Early Platelet Dysfunction in a Rodent Model of Blunt Traumatic Brain Injury Reflects the Acute Traumatic Coagulopathy Found in Humans

Abstract

Acute coagulopathy is a serious complication of traumatic brain injury (TBI) and is of uncertain etiology because of the complex nature of TBI. However, recent work has shown a correlation between mortality and abnormal hemostasis resulting from early platelet dysfunction. The aim of the current study was to develop and characterize a rodent model of TBI that mimics the human coagulopathic condition so that mechanisms of the early acute coagulopathy in TBI can be more readily assessed. Studies utilizing a highly reproducible constrained blunt-force brain injury in rats demonstrate a strong correlation with important postinjury pathological changes that are observed in human TBI patients, namely, diminished platelet responses to agonists, especially adenosine diphosphate (ADP), and subarachnoid bleeding. Additionally, administration of a direct thrombin inhibitor, preinjury, recovers platelet functionality to ADP stimulation, indicating a direct role for excess thrombin production in TBI-induced early platelet dysfunction.

Systemic Platelet Dysfunction Is the Result of Local Dysregulated Coagulation and Platelet Activation in the Brain in a Rat Model of Isolated Traumatic Brain Injury

“…15 To further characterize downstream events after injury, we assessed activation of the blood coagulation pathway as well as platelet activation and function. In this study, a fibrin-enriched clot was observed in the superior sagittal sinus close to the site of impact (Fig.…”

“…Further, administration of the thrombin inhibitor, Refludan, Ò before injury, protected systemic platelet responses to ADP indicating a potential role for thrombin in the regulation of systemic platelet dysfunction after TBI. 15 In the current study, we correlated temporal changes in ADPand AA-induced platelet activation, as measured by TEG PM, with altered expression of coagulation markers TF, fibrin(ogen), and P-selectin in the rat brain after injury. In all three markers, the extent of localized expression of these proteins inversely correlated with systemic platelet responses to ADP and AA agonists, potentially supporting the hypothesis that there is an immediate but recoverable systemic exhausted platelet effect.…”

“…15 All animal studies were performed with prior approval from the University of Notre Dame Institutional Animal Care and Use Committee.…”

Treatment of Disseminated Intravascular Coagulation (DIC)

“…In surgical or trauma patients with DIC, over 80 % of patients have platelet counts less than 100 × 10 9 /L. In traumatic brain injury an early occurring platelet dysfunction had been described as well [ 24 ].…”

Validation of acute traumatic coagulopathy in an ovine model of trauma and haemorrhage

“…It has been suggested that initial platelet hyperactivation in trauma may render platelets unresponsive to subsequent stimulation, resulting in reduced aggregation parameters and decreased clot strength (143). A similar phenomenon has been observed in conditions such as transplant rejection and thrombotic thrombocytopaenic purpura, in which acquired defects in platelet function develop following prolonged activation in vivo (144).…”