This site is intended for healthcare professionals
Fibrinogen Deficiency in Bleeding

Fibrinogen Deficiency

Read time: 25 mins
Fibrinogen is important for blood clot formation and breakdown. It is the first coagulant factor to be reduced to critical levels during massive trauma, cardiac surgery and postpartum haemorrhage that involve excessive bleeding.

Persistent fibrinogen deficiency can lead to bleeding complications and an increased risk in mortality. Early identification and treatment of fibrinogen deficiency could therefore save lives.

Correct perioperative management of fibrinogen loss experienced during heart surgery and postpartum haemorrhage is key to treatment success.

Fibrinogen role in haemostasis

Fibrinogen (Factor I) has many functions in haemostasis, a process that stops bleeding from damaged tissue. Such functions include coagulation (the creation of blood clots), fibrinolysis (the breaking down of blood clots), wound healing, inflammation and cell–cell interactions.


Role for fibrinogen in coagulation 

Coagulation, or blood clotting, is a highly regulated process that can be separated into four distinct stages (Monroe and Hoffman et al., 2007) (Figure 1):

Register now for full access to

Congenital fibrinogen deficiency

Low fibrinogen levels and quality impacts negatively on blood clot formation and can lead to excessive bleeding and death if left untreated. Fibrinogen deficiencies can either be inherited (congenital fibrinogen deficiency) or acquired (acquired fibrinogen deficiency). Congenital fibrinogen deficiency manifests from no detectable fibrinogen (such as for congenital afibrinogenaemia) to some detectable fibrinogen (such as for congenital hypofibrinogenaemia) (Figure 5). 

It is usually the result of a heterozygous or homozygous mutation in one of the three fibrinogen genes (FGA, FGB and FGG) that are located on the long arm of chromosome 4 (4q31.3). Key symptoms include uncontrollable bleeding and thrombolytic complications. The onset of bleeding can be spontaneous, or as a result of both minor and major traumas. Bleeding phenotypes can range from being asymptomatic to severe and is partially dependent on both the level and quality of fibrinogen available (Peyvandi et al., 2012). There are two types of congenital deficiency:

Register now for full access to

Acquired fibrinogen deficiency

Acquired hypofibrinogenaemia is much more common than congenital fibrinogen deficiency and is defined by a fibrinogen level of less than 1.5 g/L (Figure 6).

Fibrinogen levels in acquired fibrinogen deficiencies

Figure 6: Fibrinogen levels in acquired fibrinogen deficiencies (Reviewed in Besser et al., 2016; Kozek-Langemecker et al., 2017).

Register now for full access to

Cardiac surgery

Major bleeding during cardiac surgery is an outcome that warrants the use of blood transfusions and reinterventions, both of which are risk factors for mortality (Moulton et al., 1996; Makar et al., 2010; Vivacqua et al., 2011). Acute coagulation defects are a common complication in cardiac surgery and can arise as a result of tissue injury and hypotension, with haemodilution, hyperfibrinolysis, and inflammatory responses all helping to sustain bleeding (Levy et al., 2005; Karkouti et al., 2010; Makar et al., 2010; Chee et al., 2016). 

An added complication is that this patient group are likely to have comorbidities and ongoing anticoagulant treatment for the prevention of heart disease, or anticoagulants administered during surgery to prevent clot formation (such as heparin) (Scrutinio & Giannuzzi, 2008).

Register now for full access to

Postpartum haemorrhage

Postpartum haemorrhage (PPH) is a bleeding complication that accounts for approximately one in four maternal deaths, making it the most common cause of maternal death worldwide (Kassebaum et al., 2014). The incidence rate in developed countries has increased in recent years, related primarily to an increase in the use of oxytocin for progressing labour (Belghiti et al., 2011). 

PPH is usually the result of uterine atony, but may be due to uterine rupture, abnormal placentation, placental abruption, genital tract trauma and coagulation defects (Abdul-Kadir et al., 2014). Comorbidities such as foetal death can also impact on PPH severity. 

Register now for full access to


Fibrinogen deficiency references

Abdul‐Kadir R, McLintock C, Ducloy A, El‐Refaey H, England A, Federici AB, et al. Evaluation and management of severe PPH. Transfusion. 2014;54:1756–68.

Adam SS, Key NS, Greenberg CS. D-dimer antigen: current concepts and future prospects. Blood. 2009;113;2878–87.

