Download PDF
Semin Thromb Hemost 2012; 38(03): 268-273
DOI: 10.1055/s-0032-1309287
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Fibrinogen as a Hemostatic Agent

Benny Sørensen
1   Haemostasis Research Unit, Centre for Haemostasis and Thrombosis, Guy's and St Thomas's NHS Foundation Trust, London, United Kingdom
2   King's College London School of Medicine, London, United Kingdom
3   Department of Clinical Biochemistry, Centre for Haemophilia and Thrombosis, Aarhus University Hospital, Skejby, Denmark
,
Ole Halfdan Larsen
1   Haemostasis Research Unit, Centre for Haemostasis and Thrombosis, Guy's and St Thomas's NHS Foundation Trust, London, United Kingdom
3   Department of Clinical Biochemistry, Centre for Haemophilia and Thrombosis, Aarhus University Hospital, Skejby, Denmark
,
Catherine J. Rea
1   Haemostasis Research Unit, Centre for Haemostasis and Thrombosis, Guy's and St Thomas's NHS Foundation Trust, London, United Kingdom
2   King's College London School of Medicine, London, United Kingdom
,
Mariann Tang
1   Haemostasis Research Unit, Centre for Haemostasis and Thrombosis, Guy's and St Thomas's NHS Foundation Trust, London, United Kingdom
3   Department of Clinical Biochemistry, Centre for Haemophilia and Thrombosis, Aarhus University Hospital, Skejby, Denmark
4   Department of Cardiothoracic and Vascular Surgery, Aarhus University Hospital, Skejby, Denmark
,
Jonathan H. Foley
1   Haemostasis Research Unit, Centre for Haemostasis and Thrombosis, Guy's and St Thomas's NHS Foundation Trust, London, United Kingdom
2   King's College London School of Medicine, London, United Kingdom
,
Christian Fenger-Eriksen
1   Haemostasis Research Unit, Centre for Haemostasis and Thrombosis, Guy's and St Thomas's NHS Foundation Trust, London, United Kingdom
3   Department of Clinical Biochemistry, Centre for Haemophilia and Thrombosis, Aarhus University Hospital, Skejby, Denmark
5   Department of Anaesthesiology, Aarhus University Hospital, Skejby, Denmark
› Author Affiliations
Further Information

Publication History

Publication Date:
29 March 2012 (online)

    Permissions and Reprints

Abstract

Coagulation factor I (fibrinogen) plays an essential role in the hemostatic system by bridging activated platelets and being the key substrate for thrombin in establishing a consolidating fibrin network. Fibrinogen is synthesized in the liver and the plasma concentration is 1 to 5–4.0 g/L. During recent 10 years, fibrinogen has been recognized to play an important role in controlling hemorrhage. Dilutional coagulopathy induced by colloid plasma expanders is characterized by fibrinogen deficiency and dysfunctional fibrin polymerization. Trauma and use of extracorporeal circulation is also known to reduce levels of fibrinogen. A series of laboratory experiments and experimental animal studies have suggested fibrinogen as a potent hemostatic agent. These data are supported by retrospective surveys as well as a series of prospective proof of principal clinical trials. This article provides a description of the biochemistry and mechanisms of fibrinogen as well as the etiology for developing fibrinogen deficiency. Furthermore, it summarizes laboratory and experimental data on the role of fibrinogen in dilutional coagulopathy and addresses laboratory monitoring issues. Finally, it lists retrospective and prospective studies, which have been designed to assess the clinical efficacy and safety of hemostatic intervention with fibrinogen concentrate.

