Indications and Risks of Fibrinogen in Surgery and Trauma

 

 Buy Article Permissions and Reprints

Abstract

Fibrinogen has a central role in coagulation. Following trauma and perioperatively, low fibrinogen levels have been found to be risk factors for exaggerated bleeding, transfusion needs, and adverse outcome. Conversely, treatment with exogenous fibrinogen in critically bleeding patients with low fibrinogen levels has been shown to decrease transfusion needs. Because following trauma and in many perioperative situations fibrinogen is the first coagulation “element” to become critically low, it appears reasonable to target fibrinogen in clinical coagulation algorithms aiming at early specific and goal-directed treatment. A low fibrinogen can be a low plasma concentration or a low functional fibrinogen as assessed by point-of-care techniques such as thromboelastography (TEG) or thromboelastometry (ROTEM). This review summarizes the evidence base for perioperative algorithm-based fibrinogen administration, including the exact thresholds for fibrinogen administration used in the different algorithms. Algorithm-based individualized goal-directed use of fibrinogen resulted in highly significant reduction in transfusion needs, adverse outcomes, in certain studies even mortality, and where investigated reduced costs, with high safety levels at the same time. Best evidence exists in cardiac surgery, followed by trauma, postpartum hemorrhage, and liver transplantation. The introduction of these concepts is highly demanding and requires a tremendous educational effort to familiarize all health care workers with the necessary knowledge and the skills of how to run TEG/ROTEM tests. Future research is needed to compare the efficacy, safety, and costs of different algorithms. This, however, should not prevent us from introducing these expedient point-of-care–based algorithms clinically today.

• References

• 1 Levy JH, Goodnough LT. How I use fibrinogen replacement therapy in acquired bleeding. Blood 2015; 125 (9) 1387-1393
  CrossrefPubMedGoogle Scholar
• 2 Mannucci PM. Treatment of von Willebrand's Disease. N Engl J Med 2004; 351 (7) 683-694
  CrossrefPubMedGoogle Scholar
• 3 Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008; 359 (9) 938-949
  CrossrefPubMedGoogle Scholar
• 4 Rourke C, Curry N, Khan S , et al. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost 2012; 10 (7) 1342-1351
  CrossrefPubMedGoogle Scholar
• 5 Inaba K, Karamanos E, Lustenberger T , et al. Impact of fibrinogen levels on outcomes after acute injury in patients requiring a massive transfusion. J Am Coll Surg 2013; 216 (2) 290-297
  CrossrefPubMedGoogle Scholar
• 6 Hagemo JS, Stanworth S, Juffermans NP , et al. Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre observational study. Crit Care 2014; 18 (2) R52
  CrossrefPubMedGoogle Scholar
• 7 Schöchl H, Cotton B, Inaba K , et al. FIBTEM provides early prediction of massive transfusion in trauma. Crit Care 2011; 15 (6) R265
  CrossrefPubMedGoogle Scholar
• 8 Hagemo JS, Christiaans SC, Stanworth SJ , et al. Detection of acute traumatic coagulopathy and massive transfusion requirements by means of rotational thromboelastometry: an international prospective validation study. Crit Care 2015; 19: 97
  CrossrefPubMedGoogle Scholar
• 9 Karlsson M, Ternström L, Hyllner M, Baghaei F, Nilsson S, Jeppsson A. Plasma fibrinogen level, bleeding, and transfusion after on-pump coronary artery bypass grafting surgery: a prospective observational study. Transfusion 2008; 48 (10) 2152-2158
  CrossrefPubMedGoogle Scholar
• 10 Mallaiah S, Barclay P, Harrod I, Chevannes C, Bhalla A. Introduction of an algorithm for ROTEM-guided fibrinogen concentrate administration in major obstetric haemorrhage. Anaesthesia 2015; 70 (2) 166-175
  CrossrefPubMedGoogle Scholar
• 11 Gielen C, Dekkers O, Stijnen T , 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 (3) 292-298
  CrossrefPubMedGoogle Scholar