Asselta R, Duga S, Tenchini ML. The molecular basis of quantitative fibrinogen disorders. J Thromb Haemost. 2006;4(10):2115–29.

Belghiti J, Kayem G, Dupont C, Rudigoz R, Bouvier-Colle M, Deneux-Tharaux C et al. Oxytocin during labour and risk of severe postpartum haemorrhage: a population-based, cohort-nested case-control study. BMJ Open. 2011;1:e000514. 

Besser MW, MacDonald SG. Acquired hypofibrinogenemia: current perspectives. J Blood Med. 2016;7:217–25.

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;157:189–96.

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;36:652–58.

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;30:1541–47.

Brenner B. Haemostatic changes in pregnancy. Thrombosis Research. 2004;114:409–14.

Brown KJ, Maynes SF, Bezos A, Maguire DJ, Ford MD, Parish CR. A novel in vitro assay for human angiogenesis. Lab Invest. 1996;75:539–55.

Casini A, Neerman-Arbez M, Ariens RA, de Moerloose P. Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management. J Thromb Haemost. 2015;13:909–19.

Casini A, de Moerloose P, Neerman-Arbez M. Clinical features and management of congenital fibrinogen deficiencies. Semin Thromb Hemost. 2016;42:366–74.

Casini A, Brungs T, Lavenu‐Bombled C, Vilar R, Neerman‐Arbez M, Moerloose P. Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation. J Thromb Haemost. 2017;15:876–88.

Chapin JC, Hajjar KA. Fibrinolysis and the control of blood coagulation. Blood Rev. 2015;29:17–24.  

Charbit B, Mandelbrot L, Samain E, Baron G, Haddaoui B, Keita H et al. The decrease of fibrinogen is an early predictor of the severity of postpartum haemorrhage. J Thromb Haemost. 2007;5:266–73.

Chauleur C, Cochery-Nouvellon E, Mercier E, Aya G, Fabbro-Peray P, Mismetti P et al. Some hemostasis variables at the end of the population distributions are risk factors for severe postpartum hemorrhages. J Thromb Haemost. 2008;6:2067–74.

Chee YE, Liu SE, Irwin MG. Management of bleeding in vascular surgery. British Journal of Anaesthesia. 2016;117:ii85–ii94.

Collins PW, Solomon C, Sutor K, et al. Theoretical modelling of fibrinogen supplementation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate. Br J Anaesth. 2014;113:585–95.

Cortet M, Deneux-Tharaux C, Dupont C, Colin C, Rudigoz RC, Bouvier-Colle MH, et al. Association between fibrinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial. Br J of Anaesth. 2012;108:984–9.

de Bosch NB, Mosesson MW, Ruiz-Saez A, Echenagucia M, Rodriguez-Lemoin A. Inhibition of thrombin generation in plasma by fibrin formation (Antithrombin I). Thromb Haemost. 2002;88:253–58.

de Lloyd L, Bovington R, Kaye A, Collis RE, Rayment R, Sanders J et al. Standard haemostatic tests following major obstetric haemorrhage. International Journal of Obstetric Anesthesia. 2011;20:135–41.

de Moerloose P, Casini A, Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Hemost. 2013;39:585–95.

Deneux-Tharaux C, Dupont C, Colin C, Rabilloud M, Touzet S, Lansac J et al. Multifaceted intervention to decrease the rate of severe postpartum haemorrhage: the PITHAGORE6 cluster-randomised controlled trial. BJOG. 2010;117:1278–87.

Dib N, Quelin F, Ternisien C, Hanss M, Michalak S, De Mazancourt P et al. Fibrinogen angers with a new deletion (gamma GVYYQ 346-350) causes hypofibrinogenemia with hepatic storage. J Thromb Haemost. 2007;5:1999–2005.

Esmon CT, Xu J, Lupu F. Innate immunity and coagulation. J Thromb Haemost. 2011;9:182–8.

Ferro D, Celestini A, Violi F. Hyperfibrinolysis in liver disease. Clin Liver Dis. 2009;13:21–31.

Franchini M, Lippi G. Fibrinogen replacement therapy: a critical review of literature. Blood Transfus. 2012;10:23–27.

Fries D, Martini WZ. Role of fibrinogen in trauma-induced coagulopathy. British Journal of Anaesthesia. 2010;105:116–21.

Fuchs RJ, Levin J, Tadel M, Merritt W. Perioperative coagulation management in a patient with afibrinogenemia undergoing liver transplantation. Liver Transpl. 2007;13:752–56.

