Fibrinogen concentrate for management of bleeding

Abstract

Massive bleeding usually leads to critically low levels of clotting factors and coagulopathy [1Fenger‐Eriksen C. Tonnesen E. Ingerslev J. Sørensen B. Mechanisms of hydroxyethyl starch‐induced dilutional coagulopathy.J Thromb Haemost. 2009; 7: 1099-105Crossref PubMed Scopus (143) Google Scholar]. In addition to blood loss and dilution, acidosis causes further depletion of key clotting factors including fibrinogen [2Martini W.Z. Dubick M.A. Pusateri A.E. Park M.S. Ryan K.L. Holcomb J.B. Does bicarbonate correct coagulation function impaired by acidosis in swine?.J Trauma. 2006; 61: 99-106Crossref PubMed Scopus (90) Google Scholar, 3Engstrom M. Schott U. Romner B. Reinstrup P. Acidosis impairs the coagulation: a thromboelastographic study.J Trauma. 2006; 61: 624-8Crossref PubMed Scopus (134) Google Scholar]. Consequently, bleeding is the major cause of mortality during extended elective surgery and 40% of trauma‐related deaths are attributable to coagulopathy [4Schöchl H. Nienaber U. Hofer G. Voelckel W. Jambor C. Scharbert G. Kozek‐Langenecker S. Solomon C. Goal‐directed coagulation management of major trauma patients using thromboelastometry (ROTEM(R))‐guided administration of fibrinogen concentrate and prothrombin complex concentrate.Crit Care. 2010; 14: R55Crossref PubMed Scopus (529) Google Scholar]. Fibrinogen is the first clotting factor to fall to critically low levels during life‐threatening bleeding [5Hiippala S.T. Myllyla G.J. Vahtera E.M. Hemostatic factors and replacement of major blood loss with plasma‐poor red cell concentrates.Anesth Analg. 1995; 81: 360-5PubMed Google Scholar, 6Stainsby D. MacLennan S. Thomas D. Isaac J. Hamilton P.J. Guidelines on the management of massive blood loss.Br J Haematol. 2006; 135: 634-41Crossref PubMed Scopus (323) Google Scholar]. It plays a fundamental role in maintaining hemostasis, serving both as the precursor of fibrin, which is cross‐linked to form blood clots, and as a mediator of platelet aggregation [7Velik‐Salchner C. Haas T. Innerhofer P. Streif W. Nussbaumer W. Klingler A. Klima G. Martinowitz U. Fries D. The effect of fibrinogen concentrate on thrombocytopenia.J Thromb Haemost. 2007; 5: 1019-25Crossref PubMed Scopus (150) Google Scholar, 8Lang T. Johanning K. Metzler H. Piepenbrock S. Solomon C. Rahe‐Meyer N. Tanaka K.A. The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia.Anesth Analg. 2009; 108: 751-8Crossref PubMed Scopus (241) Google Scholar, 9Fries D. Martini W.Z. Role of fibrinogen in trauma‐induced coagulopathy.Br J Anaesth. 2010; 105: 116-21Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar]. Tissue trauma and hypoperfusion inevitably lead to acidosis, with the reduction in pH both accelerating fibrinogen consumption and impairing clotting factor function [10Martini W.Z. Holcomb J.B. Acidosis and coagulopathy: the differential effects on fibrinogen synthesis and breakdown in pigs.Ann Surg. 2007; 246: 831-5Crossref PubMed Scopus (113) Google Scholar]. Additionally, acute traumatic coagulopathy leads to the onset of hyperfibrinolysis [9Fries D. Martini W.Z. Role of fibrinogen in trauma‐induced coagulopathy.Br J Anaesth. 2010; 105: 116-21Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, 11Brohi K. Cohen M.J. Ganter M.T. Schultz M.J. Levi M. Mackersie R.C. Pittet J.F. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis.J Trauma. 2008; 64: 1211-7Crossref PubMed Scopus (32) Google Scholar], and the use of anti‐fibrinolytic drugs in these cases can reduce blood loss and mortality rates [12Shakur H. Roberts R. Bautista R. Caballero J. Coats T. Dewan Y. El‐Sayed H. Gogichaishvili T. Gupta S. Herrera J. Hunt B. Iribhogbe P. Izurieta M. Khamis H. Komolafe E. Marrero M.A. Mejia‐Mantilla J. Miranda J. Morales C. Olaomi O. et al.Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH‐2): a randomised, placebo‐controlled trial.Lancet. 