Extended Coagulation Profiling in Isolated Traumatic Brain Injury: A CENTER-TBI Analysis

Schaeben, V.; Schafer, N.; Guting, H.; Lefering, R.; Thorn, S.; Schochl, H.; Zipperle, J.; Grottke, O.; Rossaint, R.; Stanworth, S.; Curry, N.; Maegele, M.; Akerlund, C.; Amrein, K.; Andelic, N.; Andreassen, L.; Anke, A.; Antoni, A.; Audibert, G.; Azouvi, P.; Azzolini, M.L.; Bartels, R.; Barzo, P.; Beauvais, R.; Beer, R.; Bellander, B.-.; Belli, A.; Benali, H.; Berardino, M.; Beretta, L.; Blaabjerg, M.; Bragge, P.; Brazinova, A.; Brinck, V.; Brooker, J.; Brorsson, C.; Buki, A.; Bullinger, M.; Cabeleira, M.; Caccioppola, A.; Calappi, E.; Calvi, M.R.; Cameron, P.; Lozano, G.C.; Carbonara, M.; Cavallo, S.; Chevallard, G.; Chieregato, A.; Citerio, G.; Ceyisakar, I.; Clusmann, H.; Coburn, M.; Coles, J.; Cooper, J.D.; Correia, M.; Covic, A.; Czeiter, E.; Czosnyka, M.; Dahyot-Fizelier, C.; Dark, P.; Dawes, H.; De Keyser, V.; Degos, V.; Della Corte, F.D.; Boogert, H.D.; Depreitere, B.; Dilvesi, D.; Dixit, A.; Donoghue, E.; Dreier, J.; Duliere, G.-.; Ercole, A.; Esser, P.; Ezer, E.; Fabricius, M.; Feigin, V.L.; Foks, K.; Frisvold, S.; Furmanov, A.; Gagliardo, P.; Galanaud, D.; Gantner, D.; Gao, G.; George, P.; Ghuysen, A.; Giga, L.; Glocker, B.; Golubovic, J.; Gomez, P.A.; Gratz, J.; Gravesteijn, B.; Grossi, F.; Gruen, R.L.; Gupta, D.; Haagsma, J.A.; Haitsma, I.; Helbok, R.; Helseth, E.; Horton, L.; Huijben, J.; Hutchinson, P.J.; Jacobs, B.; Jankowski, S.; Jarrett, M.; Jiang, J.-.; Johnson, F.; Jones, K.; Karan, M.; Kolias, A.G.; Kompanje, E.; Kondziella, D.; Koraropoulos, E.; Koskinen, L.-.; Kovacs, N.; Kowark, A.; Lagares, A.; Lanyon, L.; Laureys, S.; Lecky, F.; Ledoux, D.; Legrand, V.; Lejeune, A.; Levi, L.; Lightfoot, R.; Lingsma, H.; Maas, A.I.R.; Castano-Leon, A.M.; Majdan, M.; Manara, A.; Manley, G.; Martino, C.; Marechal, H.; Mattern, J.; Mcmahon, C.; Melegh, B.; Menon, D.; Menovsky, T.; Mikolic, A.; Misset, B.; Muraleedharan, V.; Murray, L.; Negru, A.; Nelson, D.; Newcombe, V.; Nieboer, D.; Nyiradi, J.; Olubukola, O.; Oresic, M.; Ortolano, F.; Palotie, A.; Parizel, P.M.; Payen, J.-.; Perera, N.; Perlbarg, V.; Persona, P.; Peul, W.; Piippo-Karjalainen, A.; Pirinen, M.; Ples, H.; Polinder, S.; Pomposo, I.; Posti, J.P.; Puybasset, L.; Radoi, A.; Ragauskas, A.; Raj, R.; Rambadagalla, M.; Rhodes, J.; Richardson, S.; Richter, S.; Ripatti, S.; Rocka, S.; Roe, C.; Roise, O.; Rosand, J.; Rosenfeld, J.V.; Rosenlund, C.; Rosenthal, G.; Rossi, S.; Rueckert, D.; Rusnak, M.; Sahuquillo, J.; Sakowitz, O.; Sanchez-Porras, R.; Sandor, J.; Schmidt, S.; Schoechl, H.; Schoonman, G.; Schou, R.F.; Schwendenwein, E.; Sewalt, C.; Skandsen, T.; Smielewski, P.; Sorinola, A.; Stamatakis, E.; Stevens, R.; Stewart, W.; Steyerberg, E.W.; Stocchetti, N.; Sundstrom, N.; Synnot, A.; Takala, R.; Tamas, V.; Tamosuitis, T.; Taylor, M.S.; B. T., A.; Tenovuo, O.; Theadom, A.; Thomas, M.; Tibboel, D.; Timmers, M.; Tolias, C.; Trapani, T.; Tudora, C.M.; Unterberg, A.; Vajkoczy, P.; Vallance, S.; Valeinis, E.; Vamos, Z.; Van Der Jagt, M.; Van Der Steen, G.; Van Der Naalt, J.; Van Dijck, J.T.J.M.; Van Essen, T.A.; Van Hecke, W.; Van Heugten, C.; Van Praag, D.; Vande Vyvere, T.; Van Wijk, R.J.; Vargiolu, A.; Vega, E.; Velt, K.; Verheyden, J.; Vespa, P.M.; Vik, A.; Vilcinis, R.; Volovici, V.; Von Steinbuchel, N.; Voormolen, D.; Vulekovic, P.; Wang, K.K.W.; Wiegers, E.; Williams, G.; Wilson, L.; Winzeck, S.; Wolf, S.; Yang, Z.; Ylen, P.; Younsi, A.; Zeiler, F.A.; Zelinkova, V.; Ziverte, A.; Zoerle, T.

