Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre observational study

Jostein S Hagemo, Simon Stanworth, Nicole P Juffermans, Karim Brohi, Mitchell Cohen, Pär I Johansson, Jo Røislien, Torsten Eken, Paal A Næss, Christine Gaarder, Jostein S Hagemo, Simon Stanworth, Nicole P Juffermans, Karim Brohi, Mitchell Cohen, Pär I Johansson, Jo Røislien, Torsten Eken, Paal A Næss, Christine Gaarder

Abstract

Introduction: Exsanguination due to trauma-induced coagulopathy is a continuing challenge in emergency trauma care. Fibrinogen is a crucial factor for haemostatic competence, and may be the factor that reaches critically low levels first. Early fibrinogen substitution is advocated by a number of authors. Little evidence exists regarding the indications for fibrinogen supplementation in the acute phase. This study aims to estimate the prevalence of hypofibrinogenaemia in a multi-center trauma population, and to explore how initial fibrinogen concentration relates to outcome. Also, factors contributing to low fibrinogen levels are identified.

Methods: Patients arriving in hospital less than 180 minutes post-injury requiring full trauma team activation in four different centers were included in the study. Time from injury, patient demographics, injury severity scores (ISS) and 28 days outcome status were recorded. Initial blood samples for coagulation and blood gas were analyzed. Generalized additive regression, piecewise linear regression, and multiple linear regression models were used for data analyses.

Results: Out of 1,133 patients we identified a fibrinogen concentration ≤1.5g/L in 8.2%, and <2 g/L in 19.2%. A non-linear relationship between fibrinogen concentration and mortality was detected in the generalized additive and piecewise linear regression models. In the piecewise linear regression model we identified a breakpoint for optimal fibrinogen concentration at 2.29 g/L (95% confidence interval (CI): 1.93 to 2.64). Below this value the odds of death by 28 days was reduced by a factor of 0.08 (95% CI: 0.03 to 0.20) for every unit increase in fibrinogen concentration. Low age, male gender, lengthened time from injury, low base excess and high ISS were unique contributors to low fibrinogen concentrations on arrival.

Conclusions: Hypofibrinogenaemia is common in trauma and strongly associated with poor outcome. Below an estimated critical fibrinogen concentration value of 2.29 g/L a dramatic increase in mortality was detected. This finding indicates that the negative impact of low fibrinogen concentrations may have been previously underestimated. A number of clinically identifiable factors are associated with hypofibrinogenaemia. They should be considered in the management of massively bleeding patients. Interventional trials with fibrinogen substitution in high-risk patients need to be undertaken.

Figures

Figure 1
Figure 1
Multivariable generalised additive model and piecewise linear model for relationship between fibrinogen concentration and 28-day survival. Results from the multivariable generalised additive model (GAM) and the piecewise linear model for the relationship between fibrinogen concentration and 28-day survival, adjusted for Injury Severity Score, age, time from injury, mechanism of injury, base excess, International Normalized Ratio, platelet count and gender. The functional relationship is clearly nonlinear (a), resulting in a corresponding nonconstant odds ratio across the observed range of fibrinogen values (b). For the piecewise linear model, the breakpoint (95% confidence interval (CI)) is estimated at 2.29 (1.93, 2.64).