Keywords

fibrinogen - trauma - cardiac surgery
 

  • References

  • 1 Fenger-Eriksen C, Anker-Møller E, Heslop J, Ingerslev J, Sørensen B. Thrombelastographic whole blood clot formation after ex vivo addition of plasma substitutes: improvements of the induced coagulopathy with fibrinogen concentrate. Br J Anaesth 2005; 94 (3) 324-329
    CrossrefPubMedSearch in Google Scholar
  • 2 Fries D, Krismer A, Klingler A , et al. Effect of fibrinogen on reversal of dilutional coagulopathy: a porcine model. Br J Anaesth 2005; 95 (2) 172-177
    CrossrefPubMedSearch in Google Scholar
  • 3 Weisel JW. Fibrinogen and fibrin. Adv Protein Chem 2005; 70: 247-299
    PubMedSearch in Google Scholar
  • 4 Martini WZ, Chinkes DL, Pusateri AE , et al. Acute changes in fibrinogen metabolism and coagulation after hemorrhage in pigs. Am J Physiol Endocrinol Metab 2005; 289 (5) E930-E934
    CrossrefPubMedSearch in Google Scholar
  • 5 Fries D, Martini WZ. Role of fibrinogen in trauma-induced coagulopathy. Br J Anaesth 2010; 105 (2) 116-121
    CrossrefPubMedSearch in Google Scholar
  • 6 Kozek-Langenecker S, Sørensen B, Hess JR, Spahn DR. Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review. Crit Care 2011; 15 (5) R239
    CrossrefPubMedSearch in Google Scholar
  • 7 O'Shaughnessy DF, Atterbury C, Bolton Maggs P , et al; British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004; 126 (1) 11-28
    CrossrefPubMedSearch in Google Scholar
  • 8 Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion 2006; 46 (8) 1279-1285
    CrossrefPubMedSearch in Google Scholar
  • 9 Chowdary P, Saayman AG, Paulus U, Findlay GP, Collins PW. 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 (1) 69-73
    CrossrefPubMedSearch in Google Scholar
  • 10 Stanworth SJ, Brunskill SJ, Hyde CJ, McClelland DB, Murphy MF. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol 2004; 126 (1) 139-152
    CrossrefPubMedSearch in Google Scholar
  • 11 Hornsey VS, Young DA, Docherty A, Hughes W, Prowse CV. Cryoprecipitate prepared from plasma treated with methylene blue plus light: increasing the fibrinogen concentration. Transfus Med 2004; 14 (5) 369-374
    CrossrefPubMedSearch in Google Scholar
  • 12 Yazer MH, Triulzi DJ, Hassett AC, Kiss JE. Cryoprecipitate prepared from plasma frozen within 24 hours after phlebotomy contains acceptable levels of fibrinogen and VIIIC. Transfusion 2010; 50 (5) 1014-1018
    PubMedSearch in Google Scholar
  • 13 Callum JL, Karkouti K, Lin Y. Cryoprecipitate: the current state of knowledge. Transfus Med Rev 2009; 23 (3) 177-188
    CrossrefPubMedSearch in Google Scholar
  • 14 Bevan DH. Cryoprecipitate: no longer the best therapeutic choice in congenital fibrinogen disorders?. Thromb Res 2009; 124 (Suppl. 02) S12-S16
    CrossrefPubMedSearch in Google Scholar
  • 15 Gröner A. Reply. Pereira A. Cryoprecipitate versus commercial fibrinogen concentrate in patients who occasionally require a therapeutic supply of fibrinogen: risk comparison in the case of an emerging transfusion-transmitted infection. Haematologica 2007;92:846-9. Haematologica 2008; 93 (2) e24-e26 , author reply e27
    CrossrefPubMedSearch in Google Scholar
  • 16 Rahe-Meyer N, Solomon C, Winterhalter M , et al. Thromboelastometry-guided administration of fibrinogen concentrate for the treatment of excessive intraoperative bleeding in thoracoabdominal aortic aneurysm surgery. J Thorac Cardiovasc Surg 2009; 138 (3) 694-702
    CrossrefPubMedSearch in Google Scholar
  • 17 Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 2006; 60 (6, Suppl) S3-S11
    CrossrefPubMedSearch in Google Scholar
  • 18 Dirkmann D, Hanke AA, Görlinger K, Peters J. Hypothermia and acidosis synergistically impair coagulation in human whole blood. Anesth Analg 2008; 106 (6) 1627-1632
    CrossrefPubMedSearch in Google Scholar
  • 19 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
    CrossrefPubMedSearch in Google Scholar
  • 20 Karkouti K, Wijeysundera DN, Yau TM , et al. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion 2004; 44 (10) 1453-1462
    CrossrefPubMedSearch in Google Scholar
  • 21 Ranucci M, Bozzetti G, Ditta A, Cotza M, Carboni G, Ballotta A. Surgical reexploration after cardiac operations: why a worse outcome?. Ann Thorac Surg 2008; 86 (5) 1557-1562
    CrossrefPubMedSearch in Google Scholar
  • 22 Solomon C, Rahe-Meyer N, Sørensen B. Fibrin formation is more impaired than thrombin generation and platelets immediately following cardiac surgery. Thromb Res 2011; 128 (3) 277-282