2010; 376: 23-32Abstract Full Text Full Text PDF PubMed Scopus (2139) Google Scholar]. Volume resuscitation is crucial when treating trauma patients with massive bleeding. However, use of synthetic colloid plasma expanders impairs fibrin polymerization (dilutional coagulopathy) and this is partially reversible by fibrinogen supplementation [13Fenger‐Eriksen C. Lindberg‐Larsen M. Christensen A.Q. Ingerslev J. Sørensen B. Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations.Br J Anaesth. 2008; 101: 769-73Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar]. Clinical evidence defining a critical fibrinogen level for triggering supplementation is lacking. Current guidelines recommend fibrinogen supplementation in all cases where ‘significant bleeding is accompanied by thrombelastometric signs of a functional fibrinogen deficit or a plasma fibrinogen level of < 1.5–2.0 g L−1’ [14Rossaint R. Bouillon B. Cerny V. Coats T.J. Duranteau J. Fernandez‐Mondejar E. Hunt B.J. Komadina R. Nardi G. Neugebauer E. Ozier Y. Riddez L. Schultz A. Stahel P.F. Vincent J.L. Spahn D.R. Management of bleeding following major trauma: an updated European guideline.Crit Care. 2010; 14: R52Crossref PubMed Scopus (578) Google Scholar]. Importantly, reduced fibrinogen levels are shown to correlate with increased bleeding [15Charbit B. Mandelbrot L. Samain E. Baron G. Haddaoui B. Keita H. Sibony O. Mahieu‐Caputo D. Hurtaud‐Roux M.F. Huisse M.G. Denninger M.H. de Prost D. The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage.J Thromb Haemost. 2007; 5: 266-73Crossref PubMed Scopus (503) Google Scholar, 16Karlsson M. Ternstrom L. Hyllner M. Baghaei F. Flinck A. Skrtic S. Jeppsson A. Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised pilot study.Thromb Haemost. 2009; 102: 137-44Crossref PubMed Scopus (206) Google Scholar] and increased mortality [17Stinger H.K. Spinella P.C. Perkins J.G. Grathwohl K.W. Salinas J. Martini W.Z. Hess J.R. Dubick M.A. Simon C.D. Beekley A.C. Wolf S.E. Wade C.E. Holcomb J.B. The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital.J Trauma. 2008; 64: S79-85Crossref PubMed Google Scholar]. In our opinion the key question for this debate is ‘How should we supplement fibrinogen levels?’ rather than ‘Should we supplement fibrinogen levels?’. Supplementation of plasma fibrinogen can be carried out via administration of fresh frozen plasma (FFP), cryoprecipitate or fibrinogen concentrate. These options vary significantly in their efficacy, safety and speed of infusion; a comparison of their properties is presented in Table 1.Table 1Comparison of attributes of FFP, cryoprecipitate and fibrinogen concentrateAttributeFibrinogen concentrateCryoprecipitateHuman plasmaConstituentsPure preparation of fibrinogen (few other constituents)Contains clotting factors VIII and XIII as well as fibrinogen Also contains von Willebrand factorContains all clotting factors and numerous other proteinsSafety and transmission of pathogensViral inactivation, therefore minimal risk of pathogen transmission No unwanted clotting factors Low thrombogenic potentialNo viral inactivation, therefore potential risk of pathogen transmission Transfusion of large quantities can raise levels of several coagulation factors Thrombotic risk establishedNo viral inactivation (except commercially produced plasma products), therefore potential risk of pathogen transmission Risk of transfusion‐related reactions (e.g. TRALI) and hypervolemiaDosing: control and consistencyWell‐defined quantity of fibrinogen Accurate and consistent dosing Low infusion volumeVariable fibrinogen levels, which are donor dependant Accurate dosing not possible Low infusion volume, albeit larger than fibrinogen concentrateVariable fibrinogen levels, which are donor dependant Accurate dosing not possible Only modest increase in fibrinogen