-
Experimental Physiology Oct 2022What is the topic of this review? The status and potential role of novel biological markers (biomarkers) that can help identify the patients at risk of organ injury or... (Review)
Review
NEW FINDINGS
What is the topic of this review? The status and potential role of novel biological markers (biomarkers) that can help identify the patients at risk of organ injury or long-term complications following heatstroke. What advances does it highlight? Numerous biomarkers were identified related to many aspects of generalized heatstroke-induced cellular injury and tissue damage, and heatstroke-provoked cardiovascular, renal, cerebral, intestinal and skeletal muscle injury. No novel biomarkers were identified for liver or lung injury.
ABSTRACT
Classic and exertional heatstroke cause acute injury and damage across numerous organ systems. Moreover, heatstroke survivors may sustain long-term neurological, cardiovascular and renal complications with a persistent risk of death. In this context, biomarkers, defined as biological samples obtained from heatstroke patients, are needed to detect early organ injury, and predict outcomes to develop novel organ preservation therapeutic strategies. This narrative review provides preliminary insights that will guide the development and future utilization of these biomarkers. To this end, we have identified numerous biomarkers of widespread heatstroke-associated cellular injury, tissue damage and repair (extracellular heat shock proteins 72 and 60, high mobility group box protein 1, histone H3, and interleukin-1α), and other organ-specific biomarkers including those related to the cardiovascular system (cardiac troponin I, endothelium-derived factors, circulation endothelial cells, adhesion molecules, thrombomodulin and von Willebrand factor antigen), the kidneys (plasma and urinary neutrophil gelatinase-associated lipocalin), the intestines (intestinal fatty acid-binding protein 2), the brain (serum S100β and neuron-specific enolase) and skeletal muscle (creatine kinase, myoglobin). No specific biomarkers have been identified so far for liver or lung injury in heatstroke. Before translating the identified biomarkers into clinical practice, additional preclinical and clinical prospective studies are required to further understand their clinical utility, particularly for the biomarkers related to long-term post-heatstroke health outcomes.
Topics: Biomarkers; Creatine Kinase; Endothelial Cells; Fatty Acid-Binding Proteins; HMGB Proteins; HSP72 Heat-Shock Proteins; Heat Stroke; Histones; Humans; Interleukin-1alpha; Lipocalin-2; Lung Injury; Myoglobin; Phosphopyruvate Hydratase; Thrombomodulin; Troponin I; von Willebrand Factor
PubMed: 35654394
DOI: 10.1113/EP090142 -
Blood Feb 2021In this issue of , Kohli et al report a noncoagulation role of thrombomodulin (TM) expressed on trophoblast cells in maintaining placental growth and healthy...
In this issue of , Kohli et al report a noncoagulation role of thrombomodulin (TM) expressed on trophoblast cells in maintaining placental growth and healthy embryogenesis. They show that (1) the inflammatory cytokine interleukin-1β (IL-1β) suppressed TM synthesis from trophoblast stem cells in culture and induced the ectodomain shedding of TM from these cells; (2) the TM shedding was also induced in pregnant C57BL/6J mice infused with endothelial cell-derived extracellular vesicles (eEVs), which cause placental inflammation; (3) the IL-1β receptor antagonist anakinra prevented TM shedding in these eEV-infused pregnant mice and reduced placental abnormalities in these mice; (4) the soluble TM that resists proteolysis and oxidation (solulin) reduced TM shedding in the pregnant C57BL/6J mice infused with eEVs and prevented fetal death, intrauterine growth restriction, placental inflammation, and growth suppression; and (5) the protection offered by solulin was reproduced in transgenic mice with enhanced expression of TM in embryonic tissue, including trophoblasts. The key findings from the pregnant mice were reproduced in well-controlled in vitro experiments using trophoblastic stem cells in culture and further validated by studying placentas collected from patients with preeclampsia.
Topics: Female; Humans; Inflammation; Placenta; Pre-Eclampsia; Pregnancy; Thrombomodulin; Thrombosis
PubMed: 33599756
DOI: 10.1182/blood.2020008659 -
JAMA May 2019Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy. (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy.
OBJECTIVE
To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy.
DESIGN, SETTING, AND PARTICIPANTS
The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019.
INTERVENTIONS
Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days.
MAIN OUTCOME AND MEASURES
The primary end point was 28-day all-cause mortality.
RESULTS
Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P = .32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group.
CONCLUSIONS AND RELEVANCE
Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01598831.