• 12 Collins PW, Lilley G, Bruynseels D , et al. Fibrin-based clot formation as an early and rapid biomarker for progression of postpartum hemorrhage: a prospective study. Blood 2014; 124 (11) 1727-1736
  CrossrefPubMedGoogle Scholar
• 13 Grottke O, Fries D, Nascimento B. Perioperatively acquired disorders of coagulation. Curr Opin Anaesthesiol 2015; 28 (2) 113-122
  CrossrefPubMedGoogle Scholar
• 14 Fenger-Eriksen C, Lindberg-Larsen M, Christensen AQ, Ingerslev J, Sørensen B. Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations. Br J Anaesth 2008; 101 (6) 769-773
  CrossrefPubMedGoogle Scholar
• 15 Nardi G, Agostini V, Rondinelli B , et al. Trauma-induced coagulopathy: impact of the early coagulation support protocol on blood product consumption, mortality and costs. Crit Care 2015; 19: 83
  CrossrefPubMedGoogle Scholar
• 16 Schöchl H, Nienaber U, Maegele M , et al. Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy. Crit Care 2011; 15 (2) R83
  CrossrefPubMedGoogle Scholar
• 17 Schoechl H, Nienaber U, Hofer G , et al. Goal-directed coagulation management of major trauma patients using rotation thromboelastometry (ROTEM)-guided administration of fibrinogen and prothrombin complex concentrate. Crit Care 2010; 14: R55
  CrossrefPubMedGoogle Scholar
• 18 Martini WZ, Chinkes DL, Sondeen J, Dubick MA. Effects of hemorrhage and lactated Ringer's resuscitation on coagulation and fibrinogen metabolism in swine. Shock 2006; 26 (4) 396-401
  CrossrefPubMedGoogle Scholar
• 19 Hiippala ST, Myllylä GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg 1995; 81 (2) 360-365
  CrossrefPubMedGoogle Scholar
• 20 Spahn DR, Bouillon B, Cerny V , et al. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care 2013; 17 (2) R76
  CrossrefPubMedGoogle Scholar
• 21 Haas T, Fries D, Tanaka KA, Asmis L, Curry NS, Schöchl H. Usefulness of standard plasma coagulation tests in the management of perioperative coagulopathic bleeding: is there any evidence?. Br J Anaesth 2015; 114 (2) 217-224
  CrossrefPubMedGoogle Scholar
• 22 Davenport R, Manson J, De'Ath H , et al. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med 2011; 39 (12) 2652-2658
  CrossrefPubMedGoogle Scholar
• 23 Solomon C, Baryshnikova E, Tripodi A , et al. Fibrinogen measurement in cardiac surgery with cardiopulmonary bypass: analysis of repeatability and agreement of Clauss method within and between six different laboratories. Thromb Haemost 2014; 112 (1) 109-117
  Article in Thieme ConnectPubMedGoogle Scholar
• 24 Fenger-Eriksen C, Moore GW, Rangarajan S, Ingerslev J, Sørensen B. Fibrinogen estimates are influenced by methods of measurement and hemodilution with colloid plasma expanders. Transfusion 2010; 50 (12) 2571-2576
  CrossrefPubMedGoogle Scholar
• 25 Kind SL, Spahn-Nett GH, Emmert MY , et al. Is dilutional coagulopathy induced by different colloids reversible by replacement of fibrinogen and factor XIII concentrates?. Anesth Analg 2013; 117 (5) 1063-1071
  CrossrefPubMedGoogle Scholar
• 26 Theusinger OM, Stein P, Spahn DR. Transfusion strategy in multiple trauma patients. Curr Opin Crit Care 2014; 20 (6) 646-655
  CrossrefPubMedGoogle Scholar
• 27 Theusinger OM, Nürnberg J, Asmis LM, Seifert B, Spahn DR. Rotation thromboelastometry (ROTEM) stability and reproducibility over time. Eur J Cardiothorac Surg 2010; 37 (3) 677-683
  CrossrefPubMedGoogle Scholar
• 28 Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg 2008; 106 (5) 1366-1375
  CrossrefPubMedGoogle Scholar
• 29 Hartog CS, Reuter D, Loesche W, Hofmann M, Reinhart K. Influence of hydroxyethyl starch (HES) 130/0.4 on hemostasis as measured by viscoelastic device analysis: a systematic review. Intensive Care Med 2011; 37 (11) 1725-1737
  CrossrefPubMedGoogle Scholar
• 30 Whiting D, DiNardo JA. TEG and ROTEM: technology and clinical applications. Am J Hematol 2014; 89 (2) 228-232
  CrossrefPubMedGoogle Scholar