doi:10.1007/s12028-021-01400-3

Background: Trauma-induced coagulopathy in traumatic brain injury (TBI) remains associated with high rates of complications, unfavorable outcomes, and mortality. The underlying mechanisms are largely unknown. Embedded in the prospective multinational Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, coagulation profiles beyond standard conventional coagulation assays were assessed in patients with isolated TBI within the very early hours of injury. Methods: Results from blood samples (citrate/EDTA) obtained on hospital admission were matched with clinical and routine laboratory data of patients with TBI captured in the CENTER-TBI central database. To minimize confounding factors, patients with strictly isolated TBI (iTBI) (n = 88) were selected and stratified for coagulopathy by routine international normalized ratio (INR): (1) INR < 1.2 and (2) INR ≥ 1.2. An INR > 1.2 has been well adopted over time as a threshold to define trauma-related coagulopathy in general trauma populations. The following parameters were evaluated: quick’s value, activated partial thromboplastin time, fibrinogen, thrombin time, antithrombin, coagulation factor activity of factors V, VIII, IX, and XIII, protein C and S, plasminogen, D-dimer, fibrinolysis-regulating parameters (thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor 1, antiplasmin), thrombin generation, and fibrin monomers. Results: Patients with iTBI with INR ≥ 1.2 (n = 16) had a high incidence of progressive intracranial hemorrhage associated with increased mortality and unfavorable outcome compared with patients with INR < 1.2 (n = 72). Activity of coagulation factors V, VIII, IX, and XIII dropped on average by 15–20% between the groups whereas protein C and S levels dropped by 20%. With an elevated INR, thrombin generation decreased, as reflected by lower peak height and endogenous thrombin potential (ETP), whereas the amount of fibrin monomers increased. Plasminogen activity significantly decreased from 89% in patients with INR < 1.2 to 76% in patients with INR ≥ 1.2. Moreover, D-dimer levels significantly increased from a mean of 943 mg/L in patients with INR < 1.2 to 1,301 mg/L in patients with INR ≥ 1.2. Conclusions: This more in-depth analysis beyond routine conventional coagulation assays suggests a counterbalanced regulation of coagulation and fibrinolysis in patients with iTBI with hemostatic abnormalities. We observed distinct patterns involving key pathways of the highly complex and dynamic coagulation system that offer windows of opportunity for further research. Whether the changes observed on factor levels may be relevant and explain the worse outcome or the more severe brain injuries by themselves remains speculative.