Topics: Aged; Anticoagulants; Blood Coagulation Disorders; Cause of Death; Female; Humans; Infusions, Intravenous; Injections, Intravenous; International Normalized Ratio; Male; Middle Aged; Recombinant Proteins; Sepsis; Thrombomodulin; Treatment Failure
PubMed: 31104069
DOI: 10.1001/jama.2019.5358 -
Journal of Thrombosis and Haemostasis :... Jul 2003Since its discovery as a critical cofactor in the initiation of the protein C (PC) anticoagulant pathway [1,2], biochemical and structural investigations, combined with... (Review)
Review
Since its discovery as a critical cofactor in the initiation of the protein C (PC) anticoagulant pathway [1,2], biochemical and structural investigations, combined with in vivo analyses of genetically engineered mice have revealed new, and in part PC- and thrombin-independent aspects of thrombomodulin (TM) function in fibrinolysis and inflammation, and in embryogenesis. This review summarizes more recent structural and functional investigations of TM, gives an overview of the association of TM gene polymorphisms with human disease, and provides a synopsis of what is know about TM function in disease states of thrombosis, stroke, arteriosclerosis, and cancer. Newly emerging aspects of TM function in inflammation and embryogenesis are presented and discussed in detail.
Topics: Animals; Anticoagulants; Humans; Models, Biological; Neoplasms; Polymorphism, Genetic; Protein C; Stroke; Thrombin; Thrombomodulin; Thrombosis
PubMed: 12871287
DOI: 10.1046/j.1538-7836.2003.00306.x -
International Journal of Molecular... Apr 2019The multifaceted role of mitogen-activated protein kinases (MAPKs) in modulating signal transduction pathways in inflammatory conditions such as infection,... (Review)
Review
The multifaceted role of mitogen-activated protein kinases (MAPKs) in modulating signal transduction pathways in inflammatory conditions such as infection, cardiovascular disease, and cancer has been well established. Recently, coagulation factors have also emerged as key players in regulating intracellular signaling pathways during inflammation. Among coagulation factors, thrombomodulin, as a high affinity receptor for thrombin on vascular endothelial cells, has been discovered to be a potent anti-inflammatory and anti-tumorigenic signaling molecule. The protective signaling function of thrombomodulin is separate from its well-recognized role in the clotting cascade, which is to function as an anti-coagulant receptor in order to switch the specificity of thrombin from a procoagulant to an anti-coagulant protease. The underlying protective signaling mechanism of thrombomodulin remains largely unknown, though a few published reports link the receptor to the regulation of MAPKs under different (patho)physiological conditions. The goal of this review is to summarize what is known about the regulatory relationship between thrombomodulin and MAPKs.
Topics: Animals; Blood Platelets; Humans; Inflammation; Leukocytes; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Neoplasm Invasiveness; Neoplasms; Protein Conformation; Thrombomodulin
PubMed: 30991642
DOI: 10.3390/ijms20081851 -
Blood Jul 2018Thrombomodulin (TM) is an integral component of a multimolecular system, localized primarily to the vascular endothelium, that integrates crucial biological processes... (Review)
Review
Thrombomodulin (TM) is an integral component of a multimolecular system, localized primarily to the vascular endothelium, that integrates crucial biological processes and biochemical pathways, including those related to coagulation, innate immunity, inflammation, and cell proliferation. These are designed to protect the host from injury and promote healing. The "traditional" role of TM in hemostasis was determined with its discovery in the 1980s as a ligand for thrombin and a critical cofactor for the major natural anticoagulant protein C system and subsequently for thrombin-mediated activation of the thrombin activatable fibrinolysis inhibitor (also known as procarboxypeptidase B2). Studies in the past 2 decades are redefining TM as a molecule with many properties, exhibited via its multiple domains, through its interacting partners, complex regulated expression, and synthesis by cells other than the endothelium. In this report, we review some of the recently reported diverse properties of TM and how these may impact on our understanding of the pathogenesis of several diseases.
Topics: Animals; Biomarkers; Blood Coagulation; Disease Susceptibility; Endothelium, Vascular; Gene Expression Regulation; Humans; Immunity, Innate; Leukocytes; Structure-Activity Relationship; Thrombomodulin
PubMed: 29866818
DOI: 10.1182/blood-2017-12-768994 -
Journal of Thrombosis and Haemostasis :... May 2022Thrombomodulin (TM) is a transmembrane glycoprotein expressed on the endothelial cell functioning as a cofactor in the anticoagulation system. However, aside from... (Review)
Review
BACKGROUND
Thrombomodulin (TM) is a transmembrane glycoprotein expressed on the endothelial cell functioning as a cofactor in the anticoagulation system. However, aside from anticoagulation, recent studies have revealed its multiple organ protective roles such as anti-inflammation, angiogenesis, and cell proliferation, which may redefine the function of TM. Although TM is predominantly expressed on placental trophoblasts, the physiological role of TM during pregnancy remains unclear. Because the understanding of TM function has drastically progressed, these new discoveries shed light on the unknown activities of placental TM. Moreover, the clinical application of recombinant TM (rTM) has opened the possibility of TM as a therapeutic target for pregnancy complications.