References

    1. Sauaia A, Moore FA, Moore EE, Moser KS, Brennan R, Read RA, Pons PT. Epidemiology of trauma deaths: a reassessment. J Trauma Injury Infect Crit Care. 1995;38:185–193. doi: 10.1097/00005373-199502000-00006.
    1. Groven S, Eken T, Skaga NO, Røise O, Naess PA, Gaarder C. Long-lasting performance improvement after formalization of a dedicated trauma service. J Trauma. 2011;70:569–574. doi: 10.1097/TA.0b013e31820d1a9b.
    1. Brohi K, Cohen MJ, Davenport RA. Acute coagulopathy of trauma: mechanism, identification and effect. Curr Opin Crit Care. 2007;13:680–685. doi: 10.1097/MCC.0b013e3282f1e78f.
    1. Mosesson MW. Fibrinogen and fibrin structure and functions. J Thromb Haemost. 2005;3:1894–1904. doi: 10.1111/j.1538-7836.2005.01365.x.
    1. Martini WZ. The effects of hypothermia on fibrinogen metabolism and coagulation function in swine. Metab Clin Exp. 2007;56:214–221. doi: 10.1016/j.metabol.2006.09.015.
    1. Martini WZ. Acute changes in fibrinogen metabolism and coagulation after hemorrhage in pigs. AJP Endocrinol Metab. 2005;289:E930–E934. doi: 10.1152/ajpendo.00137.2005.
    1. Fries D, Martini WZ. Role of fibrinogen in trauma-induced coagulopathy. Br J Anaesth. 2010;105:116–121. doi: 10.1093/bja/aeq161.
    1. Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, Pittet JF. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma Injury Infect Crit Care. 2008;64:1211–1217. doi: 10.1097/TA.0b013e318169cd3c.
    1. Cohen MJ, Call M, Nelson M, Calfee CS, Esmon CT, Brohi K, Pittet JF. Critical role of activated protein C in early coagulopathy and later organ failure, infection and death in trauma patients. Ann Surg. 2012;255:379–385. doi: 10.1097/SLA.0b013e318235d9e6.
    1. Levy JH, Szlam F, Tanaka KA, Sniecienski RM. Fibrinogen and hemostasis. Anesth Analg. 2012;114:261–274. doi: 10.1213/ANE.0b013e31822e1853.
    1. Stanworth SJ, Hunt BJ. The desperate need for good-quality clinical trials to evaluate the optimal source and dose of fibrinogen in managing bleeding. Crit Care. 2011;15:1006. doi: 10.1186/cc10510.
    1. Tisherman SA. Is fibrinogen the answer to coagulopathy after massive transfusions? Crit Care. 2010;14:154. doi: 10.1186/cc9000.
    1. Schöchl H, Maegele M, Solomon C, Görlinger K, Voelckel W. Early and individualized goal-directed therapy for trauma-induced coagulopathy. Scand J Trauma Resusc Emerg Med. 2012;20:15. doi: 10.1186/1757-7241-20-15.
    1. Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernández-Mondéjar E, Filipescu D, Hunt B, Komadina R, Nardi G, Neugebauer E, Ozier Y, Riddez L, Schultz A, Vincent JL, Rossaint R. Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care. 2013;17:R76. doi: 10.1186/cc12685.
    1. Fries D. The early use of fibrinogen, prothrombin complex concentrate, and recombinant-activated factor VIIa in massive bleeding. Transfusion. 2013;53:91S–95S.
    1. Schöchl H, Cotton B, Inaba K, Nienaber U, Fischer H, Voelckel W, Solomon C. FIBTEM provides early prediction of massive transfusion in trauma. Crit Care. 2011;15:R265. doi: 10.1186/cc10539.
    1. Brohi K, Singh J, Heron M, Coats T. Acute traumatic coagulopathy. J Trauma Injury Infect Crit Care. 2003;54:1127–1130. doi: 10.1097/01.TA.0000069184.82147.06.
    1. Rixen D, Siegel JH. Bench-to-bedside review: oxygen debt and its metabolic correlates as quantifiers of the severity of hemorrhagic and post-traumatic shock. Crit Care. 2005;9:441–453. doi: 10.1186/cc3526.
    1. Hess JR, Lindell AL, Stansbury LG, Dutton RP, Scalea TM. The prevalence of abnormal results of conventional coagulation tests on admission to a trauma center. Transfusion. 2009;49:34–39. doi: 10.1111/j.1537-2995.2008.01944.x.
    1. Muggeo VMR. Estimating regression models with unknown break-points. Stat Med. 2003;22:3055–3071. doi: 10.1002/sim.1545.
    1. Wood SN. Generalized Additive Models: An Introduction with R. Boca Raton, FL: Chapman & Hall/CRC; 2006.
    1. Akaike H. A new look at the statistical model identification. Automat Contr. 1974;19:716–723. doi: 10.1109/TAC.1974.1100705.
    1. Rourke C, Curry N, Khan S, Taylor R, Raza I, Davenport R, Stanworth S, Brohi K. Fibrinogen levels during trauma hemorrhage, response to replacement therapy, and association with patient outcomes. J Thromb Haemost. 2012;10:1342–1351. doi: 10.1111/j.1538-7836.2012.04752.x.
