Pathophysiology of Coagulopathy Induced by Traumatic Brain Injury Is Identical to That of Disseminated Intravascular Coagulation With Hyperfibrinolysis

Abstract

Background: Traumatic brain injury (TBI)-associated coagulopathy is a widely recognized risk factor for secondary brain damage and contributes to poor clinical outcomes. Various theories, including disseminated intravascular coagulation (DIC), have been proposed regarding its pathomechanisms; no consensus has been reached thus far. This study aimed to elucidate the pathophysiology of TBI-induced coagulopathy by comparing coagulofibrinolytic changes in isolated TBI (iTBI) to those in non-TBI, to determine the associated factors, and identify the clinical significance of DIC diagnosis in patients with iTBI.Methods: This secondary multicenter, prospective study assessed patients with severe trauma. iTBI was defined as Abbreviated Injury Scale (AIS) scores ≥4 in the head and neck, and ≤2 in other body parts. Non-TBI was defined as AIS scores ≥4 in single body parts other than the head and neck, and the absence of AIS scores ≥3 in any other trauma-affected parts. Specific biomarkers for thrombin and plasmin generation, anticoagulation, and fibrinolysis inhibition were measured at the presentation to the emergency department (0 h) and 3 h after arrival.Results: We analyzed 34 iTBI and 40 non-TBI patients. Baseline characteristics, transfusion requirements and in-hospital mortality did not significantly differ between groups. The changes in coagulation/fibrinolysis-related biomarkers were similar. Lactate levels in the iTBI group positively correlated with DIC scores (rho = −0.441, p = 0.017), but not with blood pressure (rho = −0.098, p = 0.614). Multiple logistic regression analyses revealed that the injury severity score was an independent predictor of DIC development in patients with iTBI (odds ratio = 1.237, p = 0.018). Patients with iTBI were further subdivided into two groups: DIC (n = 15) and non-DIC (n = 19) groups. Marked thrombin and plasmin generation were observed in all patients with iTBI, especially those with DIC. Patients with iTBI and DIC had higher requirements for massive transfusion and emergency surgery, and higher in-hospital mortality than those without DIC. Furthermore, DIC development significantly correlated with poor hospital survival; DIC scores at 0 h were predictive of in-hospital mortality.Conclusions: Coagulofibrinolytic changes in iTBI and non-TBI patients were identical, and consistent with the pathophysiology of DIC. DIC diagnosis in the early phase of TBI is key in predicting the outcomes of severe TBI.

Hyperfibrinolysis and fibrinolysis shutdown in patients with traumatic brain injury

“…The fibrin clots formed by thrombin involvement are degraded by plasmin produced after plasminogen activation by tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA) to produce the fibrin degradation product, D-dimer 29 , 30 . In addition, tissue hypoperfusion associated with trauma results in the release of large amounts of t-PA from injured brain tissue, further activating fibrinolysis 31 . Thus, hyperfibrinolysis secondary to hypercoagulation and hyperfibrinolysis associated with direct t-PA release from the injured brain are the hallmarks of TBI and contribute to the bleeding diathesis.…”

Association of Histones With Coagulofibrinolytic Responses and Organ Dysfunction in Adult Post-cardiac Arrest Syndrome

“…Third, medical students and medical staff from our hospital were recruited as healthy volunteers using a selection method employed in our previous studies: however, they were not age-or sex-matched to the patients. Fourth, we centrifuged collected blood samples at 4 • C to avoid false high value of measurements in accordance with our previous studies (19)(20)(21). However, one-time centrifugation of blood samples at low temperature without checking platelet counts can lead to residual platelets in the processed samples, which could have affected the measurements, especially PAI-1 values.…”

“…The tPA ELISA kit does not detect t-PA associated with PAI-1; it only detects free t-PA as supported by the protocol provided along with this kit specifying that functionally active tPA will form a covalent complex with biotinylated human PAI-1, which is bound to the avidin coated on the microtiter plate, and that complexed tPA will not bind to the PAI-1 and will not be detected by the assay. The reliability of these assay reagents has been verified, and the studies quantifying soluble fibrin measured using these reagents have been published (19)(20)(21).…”

Neurovascular Unit-Derived Extracellular Vesicles: From Their Physiopathological Roles to Their Clinical Applications in Acute Brain Injuries

“…The concomitant expression of TF and PS on EV membranes has been shown to enhance the procoagulant activity of EVs, even if the mechanism of activation of TF from its encrypted noncoagulant state to active coagulant form is not clearly established [ 85 ]. In the case of traumatic brain injury (TBI)-associated coagulopathy, EVs were described in in vivo studies to act as mediators via their procoagulant activity and through platelet activation to promote inflammation and BBB disruption [ 86 , 87 , 88 ]. The investigation of small TBI cohorts of patients reported significantly increased levels of procoagulant vesicles in the CSF and blood of severe TBI patients in comparison to control samples [ 79 , 80 ].…”