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Disorders of fibrinogen

Caroline Bérubé, MD
Section Editor
Lawrence LK Leung, MD
Deputy Editor
Jennifer S Tirnauer, MD


Fibrinogen plays a pivotal role in normal hemostasis as a substrate for conversion to fibrin, a support for thrombin generation and platelet aggregation, and a facilitator of wound healing. Fibrin also forms a template for subsequent fibrinolysis and wound healing. A number of inherited and acquired fibrinogen disorders have been described; these can have both hemorrhagic and thrombotic manifestations, as well as effects on pregnancy, depending on the specific defect.

This topic describes the pathophysiology, clinical presentation, diagnosis, and treatment of inherited and acquired fibrinogen disorders.

Separate topic reviews discuss other disorders of hemostasis and thrombosis:

Other rare inherited coagulation factor disorders – (see "Rare inherited coagulation disorders" and "Factor XI deficiency")

Hemophilia – (see "Clinical manifestations and diagnosis of hemophilia")

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Literature review current through: Nov 2017. | This topic last updated: Aug 28, 2017.
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  1. 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; 7:355.
  2. de Moerloose P, Neerman-Arbez M. Congenital fibrinogen disorders. Semin Thromb Hemost 2009; 35:356.
  3. Levy JH, Goodnough LT. How I use fibrinogen replacement therapy in acquired bleeding. Blood 2015; 125:1387.
  4. Collen D, Tytgat GN, Claeys H, Piessens R. Metabolism and distribution of fibrinogen. I. Fibrinogen turnover in physiological conditions in humans. Br J Haematol 1972; 22:681.
  5. Meade TW, Chakrabarti R, Haines AP, et al. Characteristics affecting fibrinolytic activity and plasma fibrinogen concentrations. Br Med J 1979; 1:153.
  6. Green F, Humphries S. Control of plasma fibrinogen levels. Baillieres Clin Haematol 1989; 2:945.
  7. Woods A, Brull DJ, Humphries SE, Montgomery HE. Genetics of inflammation and risk of coronary artery disease: the central role of interleukin-6. Eur Heart J 2000; 21:1574.
  8. Rosenson RS. Myocardial injury: the acute phase response and lipoprotein metabolism. J Am Coll Cardiol 1993; 22:933.
  9. Tennent GA, Brennan SO, Stangou AJ, et al. Human plasma fibrinogen is synthesized in the liver. Blood 2007; 109:1971.
  10. Behague I, Poirier O, Nicaud V, et al. Beta fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. The ECTIM Study. Etude Cas-Temoins sur l'Infarctus du Myocarde. Circulation 1996; 93:440.
  11. Lee AJ, Fowkes FG, Lowe GD, et al. Fibrinogen, factor VII and PAI-1 genotypes and the risk of coronary and peripheral atherosclerosis: Edinburgh Artery Study. Thromb Haemost 1999; 81:553.
  12. Falls LA, Farrell DH. Resistance of gammaA/gamma' fibrin clots to fibrinolysis. J Biol Chem 1997; 272:14251.
  13. Cooper AV, Standeven KF, Ariëns RA. Fibrinogen gamma-chain splice variant gamma' alters fibrin formation and structure. Blood 2003; 102:535.
  14. Collet JP, Nagaswami C, Farrell DH, et al. Influence of gamma' fibrinogen splice variant on fibrin physical properties and fibrinolysis rate. Arterioscler Thromb Vasc Biol 2004; 24:382.
  15. Uitte de Willige S, Standeven KF, Philippou H, Ariëns RA. The pleiotropic role of the fibrinogen gamma' chain in hemostasis. Blood 2009; 114:3994.
  16. Martinez J. Congenital dysfibrinogenemia. Curr Opin Hematol 1997; 4:357.
  17. Chernysh IN, Weisel JW. Dynamic imaging of fibrin network formation correlated with other measures of polymerization. Blood 2008; 111:4854.
  18. Standeven KF, Carter AM, Grant PJ, et al. Functional analysis of fibrin {gamma}-chain cross-linking by activated factor XIII: determination of a cross-linking pattern that maximizes clot stiffness. Blood 2007; 110:902.
  19. Standeven KF, Grant PJ, Carter AM, et al. Functional analysis of the fibrinogen Aalpha Thr312Ala polymorphism: effects on fibrin structure and function. Circulation 2003; 107:2326.
  20. Ajjan R, Lim BC, Standeven KF, et al. Common variation in the C-terminal region of the fibrinogen beta-chain: effects on fibrin structure, fibrinolysis and clot rigidity. Blood 2008; 111:643.