    1. Sørensen B, Larsen O, Rea C, Tang M, Foley J, Fenger-Eriksen C. Fibrinogen as a hemostatic agent. Semin Thromb Hemost. 2012;38:268–273.
    1. Karlsson M, Ternström 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;102:137–144.
    1. Schultz DR, Arnold PI. Properties of four acute phase proteins: C-reactive protein, serum amyloid A protein, alpha 1-acid glycoprotein, and fibrinogen. Semin Arthritis Rheum. 1990;20:129–147. doi: 10.1016/0049-0172(90)90055-K.
    1. Corrado E, Rizzo M, Coppola G, Fattouch K, Novo G, Marturana I, Ferrara F, Novo S. An update on the role of markers of inflammation in atherosclerosis. J Atheroscler Thromb. 2010;17:1–11. doi: 10.5551/jat.2600.
    1. Champion HR, Copes WS, Sacco WJ, Lawnick MM, Bain LW, Gann DS, Gennarelli T, Mackenzie E, Schwaitzberg S. A new characterization of injury severity. J Trauma Injury Infect Crit Care. 1990;30:539–545. doi: 10.1097/00005373-199005000-00003. discussion 545–546.
    1. MacLeod JBA, Lynn M, McKenney MG, Cohn SM, Murtha M. Early coagulopathy predicts mortality in trauma. J Trauma Injury Infect Crit Care. 2003;55:39–44. doi: 10.1097/01.TA.0000075338.21177.EF.
    1. Brown LM, Call MS, Margaret Knudson M, Cohen MJ. A normal platelet count may not be enough: the impact of admission platelet count on mortality and transfusion in severely injured trauma patients. J Trauma Injury Infect Crit Care. 2011;71:S337–S342.
    1. Holcomb JB, Zarzabal LA, Michalek JE, Kozar RA, Spinella PC, Perkins JG, Matijevic N, Dong JF, Pati S, Wade CE. Increased platelet:RBC ratios are associated with improved survival after massive transfusion. J Trauma Injury Infect Crit Care. 2011;71:S318–S328.
    1. Wohlauer MV, Moore EE, Thomas S, Sauaia A, Evans E, Harr J, Silliman CC, Ploplis V, Castellino FJ, Walsh M. Early platelet dysfunction: an unrecognized role in the acute coagulopathy of trauma. ACS. J Am Coll Surg. 2012;214:739–746. doi: 10.1016/j.jamcollsurg.2012.01.050.
    1. Martini WZ, Holcomb JB. Acidosis and coagulopathy: the differential effects on fibrinogen synthesis and breakdown in pigs. Ann Surg. 2007;246:831–835. doi: 10.1097/SLA.0b013e3180cc2e94.
    1. Amin H, Mohsin S, Aslam M, Hussain S, Saeed T, Ullah MI, Sami W. Coagulation factors and antithrombin levels in young and elderly subjects in Pakistani population. Blood Coagul Fibrinolysis. 2012;23:745–750. doi: 10.1097/MBC.0b013e328358e913.
    1. Husebye EE, Lyberg T, Opdahl H, Aspelin T, Støen RØ, Madsen JE, Røise O. Intramedullary nailing of femoral shaft fractures in polytraumatized patients. A longitudinal, prospective and observational study of the procedure-related impact on cardiopulmonary- and inflammatory responses. Scand J Trauma Resusc Emerg Med. 2012;20:2. doi: 10.1186/1757-7241-20-2.
    1. Dahl OE, Johnsen H, Kierulf P, Molnar I, Rø JS, Vinje A, Pape HC, Schmidt RE, Rice J, van Griensven M, das Gupta R, Krettek C, Tscherne H. Biochemical changes after trauma and skeletal surgery of the lower extremity: quantification of the operative burden. Crit Care Med. 2000;28:3441–3448. doi: 10.1097/00003246-200010000-00012.
    1. Wozasek GE, Simon P, Redl H, Schlag G. Intramedullary pressure changes and fat intravasation during intramedullary nailing: an experimental study in sheep. J Trauma Injury Infect Crit Care. 1994;36:202–207. doi: 10.1097/00005373-199402000-00010.
    1. Dahl OE, Johnsen H, Kierulf P, Molnar I, Rø JS, Vinje A, Mowinckel P. Intrapulmonary thrombin generation and its relation to monomethylmethacrylate plasma levels during hip arthroplasty. Acta Anaesthesiol Scand. 1992;36:331–335. doi: 10.1111/j.1399-6576.1992.tb03477.x.
    1. Dahl OE, Pedersen T, Kierulf P, Westvik AB, Lund P, Arnesen H, Seljeflot I, Abdelnoor M, Lyberg T. Sequential intrapulmonary and systemic activation of coagulation and fibrinolysis during and after total hip replacement surgery. Thromb Res. 1993;70:451–458. doi: 10.1016/0049-3848(93)90087-5.
    1. Hiippala ST. Dextran and hydroxyethyl starch interfere with fibrinogen assays. Blood Coagul Fibrinolysis. 1995;6:743–746. doi: 10.1097/00001721-199512000-00008.

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