Extended Coagulation Profiling in Isolated Traumatic Brain Injury: A CENTER-TBI Analysis / V. Schaeben, N. Schafer, H. Guting, R. Lefering, S. Thorn, H. Schochl, J. Zipperle, O. Grottke, R. Rossaint, S. Stanworth, N. Curry, M. Maegele, C. Akerlund, K. Amrein, N. Andelic, L. Andreassen, A. Anke, A. Antoni, G. Audibert, P. Azouvi, M.L. Azzolini, R. Bartels, P. Barzo, R. Beauvais, R. Beer, B.-. Bellander, A. Belli, H. Benali, M. Berardino, L. Beretta, M. Blaabjerg, P. Bragge, A. Brazinova, V. Brinck, J. Brooker, C. Brorsson, A. Buki, M. Bullinger, M. Cabeleira, A. Caccioppola, E. Calappi, M.R. Calvi, P. Cameron, G.C. Lozano, M. Carbonara, S. Cavallo, G. Chevallard, A. Chieregato, G. Citerio, I. Ceyisakar, H. Clusmann, M. Coburn, J. Coles, J.D. Cooper, M. Correia, A. Covic, E. Czeiter, M. Czosnyka, C. Dahyot-Fizelier, P. Dark, H. Dawes, V. De Keyser, V. Degos, F.D. Della Corte, H.D. Boogert, B. Depreitere, D. Dilvesi, A. Dixit, E. Donoghue, J. Dreier, G.-. Duliere, A. Ercole, P. Esser, E. Ezer, M. Fabricius, V.L. Feigin, K. Foks, S. Frisvold, A. Furmanov, P. Gagliardo, D. Galanaud, D. Gantner, G. Gao, P. George, A. Ghuysen, L. Giga, B. Glocker, J. Golubovic, P.A. Gomez, J. Gratz, B. Gravesteijn, F. Grossi, R.L. Gruen, D. Gupta, J.A. Haagsma, I. Haitsma, R. Helbok, E. Helseth, L. Horton, J. Huijben, P.J. Hutchinson, B. Jacobs, S. Jankowski, M. Jarrett, J.-. Jiang, F. Johnson, K. Jones, M. Karan, A.G. Kolias, E. Kompanje, D. Kondziella, E. Koraropoulos, L.-. Koskinen, N. Kovacs, A. Kowark, A. Lagares, L. Lanyon, S. Laureys, F. Lecky, D. Ledoux, V. Legrand, A. Lejeune, L. Levi, R. Lightfoot, H. Lingsma, A.I.R. Maas, A.M. Castano-Leon, M. Majdan, A. Manara, G. Manley, C. Martino, H. Marechal, J. Mattern, C. Mcmahon, B. Melegh, D. Menon, T. Menovsky, A. Mikolic, B. Misset, V. Muraleedharan, L. Murray, A. Negru, D. Nelson, V. Newcombe, D. Nieboer, J. Nyiradi, O. Olubukola, M. Oresic, F. Ortolano, A. Palotie, P.M. Parizel, J.-. Payen, N. Perera, V. Perlbarg, P. Persona, W. Peul, A. Piippo-Karjalainen, M. Pirinen, H. Ples, S. Polinder, I. Pomposo, J.P. Posti, L. Puybasset, A. Radoi, A. Ragauskas, R. Raj, M. Rambadagalla, J. Rhodes, S. Richardson, S. Richter, S. Ripatti, S. Rocka, C. Roe, O. Roise, J. Rosand, J.V. Rosenfeld, C. Rosenlund, G. Rosenthal, S. Rossi, D. Rueckert, M. Rusnak, J. Sahuquillo, O. Sakowitz, R. Sanchez-Porras, J. Sandor, S. Schmidt, H. Schoechl, G. Schoonman, R.F. Schou, E. Schwendenwein, C. Sewalt, T. Skandsen, P. Smielewski, A. Sorinola, E. Stamatakis, R. Stevens, W. Stewart, E.W. Steyerberg, N. Stocchetti, N. Sundstrom, A. Synnot, R. Takala, V. Tamas, T. Tamosuitis, M.S. Taylor, B.T. Ao, O. Tenovuo, A. Theadom, M. Thomas, D. Tibboel, M. Timmers, C. Tolias, T. Trapani, C.M. Tudora, A. Unterberg, P. Vajkoczy, S. Vallance, E. Valeinis, Z. Vamos, M. Van Der Jagt, G. Van Der Steen, J. Van Der Naalt, J.T.J.M. Van Dijck, T.A. Van Essen, W. Van Hecke, C. Van Heugten, D. Van Praag, T. Vande Vyvere, R.J. Van Wijk, A. Vargiolu, E. Vega, K. Velt, J. Verheyden, P.M. Vespa, A. Vik, R. Vilcinis, V. Volovici, N. Von Steinbuchel, D. Voormolen, P. Vulekovic, K.K.W. Wang, E. Wiegers, G. Williams, L. Wilson, S. Winzeck, S. Wolf, Z. Yang, P. Ylen, A. Younsi, F.A. Zeiler, V. Zelinkova, A. Ziverte, T. Zoerle. - In: NEUROCRITICAL CARE. - ISSN 1541-6933. - 36:3(2022 Jun), pp. 927-941. [10.1007/s12028-021-01400-3]