    CrossrefPubMedSearch in Google Scholar
  • 23 Tang M., Wierup P, Christiansen K, Greisen J, Sorensen B. Post cardiac coagulopathy; a 48 hours longitudinal descriptive study based on whole blood clot formation and thrombin generation. J Thromb Haemost 2011; 9 (Suppl. 02) 51 (Abstract O-MO-126)
    PubMedSearch in Google Scholar
  • 24 De Cristofaro R, Landolfi R. Measurement of plasma fibrinogen concentration by the prothrombin-time-derived method: applicability and limitations. Blood Coagul Fibrinolysis 1998; 9 (3) 251-259
    CrossrefPubMedSearch in Google Scholar
  • 25 Solomon C, Cadamuro J, Ziegler B , et al. A comparison of fibrinogen measurement methods with fibrin clot elasticity assessed by thromboelastometry, before and after administration of fibrinogen concentrate in cardiac surgery patients. Transfusion 2011; 51 (8) 1695-1706
    CrossrefPubMedSearch in Google Scholar
  • 26 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
    CrossrefPubMedSearch in Google Scholar
  • 27 Rahe-Meyer N, Pichlmaier M, Haverich A , et al. Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study. Br J Anaesth 2009; 102 (6) 785-792
    CrossrefPubMedSearch in Google Scholar
  • 28 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: 2571-2576
    CrossrefPubMedSearch in Google Scholar
  • 29 Lindahl TL, Baghaei F, Blixter IF , et al; Expert Group on Coagulation of the External Quality Assurance in Laboratory Medicine in Sweden. Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost 2011; 105 (2) 371-378
    PubMedSearch in Google Scholar
  • 30 Ariëns RA. Elevated fibrinogen causes thrombosis. Blood 2011; 117 (18) 4687-4688
    CrossrefPubMedSearch in Google Scholar
  • 31 Danesh J, Lewington S, Thompson SG , et al; Fibrinogen Studies Collaboration. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 2005; 294 (14) 1799-1809
    CrossrefPubMedSearch in Google Scholar
  • 32 Van Hylckama Vlieg A, Callas PW, Cushman M, Bertina RM, Rosendaal FR. Inter-relation of coagulation factors and d-dimer levels in healthy individuals. J Thromb Haemost 2003; 1 (3) 516-522
    CrossrefPubMedSearch in Google Scholar
  • 33 Machlus KR, Cardenas JC, Church FC, Wolberg AS. Causal relationship between hyperfibrinogenemia, thrombosis, and resistance to thrombolysis in mice. Blood 2011; 117 (18) 4953-4963
    CrossrefPubMedSearch in Google Scholar
  • 34 Rea CJ, Sorensen B, Ingerslev J, Laursen PN. Fibrinogen: a procoagulant and an anticoagulant. Blood 2011; ; ASH Annual Meeting Abstracts;116:384
    PubMedSearch in Google Scholar
  • 35 de Bosch NB, Mosesson MW, Ruiz-Sáez A, Echenagucia M, Rodriguez-Lemoin A. Inhibition of thrombin generation in plasma by fibrin formation (antithrombin I). Thromb Haemost 2002; 88 (2) 253-258
    PubMedSearch in Google Scholar
  • 36 Weinkove R, Rangarajan S. Fibrinogen concentrate for acquired hypofibrinogenaemic states. Transfus Med 2008; 18 (3) 151-157
    CrossrefPubMedSearch in Google Scholar
  • 37 Thorarinsdottir HR, Sigurbjornsson FT, Hreinsson K, Onundarson PT, Gudbjartsson T, Sigurdsson GH. Effects of fibrinogen concentrate administration during severe hemorrhage. Acta Anaesthesiol Scand 2010; 54 (9) 1077-1082
    CrossrefPubMedSearch in Google Scholar
  • 38 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
    CrossrefPubMedSearch in Google Scholar
  • 39 Danés AF, Cuenca LG, Bueno SR, Mendarte Barrenechea L, Ronsano JB. 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 (3) 221-226
    CrossrefPubMedSearch in Google Scholar
  • 40 Schöchl H, Nienaber U, Hofer G , et al. Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care 2010; 14 (2) R55
    CrossrefPubMedSearch in Google Scholar
  • 41 Stinger HK, Spinella PC, Perkins JG , et al. 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 (2, Suppl) S79-S85 , discussion S85
    CrossrefPubMedSearch in Google Scholar
  • 42 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
    PubMedSearch in Google Scholar
  • 43 Fenger-Eriksen C, Jensen TM, Kristensen BS , et al. Fibrinogen substitution improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: a randomized, placebo-controlled clinical trial. J Thromb Haemost 2009; 7 (5) 795-802
    CrossrefPubMedSearch in Google Scholar
  • 44 Rahe-Meyer N. Fibrinogen concentrate in the treatment of severe bleeding after aortic aneurysm graft surgery. Thromb Res 2011; 128 (Suppl. 01) S17-S19
    CrossrefPubMedSearch in Google Scholar