  21. Lovely RS, Falls LA, Al-Mondhiry HA, et al. Association of gammaA/gamma' fibrinogen levels and coronary artery disease. Thromb Haemost 2002; 88:26.
  22. Mannila MN, Lovely RS, Kazmierczak SC, et al. Elevated plasma fibrinogen gamma' concentration is associated with myocardial infarction: effects of variation in fibrinogen genes and environmental factors. J Thromb Haemost 2007; 5:766.
  23. Mosesson MW. Dysfibrinogenemia and thrombosis. Semin Thromb Hemost 1999; 25:311.
  24. Gabriel DA, Muga K, Boothroyd EM. The effect of fibrin structure on fibrinolysis. J Biol Chem 1992; 267:24259.
  25. Wada Y, Lord ST. A correlation between thrombotic disease and a specific fibrinogen abnormality (A alpha 554 Arg-->Cys) in two unrelated kindred, Dusart and Chapel Hill III. Blood 1994; 84:3709.
  26. Sugo T, Nakamikawa C, Takebe M, et al. Factor XIIIa cross-linking of the Marburg fibrin: formation of alpham.gamman-heteromultimers and the alpha-chain-linked albumin. gamma complex, and disturbed protofibril assembly resulting in acquisition of plasmin resistance relevant to thrombophila. Blood 1998; 91:3282.
  27. Doolittle RF. Fibrinogen and fibrin. Sci Am 1981; 245:126.
  28. Everse SJ, Spraggon G, Doolittle RF. A three-dimensional consideration of variant human fibrinogens. Thromb Haemost 1998; 80:1.
  29. Mosesson MW. The roles of fibrinogen and fibrin in hemostasis and thrombosis. Semin Hematol 1992; 29:177.
  30. Peyvandi F, Haertel S, Knaub S, Mannucci PM. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost 2006; 4:1634.
  31. 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; 116:722.
  32. Casini A, de Moerloose P, Neerman-Arbez M. Clinical Features and Management of Congenital Fibrinogen Deficiencies. Semin Thromb Hemost 2016; 42:366.
  33. Morris TA, Marsh JJ, Chiles PG, et al. High prevalence of dysfibrinogenemia among patients with chronic thromboembolic pulmonary hypertension. Blood 2009; 114:1929.
  34. Suh TT, Holmbäck K, Jensen NJ, et al. Resolution of spontaneous bleeding events but failure of pregnancy in fibrinogen-deficient mice. Genes Dev 1995; 9:2020.
  35. Acharya SS, Dimichele DM. Rare inherited disorders of fibrinogen. Haemophilia 2008; 14:1151.
  36. de Moerloose P, Casini A, Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Hemost 2013; 39:585.
  37. Hanss M, Biot F. A database for human fibrinogen variants. Ann N Y Acad Sci 2001; 936:89.
  38. http://www1.wfh.org/publications/files/pdf-1627.pdf (Accessed on June 13, 2017).
  39. Casini A, Blondon M, Lebreton A, et al. Natural history of patients with congenital dysfibrinogenemia. Blood 2015; 125:553.
  40. Peyvandi F, Palla R, Menegatti M, et al. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost 2012; 10:615.
  41. Roberts HR, Stinchcombe TE, Gabriel DA. The dysfibrinogenaemias. Br J Haematol 2001; 114:249.
  42. Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen. Thromb Haemost 1995; 73:151.
  43. Shapiro SE, Phillips E, Manning RA, et al. Clinical phenotype, laboratory features and genotype of 35 patients with heritable dysfibrinogenaemia. Br J Haematol 2013; 160:220.
  44. Spena S, Duga S, Asselta R, et al. Congenital afibrinogenemia: first identification of splicing mutations in the fibrinogen Bbeta-chain gene causing activation of cryptic splice sites. Blood 2002; 100:4478.
  45. 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 1:125.
  46. al-Mondhiry H, Ehmann WC. Congenital afibrinogenemia. Am J Hematol 1994; 46:343.
  47. 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.
  48. Asselta R, Platè M, Robusto M, et al. Clinical and molecular characterisation of 21 patients affected by quantitative fibrinogen deficiency. Thromb Haemost 2015; 113:567.
  49. Maghzal GJ, Brennan SO, Homer VM, George PM. The molecular mechanisms of congenital hypofibrinogenaemia. Cell Mol Life Sci 2004; 61:1427.
