Extended Coagulation Profiling in Isolated Traumatic Brain Injury: A CENTER-TBI Analysis
Authors: Böhm Julia K. , Schaeben Victoria , Schäfer Nadine , Güting Helge , Lefering Rolf , Thorn Sophie , Schöchl Herbert , Zipperle Johannes , Grottke Oliver , Rossaint Rolf , Stanworth Simon , Curry Nicola , Maegele Marc ,   CENTER-TBI Participants and Investigators, Åkerlund Cecilia , Amrein Krisztina , Andelic Nada , Andreassen Lasse , Anke Audny , Antoni Anna , Audibert Gérard , Azouvi Philippe , Azzolini Maria Luisa , Bartels Ronald , Barzó Pál , Beauvais Romuald , Beer Ronny , Bellander Bo-Michael , Belli Antonio , Benali Habib , Berardino Maurizio , Beretta Luigi , Blaabjerg Morten , Bragge Peter , Brazinova Alexandra , Brinck Vibeke , Brooker Joanne , Brorsson Camilla , Buki Andras , Bullinger Monika , Cabeleira Manuel , Caccioppola Alessio , Calappi Emiliana , Calvi Maria Rosa , Cameron Peter , Lozano Guillermo Carbayo , Carbonara Marco , Cavallo Simona , Chevallard Giorgio , Chieregato Arturo , Citerio Giuseppe , Ceyisakar Iris , Clusmann Hans , Coburn Mark , Coles Jonathan , Cooper Jamie D. , Correia Marta , Čović Amra , Curry Nicola , Czeiter Endre , Czosnyka Marek , Dahyot-Fizelier Claire , Dark Paul , Dawes Helen , De Keyser Véronique , Degos Vincent , Corte Francesco Della , Boogert Hugo den , Depreitere Bart , Đilvesi Đula , Dixit Abhishek , Donoghue Emma , Dreier Jens , Dulière Guy-Loup , Ercole Ari , Esser Patrick , Ezer Erzsébet , Fabricius Martin , Feigin Valery L. , Foks Kelly , Frisvold Shirin , Furmanov Alex , Gagliardo Pablo , Galanaud Damien , Gantner Dashiell , Gao Guoyi , George Pradeep , Ghuysen Alexandre , Giga Lelde , Glocker Ben , Golubovic Jagoš , Gomez Pedro A. , Gratz Johannes , Gravesteijn Benjamin , Grossi Francesca , Gruen Russell L. , Gupta Deepak , Haagsma Juanita A. , Haitsma Iain , Helbok Raimund , Helseth Eirik , Horton Lindsay , Huijben Jilske , Hutchinson Peter J. , Jacobs Bram , Jankowski Stefan , Jarrett Mike , Jiang Ji-yao , Johnson Faye , Jones Kelly , Karan Mladen , Kolias Angelos G. , Kompanje Erwin , Kondziella Daniel , Koraropoulos Evgenios , Koskinen Lars-Owe , Kovács Noémi , Kowark Ana , Lagares Alfonso , Lanyon Linda , Laureys Steven , Lecky Fiona , Ledoux Didier , Lefering Rolf , Legrand Valerie , Lejeune Aurelie , Levi Leon , Lightfoot Roger , Lingsma Hester , Maas Andrew I. R. , Castaño-León Ana M. , Maegele Marc , Majdan Marek , Manara Alex , Manley Geoffrey , Martino Costanza , Maréchal Hugues , Mattern Julia , McMahon Catherine , Melegh Béla , Menon David , Menovsky Tomas , Mikolic Ana , Misset Benoit , Muraleedharan Visakh , Murray Lynnette , Negru Ancuta , Nelson David , Newcombe Virginia , Nieboer Daan , Nyirádi József , Olubukola Otesile , Oresic Matej , Ortolano Fabrizio , Palotie Aarno , Parizel Paul M. , Payen Jean-François , Perera Natascha , Perlbarg Vincent , Persona Paolo , Peul Wilco , Piippo-Karjalainen Anna , Pirinen Matti , Ples Horia , Polinder Suzanne , Pomposo Inigo , Posti Jussi P. , Puybasset Louis , Radoi Andreea , Ragauskas Arminas , Raj Rahul , Rambadagalla Malinka , Rhodes Jonathan , Richardson Sylvia , Richter Sophie , Ripatti Samuli , Rocka Saulius , Roe Cecilie , Roise Olav , Rosand Jonathan , Rosenfeld Jeffrey V. , Rosenlund Christina , Rosenthal Guy , Rossaint Rolf , Rossi Sandra , Rueckert Daniel , Rusnák Martin , Sahuquillo Juan , Sakowitz Oliver , Sanchez-Porras Renan , Sandor Janos , Schäfer Nadine , Schmidt Silke , Schoechl Herbert , Schoonman Guus , Schou Rico Frederik , Schwendenwein Elisabeth , Sewalt Charlie , Skandsen Toril , Smielewski Peter , Sorinola Abayomi , Stamatakis Emmanuel , Stanworth Simon , Stevens Robert , Stewart William , Steyerberg Ewout W. , Stocchetti Nino , Sundström Nina , Synnot Anneliese , Takala Riikka , Tamás Viktória , Tamosuitis Tomas , Taylor Mark Steven , Ao Braden Te , Tenovuo Olli , Theadom Alice , Thomas Matt , Tibboel Dick , Timmers Marjolein , Tolias Christos , Trapani Tony , Tudora Cristina Maria , Unterberg Andreas , Vajkoczy Peter , Vallance Shirley , Valeinis Egils , Vámos Zoltán , van der Jagt Mathieu , Van der Steen Gregory , Naalt Joukje van der , van Dijck Jeroen T. J. M. , van Essen Thomas A. , Van Hecke Wim , van Heugten Caroline , Van Praag Dominique , Vyvere Thijs Vande , van Wijk Roel P. J. , Vargiolu Alessia , Vega Emmanuel , Velt Kimberley , Verheyden Jan , Vespa Paul M. , Vik Anne , Vilcinis Rimantas , Volovici Victor , von Steinbüchel Nicole , Voormolen Daphne , Vulekovic Petar , Wang Kevin K. W. , Wiegers Eveline , Williams Guy , Wilson Lindsay , Winzeck Stefan , Wolf Stefan , Yang Zhihui , Ylén Peter , Younsi Alexander , Zeiler Frederick A. , Zelinkova Veronika , Ziverte Agate , Zoerle Tommaso 
Published: December 2021

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.