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Hamostaseologie 2020; 40(04): 460-466
DOI: 10.1055/a-1182-3510
Review Article

From Routine to Research Laboratory: Strategies for the Diagnosis of Congenital Fibrinogen Disorders

Alessandro Casini
1   Division of Angiology and Hemostasis, University Hospitals of Geneva, Geneva, Switzerland
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Abstract

Congenital fibrinogen disorders (CFDs) encompass a heterogeneous group of fibrinogen defects with a wide spectrum of biological and clinical features. An accurate diagnosis is thus essential to assure the optimal management for the patient. Diagnosis involves a multistep approach starting with routine coagulation assays and assessment of functional and antigenic fibrinogen followed by identification of the molecular anomaly. However, the diagnosis of CFD can be challenging as the sensitivity and specificity of coagulation assays depend on the fibrinogen level as well as on the fibrinogen variant. In addition, patients suffering from CFD have a heterogeneous clinical course which is often unpredictable by routine coagulation assays. To better determine the patient's clinical phenotype, global hemostasis assays and an assessment of the fibrin clot properties are performed in research laboratories. In this review, we summarize the fibrinogen work-up highlighting some common pitfalls and provide an update of the research on CFD.

Keywords

fibrinogen - fibrin - coagulation factors - mutations - diagnosis


Publication History

Received: 23 April 2020

Accepted: 19 May 2020

Article published online:
09 July 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Pieters M, Wolberg AS. Fibrinogen and fibrin: an illustrated review. Res Pract Thromb Haemost 2019; 3 (02) 161-172
    CrossrefPubMedGoogle Scholar
  • 2 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 (02) 355-359
    CrossrefPubMedGoogle Scholar
  • 3 Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost 2005; 3 (08) 1894-1904
    CrossrefPubMedGoogle Scholar
  • 4 Menegatti M, Peyvandi F. Treatment of rare factor deficiencies other than hemophilia. Blood 2019; 133 (05) 415-424
    CrossrefPubMedGoogle Scholar
  • 5 de Moerloose P, Neerman-Arbez M. Congenital fibrinogen disorders. Semin Thromb Hemost 2009; 35 (04) 356-366
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 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) E2711
    Google Scholar
  • 7 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
    CrossrefPubMedGoogle Scholar
  • 8 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
    CrossrefPubMedGoogle Scholar
  • 9 Stanciakova L, Kubisz P, Dobrotova M, Stasko J. Congenital afibrinogenemia: from etiopathogenesis to challenging clinical management. Expert Rev Hematol 2016; 9 (07) 639-648
    CrossrefPubMedGoogle Scholar
  • 10 Nagler M, Kremer Hovinga JA, Alberio L. et al. Thromboembolism in patients with congenital afibrinogenaemia. Long-term observational data and systematic review. Thromb Haemost 2016; 116 (04) 722-732
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Castaman G, Giacomelli SH, Biasoli C, Contino L, Radossi P. Risk of bleeding and thrombosis in inherited qualitative fibrinogen disorders. Eur J Haematol 2019; 103 (04) 379-384
    CrossrefPubMedGoogle Scholar
  • 12 Casini A, Blondon M, Lebreton A. et al. Natural history of patients with congenital dysfibrinogenemia. Blood 2015; 125 (03) 553-561
    CrossrefPubMedGoogle Scholar
  • 13 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Undas A. How to assess fibrinogen levels and fibrin clot properties in clinical practice?. Semin Thromb Hemost 2016; 42 (04) 381-388
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Verhovsek M, Moffat KA, Hayward CP. Laboratory testing for fibrinogen abnormalities. Am J Hematol 2008; 83 (12) 928-931
    CrossrefPubMedGoogle Scholar
  • 16 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 (02) 220-227
    CrossrefPubMedGoogle Scholar
  • 17 Jennings I, Kitchen S, Menegatti M. et al. Potential misdiagnosis of dysfibrinogenaemia: data from multicentre studies amongst UK NEQAS and PRO-RBDD project laboratories. Int J Lab Hematol 2017; 39 (06) 653-662
    CrossrefPubMedGoogle Scholar
  • 18 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 (03) 396-404
    CrossrefPubMedGoogle Scholar
  • 19 Casini A, Neerman-Arbez M, Ariëns RA, de Moerloose P. Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. J Thromb Haemost 2015; 13 (06) 909-919
    CrossrefPubMedGoogle Scholar
  • 20 Peyvandi F. Epidemiology and treatment of congenital fibrinogen deficiency. Thromb Res 2012; 130 (Suppl. 02) S7-S11
    CrossrefPubMedGoogle Scholar
