Semin Thromb Hemost 2020; 46(02): 125-133
DOI: 10.1055/s-0039-1701017
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Platelets and Fibrinogen: Emerging Complexity in Trauma-Induced Coagulopathy

St.
Alexander E. John
1   Department of Emergency Medicine, University of Washington School of Medicine, Seattle, Washington
,
Nathan J. White
1   Department of Emergency Medicine, University of Washington School of Medicine, Seattle, Washington
› Author Affiliations
Further Information

Publication History

Publication Date:
11 March 2020 (online)

Abstract

Trauma induces a change in nearly every observable aspect of hemostasis, generally tipping the balance toward trauma-induced coagulopathy (TIC) and bleeding in the critical early stages. Two particularly important aspects of TIC are platelets and fibrinogen, which are the primary determinants of clot formation and hemostasis. Their loss and dysfunction represent important transition points between coagulopathy phenotypes, highlighting their mechanistic roles in TIC as well as unveiling new potential avenues toward important diagnostic and therapeutic interventions. This review synthesizes current knowledge of platelets and fibrinogen during TIC, with a focus on emerging concepts related to their dysfunction and development of new therapeutic approaches.

 
  • References

  • 1 White NJ, Contaifer Jr D, Martin EJ. , et al. Early hemostatic responses to trauma identified with hierarchical clustering analysis. J Thromb Haemost 2015; 13 (06) 978-988
  • 2 White NJ, Newton JC, Martin EJ. , et al. Clot formation is associated with fibrinogen and platelet forces in a cohort of severely injured emergency department trauma patients. Shock 2015; 44 (Suppl. 01) 39-44
  • 3 Stansbury LG, Hess AS, Thompson K, Kramer B, Scalea TM, Hess JR. The clinical significance of platelet counts in the first 24 hours after severe injury. Transfusion 2013; 53 (04) 783-789
  • 4 Henriksen HH, Grand AG, Viggers S. , et al. Impact of blood products on platelet function in patients with traumatic injuries: a translational study. J Surg Res 2017; 214: 154-161
  • 5 Brown LM, Call MS, Margaret Knudson M. , et al; Trauma Outcomes Group. 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 2011; 71 (02) (Suppl. 03) S337-S342
  • 6 Jacoby RC, Owings JT, Holmes J, Battistella FD, Gosselin RC, Paglieroni TG. Platelet activation and function after trauma. J Trauma 2001; 51 (04) 639-647
  • 7 Kutcher ME, Redick BJ, McCreery RC. , et al. Characterization of platelet dysfunction after trauma. J Trauma Acute Care Surg 2012; 73 (01) 13-19
  • 8 Solomon C, Traintinger S, Ziegler B. , et al. Platelet function following trauma. A multiple electrode aggregometry study. Thromb Haemost 2011; 106 (02) 322-330
  • 9 Sillesen M, Johansson PI, Rasmussen LS. , et al. Platelet activation and dysfunction in a large-animal model of traumatic brain injury and hemorrhage. J Trauma Acute Care Surg 2013; 74 (05) 1252-1259
  • 10 Ramsey MT, Fabian TC, Shahan CP. , et al. A prospective study of platelet function in trauma patients. J Trauma Acute Care Surg 2016; 80 (05) 726-732 , discussion 732–733
  • 11 Wohlauer MV, Moore EE, Thomas S. , et al. Early platelet dysfunction: an unrecognized role in the acute coagulopathy of trauma. J Am Coll Surg 2012; 214 (05) 739-746
  • 12 Pareti FI, Capitanio A, Mannucci L, Ponticelli C, Mannucci PM. Acquired dysfunction due to the circulation of “exhausted” platelets. Am J Med 1980; 69 (02) 235-240
  • 13 Szasz R, Dale GL. COAT platelets. Curr Opin Hematol 2003; 10 (05) 351-355
  • 14 Jobe SM, Leo L, Eastvold JS. , et al. Role of FcRgamma and factor XIIIA in coated platelet formation. Blood 2005; 106 (13) 4146-4151
  • 15 Kholmukhamedov A, Janecke R, Choo HJ, Jobe SM. The mitochondrial calcium uniporter regulates procoagulant platelet formation. J Thromb Haemost 2018; 16 (11) 2315-2321