• 31 Wikkelsø A, Lunde J, Johansen M , et al. Fibrinogen concentrate in bleeding patients. Cochrane Database Syst Rev 2013; 8: CD008864
  PubMedGoogle Scholar
• 32 Kozek-Langenecker S, Fries D, Spahn DR, Zacharowski K. III. Fibrinogen concentrate: clinical reality and cautious Cochrane recommendation. Br J Anaesth 2014; 112 (5) 784-787
  CrossrefPubMedGoogle Scholar
• 33 Spahn DR. TEG®- or ROTEM®-based individualized goal-directed coagulation algorithms: don't wait—act now!. Crit Care 2014; 18 (6) 637
  CrossrefPubMedGoogle Scholar
• 34 Frith D, Goslings JC, Gaarder C , et al. Definition and drivers of acute traumatic coagulopathy: clinical and experimental investigations. J Thromb Haemost 2010; 8 (9) 1919-1925
  CrossrefPubMedGoogle Scholar
• 35 Brohi K, Cohen MJ, Ganter MT, Matthay MA, Mackersie RC, Pittet JF. Acute traumatic coagulopathy: initiated by hypoperfusion: modulated through the protein C pathway?. Ann Surg 2007; 245 (5) 812-818
  CrossrefPubMedGoogle Scholar
• 36 Theusinger OM, Baulig W, Seifert B, Müller SM, Mariotti S, Spahn DR. Changes in coagulation in standard laboratory tests and ROTEM in trauma patients between on-scene and arrival in the emergency department. Anesth Analg 2015; 120 (3) 627-635
  CrossrefPubMedGoogle Scholar
• 37 Da Luz LT, Nascimento B, Shankarakutty AK, Rizoli S, Adhikari NK. Effect of thromboelastography (TEG®) and rotational thromboelastometry (ROTEM®) on diagnosis of coagulopathy, transfusion guidance and mortality in trauma: descriptive systematic review. Crit Care 2014; 18 (5) 518
  CrossrefPubMedGoogle Scholar
• 38 Brohi K, Cohen MJ, Ganter MT , et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 2008; 64 (5) 1211-1217 , discussion 1217
  CrossrefPubMedGoogle Scholar
• 39 Cardenas JC, Matijevic N, Baer LA, Holcomb JB, Cotton BA, Wade CE. Elevated tissue plasminogen activator and reduced plasminogen activator inhibitor promote hyperfibrinolysis in trauma patients. Shock 2014; 41 (6) 514-521
  CrossrefPubMedGoogle Scholar
• 40 Raza I, Davenport R, Rourke C , et al. The incidence and magnitude of fibrinolytic activation in trauma patients. J Thromb Haemost 2013; 11 (2) 307-314
  CrossrefPubMedGoogle Scholar
• 41 Davenport R, Brohi K. Fibrinogen depletion in trauma: early, easy to estimate and central to trauma-induced coagulopathy. Crit Care 2013; 17 (5) 190
  CrossrefPubMedGoogle Scholar
• 42 Kozek-Langenecker SA, Afshari A, Albaladejo P , et al. Management of severe perioperative bleeding: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol 2013; 30 (6) 270-382
  CrossrefPubMedGoogle Scholar
• 43 Nienaber U, Innerhofer P, Westermann I , et al. The impact of fresh frozen plasma vs coagulation factor concentrates on morbidity and mortality in trauma-associated haemorrhage and massive transfusion. Injury 2011; 42 (7) 697-701
  CrossrefPubMedGoogle Scholar
• 44 Nascimento B, Callum J, Tien H , et al. Effect of a fixed-ratio (1:1:1) transfusion protocol versus laboratory-results-guided transfusion in patients with severe trauma: a randomized feasibility trial. CMAJ 2013; 185 (12) E583-E589
  CrossrefPubMedGoogle Scholar
• 45 Schöchl H, Voelckel W, Maegele M, Kirchmair L, Schlimp CJ. Endogenous thrombin potential following hemostatic therapy with 4-factor prothrombin complex concentrate: a 7-day observational study of trauma patients. Crit Care 2014; 18 (4) R147
  CrossrefPubMedGoogle Scholar
• 46 Görlinger K, Dirkmann D, Hanke AA , et al. First-line therapy with coagulation factor concentrates combined with point-of-care coagulation testing is associated with decreased allogeneic blood transfusion in cardiovascular surgery: a retrospective, single-center cohort study. Anesthesiology 2011; 115 (6) 1179-1191
  CrossrefPubMedGoogle Scholar
• 47 Weber CF, Görlinger K, Meininger D , et al. Point-of-care testing: a prospective, randomized clinical trial of efficacy in coagulopathic cardiac surgery patients. Anesthesiology 2012; 117 (3) 531-547
  CrossrefPubMedGoogle Scholar
