Fibrinogen Replacement: A Questionable Dogma

Abstract

Management of hemostasis in the perioperative setting, in trauma or in acute care, has considerably changed over the last two decades. Viscoelastic testing and single-factor replacement therapies have become cornerstones of the respective clinical approaches. Here, we illuminate the basic theories for these approaches as well as the important evidence available. Both viscoelastic assays and single-factor replacements are important improvements; their use must be based on the strongest scientific evidence available.

Keywords

viscoelastic assays - factor concentrates - fibrinogen/fibrin - factor XIII/transglutaminases - resuscitation

Other Financial or Nonfinancial Interests

Director, HICC—Haemostasis in Critical Care GmbH.

Publication History

Received: 11 November 2024

Accepted: 09 February 2025

Article published online:
27 April 2025

• References

• 1 Duque P, Mora L, Levy JH, Schöchl H. Pathophysiological response to trauma-induced coagulopathy: a comprehensive review. Anesth Analg 2020; 130 (03) 654-664
• 2 Kietaibl S, Ahmed A, Afshari A. et al. Management of severe peri-operative bleeding: guidelines from the European Society of Anaesthesiology and Intensive Care: second update 2022. Eur J Anaesthesiol 2023; 40 (04) 226-304
• 3 Brummel KE, Paradis SG, Butenas S, Mann KG. Thrombin functions during tissue factor-induced blood coagulation. Blood 2002; 100 (01) 148-152
• 4 Schlimp CJ, Schöchl H. The role of fibrinogen in trauma-induced coagulopathy. Hamostaseologie 2014; 34 (01) 29-39
• 5 He S, Blombäck M, Boström F, Wallen H, Svensson J, Östlund A. An increased tendency in fibrinogen activity and its association with a hypo-fibrinolytic state in early stages after injury in patients without acute traumatic coagulopathy (ATC). J Thromb Thrombolysis 2018; 45 (04) 477-485
• 6 Martini WZ. Fibrinogen metabolic responses to trauma. Scand J Trauma Resusc Emerg Med 2009; 17: 2
• 7 Meizoso JP, Moore EE, Pieracci FM. et al. Role of fibrinogen in trauma-induced coagulopathy. J Am Coll Surg 2022; 234 (04) 465-473
• 8 Schlimp CJ, Voelckel W, Inaba K, Maegele M, Ponschab M, Schöchl H. Estimation of plasma fibrinogen levels based on hemoglobin, base excess and Injury Severity Score upon emergency room admission. Crit Care 2013; 17 (04) R137
• 9 Holcomb JB, del Junco DJ, Fox EE. et al; PROMMTT Study Group. The prospective, observational, multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-varying treatment with competing risks. JAMA Surg 2013; 148 (02) 127-136
• 10 Holcomb JB, Tilley BC, Baraniuk S. et al; PROPPR Study Group. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 2015; 313 (05) 471-482
• 11 Hynes AM, Geng Z, Schmulevich D. et al; PROMMTT Study Group. Staying on target: maintaining a balanced resuscitation during damage-control resuscitation improves survival. J Trauma Acute Care Surg 2021; 91 (05) 841-848
• 12 Gonzalez E, Moore EE, Moore HB. et al. Goal-directed hemostatic resuscitation of trauma-induced coagulopathy: a pragmatic randomized clinical trial comparing a viscoelastic assay to conventional coagulation assays. Ann Surg 2016; 263 (06) 1051-1059
• 13 Walsh M, Fritz S, Hake D. et al. Targeted thromboelastographic (TEG) blood component and pharmacologic hemostatic therapy in traumatic and acquired coagulopathy. Curr Drug Targets 2016; 17 (08) 954-970
• 14 Blayney A, McCullough J, Wake E. et al. Substitution of ROTEM FIBTEM A5 for A10 in trauma: an observational study building a case for more rapid analysis of coagulopathy. Eur J Trauma Emerg Surg 2022; 48 (02) 1077-1084
• 15 Barmparas G, Huang R, Lee WG. et al. Overtransfusion of packed red blood cells during massive transfusion activation: a potential quality metric for trauma resuscitation. Trauma Surg Acute Care Open 2022; 7 (01) e000896