  • 16 Ogura H, Kawasaki T, Tanaka H. , et al. Activated platelets enhance microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis. J Trauma 2001; 50 (05) 801-809
  • 17 St John AE, Newton JC, Martin EJ. , et al. Platelets retain inducible alpha granule secretion by P-selectin expression but exhibit mechanical dysfunction during trauma-induced coagulopathy. J Thromb Haemost 2019; 17 (05) 771-781
  • 18 Mirramezani M, Herbig BA, Stalker TJ. , et al. Platelet packing density is an independent regulator of the hemostatic response to injury. J Thromb Haemost 2018; 16 (05) 973-983
  • 19 Ting LH, Feghhi S, Taparia N. , et al. Contractile forces in platelet aggregates under microfluidic shear gradients reflect platelet inhibition and bleeding risk. Nat Commun 2019; 10 (01) 1204
  • 20 Lee MY, Verni CC, Herbig BA, Diamond SL. Soluble fibrin causes an acquired platelet glycoprotein VI signaling defect: implications for coagulopathy. J Thromb Haemost 2017; 15 (12) 2396-2407
  • 21 Hayakawa M, Sawamura A, Gando S. , et al. Disseminated intravascular coagulation at an early phase of trauma is associated with consumption coagulopathy and excessive fibrinolysis both by plasmin and neutrophil elastase. Surgery 2011; 149 (02) 221-230
  • 22 Bach-Gansmo ET, Godal HC, Skjønsberg OH. Degradation of fibrinogen and cross-linked fibrin by human neutrophil elastase generates D-like fragments detected by ELISA but not latex D-dimer test. Thromb Res 1998; 92 (03) 125-134
  • 23 Adelman B, Michelson AD, Loscalzo J, Greenberg J, Handin RI. Plasmin effect on platelet glycoprotein Ib-von Willebrand factor interactions. Blood 1985; 65 (01) 32-40
  • 24 Brower MS, Levin RI, Garry K. Human neutrophil elastase modulates platelet function by limited proteolysis of membrane glycoproteins. J Clin Invest 1985; 75 (02) 657-666
  • 25 Wu K, Urano T, Ihara H. , et al. The cleavage and inactivation of plasminogen activator inhibitor type 1 by neutrophil elastase: the evaluation of its physiologic relevance in fibrinolysis. Blood 1995; 86 (03) 1056-1061
  • 26 Bonnefoy A, Legrand C. Proteolysis of subendothelial adhesive glycoproteins (fibronectin, thrombospondin, and von Willebrand factor) by plasmin, leukocyte cathepsin G, and elastase. Thromb Res 2000; 98 (04) 323-332
  • 27 Servia L, Serrano JCE, Pamplona R. , et al. Location-dependent effects of trauma on oxidative stress in humans. PLoS One 2018; 13 (10) e0205519
  • 28 Denk S, Weckbach S, Eisele P. , et al. Role of hemorrhagic shock in experimental polytrauma. Shock 2018; 49 (02) 154-163
  • 29 Rodríguez-Rodríguez A, Egea-Guerrero JJ, Murillo-Cabezas F, Carrillo-Vico A. Oxidative stress in traumatic brain injury. Curr Med Chem 2014; 21 (10) 1201-1211
  • 30 Fu X, Chen J, Gallagher R, Zheng Y, Chung DW, López JA. Shear stress-induced unfolding of VWF accelerates oxidation of key methionine residues in the A1A2A3 region. Blood 2011; 118 (19) 5283-5291
  • 31 Chen J, Fu X, Wang Y. , et al. Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13. Blood 2010; 115 (03) 706-712
  • 32 White NJ, Wang Y, Fu X. , et al. Post-translational oxidative modification of fibrinogen is associated with coagulopathy after traumatic injury. Free Radic Biol Med 2016; 96: 181-189
  • 33 Misztal T, Golaszewska A, Tomasiak-Lozowska MM. , et al. The myeloperoxidase product, hypochlorous acid, reduces thrombus formation under flow and attenuates clot retraction and fibrinolysis in human blood. Free Radic Biol Med 2019; 141: 426-437
  • 34 Misztal T, Rusak T, Brańska-Januszewska J, Ostrowska H, Tomasiak M. Peroxynitrite may affect fibrinolysis via the reduction of platelet-related fibrinolysis resistance and alteration of clot structure. Free Radic Biol Med 2015; 89: 533-547
  • 35 Misztal T, Rusak T, Tomasiak M. Clinically relevant HOCl concentrations reduce clot retraction rate via the inhibition of energy production in platelet mitochondria. Free Radic Res 2014; 48 (12) 1443-1453
