fibrinogen γ chain, presenting as massive splanchnic venous thrombosis. Blood Coagul Fibrinolysis 2012; 23 (6) 563-565
72 Ikeda M, Kobayashi T, Arai S , et al. Recombinant γT305A fibrinogen indicates severely impaired fibrin polymerization due to the aberrant function of hole ‘A’ and calcium binding sites. Thromb Res 2014; 134 (2) 518-525
73 Ikeda M, Arai S, Mukai S, Takezawa Y, Terasawa F, Okumura N. Novel heterozygous dysfibrinogenemia, Sumida (AαC472S), showed markedly impaired lateral aggregation of protofibrils and mildly lower functional fibrinogen levels. Thromb Res 2015; 135 (4) 710-717
74 Sugo T, Nakamikawa C, Takano H , et al. Fibrinogen Niigata with impaired fibrin assembly: an inherited dysfibrinogen with a Bbeta Asn-160 to Ser substitution associated with extra glycosylation at Bbeta Asn-158. Blood 1999; 94 (11) 3806-3813
75 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 (1) 168-174
76 Hua B, Li K, Lee A, Poon MC, Zhao Y. Coexisting congenital dysfibrinogenemia with a novel mutation in fibrinogen γ chain (γ322 Phe→Ile, Fibrinogen Beijing) and haemophilia B in a family. Haemophilia 2015; 21 (6) 846-851
77 Martinez J, MacDonald KA, Palascak JE. The role of sialic acid in the dysfibrinogenemia associated with liver disease: distribution of sialic acid on the constituent chains. Blood 1983; 61 (6) 1196-1202
78 Lefebvre P, Velasco PT, Dear A , et al. Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AalphaIVS4 + 1G>T mutation and an AalphaGln328 truncation (fibrinogen Keokuk). Blood 2004; 103 (7) 2571-2576
79 Meyer M, Dietzel H, Kaetzel R, Schmidt D, Liebscher K, Brennan SO. Fibrinogen Leipzig II (gamma351Gly—>Ser and gamma82Ala—>Gly): hypodysfibrinogenaemia due to two independent amino acid substitutions within the same polypeptide chain. Thromb Haemost 2007; 98 (4) 903-905
80 Ridgway HJ, Brennan SO, Faed JM, George PM. Fibrinogen Otago: a major alpha chain truncation associated with severe hypofibrinogenaemia and recurrent miscarriage. Br J Haematol 1997; 98 (3) 632-639
81 Koopman J, Haverkate F, Grimbergen J, Egbring R, Lord ST. Fibrinogen Marburg: a homozygous case of dysfibrinogenemia, lacking amino acids A alpha 461-610 (Lys 461 AAA—>stop TAA). Blood 1992; 80 (8) 1972-1979