• 16 Cowan T, Weaver N, Whitfield A. et al. The epidemiology of overtransfusion of red cells in trauma resuscitation patients in the context of a mature massive transfusion protocol. Eur J Trauma Emerg Surg 2022; 48 (04) 2725-2730
• 17 Charbit B, Mandelbrot L, Samain E. et al; PPH Study Group. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage. J Thromb Haemost 2007; 5 (02) 266-273
• 18 Cortet M, Deneux-Tharaux C, Dupont C. et al. Association between fibrinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial. Br J Anaesth 2012; 108 (06) 984-989
• 19 Kaufner L, Henkelmann A, von Heymann C. et al. Can prepartum thromboelastometry-derived parameters and fibrinogen levels really predict postpartum hemorrhage?. J Perinat Med 2017; 45 (04) 427-435
• 20 Haslinger C, Korte W, Hothorn T, Brun R, Greenberg C, Zimmermann R. The impact of prepartum factor XIII activity on postpartum blood loss. J Thromb Haemost 2020; 18 (06) 1310-1319
• 21 Waldén 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 (04) 1199-1206
• 22 Karkouti K, Callum J, Crowther MA. et al. The relationship between fibrinogen levels after cardiopulmonary bypass and large volume red cell transfusion in cardiac surgery: an observational study. Anesth Analg 2013; 117 (01) 14-22
• 23 Davidson SJ, McGrowder D, Roughton M, Kelleher AA. Can ROTEM thromboelastometry predict postoperative bleeding after cardiac surgery?. J Cardiothorac Vasc Anesth 2008; 22 (05) 655-661
• 24 Lee GC, Kicza AM, Liu KY, Nyman CB, Kaufman RM, Body SC. Does rotational thromboelastometry (ROTEM) improve prediction of bleeding after cardiac surgery?. Anesth Analg 2012; 115 (03) 499-506
• 25 Fricault P, Piot J, Estève C. et al. Preoperative fibrinogen level and postcardiac surgery morbidity and mortality rates. Ann Card Anaesth 2022; 25 (04) 485-489
• 26 Tsantes AG, Papadopoulos DV, Roustemis AG. et al. Rotational thromboelastometry predicts transfusion requirements in total joint arthroplasties. Semin Thromb Hemost 2023; 49 (02) 134-144
• 27 Drotarova M, Zolkova J, Belakova KM. et al. Basic Principles of Rotational Thromboelastometry (ROTEM^®) and the role of ROTEM-guided fibrinogen replacement therapy in the management of coagulopathies. Diagnostics (Basel) 2023; 13 (20) 3219
• 28 Mace H, Lightfoot N, McCluskey S. et al. Validity of thromboelastometry for rapid assessment of fibrinogen levels in heparinized samples during cardiac surgery: a retrospective, single-center, observational study. J Cardiothorac Vasc Anesth 2016; 30 (01) 90-95
• 29 Jámbor C, Reul V, Schnider TW, Degiacomi P, Metzner H, Korte WC. In vitro inhibition of factor XIII retards clot formation, reduces clot firmness, and increases fibrinolytic effects in whole blood. Anesth Analg 2009; 109 (04) 1023-1028
• 30 Harr JN, Moore EE, Chin TL. et al. Viscoelastic hemostatic fibrinogen assays detect fibrinolysis early. Eur J Trauma Emerg Surg 2015; 41 (01) 49-56
• 31 de Vries JJ, Veen CSB, Snoek CJM, Kruip MJHA, de Maat MPM. FIBTEM clot firmness parameters correlate well with the fibrinogen concentration measured by the Clauss assay in patients and healthy subjects. Scand J Clin Lab Invest 2020; 80 (07) 600-605
• 32 Maslow A, Cheves T, Joyce MF, Apruzzese P, Sweeney J. Interaction between platelet and fibrinogen on clot strength in healthy patients. J Cardiothorac Vasc Anesth 2023; 37 (06) 942-947
• 33 Innerhofer P, Fries D, Mittermayr M. et al. Reversal of trauma-induced coagulopathy using first-line coagulation factor concentrates or fresh frozen plasma (RETIC): a single-centre, parallel-group, open-label, randomised trial. Lancet Haematol 2017; 4 (06) e258-e271