  • 21 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 (06) 577-579
    CrossrefPubMedGoogle Scholar
  • 22 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
    CrossrefPubMedGoogle Scholar
  • 23 Chandler JB, Siddon AJ, Bahel P, Torres R, Rinder HM, Tormey CA. Modified approach to fibrinogen replacement in the setting of dysfibrinogenaemia. J Clin Pathol 2019; 72 (02) 177-180
    CrossrefPubMedGoogle Scholar
  • 24 Asselta R, Duga S, Spena S. et al. Missense or splicing mutation? The case of a fibrinogen Bbeta-chain mutation causing severe hypofibrinogenemia. Blood 2004; 103 (08) 3051-3054
    CrossrefPubMedGoogle Scholar
  • 25 Casini A, de Moerloose P. Can the phenotype of inherited fibrinogen disorders be predicted?. Haemophilia 2016; 22 (05) 667-675
    CrossrefPubMedGoogle Scholar
  • 26 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 (03) 632-639
    CrossrefPubMedGoogle Scholar
  • 27 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 (04) 679-684
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Vasse M, Francois D, Van Dreden P, de Mazancourt P. Different sensitivity of von Clauss reagents for the diagnosis of dysfibrinogenemia. Eur J Haematol 2020; 104 (01) 70-71
    CrossrefPubMedGoogle Scholar
  • 29 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 (03) 149-155
    CrossrefPubMedGoogle Scholar
  • 30 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 (06) e428-e433
    CrossrefPubMedGoogle Scholar
  • 31 Xiang L, Luo M, Yan J. et al. Combined use of Clauss and prothrombin time-derived methods for determining fibrinogen concentrations: screening for congenital dysfibrinogenemia. J Clin Lab Anal 2018; 32 (04) e22322
    CrossrefPubMedGoogle Scholar
  • 32 Suzuki A, Suzuki N, Kanematsu T. et al. Clot waveform analysis in Clauss fibrinogen assay contributes to classification of fibrinogen disorders. Thromb Res 2019; 174: 98-103
    CrossrefPubMedGoogle Scholar
  • 33 Casini A, Blondon M, Tintillier V. et al. Mutational epidemiology of congenital fibrinogen disorders. Thromb Haemost 2018; 118 (11) 1867-1874
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Moret A, Zúñiga Á, Ibáñez M. et al. Clinical and molecular characterization by next generation sequencing of Spanish patients affected by congenital deficiencies of fibrinogen. Thromb Res 2019; 180: 115-117
    CrossrefPubMedGoogle Scholar
  • 35 Hanss M, Biot F. A database for human fibrinogen variants. Ann N Y Acad Sci 2001; 936: 89-90
    CrossrefPubMedGoogle Scholar
  • 36 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 (06) 540-553
    CrossrefPubMedGoogle Scholar
  • 37 Asselta R, Duga S, Tenchini ML. The molecular basis of quantitative fibrinogen disorders. J Thromb Haemost 2006; 4 (10) 2115-2129
    CrossrefPubMedGoogle Scholar
  • 38 Neerman-Arbez M, Casini A. Clinical consequences and molecular bases of low fibrinogen levels. Int J Mol Sci 2018; 19 (01) E192
    Google Scholar
  • 39 Callea F, Giovannoni I, Sari S. et al. Fibrinogen gamma chain mutations provoke fibrinogen and apolipoprotein B plasma deficiency and liver storage. Int J Mol Sci 2017; 18 (12) E2717
    CrossrefPubMedGoogle Scholar
  • 40 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 (08) 1459-1467
    CrossrefPubMedGoogle Scholar
  • 41 Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen. Thromb Haemost 1995; 73 (01) 151-161
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Meh DA, Mosesson MW, Siebenlist KR. et al. Fibrinogen naples I (B beta A68T) nonsubstrate thrombin-binding capacities. Thromb Res 2001; 103 (01) 63-73
    CrossrefPubMedGoogle Scholar
  • 43 Weisel JW, Litvinov RI. Mechanisms of fibrin polymerization and clinical implications. Blood 2013; 121 (10) 1712-1719
    CrossrefPubMedGoogle Scholar
  • 44 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
    CrossrefPubMedGoogle Scholar
  • 45 Smith N, Bornikova L, Noetzli L. et al. Identification and characterization of novel mutations implicated in congenital fibrinogen disorders. Res Pract Thromb Haemost 2018; 2 (04) 800-811
    CrossrefPubMedGoogle Scholar
  • 46 Asselta R, Platè M, Robusto M. et al. Clinical and molecular characterisation of 21 patients affected by quantitative fibrinogen deficiency. Thromb Haemost 2015; 113 (03) 567-576
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Korte W, Poon MC, Iorio A, Makris M. Thrombosis in inherited fibrinogen disorders. Transfus Med Hemother 2017; 44 (02) 70-76
    CrossrefPubMedGoogle Scholar
  • 48 Mosesson MW. Update on antithrombin I (fibrin). Thromb Haemost 2007; 98 (01) 105-108
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Santoro C, Massaro F, Venosi S. et al. Severe thrombotic complications in congenital afibrinogenemia: a pathophysiological and management dilemma. Semin Thromb Hemost 2016; 42 (05) 577-582