is possible High infusion volumeAdministrationRapidly reconstituted – administered with minimal delay (5 min) No cross‐matching requiredMust first be thawed, delaying administration (45 min) Cross‐matching is requiredMust first be thawed, delaying administration (45 min) High volume: time‐consuming infusion Donor‐recipient AB compatibility is requiredTRALI, transfusion‐related lung injury. Open table in a new tab TRALI, transfusion‐related lung injury. FFP is an allogeneic blood product, requiring both donor‐recipient AB compatibility and thawing before administration. It includes all components of human plasma at concentrations at or below normal physiological concentrations (the production process reduces coagulation factor levels, and young healthy donors tend to have relatively low levels of fibrinogen) [18Armand R. Hess J.R. Treating coagulopathy in trauma patients.Transfus Med Rev. 2003; 17: 223-31Crossref PubMed Scopus (236) Google Scholar]. The average concentration of fibrinogen in FFP is ∼2.5 g L−1 and only slightly above the likely target concentration of 2 g L−1. Hence, infusion volumes to reach the target are high, often to the point of being unfeasible, transfusion is slow, and there is a risk of fluid overload. Accurate dosing is impossible due to significant inter‐individual variability in concentration of coagulation factors in single‐donor FFP. Standard FFP does not undergo viral inactivation and is therefore associated with a theoretical risk of pathogen transmission. Allogeneic blood products also contain antigens and antibodies that can cause immunological and allergic reactions. Notably, some commercially produced plasma substitutes are virally inactivated, but the use of these products is still less common than standard FFP. These products can also have other drawbacks: a low concentration of fibrinogen in methylene blue inactivated plasma has been shown to increase transfusion requirements by > 50% vs. FFP [19Atance R. Pereira A. Ramirez B. Transfusing methylene blue‐photoinactivated plasma instead of FFP is associated with an increased demand for plasma and cryoprecipitate.Transfusion. 2001; 41: 1548-52Crossref PubMed Scopus (55) Google Scholar]. Furthermore, despite purification processes, some antibodies and antigens may still be present. Cryoprecipitate is a human plasma concentrate, containing fibrinogen, factor VIII, factor XIII and von Willebrand factor. Cryoprecipitate, like FFP, is an allogeneic product requiring cross‐matching and thawing before administration. Likewise, there are no viral inactivation processes with cryoprecipitate, meaning that transmission of emergent pathogens remains a risk [20Sørensen B. Bevan D. A critical evaluation of cryoprecipitate for replacement of fibrinogen.Br J Haematol. 2010; 149: 834-43Crossref PubMed Scopus (131) Google Scholar]. Cryoprecipitate is usually administered as a pool of four to six units. This reduces the variability of fibrinogen concentration (typically ∼1 g 60 mL−1), but increases safety issues because of the exposure to four to six donors per transfusion. Based on safety concerns, cryoprecipitate is not used in most European countries [20Sørensen B. Bevan D. A critical evaluation of cryoprecipitate for replacement of fibrinogen.Br J Haematol. 2010; 149: 834-43Crossref PubMed Scopus (131) Google Scholar]. Fibrinogen concentrate is a pasteurized drug stored as a lyophilized powder at room temperature. It can be reconstituted quickly with sterile water and infusion volumes are low, allowing for prompt administration without delays caused by thawing or cross‐matching. The concentration of fibrinogen (1 g 50 mL−1) is more consistent than that of either FFP or cryoprecipitate. Viral inactivation by pasteurization minimizes the risk of pathogen transmission; additional purification steps remove antigens and antibodies, minimizing the risk of immunological and allergic reactions [20Sørensen B. Bevan D. A critical evaluation of cryoprecipitate for replacement of fibrinogen.Br J Haematol. 