  • 36 Misztal T, Rusak T, Tomasiak M. Peroxynitrite may affect clot retraction in human blood through the inhibition of platelet mitochondrial energy production. Thromb Res 2014; 133 (03) 402-411
  • 37 Gregg D, de Carvalho DD, Kovacic H. Integrins and coagulation: a role for ROS/redox signaling?. Antioxid Redox Signal 2004; 6 (04) 757-764
  • 38 Wang Y, Chen J, Ling M, López JA, Chung DW, Fu X. Hypochlorous acid generated by neutrophils inactivates ADAMTS13: an oxidative mechanism for regulating ADAMTS13 proteolytic activity during inflammation. J Biol Chem 2015; 290 (03) 1422-1431
  • 39 Zhao Z, Zhou Y, Hilton T. , et al. Extracellular mitochondria released from traumatized brains induced platelet procoagulant activity. Haematologica 2019 (e-pub ahead of print) Doi: 10.3324/haematol.2018.214932
  • 40 Tian Y, Salsbery B, Wang M. , et al. Brain-derived microparticles induce systemic coagulation in a murine model of traumatic brain injury. Blood 2015; 125 (13) 2151-2159
  • 41 Wu Y, Liu W, Zhou Y. , et al. von Willebrand factor enhances microvesicle-induced vascular leakage and coagulopathy in mice with traumatic brain injury. Blood 2018; 132 (10) 1075-1084
  • 42 Wang L, Wu Q, Fan Z, Xie R, Wang Z, Lu Y. Platelet mitochondrial dysfunction and the correlation with human diseases. Biochem Soc Trans 2017; 45 (06) 1213-1223
  • 43 Atefi G, Aisiku O, Shapiro N. , et al. Complement activation in trauma patients alters platelet function. Shock 2016; 46 (03) (Suppl. 01) 83-88
  • 44 Verni CC, Davila Jr A, Balian S, Sims CA, Diamond SL. Platelet dysfunction during trauma involves diverse signaling pathways and an inhibitory activity in patient-derived plasma. J Trauma Acute Care Surg 2019; 86 (02) 250-259
  • 45 Hartwig JH. Mechanisms of actin rearrangements mediating platelet activation. J Cell Biol 1992; 118 (06) 1421-1442
  • 46 George MJ, Burchfield J, MacFarlane B. , et al. Multiplate and TEG platelet mapping in a population of severely injured trauma patients. Transfus Med 2018; 28 (03) 224-230
  • 47 Li R, Elmongy H, Sims C, Diamond SL. Ex vivo recapitulation of trauma-induced coagulopathy and preliminary assessment of trauma patient platelet function under flow using microfluidic technology. J Trauma Acute Care Surg 2016; 80 (03) 440-449
  • 48 Dzik W. Misunderstanding the PROPPR trial. Transfusion 2017; 57 (08) 2056
  • 49 Holcomb JB, Hess JR. ; PROPPR Study Group. Response to: “Misunderstanding the PROPPR trial.”. Transfusion 2017; 57 (08) 2057-2058
  • 50 McQuilten ZK, Crighton G, Brunskill S. , et al. Optimal dose, timing and ratio of blood products in massive transfusion: results from a systematic review. Transfus Med Rev 2018; 32 (01) 6-15
  • 51 Moore HB, Moore EE, Gonzalez E. Mortality and ratio of blood products used in patients with severe trauma. JAMA 2015; 313 (20) 2077
  • 52 Cardenas JC, Zhang X, Fox EE. , et al; PROPPR Study Group. Platelet transfusions improve hemostasis and survival in a substudy of the prospective, randomized PROPPR trial. Blood Adv 2018; 2 (14) 1696-1704
  • 53 Perkins JG, Cap AP, Spinella PC. , et al. An evaluation of the impact of apheresis platelets used in the setting of massively transfused trauma patients. J Trauma 2009; 66 (4, Suppl): S77-S84 , discussion S84–S85
  • 54 Wu X, Darlington DN, Montgomery RK. , et al. Platelets derived from fresh and cold-stored whole blood participate in clot formation in rats with acute traumatic coagulopathy. Br J Haematol 2017; 179 (05) 802-810
  • 55 Walsh M, Shreve J, Thomas S. The value of cold storage whole blood platelets in trauma resuscitation is like real estate: a function of ‘location, location, location’. Br J Haematol 2017; 179 (05) 699-702
  • 56 Inaba K, Barmparas G, Rhee P. , et al. Dried platelets in a swine model of liver injury. Shock 2014; 41 (05) 429-434
  • 57 Chan V, Sarkari M, Sunderland R, St John AE, White NJ, Kastrup CJ. Platelets loaded with liposome-encapsulated thrombin have increased coagulability. J Thromb Haemost 2018; 16 (06) 1226-1235
