Mild traumatic brain injury alters pneumonia-induced coagulopathy in mice

Abstract

Traumatic brain injury (TBI) is a major cause of death among trauma patients and is associated with a high rate of mortality due to complications such as bacterial pneumonia, sepsis, and subsequent coagulopathies. While severe TBI is positively associated with the development of pneumonia, mild traumatic brain injury (mTBI) results in a paradoxical decrease in mortality following bacterial pneumonia via an unidentified mechanism. New evidence suggests that mTBI stimulates vagus nerve signaling resulting in an anti-inflammatory state that is mediated by neurotransmitters (NT) such as acetylcholine (ACh) and substance P (Sub P). This anti-inflammatory state induced by mTBI has been correlated with an increased resistance to pneumonia (PNA) in mice and has been shown to be mediated in part by increased bacterial clearance in the lungs via enhanced neutrophil recruitment. However, it has not been investigated whether this reduced mortality is due to alterations in the coagulation system and if they have any effect on either the severity or occurrence of disseminated intravascular coagulation (DIC), a common sequelae of pneumonia-induced sepsis. Our study investigates whether administration of mTBI prior to pneumonia challenge in mice decreases mortality by ameliorating DIC. We assess and define DIC in our mouse models by changes in plasma coagulation parameters including fibrinogen, D-dimer, and plasminogen activator inhibitor-1 (PAI-1) Our study found that mTBI administration prior to pneumonia significantly decreased mortality in mice gavaged with high concentrations of Pseudomonas aeruginosa (Psd.). We also found that mTBI administration prior to pneumonia rescued fibrinogen levels and increased D-dimer levels in plasma, suggesting a compensated fibrinolytic state and amelioration of DIC. Circulating neutrophil and absolute leukocyte counts were also increased in mTBI/pneumonia models compared to those with pneumonia alone, supporting previous evidence implicating mTBI as the origin of enhanced bacterial clearance in lungs. Taken together, these data suggest that the increase in survival seen in patients with mTBI is in part due to alterations in coagulation.