Extended Coagulation Profiling in Isolated Traumatic Brain Injury: A CENTER-TBI Analysis

Schaeben V.;Schafer N.;Guting H.;Lefering R.;Thorn S.;Schochl H.;Zipperle J.;Grottke O.;Rossaint R.;Stanworth S.;Curry N.;Maegele M.;Akerlund C.;Amrein K.;Andelic N.;Andreassen L.;Anke A.;Antoni A.;Audibert G.;Azouvi P.;Azzolini M. L.;Bartels R.;Barzo P.;Beauvais R.;Beer R.;Bellander B. -M.;Belli A.;Benali H.;Berardino M.;Beretta L.;Blaabjerg M.;Bragge P.;Brazinova A.;Brinck V.;Brooker J.;Brorsson C.;Buki A.;Bullinger M.;Cabeleira M.;A. Caccioppola;Calappi E.;Calvi M. R.;Cameron P.;Lozano G. C.;Carbonara M.;Cavallo S.;G. Chevallard;Chieregato A.;Citerio G.;Ceyisakar I.;Clusmann H.;Coburn M.;Coles J.;Cooper J. D.;Correia M.;Covic A.;Czeiter E.;Czosnyka M.;Dahyot-Fizelier C.;Dark P.;Dawes H.;De Keyser V.;Degos V.;Della Corte F. D.;Boogert H. D.;Depreitere B.;Dilvesi D.;Dixit A.;Donoghue E.;Dreier J.;Duliere G. -L.;Ercole A.;Esser P.;Ezer E.;Fabricius M.;Feigin V. L.;Foks K.;Frisvold S.;Furmanov A.;Gagliardo P.;Galanaud D.;Gantner D.;Gao G.;George P.;Ghuysen A.;Giga L.;Glocker B.;Golubovic J.;Gomez P. A.;Gratz J.;Gravesteijn B.;Grossi F.;Gruen R. L.;Gupta D.;Haagsma J. A.;Haitsma I.;Helbok R.;Helseth E.;Horton L.;Huijben J.;Hutchinson P. J.;Jacobs B.;Jankowski S.;Jarrett M.;Jiang J. -Y.;Johnson F.;Jones K.;Karan M.;Kolias A. G.;Kompanje E.;Kondziella D.;Koraropoulos E.;Koskinen L. -O.;Kovacs N.;Kowark A.;Lagares A.;Lanyon L.;Laureys S.;Lecky F.;Ledoux D.;Legrand V.;Lejeune A.;L. Levi;Lightfoot R.;Lingsma H.;Maas A. I. R.;Castano-Leon A. M.;Majdan M.;Manara A.;Manley G.;Martino C.;Marechal H.;Mattern J.;McMahon C.;Melegh B.;Menon D.;Menovsky T.;Mikolic A.;Misset B.;Muraleedharan V.;L. Murray;Negru A.;Nelson D.;Newcombe V.;Nieboer D.;Nyiradi J.;Olubukola O.;Oresic M.;F. Ortolano;Palotie A.;Parizel P. M.;Payen J. -F.;Perera N.;Perlbarg V.;Persona P.;Peul W.;Piippo-Karjalainen A.;Pirinen M.;Ples H.;Polinder S.;Pomposo I.;Posti J. P.;Puybasset L.;Radoi A.;Ragauskas A.;Raj R.;Rambadagalla M.;Rhodes J.;Richardson S.;Richter S.;Ripatti S.;Rocka S.;Roe C.;Roise O.;Rosand J.;Rosenfeld J. V.;Rosenlund C.;Rosenthal G.;Rossi S.;Rueckert D.;Rusnak M.;Sahuquillo J.;Sakowitz O.;Sanchez-Porras R.;Sandor J.;Schmidt S.;Schoechl H.;Schoonman G.;Schou R. F.;Schwendenwein E.;Sewalt C.;Skandsen T.;Smielewski P.;Sorinola A.;Stamatakis E.;Stevens R.;Stewart W.;Steyerberg E. W.;N. Stocchetti;Sundstrom N.;Synnot A.;Takala R.;Tamas V.;Tamosuitis T.;Taylor M. S.;Ao B. T.;Tenovuo O.;Theadom A.;Thomas M.;Tibboel D.;Timmers M.;Tolias C.;Trapani T.;Tudora C. M.;Unterberg A.;Vajkoczy P.;Vallance S.;Valeinis E.;Vamos Z.;van der Jagt M.;Van der Steen G.;van der Naalt J.;van Dijck J. T. J. M.;van Essen T. A.;Van Hecke W.;van Heugten C.;Van Praag D.;Vande Vyvere T.;van Wijk R. J.;Vargiolu A.;Vega E.;Velt K.;Verheyden J.;Vespa P. M.;Vik A.;Vilcinis R.;Volovici V.;von Steinbuchel N.;Voormolen D.;Vulekovic P.;Wang K. K. W.;Wiegers E.;Williams G.;Wilson L.;Winzeck S.;Wolf S.;Yang Z.;Ylen P.;Younsi A.;Zeiler F. A.;Zelinkova V.;Ziverte A.;T. Zoerle^Ultimo