  • 58 Caspers M, Schäfer N, Fröhlich M. , et al. Microparticles profiling in trauma patients: high level of microparticles induce activation of platelets in vitro. Eur J Trauma Emerg Surg 2019
  • 59 Dyer MR, Alexander W, Hassoune A. , et al. Platelet-derived extracellular vesicles released after trauma promote hemostasis and contribute to DVT in mice. J Thromb Haemost 2019; 17 (10) 1733-1745
  • 60 Fröhlich M, Schäfer N, Caspers M. , et al. Temporal phenotyping of circulating microparticles after trauma: a prospective cohort study. Scand J Trauma Resusc Emerg Med 2018; 26 (01) 33
  • 61 Windeløv NA, Johansson PI, Sørensen AM. , et al. Low level of procoagulant platelet microparticles is associated with impaired coagulation and transfusion requirements in trauma patients. J Trauma Acute Care Surg 2014; 77 (05) 692-700
  • 62 Park MS, Xue A, Spears GM. , et al. Thrombin generation and procoagulant microparticle profiles after acute trauma: a prospective cohort study. J Trauma Acute Care Surg 2015; 79 (05) 726-731
  • 63 Miyazawa B, Trivedi A, Togarrati PP. , et al. Regulation of endothelial cell permeability by platelet-derived extracellular vesicles. J Trauma Acute Care Surg 2019 (e-pub ahead of print) Doi: 10.1097/TA.0000000000002230
  • 64 Zhou Y, Cai W, Zhao Z. , et al. Lactadherin promotes microvesicle clearance to prevent coagulopathy and improves survival of severe TBI mice. Blood 2018; 131 (05) 563-572
  • 65 Nandi S, Brown AC. Platelet-mimetic strategies for modulating the wound environment and inflammatory responses. Exp Biol Med (Maywood) 2016; 241 (10) 1138-1148
  • 66 Nandi S, Sproul EP, Nellenbach K. , et al. Platelet-like particles dynamically stiffen fibrin matrices and improve wound healing outcomes. Biomater Sci 2019; 7 (02) 669-682
  • 67 Welsch N, Brown AC, Barker TH, Lyon LA. Enhancing clot properties through fibrin-specific self-cross-linked PEG side-chain microgels. Colloids Surf B Biointerfaces 2018; 166: 89-97
  • 68 Shukla M, Sekhon UD, Betapudi V. , et al. In vitro characterization of SynthoPlate™ (synthetic platelet) technology and its in vivo evaluation in severely thrombocytopenic mice. J Thromb Haemost 2017; 15 (02) 375-387
  • 69 Anselmo AC, Modery-Pawlowski CL, Menegatti S. , et al. Platelet-like nanoparticles: mimicking shape, flexibility, and surface biology of platelets to target vascular injuries. ACS Nano 2014; 8 (11) 11243-11253
  • 70 Ravikumar M, Modery CL, Wong TL, Gupta AS. Peptide-decorated liposomes promote arrest and aggregation of activated platelets under flow on vascular injury relevant protein surfaces in vitro. Biomacromolecules 2012; 13 (05) 1495-1502
  • 71 Hickman DA, Pawlowski CL, Shevitz A. , et al. Intravenous synthetic platelet (SynthoPlate) nanoconstructs reduce bleeding and improve ‘golden hour’ survival in a porcine model of traumatic arterial hemorrhage. Sci Rep 2018; 8 (01) 3118
  • 72 Girish A, Hickman DA, Banerjee A. , et al. Trauma-targeted delivery of tranexamic acid improves hemostasis and survival in rat liver hemorrhage model. J Thromb Haemost 2019; 17 (10) 1632-1644
  • 73 Dyer MR, Hickman D, Luc N. , et al. Intravenous administration of synthetic platelets (SynthoPlate) in a mouse liver injury model of uncontrolled hemorrhage improves hemostasis. J Trauma Acute Care Surg 2018; 84 (06) 917-923
  • 74 Hayakawa M, Gando S, Ono Y, Wada T, Yanagida Y, Sawamura A. Fibrinogen level deteriorates before other routine coagulation parameters and massive transfusion in the early phase of severe trauma: a retrospective observational study. Semin Thromb Hemost 2015; 41 (01) 35-42
  • 75 Hagemo JS, Stanworth S, Juffermans NP. , et al. Prevalence, predictors and outcome of hypofibrinogenaemia in trauma: a multicentre observational study. Crit Care 2014; 18 (02) R52