  50. Francis JL, Armstrong DJ. Acquired dysfibrinogenaemia in liver disease. J Clin Pathol 1982; 35:667.
  51. Ballard JO, Kelly GA, Kukrika MD, et al. Acquired dysfibrinogenemia in a hemophiliac with hepatoma: resolution of fibrinogen dysfunction following chemotherapy. Cancer 1981; 48:686.
  52. Gralnick HR, Givelber H, Abrams E. Dysfibrinogenemia associated with hepatoma. Increased carbohydrate content of the fibrinogen molecule. N Engl J Med 1978; 299:221.
  53. Regañón E, Vila V, Aznar J, et al. Study of the formation of fibrin clot in cirrhotic patients. An approach to study of acquired dysfibrinogenemia. Thromb Res 1987; 46:705.
  54. von Felten A, Straub PW, Frick PG. Dysfibrinogenemia in a patient with primary hepatoma. First observation of an acquired abnormality of fibrin monomer aggregation. N Engl J Med 1969; 280:405.
  55. Mammen EF. Coagulopathies of liver disease. Clin Lab Med 1994; 14:769.
  56. 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; 61:1196.
  57. Martinez J, Keane PM, Gilman PB, Palascak JE. The abnormal carbohydrate composition of the dysfibrinogenemia associated with liver disease. Ann N Y Acad Sci 1983; 408:388.
  58. Kwaan HC, Levin M, Sakurai S, et al. Digital ischemia and gangrene due to red blood cell aggregation induced by acquired dysfibrinogenemia. J Vasc Surg 1997; 26:1061.
  59. Dear A, Brennan SO, Sheat MJ, et al. Acquired dysfibrinogenemia caused by monoclonal production of immunoglobulin lambda light chain. Haematologica 2007; 92:e111.
  60. Lee N, Kim JE, Yoo HJ, et al. Acquired Dysfibrinogenemia Caused by Autoantibody Inhibiting Fibrin Polymerization in a Patient with MELAS Syndrome and Bleeding Tendency. Ann Clin Lab Sci 2016; 46:696.
  61. Joshua V, Schobers L, Titcombe PJ, et al. Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells. Arthritis Res Ther 2016; 18:284.
  62. Liao KP, Sparks JA, Hejblum BP, et al. Phenome-Wide Association Study of Autoantibodies to Citrullinated and Noncitrullinated Epitopes in Rheumatoid Arthritis. Arthritis Rheumatol 2017; 69:742.
  63. Hill JA, Al-Bishri J, Gladman DD, et al. Serum autoantibodies that bind citrullinated fibrinogen are frequently found in patients with rheumatoid arthritis. J Rheumatol 2006; 33:2115.
  64. Chouhan VD, De La Cadena RA, Nagaswami C, et al. Simultaneous occurrence of human antibodies directed against fibrinogen, thrombin, and factor V following exposure to bovine thrombin: effects on blood coagulation, protein C activation and platelet function. Thromb Haemost 1997; 77:343.
  65. Dawson NA, Barr CF, Alving BM. Acquired dysfibrinogenemia. Paraneoplastic syndrome in renal cell carcinoma. Am J Med 1985; 78:682.
  66. Aurousseau MH, Levacher S, Bénéton C, et al. [Transient dysfibrinogenemia and thrombocytopenia associated with recurrent acute pancreatitis in the course of isotretinoin therapy]. Rev Med Interne 1995; 16:622.
  67. Gralnick HR, Henderson E. Hypofibrinogenemia and coagulation factor deficiencies with L-asparaginase treatment. Cancer 1971; 27:1313.
  68. Whitecar JP Jr, Bodey GP, Harris JE, Freireich EJ. L-asparaginase. N Engl J Med 1970; 282:732.
  69. Hauser E, Seidl R, Freilinger M, et al. Hematologic manifestations and impaired liver synthetic function during valproate monotherapy. Brain Dev 1996; 18:105.
  70. Yin Z, Xu J, Li Y, et al. Transient hypofibrinogenemia due to allopurinol. Drug Des Devel Ther 2014; 8:1231.
  71. Camilleri RS, Peebles D, Portmann C, et al. -455G/A beta-fibrinogen gene polymorphism, factor V Leiden, prothrombin G20210A mutation and MTHFR C677T, and placental vascular complications. Blood Coagul Fibrinolysis 2004; 15:139.
  72. Javorský M, Kozárová M, Salagovic J, Tkác I. Relationship among urinary albumin excretion rate, lipoprotein lipase PvuII polymorphism and plasma fibrinogen in type 2 diabetic patients. Physiol Res 2006; 55:55.