• 34 Davenport R, Curry N, Fox EE. et al; CRYOSTAT-2 Principal Investigators. Early and empirical high-dose cryoprecipitate for hemorrhage after traumatic injury: the CRYOSTAT-2 randomized clinical trial. JAMA 2023; 330 (19) 1882-1891
• 35 Theusinger OM, Schröder CM, Eismon J. et al. The influence of laboratory coagulation tests and clotting factor levels on Rotation Thromboelastometry (ROTEM(R)) during major surgery with hemorrhage. Anesth Analg 2013; 117 (02) 314-321
• 36 Rugeri L, Levrat A, David JS. et al. Diagnosis of early coagulation abnormalities in trauma patients by rotation thrombelastography. J Thromb Haemost 2007; 5 (02) 289-295
• 37 Auty T, McCullough J, Hughes I, Fanning JP, Czuchwicki S, Winearls J. Fibrinogen levels in severe trauma: a preliminary comparison of Clauss Fibrinogen, ROTEM Sigma, ROTEM Delta and TEG 6s assays from the FEISTY pilot randomised clinical trial. Emerg Med Australas 2024; 36 (03) 363-370
• 38 Bell SF, Roberts TCD, Freyer Martins Pereira J. et al. The sensitivity and specificity of rotational thromboelastometry (ROTEM) to detect coagulopathy during moderate and severe postpartum haemorrhage: a prospective observational study. Int J Obstet Anesth 2022; 49: 103238
• 39 Yurashevich M, Rosser M, Small M. et al. Evaluating the association between fibrinogen and rotational thromboelastometry and the progression to severe obstetric hemorrhage. Clin Appl Thromb Hemost 2023 29. 10 760296231175089
• 40 A Matzelle S, F Preuss J, M Weightman W, M Gibbs N. An audit of the diagnostic accuracy of the ROTEM®sigma for the identification of hypofibrinogenaemia in cardiac surgical patients. Anaesth Intensive Care 2022; 50 (05) 388-395
• 41 Blasi A, Sabate A, Beltran J, Costa M, Reyes R, Torres F. Correlation between plasma fibrinogen and FIBTEM thromboelastometry during liver transplantation: a comprehensive assessment. Vox Sang 2017; 112 (08) 788-795
• 42 Inoue M, Mizuno T, Kitagawa H. Thromboelastography may overestimate fibrinogen contribution to clot firmness in the presence of a high platelet count. J Cardiothorac Vasc Anesth 2024; 38 (01) 349
• 43 Preuss JF, Matzelle SA, Weightman WM, Gibbs NM. The influence of FIBTEM and EXTEM clotting times on the diagnostic accuracy of ROTEM^® sigma identification of hypofibrinogenaemia during cardiac surgery. Anaesthesia 2022; 77 (07) 829-830
• 44 Schlimp CJ, Solomon C, Ranucci M, Hochleitner G, Redl H, Schöchl H. The effectiveness of different functional fibrinogen polymerization assays in eliminating platelet contribution to clot strength in thromboelastometry. Anesth Analg 2014; 118 (02) 269-276
• 45 Solomon C, Rahe-Meyer N, Schöchl H, Ranucci M, Görlinger K. Effect of haematocrit on fibrin-based clot firmness in the FIBTEM test. Blood Transfus 2013; 11 (03) 412-418
• 46 Schlimp CJ, Cadamuro J, Solomon C, Redl H, Schöchl H. The effect of fibrinogen concentrate and factor XIII on thromboelastometry in 33% diluted blood with albumin, gelatine, hydroxyethyl starch or saline in vitro. Blood Transfus 2013; 11 (04) 510-517
• 47 Korte W. F. XIII in perioperative coagulation management. Best Pract Res Clin Anaesthesiol 2010; 24 (01) 85-93
• 48 Duque P, Chasco-Ganuza M, Ortuzar A. et al. Acquired FXIII deficiency is associated with high morbidity. Thromb Haemost 2022; 122 (01) 48-56
• 49 Hetz M, Juratli T, Tiebel O. et al. Acquired factor XIII deficiency in patients with multiple trauma. Injury 2023; 54 (05) 1257-1264
• 50 Duque P, Korte W. Factor XIII in the acute care setting and its relevance in obstetric bleeding. Transfus Med Hemother 2022; 50 (01) 10-17
• 51 Korte WC, Szadkowski C, Gähler A. et al. Factor XIII substitution in surgical cancer patients at high risk for intraoperative bleeding. Anesthesiology 2009; 110 (02) 239-245