  • 76 McQuilten ZK, Wood EM, Bailey M, Cameron PA, Cooper DJ. Fibrinogen is an independent predictor of mortality in major trauma patients: a five-year statewide cohort study. Injury 2017; 48 (05) 1074-1081
  • 77 Nakamura Y, Ishikura H, Kushimoto S. , et al. Fibrinogen level on admission is a predictor for massive transfusion in patients with severe blunt trauma: analyses of a retrospective multicentre observational study. Injury 2017; 48 (03) 674-679
  • 78 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 (07) 1342-1351
  • 79 Bouzat P, Ageron FX, Charbit J. , et al. Modelling the association between fibrinogen concentration on admission and mortality in patients with massive transfusion after severe trauma: an analysis of a large regional database. Scand J Trauma Resusc Emerg Med 2018; 26 (01) 55
  • 80 Singbartl K, Innerhofer P, Radvan J. , et al. Hemostasis and hemodilution: a quantitative mathematical guide for clinical practice. Anesth Analg 2003; 96 (04) 929-935
  • 81 Hiippala ST, Myllylä GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg 1995; 81 (02) 360-365
  • 82 Dempfle CE, Kälsch T, Elmas E. , et al. Impact of fibrinogen concentration in severely ill patients on mechanical properties of whole blood clots. Blood Coagul Fibrinolysis 2008; 19 (08) 765-770
  • 83 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
  • 84 Harr JN, Moore EE, Ghasabyan A. , et al. Functional fibrinogen assay indicates that fibrinogen is critical in correcting abnormal clot strength following trauma. Shock 2013; 39 (01) 45-49
  • 85 Peng HT, Nascimento B, Beckett A. Thromboelastography and thromboelastometry in assessment of fibrinogen deficiency and prediction for transfusion requirement: a descriptive review. BioMed Res Int 2018; 2018: 7020539
  • 86 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
  • 87 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 (05) E930-E934
  • 88 Martini WZ, Chung KK, Dubick MA. Differential changes in hepatic synthesis of albumin and fibrinogen after severe hemorrhagic shock in pigs. Shock 2014; 41 (01) 67-71
  • 89 Martini WZ, Holcomb JB. Acidosis and coagulopathy: the differential effects on fibrinogen synthesis and breakdown in pigs. Ann Surg 2007; 246 (05) 831-835
  • 90 Martini WZ. The effects of hypothermia on fibrinogen metabolism and coagulation function in swine. Metabolism 2007; 56 (02) 214-221
  • 91 Ishikawa K, Omori K, Jitsuiki K. , et al. Clinical significance of fibrinogen degradation product among traumatized patients. Air Med J 2017; 36 (02) 59-61
  • 92 Lee DH, Lee BK, Noh SM, Cho YS. High fibrin/fibrinogen degradation product to fibrinogen ratio is associated with 28-day mortality and massive transfusion in severe trauma. Eur J Trauma Emerg Surg 2018; 44 (02) 291-298
  • 93 Chapman MP, Moore EE, Moore HB. , et al. Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients. J Trauma Acute Care Surg 2016; 80 (01) 16-23 , discussion 23–25
  • 94 Nussenzweig V, Seligmann M, Pelmont J, Grabar P. The products of degradation of human fibrinogen by plasmin. I. Separation and physicochemical properties [in French]. Ann Inst Pasteur (Paris) 1961; 100: 377-389
  • 95 Schaefer AV, Leslie BA, Rischke JA, Stafford AR, Fredenburgh JC, Weitz JI. Incorporation of fragment X into fibrin clots renders them more susceptible to lysis by plasmin. Biochemistry 2006; 45 (13) 4257-4265
  • 96 Suenson E, Bjerrum P, Holm A. , et al. The role of fragment X polymers in the fibrin enhancement of tissue plasminogen activator-catalyzed plasmin formation. J Biol Chem 1990; 265 (36) 22228-22237
  • 97 Shacter E, Williams JA, Lim M, Levine RL. Differential susceptibility of plasma proteins to oxidative modification: examination by western blot immunoassay. Free Radic Biol Med 1994; 17 (05) 429-437
  • 98 Martinez M, Weisel JW, Ischiropoulos H. Functional impact of oxidative posttranslational modifications on fibrinogen and fibrin clots. Free Radic Biol Med 2013; 65: 411-418