2010; 149: 834-43Crossref PubMed Scopus (131) Google Scholar]. Preclinical data demonstrate that fibrinogen concentrate improves clot quality and attenuates bleeding [7Velik‐Salchner C. Haas T. Innerhofer P. Streif W. Nussbaumer W. Klingler A. Klima G. Martinowitz U. Fries D. The effect of fibrinogen concentrate on thrombocytopenia.J Thromb Haemost. 2007; 5: 1019-25Crossref PubMed Scopus (150) Google Scholar, 8Lang T. Johanning K. Metzler H. Piepenbrock S. Solomon C. Rahe‐Meyer N. Tanaka K.A. The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia.Anesth Analg. 2009; 108: 751-8Crossref PubMed Scopus (241) Google Scholar, 21Bolliger D. Szlam F. Molinaro R.J. Rahe‐Meyer N. Levy J.H. Tanaka K.A. Finding the optimal concentration range for fibrinogen replacement after severe haemodilution: an in vitro model.Br J Anaesth. 2009; 102: 793-9Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 22Grottke O. Braunschweig T. Henzler D. Coburn M. Tolba R. Rossaint R. Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury.Crit Care. 2010; 14: R62Crossref PubMed Scopus (58) Google Scholar]. In vitro data have shown that thromboelastometry parameters, including clot firmness, improve as the concentration of fibrinogen is increased, with the optimal rate of clot formation being seen only at levels above 2 g L−1 [8Lang T. Johanning K. Metzler H. Piepenbrock S. Solomon C. Rahe‐Meyer N. Tanaka K.A. The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia.Anesth Analg. 2009; 108: 751-8Crossref PubMed Scopus (241) Google Scholar, 21Bolliger D. Szlam F. Molinaro R.J. Rahe‐Meyer N. Levy J.H. Tanaka K.A. Finding the optimal concentration range for fibrinogen replacement after severe haemodilution: an in vitro model.Br J Anaesth. 2009; 102: 793-9Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar]. Experimental porcine studies have shown that supplementation with fibrinogen concentrate significantly improves coagulation and attenuated blood loss in cases of both severe dilutional coagulopathy and thrombocytopenia [7Velik‐Salchner C. Haas T. Innerhofer P. Streif W. Nussbaumer W. Klingler A. Klima G. Martinowitz U. Fries D. The effect of fibrinogen concentrate on thrombocytopenia.J Thromb Haemost. 2007; 5: 1019-25Crossref PubMed Scopus (150) Google Scholar, 22Grottke O. Braunschweig T. Henzler D. Coburn M. Tolba R. Rossaint R. Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury.Crit Care. 2010; 14: R62Crossref PubMed Scopus (58) Google Scholar, 23Fries D. Innerhofer P. Reif C. Streif W. Klingler A. Schobersberger W. Velik‐Salchner C. Friesenecker B. The effect of fibrinogen substitution on reversal of dilutional coagulopathy: an in vitro model.Anesth Analg. 2006; 102: 347-51Crossref PubMed Scopus (132) Google Scholar, 24Fries D. Krismer A. Klingler A. Streif W. Klima G. Wenzel V. Haas T. Innerhofer P. Effect of fibrinogen on reversal of dilutional coagulopathy: a porcine model.Br J Anaesth. 2005; 95: 172-7Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar]. Numerous retrospective and prospective clinical studies of patients with acquired hypofibrinogenemia, in settings such as trauma, cardiothoracic surgery and obstetric hemorrhage, all show that fibrinogen concentrate improves clotting function and reduces blood loss [4Schöchl H. Nienaber U. Hofer G. Voelckel W. Jambor C. Scharbert G. Kozek‐Langenecker S. Solomon C. Goal‐directed coagulation management of major trauma patients using thromboelastometry (ROTEM(R))‐guided administration of fibrinogen concentrate and prothrombin complex concentrate.Crit Care. 2010; 14: R55Crossref PubMed Scopus (529) Google Scholar, 8Lang T. Johanning K. Metzler H. Piepenbrock S. Solomon C. Rahe‐Meyer N. Tanaka K.A. The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia.Anesth Analg. 