• 48 Rahe-Meyer N, Solomon C, Hanke A , et al. Effects of fibrinogen concentrate as first-line therapy during major aortic replacement surgery: a randomized, placebo-controlled trial. Anesthesiology 2013; 118 (1) 40-50
  CrossrefPubMedGoogle Scholar
• 49 Ranucci M, Baryshnikova E, Crapelli GB , et al. Randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery. J Am Heart Assoc 2015; 4
  PubMedGoogle Scholar
• 50 Karlsson M, Ternström L, Hyllner M , et al. Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised pilot study. Thromb Haemost 2009; 102 (1) 137-144
  PubMedGoogle Scholar
• 51 Sadeghi M, Atefyekta R, Azimaraghi O , et al. A randomized, double blind trial of prophylactic fibrinogen to reduce bleeding in cardiac surgery. Rev Bras Anestesiol 2014; 64: 253-257
  CrossrefPubMedGoogle Scholar
• 52 Tanaka KA, Egan K, Szlam F , et al. Transfusion and hematologic variables after fibrinogen or platelet transfusion in valve replacement surgery: preliminary data of purified lyophilized human fibrinogen concentrate versus conventional transfusion. Transfusion 2014; 54 (1) 109-118
  CrossrefPubMedGoogle Scholar
• 53 Solomon C, Hagl C, Rahe-Meyer N. Time course of haemostatic effects of fibrinogen concentrate administration in aortic surgery. Br J Anaesth 2013; 110 (6) 947-956
  CrossrefPubMedGoogle Scholar
• 54 Bolliger D, Tanaka KA. Roles of thrombelastography and thromboelastometry for patient blood management in cardiac surgery. Transfus Med Rev 2013; 27 (4) 213-220
  CrossrefPubMedGoogle Scholar
• 55 Nakayama Y, Nakajima Y, Tanaka KA , et al. Thromboelastometry-guided intraoperative haemostatic management reduces bleeding and red cell transfusion after paediatric cardiac surgery. Br J Anaesth 2015; 114 (1) 91-102
  CrossrefPubMedGoogle Scholar
• 56 Karkouti K, McCluskey SA, Callum J , et al. Evaluation of a novel transfusion algorithm employing point-of-care coagulation assays in cardiac surgery: a retrospective cohort study with interrupted time-series analysis. Anesthesiology 2015; 122 (3) 560-570
  CrossrefPubMedGoogle Scholar
• 57 Kirchner C, Dirkmann D, Treckmann JW , et al. Coagulation management with factor concentrates in liver transplantation: a single-center experience. Transfusion 2014; 54 (10 Pt 2) 2760-2768
  CrossrefPubMedGoogle Scholar
• 58 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (2) 147-156
  CrossrefPubMedGoogle Scholar
• 59 Roullet S, Freyburger G, Cruc M , et al. Management of bleeding and transfusion during liver transplantation before and after the introduction of a rotational thromboelastometry-based algorithm. Liver Transpl 2015; 21 (2) 169-179
  CrossrefPubMedGoogle Scholar
• 60 Roullet S, Pillot J, Freyburger G , et al. Rotation thromboelastometry detects thrombocytopenia and hypofibrinogenaemia during orthotopic liver transplantation. Br J Anaesth 2010; 104 (4) 422-428
  CrossrefPubMedGoogle Scholar
• 61 Tripodi A, Primignani M, Chantarangkul V , et al. The coagulopathy of cirrhosis assessed by thromboelastometry and its correlation with conventional coagulation parameters. Thromb Res 2009; 124 (1) 132-136
  CrossrefPubMedGoogle Scholar
• 62 Clevenger B, Mallett SV. Transfusion and coagulation management in liver transplantation. World J Gastroenterol 2014; 20 (20) 6146-6158
  CrossrefPubMedGoogle Scholar
• 63 Rana A, Petrowsky H, Hong JC , et al. Blood transfusion requirement during liver transplantation is an important risk factor for mortality. J Am Coll Surg 2013; 216 (5) 902-907
  CrossrefPubMedGoogle Scholar
• 64 Kang YG, Martin DJ, Marquez J , et al. Intraoperative changes in blood coagulation and thrombelastographic monitoring in liver transplantation. Anesth Analg 1985; 64 (9) 888-896
  PubMedGoogle Scholar
• 65 Leon-Justel A, Noval-Padillo JA, Alvarez-Rios AI , et al. Point-of-care haemostasis monitoring during liver transplantation reduces transfusion requirements and improves patient outcome. Clin Chim Acta 2015; 446: 277-283
  CrossrefPubMedGoogle Scholar