Gielen C, Dekkers O, Stijnen T, Schoones J, Brand A, Klautz R et al. The effects of pre- and postoperative fibrinogen levels on blood loss after cardiac surgery: a systematic review and meta-analysis. Interact Cardiovasc Thorac Surg. 2014;18:292–8.

Guasch E, Gilsanz F. Treatment of postpartum haemorrhage with blood products in a tertiary hospital: outcomes and predictive factors associated with severe haemorrhage. Clin Appl Thromb Hemost. 2016;22:685–92.

Hill MB, Brennan SO, Dear A, Strong J, Nejim T, Dolan G. Fibrinogen Nottingham II: a novel Bbeta Arg264gly substitution causing hypofibrinogenaemia. Thromb Haemost. 2006;96:378–80.

Hoffman M, Monroe DM. Coagulation 2006: a modern view on hemostasis. Hematol Oncol Clin North Am. 2007;21:1–11.

Horrevoets AJ, Pannekoek H, Nesheim ME. A steady-state template model that describes the kinetics of fibrin-stimulated [Glu1]- and [Lys78] plasminogen activation by native tissue-type plasminogen activator and variants that lack either the finger or kringle-2 domain. J Biol Chem. 1997;272:2183–91.

Hoylaerts M, Rijken DC, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. Role of fibrin. J Biol Chem. 1982;257:2912–19.

Huissoud C, Carrabin N, Benchaib M, Fontaine O, Levrat A, Massingnon D et al. Coagulation assessment by rotation thrombelastometry in normal pregnancy. Thromb Haemost. 2009;101:755–61.

JPAC Transfusion Handbook (Joint United Kingdom [UK] Blood Transfusion and Tissue Transplantation Services Professional Advisory Committee). 2014. Available at: (accessed April 2019).

Karkouti K, McCluskey S, Syed S, Pazaratz C, Poonawala H, Crowther M. The influence of perioperative coagulation status on postoperative blood loss in complex cardiac surgery: A prospective observational study. Anesth Analg. 2010;110:1533–40.

Kassebaum NJ, Bertozzi-Villa A, Coggesshall MS. Global, regional, and national levels and causes of maternal mortality during 1990–2013; a systematic analysis for the Global Burden of Disease Study. Lancet. 2014;384:980–1004.

Kindo M, Hoang Minh T, Gerelli S, Perrier S, Meyer N, Schaeffer M et al. Plasma fibrinogen level on admission to the intensive care unit is a powerful predictor of postoperative bleeding after cardiac surgery with cardiopulmonary bypass. Thromb Res. 2014;134:360–8.

Kohler HP, Grant PJ. Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med. 2000;15:1792–801.

Korte W, Feldges A. Increased prothrombin activation in a patient with congenital afibrinogenemia is reversible by fibrinogen substitution. Clin Investig. 1994;72:396–98.

Kozek-Langenecker SA, Ahmed AB, Afshari A, Albaladejo P, Aldecoa C, Barauskas G et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology: First update 2016. Eur J Anaesthesiol. 2017;34:332–95.

Lak M, Keihani M, Elahi F, Peyvandi F, Mannucci PM. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia. Br J Haematol. 1999;107:204–06. 

Levy JH, Tanaka KA, Steiner ME. Evaluation and management of bleeding during cardiac surgery. Curr Hematol Rep. 2005;4:368–72.

Liu J, Sun L, Wang J, Ji G. The relationship between fibrinogen and in-hospital mortality in patients with type A acute aortic dissection. Am J Emerg Med. 2018;36:741–4.

Laurens N, Koolwijk P, de Maat MP. Fibrin structure and wound healing. J Thromb Haemost. 2006;4:932–9.

Maegele M, Gu ZT, Huang QB, Yang H. Updated concepts on the pathophysiology and the clinical management of trauma hemorrhage and coagulopathy. Chin J Traumatol. 2017;20:125–32.

Makar M, Taylor J, Zhao M, Farrohi A, Trimming M, D’Attellis N et al. Perioperative coagulopathy, bleeding, and hemostasis during cardiac surgery: a comprehensive review. ICU Director. 2010;1:17–27.

Mosesson MW. Antithrombin I. Inhibition of thrombin generation in plasma by fibrin formation. Thromb Haemost. 2003;89:9–12. 

