ABSTRACT
Among the U.S. military personnel, blast injury is among the leading causes of brain injury. During the past decade, it has become apparent that even blast injury as a form of mild traumatic brain injury (mTBI) may lead to multiple different adverse outcomes, such as neuropsychiatric symptoms and long-term cognitive disability. Blast injury is characterized by blast overpressure, blast duration, and blast impulse. While the blast injuries of a victim close to the explosion will be severe, majority of victims are usually at a distance leading to milder form described as mild blast TBI (mbTBI). A major feature of mbTBI is its complex manifestation occurring in concert at different organ levels involving systemic, cerebral, neuronal, and neuropsychiatric responses; some of which are shared with other forms of brain trauma such as acute brain injury and other neuropsychiatric disorders such as post-traumatic stress disorder. The pathophysiology of blast injury exposure involves complex cascades of chronic psychological stress, autonomic dysfunction, and neuro/systemic inflammation. These factors render blast injury as an arduous challenge in terms of diagnosis and treatment as well as identification of sensitive and specific biomarkers distinguishing mTBI from other non-TBI pathologies and from neuropsychiatric disorders with similar symptoms. This is due to the "distinct" but shared and partially identified biochemical pathways and neuro-histopathological changes that might be linked to behavioral deficits observed. Taken together, this article aims to provide an overview of the current status of the cellular and pathological mechanisms involved in blast overpressure injury and argues for the urgent need to identify potential biomarkers that can hint at the different mechanisms involved.
ABSTRACT
Randomized trials suggest superior and safe stroke prevention in patients with atrial fibrillation after anticoagulation with dabigatran (D) at a 150 mg BID as described in the RE-LY prospective randomized open-label trial when compared to warfarin. Thrombin generation (TG) is a cornerstone of coagulation cascade, and represents a critical biomarker of atherothrombosis. We, therefore, sought to define the effect of D in escalating concentrations on the time course of TG using the Calibrated Automated Thrombogram(®) (CAT) technology in patients after ischemic stroke. Serial plasma samples were obtained from 20 patients with ischemic stroke documented by neuroimaging, who were treated with aspirin for at least 30 days. The impact of 0.1, 0.23, 0.46, 0.69 mM D in platelet-poor plasma (PPP) on TG indices was assessed using fluorogenic substrate CAT device. The following integrated CAT parameters: TGmax, start time (t-start) peak time (t-peak), and mean time (t-mean) were calculated for each D dose and compared with those of the vehicle. Preincubation of PPP with D resulted in dose-dependent significant inhibition of most TG indices. The TGmax was gradually reduced from 447 ± 21 nM at baseline and reach significance for 0.46 mM D (355 ± 44 nM, P = 0.03); and decreased further at 0.69 mM D to 302 ± 27 nM (P = 0.01). The t-peak has been achieved 2-3 times later than after vehicle already at 0.23 nM D. The t-start was delayed 3-4 fold starting from 0.23 mM concentration of D (P < 0.001 for all), but not different from D 0.1 mM (1.5 vs. 1.6; P = 0.34). The t-mean was not significantly affected by D. D in vitro impacts indices of TG predominantly by dose dependent inhibition of endogenous TG, and delayed thrombin production. This preliminary evidence, while intriguing, requires confirmation in post-stroke patients receiving orally dosed D in order to determine whether these findings are clinically relevant.