2009; 108: 751-8Crossref PubMed Scopus (241) Google Scholar, 13Fenger‐Eriksen C. Lindberg‐Larsen M. Christensen A.Q. Ingerslev J. Sørensen B. Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations.Br J Anaesth. 2008; 101: 769-73Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar, 16Karlsson M. Ternstrom L. Hyllner M. Baghaei F. Flinck A. Skrtic S. Jeppsson A. Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. 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Bleeding management with fibrinogen concentrate targeting a high‐normal plasma fibrinogen level: a pilot study.Br J Anaesth. 2009; 102: 785-92Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 36Rahe‐Meyer N. Solomon C. Winterhalter M. Piepenbrock S. Tanaka K. Haverich A. Pichlmaier M. Thromboelastometry‐guided administration of fibrinogen concentrate for the treatment of excessive intraoperative bleeding in thoracoabdominal aortic aneurysm surgery.J Thorac Cardiovasc Surg. 2009; 138: 694-702Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 37Schöchl H. Forster L. Woidke R. Solomon C. Voelckel W. Use of rotation thromboelastometry (ROTEM) to achieve successful treatment of polytrauma with fibrinogen concentrate and prothrombin complex concentrate.Anaesthesia. 2010; 65: 199-203Crossref PubMed Scopus (113) Google Scholar, 38Weinkove R. Rangarajan S. Fibrinogen concentrate for acquired hypofibrinogenaemic states.Transfus Med. 2008; 18: 151-7Crossref PubMed Scopus (103) Google Scholar]. For example, in a prospective clinical study of orthopedic patients receiving volume replacement, fibrinogen concentrate restored clotting function, reversing the effects of dilutional coagulopathy [34Mittermayr M. Streif W. Haas T. Fries D. Velik‐Salchner C. Klingler A. Oswald E. Bach C. Schnapka‐Koepf M. Innerhofer P. Hemostatic changes after crystalloid or colloid fluid administration during major orthopedic surgery: the role of fibrinogen administration.Anesth Analg. 2007; 105: 905-17Crossref PubMed Scopus (237) Google Scholar]. A randomized, placebo‐controlled study assessed the efficacy of perioperatively administered fibrinogen concentrate for excessive bleeding during radical cystectomy. Fibrinogen concentrate increased maximum clot firmness and reduced the need for postoperative transfusion of red blood cells [1Fenger‐Eriksen C. Tonnesen E. Ingerslev J. Sørensen B. Mechanisms of hydroxyethyl starch‐induced dilutional coagulopathy.J Thromb Haemost. 2009; 7: 1099-105Crossref PubMed Scopus (143) Google Scholar]. Fibrinogen concentrate also appears to be effective in patients with thrombocytopenia [8Lang T. Johanning K. Metzler H. Piepenbrock S. Solomon C. Rahe‐Meyer N. Tanaka K.A. The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia.Anesth Analg. 2009; 108: 751-8Crossref PubMed Scopus (241) Google Scholar]; both the density of the fibrin network and fibrinogen‐mediated platelet aggregation are increased, compensating for reduced platelet levels. FFP is not appropriate for treating severe fibrinogen deficiency as it contains insufficient concentrations of fibrinogen [20Sørensen B. Bevan D. A critical evaluation of cryoprecipitate for replacement of fibrinogen.Br J Haematol. 2010; 149: 834-43Crossref PubMed Scopus (131) Google Scholar, 28Danes A.F. Cuenca L.G. Bueno S.R. Mendarte Barrenechea L. Ronsano J.B. 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: 221-6Crossref PubMed Scopus (113) Google Scholar, 39Chowdhury P. Saayman A.G. Paulus U. Findlay G.P. Collins P.W. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients.Br J Haematol. 2004; 125: 69-73Crossref PubMed Scopus (316) Google Scholar]. Results from randomized controlled trials of FFP are insufficient to either support or refute its efficacy in most clinical settings. The strongest evidence, regarding prophylactic use, shows a lack of significant or consistent efficacy [40Stanworth S.J. Brunskill S.J. Hyde C.J. McClelland D.B. Murphy M.F. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials.Br J Haematol. 2004; 126: 139-52Crossref PubMed Scopus (345) Google Scholar]. The clinical efficacy of cryoprecipitate is also questionable, with no published studies specifically designed to assess its efficacy in the management of bleeding. Sørensen and Bevan [20Sørensen B. Bevan D. A critical evaluation of cryoprecipitate for replacement of fibrinogen.Br J Haematol. 2010; 149: 834-43Crossref PubMed Scopus (131) Google Scholar] commented: ‘Where cryoprecipitate is still used, replacement with fibrinogen concentrate would offer improvements in efficacy and safety, bringing the standard of treatment for surgical patients in line with that offered to hemophilia patients’. Point of care assessment of fibrinogen and fibrin polymerization may guide diagnosis and rapid infusion of fibrinogen in the management of acquired bleeding [37Schöchl H. Forster L. Woidke R. Solomon C. Voelckel W. Use of rotation thromboelastometry (ROTEM) to achieve successful treatment of polytrauma with fibrinogen concentrate and prothrombin complex concentrate.Anaesthesia. 2010; 65: 199-203Crossref PubMed Scopus (113) Google Scholar, 41Holcomb J.B. Traditional transfusion practices are changing.Crit Care. 2010; 14: 162Crossref PubMed Scopus (17) Google Scholar, 42Spahn D.R. Ganter M.T. Towards early individual goal‐directed coagulation management in trauma patients.Br J Anaesth. 2010; 105: 103-5Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. A recent study reported thromboelastometry (TEM)‐guided goal‐directed treatment of 131 trauma patients [4Schöchl H. Nienaber U. Hofer G. Voelckel W. Jambor C. Scharbert G. Kozek‐Langenecker S. Solomon C. Goal‐directed coagulation management of major trauma patients using thromboelastometry (ROTEM(R))‐guided administration of fibrinogen concentrate and prothrombin complex concentrate.Crit Care. 2010; 14: R55Crossref PubMed Scopus (529) Google Scholar]. Fibrinogen concentrate was used as primary hemostatic therapy in combination with prothrombin complex concentrate, and this reduced the mortality rate compared with that predicted by the trauma injury severity score (TRISS) and the revised injury severity classification (RISC) score [4Schöchl H. Nienaber U. Hofer G. Voelckel W. Jambor C. Scharbert G. Kozek‐Langenecker S. Solomon C. Goal‐directed coagulation management of major trauma patients using thromboelastometry (ROTEM(R))‐guided administration of fibrinogen concentrate and prothrombin complex concentrate.Crit Care. 2010; 14: R55Crossref PubMed Scopus (529) Google Scholar]. Our research units have also reported on optimized speed, safety and efficacy of TEM‐guided therapy with fibrinogen and coagulation factor concentrate [35Rahe‐Meyer N. Pichlmaier M. Haverich A. Solomon C. Winterhalter M. Piepenbrock S. Tanaka K.A. Bleeding management with fibrinogen concentrate targeting a high‐normal plasma fibrinogen level: a pilot study.Br J Anaesth. 2009; 102: 785-92Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 36Rahe‐Meyer N. Solomon C. Winterhalter M. Piepenbrock S. Tanaka K. Haverich A. Pichlmaier M. Thromboelastometry‐guided administration of fibrinogen concentrate for the treatment of excessive intraoperative bleeding in thoracoabdominal aortic aneurysm surgery.J Thorac Cardiovasc Surg. 2009; 138: 694-702Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar]. A further benefit of point of care assessment is reliable measurement of fibrinogen levels [43Carroll R.C. Craft R.M. Chavez J.J. Snider C.C. Kirby R.K. Cohen E. Measurement of functional fibrinogen levels using the Thrombelastograph.J Clin Anesth. 2008; 20: 186-90Crossref PubMed Scopus (49) Google Scholar, 44Kalina U. Stohr H.A. Bickhard H. Knaub S. Siboni S.M. Mannucci P.M. Peyvandi F. Rotational thromboelastography for monitoring of fibrinogen concentrate therapy in fibrinogen deficiency.Blood Coagul Fibrinolysis. 