Thrombomodulin, alarmin signaling, and copeptin: cross-talk between obesity and acute ischemic stroke initiation and severity in Egyptians

Abstract

Acute ischemic stroke (AIS) is followed by a strong inflammatory response contributing to brain damage and making early diagnosis and treatment inevitable. Hence, obesity is a state of chronic inflammation with amplified oxidative stress; this study aimed to assess the role played by thrombomodulin (TM)/alarmin signaling pathway and copeptin in AIS initiation and severity in addition to the implication of abnormal body weight. The study was conducted on 50 participants; 30 were patients with AIS (15 overweight/obese and 15 normal weight), 10 were overweight/obese, and 10 were normal weight. Plasma TM, copeptin, high mobility group box1 (HMGB1), and lipocalin 2 (LCN2) levels were immunoassayed. Toll-like receptor 4 (TLR4) mRNA expression was evaluated by real-time PCR, National Institutes of Health Stroke Scale (NIHSS), carotid intima media thickness; atherogenic index and glycemic status were also assessed. TM, copeptin, HMGB1, and LCN2 levels were significantly increased in overweight/obese AIS patients and in AIS patients with NIHSS score ≥ 7 when compared to other groups (p value=, ˂ 0.001*). Receiver operating characteristic (ROC) curve elaborated HMGB-1 and LCN2 as the best biomarker for diagnosis and prediction of AIS severity, respectively. Regression analysis avails LCN2 and TM as best biomarker for AIS severity predication. In conclusion, these results highlighted detrimental role of alarmin signaling with increased adaptive response to block this pathway through TM in addition to increased copeptin level as an acute damage marker and their tight relation to WC not to BMI in AIS which clarify the implication of central adiposity.

Thrombomodulin Serum Levels—A Predictable Biomarker for the Acute Onset of Ischemic Stroke

“…In recent studies, TM has been shown to reduce cerebral infarct size in stroke models [14,20]. Compared to other anticoagulants, the risk of bleeding appears to be lower in animals and humans treated with sTM, suggesting its protective role in preventing brain damage in stroke [20,21].…”

“…It is worth discussing the contrasting observation that populations with genetically determined elevated pTM levels appear to experience worse long-term vascular status, leading to increased risks of ischemic stroke and adverse clinical outcomes [14]. Hongzhou et al conducted a two-sample mendelian randomized study and demonstrated that a genetic predisposition to elevated pTM levels was associated with an increased risk of ischemic stroke [20].…”

“…Moreover, it promotes fibrinolysis through the proteolytic inactivation of plasminogen activator inhibitor (PAI), helping the remodeling of the secondary clot [10,12,13]. Apart from being part of the protein C anticoagulant system, TM has been discovered to interfere with inflammation, stabilize barrier function and increase blood flow under pathological conditions [10,14,15]. Moreover, the administration of recombinant soluble TM has been shown to protect against tissue damage and partially restore normal functions after ischemia in several organs [9,10].…”