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Kumar R, Béguin S, Hemker HC. The influence of fibrinogen and fibrin on thrombin generation--evidence for feedback activation of the clotting system by clot bound thrombin. Thromb Haemost 1994; 72 (05) 713-721
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Korte W, Feldges A. Increased prothrombin activation in a patient with congenital afibrinogenemia is reversible by fibrinogen substitution. Clin Investig 1994; 72 (05) 396-398
    CrossrefPubMedGoogle Scholar
  • 52 Young GA, Carmona R, Cano Garcia V. Thromboelastography and thrombin generation assay in inherited afibrinogenemia. Haemophilia 2018; 24 (06) e410-e416
    CrossrefPubMedGoogle Scholar
  • 53 Ross C, Rangarajan S, Karimi M. et al. Pharmacokinetics, clot strength and safety of a new fibrinogen concentrate: randomized comparison with active control in congenital fibrinogen deficiency. J Thromb Haemost 2018; 16 (02) 253-261
    CrossrefPubMedGoogle Scholar
  • 54 Simurda T, Casini A, Stasko J. et al. Perioperative management of a severe congenital hypofibrinogenemia with thrombotic phenotype. Thromb Res 2020; 188: 1-4
    CrossrefPubMedGoogle Scholar
  • 55 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 (06) 1115-1123
    CrossrefPubMedGoogle Scholar
  • 56 Kalina U, Stöhr HA, Bickhard H. et al. Rotational thromboelastography for monitoring of fibrinogen concentrate therapy in fibrinogen deficiency. Blood Coagul Fibrinolysis 2008; 19 (08) 777-783
    CrossrefPubMedGoogle Scholar
  • 57 Treliński J, Pachniewska K, Matczak J, Robak M, Chojnowski K. Assessment of selected ROTEM parameters, kinetics of fibrinogen polymerization and plasmin amidolytic activity in patients with congenital fibrinogen defects. Adv Clin Exp Med 2016; 25 (06) 1255-1263
    CrossrefPubMedGoogle Scholar
  • 58 Zhou J, Xin Y, Ding Q. et al. Thromboelastography predicts risks of obstetric complication occurrence in (hypo)dysfibrinogenemia patients under non-pregnant state. Clin Exp Pharmacol Physiol 2016; 43 (02) 149-156
    CrossrefPubMedGoogle Scholar
  • 59 Bridge KI, Philippou H, Ariëns R. Clot properties and cardiovascular disease. Thromb Haemost 2014; 112 (05) 901-908
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 Kattula S, Byrnes JR, Wolberg AS. Fibrinogen and fibrin in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 2017; 37 (03) e13-e21
    CrossrefPubMedGoogle Scholar
  • 61 Mihalko E, Brown AC. Clot structure and implications for bleeding and thrombosis. Semin Thromb Hemost 2020; 46 (01) 96-104
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 Pieters M, Philippou H, Undas A, de Lange Z, Rijken DC, Mutch NJ. Subcommittee on Factor XIII and Fibrinogen, and the Subcommittee on Fibrinolysis. An international study on the feasibility of a standardized combined plasma clot turbidity and lysis assay: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (05) 1007-1012
    CrossrefPubMedGoogle Scholar
  • 63 Pieters M, Guthold M, Nunes CM, de Lange Z. Interpretation and validation of maximum absorbance data obtained from turbidimetry analysis of plasma clots. Thromb Haemost 2020; 120 (01) 44-54
    Article in Thieme ConnectPubMedGoogle Scholar
  • 64 Longstaff C. Measuring fibrinolysis: from research to routine diagnostic assays. J Thromb Haemost 2018; 16 (04) 652-662
    CrossrefPubMedGoogle Scholar
  • 65 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
    CrossrefPubMedGoogle Scholar
  • 66 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
    CrossrefPubMedGoogle Scholar
  • 67 Ariëns RA. Fibrin(ogen) and thrombotic disease. J Thromb Haemost 2013; 11 (Suppl. 01) 294-305
    CrossrefPubMedGoogle Scholar
  • 68 Panteleev MA, Ovanesov MV, Kireev DA. et al. Spatial propagation and localization of blood coagulation are regulated by intrinsic and protein C pathways, respectively. Biophys J 2006; 90 (05) 1489-1500
    CrossrefPubMedGoogle Scholar
  • 69 Domingues MM, Macrae FL, Duval C. et al. Thrombin and fibrinogen γ′ impact clot structure by marked effects on intrafibrillar structure and protofibril packing. Blood 2016; 127 (04) 487-495
    CrossrefPubMedGoogle Scholar
  • 70 Pieters M, Guthold M, Nunes CM, de Lange Z. Interpretation and validation of maximum absorbance data obtained from turbidimetry analysis of plasma clots. Thromb Haemost 2020; 120 (01) 44-54
    Article in Thieme ConnectPubMedGoogle Scholar
  • 71 Tutwiler V, Litvinov RI, Lozhkin AP. et al. Kinetics and mechanics of clot contraction are governed by the molecular and cellular composition of the blood. Blood 2016; 127 (01) 149-159
    CrossrefPubMedGoogle Scholar