2008; 19: 777-83Crossref PubMed Scopus (66) Google Scholar]. Functional fibrinogen measurement is commonly carried out using the Clauss method, which is based upon a photometric or mechanical detection. However, both fibrin degradation products and the colloid plasma expanders can produce artificially high results when fibrinogen levels are measured in this way [45Fenger‐Eriksen C. Moore G.W. Rangarajan S. Ingerslev J. Sørensen B. Fibrinogen estimates are influenced by methods of measurement and hemodilution with colloid plasma expanders.Transfusion. 2010; 50: 2571-6Crossref PubMed Scopus (109) Google Scholar]. Preclinical models have shown no evidence of thrombosis formation during venous stasis in animals treated with fibrinogen concentrate [46Dickneite G. Pragst I. Joch C. Bergman G.E. Animal model and clinical evidence indicating low thrombogenic potential of fibrinogen concentrate (Haemocomplettan P).Blood Coagul Fibrinolysis. 2009; 20: 535-40Crossref PubMed Scopus (81) Google Scholar]. A 22‐year pharmacosurveillance report and review of clinical study data showed no significant safety concerns associated with fibrinogen concentrate used in perioperative bleeding situations, either with regard to thrombogenicity or viral transmission [46Dickneite G. Pragst I. Joch C. Bergman G.E. Animal model and clinical evidence indicating low thrombogenic potential of fibrinogen concentrate (Haemocomplettan P).Blood Coagul Fibrinolysis. 2009; 20: 535-40Crossref PubMed Scopus (81) Google Scholar]. Pasteurization has proved a reliable viral inactivation method with an excellent safety record. Some observers have questioned the safety of fibrinogen concentrate because of the relationship between cardiovascular disease and raised plasma fibrinogen levels [20Sørensen B. Bevan D. A critical evaluation of cryoprecipitate for replacement of fibrinogen.Br J Haematol. 2010; 149: 834-43Crossref PubMed Scopus (131) Google Scholar]. However, good evidence exists that raised fibrinogen is a long‐term marker, rather than a cause of cardiovascular disease [47Reinhart W.H. Fibrinogen‐‐marker or mediator of vascular disease?.Vasc Med. 2003; 8: 211-6Crossref PubMed Scopus (88) Google Scholar]. In contrast to fibrinogen concentrate, there are numerous safety concerns with both cryoprecipitate and FFP. Neither standard FFP nor cryoprecipitate undergo viral attenuation procedures, placing patients at potential risk of pathogen transmission. There is an innate risk of immunological and allergic reactions to both FFP and cryoprecipitate [48Stainsby D. Jones H. Asher D. Atterbury C. 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Recovery of fibrinogen after administration of fibrinogen concentrate to patients with severe bleeding after cardiopulmonary bypass surgery.Br J Anaesth. 2010; 104: 555-62Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar]. Fibrinogen plays a critical role in clot formation. Bleeding patients are prone to develop low levels of fibrinogen and abnormal fibrin polymerization, therefore fibrinogen supplementation is essential. Rapid intervention is needed, and fibrinogen concentrate can be administered promptly. Considering both safety and effectiveness, we believe that fibrinogen concentrate is preferable to either FFP or cryoprecipitate. So far clinical studies have shown that fibrinogen concentrate therapy supplements fibrinogen levels rapidly and effectively, facilitating hemostasis in a high proportion of patients. Thus, we argue that fibrinogen concentrate is indispensable in the management of bleeding and should be first‐line treatment if no underlying coagulopathy is complicating the case. Additional prospective phase II/III clinical trials focusing on dosing, efficacy and safety would be desirable.