2022

Abstract

Background: Trauma-induced coagulopathy in traumatic brain injury (TBI) remains associated with high rates of complications, unfavorable outcomes, and mortality. The underlying mechanisms are largely unknown. Embedded in the prospective multinational Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study, coagulation profiles beyond standard conventional coagulation assays were assessed in patients with isolated TBI within the very early hours of injury. Methods: Results from blood samples (citrate/EDTA) obtained on hospital admission were matched with clinical and routine laboratory data of patients with TBI captured in the CENTER-TBI central database. To minimize confounding factors, patients with strictly isolated TBI (iTBI) (n = 88) were selected and stratified for coagulopathy by routine international normalized ratio (INR): (1) INR < 1.2 and (2) INR ≥ 1.2. An INR > 1.2 has been well adopted over time as a threshold to define trauma-related coagulopathy in general trauma populations. The following parameters were evaluated: quick’s value, activated partial thromboplastin time, fibrinogen, thrombin time, antithrombin, coagulation factor activity of factors V, VIII, IX, and XIII, protein C and S, plasminogen, D-dimer, fibrinolysis-regulating parameters (thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor 1, antiplasmin), thrombin generation, and fibrin monomers. Results: Patients with iTBI with INR ≥ 1.2 (n = 16) had a high incidence of progressive intracranial hemorrhage associated with increased mortality and unfavorable outcome compared with patients with INR < 1.2 (n = 72). Activity of coagulation factors V, VIII, IX, and XIII dropped on average by 15–20% between the groups whereas protein C and S levels dropped by 20%. With an elevated INR, thrombin generation decreased, as reflected by lower peak height and endogenous thrombin potential (ETP), whereas the amount of fibrin monomers increased. Plasminogen activity significantly decreased from 89% in patients with INR < 1.2 to 76% in patients with INR ≥ 1.2. Moreover, D-dimer levels significantly increased from a mean of 943 mg/L in patients with INR < 1.2 to 1,301 mg/L in patients with INR ≥ 1.2. Conclusions: This more in-depth analysis beyond routine conventional coagulation assays suggests a counterbalanced regulation of coagulation and fibrinolysis in patients with iTBI with hemostatic abnormalities. We observed distinct patterns involving key pathways of the highly complex and dynamic coagulation system that offer windows of opportunity for further research. Whether the changes observed on factor levels may be relevant and explain the worse outcome or the more severe brain injuries by themselves remains speculative.

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	Parole chiave
	
				CENTER-TBI; Coagulopathy; Fibrin monomers; Progressive intracranial hemorrhage; Thrombin generation; Traumatic brain injury
			
	Settori scientifico-disciplinari dell'articolo (validi dal 09/05/2024)
	
				Settore MEDS-23/A - Anestesiologia
			
	Data di pubblicazione
	
				giu-2022
			
	Data ahead of print o data di stampa
	
				dic-2021
			
	Rivista in ANCE
	
				NEUROCRITICAL CARE
			
	DOI
	
				https://dx.doi.org/10.1007/s12028-021-01400-3
			
	Tipologia
	
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				01 - Articolo su periodico

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