  • 99 Vadseth C, Souza JM, Thomson L. , et al. Pro-thrombotic state induced by post-translational modification of fibrinogen by reactive nitrogen species. J Biol Chem 2004; 279 (10) 8820-8826
  • 100 Pignatelli B, Li CQ, Boffetta P. , et al. Nitrated and oxidized plasma proteins in smokers and lung cancer patients. Cancer Res 2001; 61 (02) 778-784
  • 101 Inada Y, Hessel B, Blombäck B. Photooxidation of fibrinogen in the presence of methylene blue and its effect on polymerization. Biochim Biophys Acta 1978; 532 (01) 161-170
  • 102 Weigandt KM, White N, Chung D. , et al. Fibrin clot structure and mechanics associated with specific oxidation of methionine residues in fibrinogen. Biophys J 2012; 103 (11) 2399-2407
  • 103 Burney PR, White N, Pfaendtner J. Structural effects of methionine oxidation on isolated subdomains of human fibrin D and αC regions. PLoS One 2014; 9 (01) e86981
  • 104 Iwamoto M. Plasminogen-plasmin system IX. Specific binding of tranexamic acid to plasmin. Thromb Diath Haemorrh 1975; 33 (03) 573-585
  • 105 Markus G, Priore RL, Wissler FC. The binding of tranexamic acid to native (Glu) and modified (Lys) human plasminogen and its effect on conformation. J Biol Chem 1979; 254 (04) 1211-1216
  • 106 Alkjaersig N, Fletcher AP, Sherry S. xi-Aminocaproic acid: an inhibitor of plasminogen activation. J Biol Chem 1959; 234 (04) 832-837
  • 107 Shakur H, Roberts I, Bautista R. , et al; CRASH-2 trial collaborators. 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 (9734): 23-32
  • 108 Anonick PK, Vasudevan J, Gonias SL. Antifibrinolytic activities of alpha-N-acetyl-L-lysine methyl ester, epsilon-aminocaproic acid, and tranexamic acid. Importance of kringle interactions and active site inhibition. Arterioscler Thromb 1992; 12 (06) 708-716
  • 109 Steinmetz J, Sørensen AM, Henriksen HH. , et al. Pilot Randomized trial of Fibrinogen in Trauma Haemorrhage (PRooF-iTH): study protocol for a randomized controlled trial. Trials 2016; 17 (01) 327
  • 110 Nascimento B, Callum J, Tien H. , et al. Fibrinogen in the initial resuscitation of severe trauma (FiiRST): a randomized feasibility trial. Br J Anaesth 2016; 117 (06) 775-782
  • 111 Winearls J, Wullschleger M, Wake E. , et al. Fibrinogen Early In Severe Trauma studY (FEISTY): study protocol for a randomised controlled trial. Trials 2017; 18 (01) 241
  • 112 Zentai C, Solomon C, van der Meijden PE. , et al. Effects of fibrinogen concentrate on thrombin generation, thromboelastometry parameters, and laboratory coagulation testing in a 24-hour porcine trauma model. Clin Appl Thromb Hemost 2016; 22 (08) 749-759
  • 113 Fries D, Krismer A, Klingler A. , et al. Effect of fibrinogen on reversal of dilutional coagulopathy: a porcine model. Br J Anaesth 2005; 95 (02) 172-177
  • 114 White NJ, Wang X, Liles C, Stern S. Fibrinogen concentrate improves survival during limited resuscitation of uncontrolled hemorrhagic shock in a Swine model. Shock 2014; 42 (05) 456-463
  • 115 Schlimp CJ, Ponschab M, Voelckel W, Treichl B, Maegele M, Schöchl H. Fibrinogen levels in trauma patients during the first seven days after fibrinogen concentrate therapy: a retrospective study. Scand J Trauma Resusc Emerg Med 2016; 24: 29
  • 116 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 (02) 290-297
  • 117 Curry N, Rourke C, Davenport R. , et al. Early cryoprecipitate for major haemorrhage in trauma: a randomised controlled feasibility trial. Br J Anaesth 2015; 115 (01) 76-83
  • 118 Curry N, Foley C, Wong H. , et al. Early fibrinogen concentrate therapy for major haemorrhage in trauma (E-FIT 1): results from a UK multi-centre, randomised, double blind, placebo-controlled pilot trial. Crit Care 2018; 22 (01) 164
  • 119 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
  • 120 Spahn DR, Bouillon B, Cerny V. , et al. The European guideline on management of major bleeding and coagulopathy following trauma: fifth edition. Crit Care 2019; 23 (01) 98