• 66 Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367 (9516) 1066-1074
  CrossrefPubMedGoogle Scholar
• 67 Hogan MC, Foreman KJ, Naghavi M , et al. Maternal mortality for 181 countries, 1980–2008: a systematic analysis of progress towards Millennium Development Goal 5. Lancet 2010; 375 (9726) 1609-1623
  CrossrefPubMedGoogle Scholar
• 68 Kramer MS, Berg C, Abenhaim H , et al. Incidence, risk factors, and temporal trends in severe postpartum hemorrhage. Am J Obstet Gynecol 2013; 209 (5) 449.e1-449.e7
  CrossrefPubMedGoogle Scholar
• 69 Prick BW, Auf Altenstadt JF, Hukkelhoven CW , et al. Regional differences in severe postpartum hemorrhage: a nationwide comparative study of 1.6 million deliveries. BMC Pregnancy Childbirth 2015; 15: 43
  CrossrefPubMedGoogle Scholar
• 70 Abdul-Kadir R, McLintock C, Ducloy AS , et al. Evaluation and management of postpartum hemorrhage: consensus from an international expert panel. Transfusion 2014; 54 (7) 1756-1768
  CrossrefPubMedGoogle Scholar
• 71 Ekelund K, Hanke G, Stensballe J, Wikkelsøe A, Albrechtsen CK, Afshari A. Hemostatic resuscitation in postpartum hemorrhage—a supplement to surgery. Acta Obstet Gynecol Scand 2015; 94 (7) 680-692
  CrossrefPubMedGoogle Scholar
• 72 Ducloy-Bouthors AS, Jude B, Duhamel A , et al; EXADELI Study Group. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care 2011; 15 (2) R117
  CrossrefPubMedGoogle Scholar
• 73 Shakur H, Elbourne D, Gülmezoglu M , et al. The WOMAN Trial (World Maternal Antifibrinolytic Trial): tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind placebo controlled trial. Trials 2010; 11: 40
  CrossrefPubMedGoogle Scholar
• 74 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 (2) 266-273
  CrossrefPubMedGoogle Scholar
• 75 Karlsson O, Jeppsson A, Thornemo M, Lafrenz H, Rådström M, Hellgren M. Fibrinogen plasma concentration before delivery is not associated with postpartum haemorrhage: a prospective observational study. Br J Anaesth 2015; 115 (1) 99-104
  CrossrefPubMedGoogle Scholar
• 76 Ahmed S, Harrity C, Johnson S , et al. The efficacy of fibrinogen concentrate compared with cryoprecipitate in major obstetric haemorrhage—an observational study. Transfus Med 2012; 22 (5) 344-349
  CrossrefPubMedGoogle Scholar
• 77 Wikkelsø AJ, Edwards HM, Afshari A , et al; FIB-PPH trial group. Pre-emptive treatment with fibrinogen concentrate for postpartum haemorrhage: randomized controlled trial. Br J Anaesth 2015; 114 (4) 623-633
  CrossrefPubMedGoogle Scholar
• 78 Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians. Obstet Gynecol 2009; 114 (6) 1326-1331
  CrossrefPubMedGoogle Scholar
• 79 Aawar N, Alikhan R, Bruynseels D , et al. Fibrinogen concentrate versus placebo for treatment of postpartum haemorrhage: study protocol for a randomised controlled trial. Trials 2015; 16: 169
  CrossrefPubMedGoogle Scholar
• 80 Girard T, Mörtl M, Schlembach D. New approaches to obstetric hemorrhage: the postpartum hemorrhage consensus algorithm. Curr Opin Anaesthesiol 2014; 27 (3) 267-274
  CrossrefPubMedGoogle Scholar
• 81 Schlembach D, Mörtl MG, Girard T , et al. [Management of postpartum hemorrhage (PPH): algorithm of the interdisciplinary D-A-CH consensus group PPH (Germany - Austria - Switzerland)]. Anaesthesist 2014; 63 (3) 234-242
  CrossrefPubMedGoogle Scholar
• 82 Beyerle A, Nolte MW, Solomon C, Herzog E, Dickneite G. Analysis of the safety and pharmacodynamics of human fibrinogen concentrate in animals. Toxicol Appl Pharmacol 2014; 280 (1) 70-77
  CrossrefPubMedGoogle Scholar
• 83 Solomon C, Gröner A, Ye J, Pendrak I. Safety of fibrinogen concentrate: analysis of more than 27 years of pharmacovigilance data. Thromb Haemost 2015; 113 (4) 759-771
  PubMedGoogle Scholar
• 84 Rana R, Fernández-Pérez ER, Khan SA , et al. Transfusion-related acute lung injury and pulmonary edema in critically ill patients: a retrospective study. Transfusion 2006; 46 (9) 1478-1483
  CrossrefPubMedGoogle Scholar