Moulton MJ, Creswell LL, Mackey ME, Cox, JL, Rosenbloom M. Reexploration for bleeding is a risk factor for adverse outcomes after cardiac operations. J Thorac Cardiovasc Surg. 1996;111:1037–46.

Nacca CR, Shah KN, Truntzer JN, Rubin LE. Total knee arthroplasty in a patient with hypofibrinogenemia. Arthroplasty. 2016;2:177–82.

Neerman-Arbez, M., Casini, A. Clinical Consequences and Molecular Bases of Low Fibrinogen Levels. International Journal of Molecular Sciences. 2018;19:1.

Niepraschk-von Dollen K, Bamberg C, Henkelmann A, Mickley L, Kaufner L, Henrich W et al. Predelivery maternal fibrinogen as a predictor of blood loss after vaginal delivery. Arch Gynecol Obstet. 2016;294:745–51.

O'Riordan MN, Higgins JR. Haemostasis in normal and abnormal pregnancy. Best Pract Res Clin Obstet Gynaecol. 2003;17:385–96.

Oruc N, Tokat Y, Killi R, Tombuloglu M, Ilter T. Budd-Chiari syndrome in an afibrinogenemic patient: a paradoxical complication. Dig Dis Sci. 2006;51:378–80.

Palmer JD, Francis DA, Roath OS, Francis JL, Iannotti F. Hyperfibrinolysis during intracranial surgery: effect of high dose aprotinin. J Neurol Neurosurg Psychiatry. 1995;58:104–6.

Peyvandi F, DiMichele D, Bolton-Maggs PH, Lee CA, Tripodi A, Srivastava A. Classification of rare bleeding disorders (RBDs) based on the association between coagulant factor activity and clinical bleeding severity. J Thromb Haemost. 2012;10:1938–43.

Roberts I, Shakur H, Fawole B, Kuti M, Olayemi O, Bello A et al. Haematological and fibrinolytic status of Nigerian women with post-partum haemorrhage. BMC pregnancy and childbirth. 2018;18:143.

Sahni A, Odrljin T, Francis CW. Binding of basic fibroblast growth factor to fibrinogen and fibrin. J Biol Chem. 1998;273:7554–59.

Saner FH, Kirchner C. Monitoring and Treatment of Coagulation Disorders in End-Stage Liver Disease. Visc Med. 2016;32:241–48.

Scrutinio D, Giannuzzi P. Comorbidity in patients undergoing coronary artery bypass graft surgery: impact on outcome and implications for cardiac rehabilitation. European Journal of Preventative Cardiology. 2008;15:379–85.

Simon L, Santi TM, Sacquin P, Hamza J. Pre-anaesthetic assessment of coagulation abnormalities in obstetric patients: usefulness, timing and clinical implications. Br J Anaesth. 1997;78:678–83.

Tennent GA, Brennan SO, Stangou AJ, O’Grady J, Hawkins PN, Pepys MB. Human plasma fibrinogen is synthesised in the liver. Blood. 2007;109:1971–4.

Teufelsbauer H, Proidl S, Havel M, Vukovich T. Early activation of hemostasis during cardiopulmonary bypass: evidence for thrombin mediated hyperfibrinolysis. Thromb Haemost. 1992;68:250–2.

Theusinger OM, Wanner GA, Emmert MY, Billeter A, Eismon J, Seifert B et al. Hyperfibrinolysis diagnosed by rotational thromboelastometry (ROTEM) is associated with higher mortality in patients with severe trauma. Anesth Analg. 2011;113:1003–12.

Tziomalos K, Vakalopoulou S, Perifanis V, Garipidou V. Treatment of congenital fibrinogen deficiency: overview and recent findings. Vasc Health Risk Manag. 2009;5:843–8.

Venugopal A. Disseminated intravascular coagulation. Indian J Anaesth. 2014;58:603–8.

Vivacqua A, Koch CG, Yousuf AM, Nowicki ER, Houghtaling PL, Blackstone EH et al. Morbidity of bleeding after cardiac surgery: is it blood transfusion, reoperation for bleeding, or both? Ann Thorac Surg. 2011;91:1780–90.

Walden K, Jeppsson A, Nasic S, Backlund E, Karlsson M. Low Preoperative Fibrinogen Plasma Concentration Is Associated With Excessive Bleeding After Cardiac Operations. Ann Thorac Surg. 2014;97:1199–206.

Developed by EPG Health for Medthority in collaboration with CSL Behring, with content provided by CSL Behring.
Not intended for Healthcare Professionals outside Europe.