Links between thrombosis and inflammation in traumatic brain injury

Abstract

Traumatic brain injury (TBI) continues to be a major healthcare problem and there is much to be explored regarding the secondary pathobiology to identify early predictive markers and new therapeutic targets. While documented changes in thrombosis and inflammation in major trauma have been well described, growing evidence suggests that isolated TBI also results in systemic alterations in these mechanisms. Here, we review recent experimental and clinical findings that demonstrate how blood-brain barrier dysfunction, systemic immune response, inflammation, platelet activation, and thrombosis contribute significantly to the pathogenesis of TBI. Despite advances in the links between thrombosis and inflammation, there is a lack of treatment options aimed at both processes and this could be crucial to treating vascular injury, local and systemic inflammation, and secondary ischemic events following TBI. With emerging evidence of newly-identified roles for platelets, leukocytes, the coagulation system and extracellular vesicles in processes of inflammation and thrombosis, there is a growing need to characterize these mechanisms within the context of TBI and whether these changes persist into the chronic phase of injury. Importantly, this review defines areas in need of further research to advance the field and presents a roadmap to identify new diagnostic and treatment options for TBI.

Keywords: Biomarkers; Blast injury; Blood-brain barrier dysfunction; Coagulopathy; Extracellular vesicles; Fibrinogen; Hemostasis; Mild TBI; Platelets; von Willebrand factor.

Figure 1.

This schematic highlights current mechanisms of systemic inflammation and coagulopathy, induced due to neurovascular dysfunction and blood-brain barrier (BBB) disruption, observed following traumatic brain injury (TBI). The BBB is the epicenter for propagation of thromboinflammation following TBI. While these processes have been modeled in the area of moderate-to-severe TBI, there are limited reports suggesting these mechanisms in mild TBI, though there are many unexplored areas. Additionally, further investigation is needed of early and late occurrence of these processes in the area of repetitive mild TBI, which is of high importance to the Veteran and civilian populations. Future Directions: Therapeutic targets for early intervention after moderate-to-severe TBI have already been identified and translational is achievable through trials of preclinical efficacy, diagnostic relevance, and eventual clinical investigation. On the other hand, much more research is needed in: 1) identifying the clinical manifestation of systemic inflammation and thrombosis following repetitive head injury, using available blood sample banks, such as the Million Veteran Program, and 2) preclinical investigation of these mechanisms using –omics and biological function approaches in a temporal manner. Long-term investigation is crucial for these studies as neurovascular/BBB impairment may worsen over time with cumulative mild TBI exposure. Though a stepwise, rigorous strategy of coagulopathic assessment, therapeutic targets, especially those applicable to chronic pathologic states, can be identified along with clinically-relevant biomarkers. Monocytes are delayed entering the brain relative to neutrophils. BDEVs – brain-derived extracellular vesicles. Illustration by Matt Hazzard, Medical Illustration, University of Kentucky.