  73. Bolton-Maggs PH, Perry DJ, Chalmers EA, et al. The rare coagulation disorders--review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation. Haemophilia 2004; 10:593.
  74. Aubrey-Bassler FK, Sowers N. 613 cases of splenic rupture without risk factors or previously diagnosed disease: a systematic review. BMC Emerg Med 2012; 12:11.
  75. Hamano A, Mimuro J, Aoshima M, et al. Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of gammaAla327Thr: formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism. Blood 2004; 103:3045.
  76. Verhovsek M, Moffat KA, Hayward CP. Laboratory testing for fibrinogen abnormalities. Am J Hematol 2008; 83:928.
  77. Goodwin TM. Congenital hypofibrinogenemia in pregnancy. Obstet Gynecol Surv 1989; 44:157.
  78. Benson MD, Liepnieks J, Uemichi T, et al. Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Genet 1993; 3:252.
  79. Uemichi T, Liepnieks JJ, Benson MD. Hereditary renal amyloidosis with a novel variant fibrinogen. J Clin Invest 1994; 93:731.
  80. Uemichi T, Liepnieks JJ, Alexander F, Benson MD. The molecular basis of renal amyloidosis in Irish-American and Polish-Canadian kindreds. QJM 1996; 89:745.
  81. Uemichi T, Liepnieks JJ, Yamada T, et al. A frame shift mutation in the fibrinogen A alpha chain gene in a kindred with renal amyloidosis. Blood 1996; 87:4197.
  82. Uemichi T, Liepnieks JJ, Gertz MA, Benson MD. Fibrinogen A alpha chain Leu 554: an African-American kindred with late onset renal amyloidosis. Amyloid 1998; 5:188.
  83. Hamidi Asl L, Liepnieks JJ, Uemichi T, et al. Renal amyloidosis with a frame shift mutation in fibrinogen aalpha-chain gene producing a novel amyloid protein. Blood 1997; 90:4799.
  84. Hamidi Asl L, Fournier V, Billerey C, et al. Fibrinogen A alpha chain mutation (Arg554 Leu) associated with hereditary renal amyloidosis in a French family. Amyloid 1998; 5:279.
  85. de Carvalho M, Linke RP, Domingos F, et al. Mutant fibrinogen A-alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy. Amyloid 2004; 11:200.
  86. Brennan SO, Maghzal G, Shneider BL, et al. Novel fibrinogen gamma375 Arg-->Trp mutation (fibrinogen aguadilla) causes hepatic endoplasmic reticulum storage and hypofibrinogenemia. Hepatology 2002; 36:652.
  87. Brennan SO, Wyatt J, Medicina D, et al. Fibrinogen brescia: hepatic endoplasmic reticulum storage and hypofibrinogenemia because of a gamma284 Gly-->Arg mutation. Am J Pathol 2000; 157:189.
  88. 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; 5:1999.
  89. Brennan SO, Davis RL, Conard K, et al. Novel fibrinogen mutation γ314Thr→Pro (fibrinogen AI duPont) associated with hepatic fibrinogen storage disease and hypofibrinogenaemia. Liver Int 2010; 30:1541.
  90. van Meegeren ME, de Rooy JW, Schreuder HW, Brons PP. Bone cysts in patients with afibrinogenaemia: a literature review and two new cases. Haemophilia 2014; 20:244.
  91. Forman WB, Kraus J. Transurethral resection in a patient with a dysfibrinogen: fibrinogen cleveland I. J Urol 1977; 118:885.
  92. Wada Y, Niwa K, Maekawa H, et al. A new type of congenital dysfibrinogen, fibrinogen Bremen, with an A alpha Gly-17 to Val substitution associated with hemorrhagic diathesis and delayed wound healing. Thromb Haemost 1993; 70:397.
  93. CLAUSS A. [Rapid physiological coagulation method in determination of fibrinogen]. Acta Haematol 1957; 17:237.
  94. Mackie IJ, Kitchen S, Machin SJ, et al. Guidelines on fibrinogen assays. Br J Haematol 2003; 121:396.
  95. Undas A. How to Assess Fibrinogen Levels and Fibrin Clot Properties in Clinical Practice? Semin Thromb Hemost 2016; 42:381.
  96. http://practical-haemostasis.com/Screening%20Tests/fibrinogen.html (Accessed on June 16, 2017).
  97. Casini A, de Moerloose P, Congenital Fibrinogen Disorders Group. Management of congenital quantitative fibrinogen disorders: a Delphi consensus. Haemophilia 2016; 22:898.
  98. Mumford AD, Ackroyd S, Alikhan R, et al. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol 2014; 167:304.
  99. Bornikova L, Peyvandi F, Allen G, et al. Fibrinogen replacement therapy for congenital fibrinogen deficiency. J Thromb Haemost 2011; 9:1687.
  100. Manco-Johnson MJ, Dimichele D, Castaman G, et al. Pharmacokinetics and safety of fibrinogen concentrate. J Thromb Haemost 2009; 7:2064.
  101. Santacroce R, Cappucci F, Pisanelli D, et al. Inherited abnormalities of fibrinogen: 10-year clinical experience of an Italian group. Blood Coagul Fibrinolysis 2006; 17:235.
  102. Peyvandi F. Results of an international, multicentre pharmacokinetic trial in congenital fibrinogen deficiency. Thromb Res 2009; 124 Suppl 2:S9.
  103. Montán C, Johansson F, Hedin U, Wahlgren CM. Preoperative hypofibrinogenemia is associated with increased intraoperative bleeding in ruptured abdominal aortic aneurysms. Thromb Res 2015; 135:443.
  104. Samama CM. Fibrinogen Concentrates for Acquired Fibrinogen Deficiencies? Semin Thromb Hemost 2016; 42:375.
  105. Rahe-Meyer N, Sørensen B. For: Fibrinogen concentrate for management of bleeding. J Thromb Haemost 2011; 9:1.
  106. Ozier Y, Hunt BJ. Against: Fibrinogen concentrate for management of bleeding: against indiscriminate use. J Thromb Haemost 2011; 9:6.
  107. Peyvandi F, Menegatti M. Treatment of rare factor deficiencies in 2016. In: Hematology 2016, Tallman MS, McCrae KR, Smith S, Crowther MA (Eds), American Society of Hematology, Washington, DC 2016. p.663.
  108. Danés AF, Cuenca LG, Bueno SR, et al. Efficacy and tolerability of human fibrinogen concentrate administration to patients with acquired fibrinogen deficiency and active or in high-risk severe bleeding. Vox Sang 2008; 94:221.
  109. Okerberg CK, Williams LA 3rd, Kilgore ML, et al. Cryoprecipitate AHF vs. fibrinogen concentrates for fibrinogen replacement in acquired bleeding patients - an economic evaluation. Vox Sang 2016; 111:292.
  110. Cronin C, Fitzpatrick D, Temperley I. Multiple pulmonary emboli in a patient with afibrinogenaemia. Acta Haematol 1988; 79:53.
  111. MacKinnon HH, Fekete JF. Congenital afibrinogenemia. Vascular changes and multiple thromboses induced by fibrinogen infusions and contraceptive medication. Can Med Assoc J 1971; 104:597.
  112. DE VRIES A, ROSENBERG T, KOCHWA S, BOSS JH. Precipitating antifibrinogen antibody appearing after fibrinogen infusions in a patient with congenital afibrinogenemia. Am J Med 1961; 30:486.
  113. Ménaché D. Congenital fibrinogen abnormalities. Ann N Y Acad Sci 1983; 408:121.
  114. Hemophilia and von Willebrand's disease: 2. Management. Association of Hemophilia Clinic Directors of Canada. CMAJ 1995; 153:147.
  115. Inamoto Y, Terao T. First report of case of congenital afibrinogenemia with successful delivery. Am J Obstet Gynecol 1985; 153:803.
  116. Grech H, Majumdar G, Lawrie AS, Savidge GF. Pregnancy in congenital afibrinogenaemia: report of a successful case and review of the literature. Br J Haematol 1991; 78:571.
  117. Trehan AK, Fergusson IL. Congenital afibrinogenaemia and successful pregnancy outcome. Case report. Br J Obstet Gynaecol 1991; 98:722.
  118. Kobayashi T, Kanayama N, Tokunaga N, et al. Prenatal and peripartum management of congenital afibrinogenaemia. Br J Haematol 2000; 109:364.
  119. Mensah PK, Oppenheimer C, Watson C, Pavord S. Congenital afibrinogenaemia in pregnancy. Haemophilia 2011; 17:167.
  120. Miesbach W, Galanakis D, Scharrer I. Treatment of patients with dysfibrinogenemia and a history of abortions during pregnancy. Blood Coagul Fibrinolysis 2009; 20:366.
  121. Munoz J, Schering J, Lambing A, et al. The dilemma of inherited dysfibrinogenemia during pregnancy. Blood Coagul Fibrinolysis 2012; 23:775.