OBJECTIVES
Here, we comprehensively review the studies elucidating the role of TM during pregnancy from both classic and newly discovered perspectives, and seek for its potential as a therapeutic target for pregnancy complications.
METHODS
Basic research using trophoblast cells and transgenic mice, as well as cohort studies of inherited TM deficiency and clinical trials of rTM were summarized, which led us to further discuss the clinical application of rTM as a novel therapeutic for pregnancy complications.
RESULTS AND CONCLUSION
Accumulating evidence suggest the relevance of placental TM deficiency in pregnancy complications such as miscarriage, fetal growth restriction, and preeclampsia. Most importantly, promising results in animal studies and clinical trials further assure the possibility of rTM as an optimal therapeutic for such conditions. The therapeutic potential of TM raised throughout this review could drastically change the clinical approach to pregnancy complication and improve maternal outcomes.
Topics: Animals; Anti-Inflammatory Agents; Anticoagulants; Female; Humans; Mice; Placenta; Pre-Eclampsia; Pregnancy; Thrombomodulin
PubMed: 35191182
DOI: 10.1111/jth.15680 -
The Journal of Thoracic and... Dec 2017
Topics: Acute Lung Injury; Animals; Cardiopulmonary Bypass; Humans; Rats; Thrombomodulin
PubMed: 28669441
DOI: 10.1016/j.jtcvs.2017.05.093 -
American Journal of Physiology. Heart... Jun 2013Thrombomodulin (TM) is a 557-amino acid protein with a broad cell and tissue distribution consistent with its wide-ranging physiological roles. When expressed on the... (Review)
Review
Thrombomodulin (TM) is a 557-amino acid protein with a broad cell and tissue distribution consistent with its wide-ranging physiological roles. When expressed on the lumenal surface of vascular endothelial cells in both large vessels and capillaries, its primary function is to mediate endothelial thromboresistance. The complete integral membrane-bound protein form displays five distinct functional domains, although shorter soluble (functional) variants comprising the extracellular domains have also been reported in fluids such as serum and urine. TM-mediated binding of thrombin is known to enhance the specificity of the latter serine protease toward both protein C and thrombin activatable fibrinolysis inhibitor (TAFI), increasing their proteolytic activation rate by almost three orders of magnitude with concomitant anticoagulant, antifibrinolytic, and anti-inflammatory benefits to the vascular wall. Recent years have seen an abundance of research into the cellular mechanisms governing endothelial TM production, processing, and regulation (including flow-mediated mechanoregulation)--from transcriptional and posttranscriptional (miRNA) regulation of TM gene expression, to posttranslational processing and release of the expressed protein--facilitating greater exploitation of its therapeutic potential. The goal of the present paper is to comprehensively review the endothelial/TM system from these regulatory perspectives and draw some fresh conclusions. This paper will conclude with a timely examination of the current status of TM's growing therapeutic appeal, from novel strategies to improve the clinical efficacy of recombinant TM analogs for resolution of vascular disorders such as disseminated intravascular coagulation (DIC), to an examination of the complex pleiotropic relationship between statin treatment and TM expression.
Topics: Animals; Endothelium, Vascular; Gene Expression; Gene Expression Regulation; Humans; Thrombomodulin; Vascular Diseases
PubMed: 23604713
DOI: 10.1152/ajpheart.00096.2013 -
Medicine Mar 2021Previous studies displayed that thrombomodulin gene polymorphisms are closely associated with venous thromboembolism (VTE), while the results are inconsistent....
BACKGROUND
Previous studies displayed that thrombomodulin gene polymorphisms are closely associated with venous thromboembolism (VTE), while the results are inconsistent. Therefore, we conducted a meta-analysis to accurately determine the association between thrombomodulin gene polymorphism and the risk of VTE.
METHODS
Wanfang, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, PubMed, EmBase, and Web of Science databases were searched, and the time to build the database was set until January 2021. The association between thrombomodulin gene polymorphism and the risk of VTE was evaluated. Meta-analysis was performed with STATA 16.0 software, and the odds ratio and its 95% confidence interval were applied to estimate the relationship between thrombomodulin gene polym'orphism and the risk of VTE.
RESULTS
The results of this meta-analysis will be submitted to a peer-reviewed journal for publication.
CONCLUSION
This meta-analysis will summarize the relationship between thrombomodulin genepolymorphism and VTE risk.
ETHICS AND DISSEMINATION
Ethical approval was not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and shared on social media platforms. This review would be disseminated in a peer-reviewed journal or conference presentations.
OSF REGISTRATION NUMBER
DOI 10.17605/OSF.IO/UEHJP.
Topics: Case-Control Studies; Genetic Predisposition to Disease; Genotype; Humans; Meta-Analysis as Topic; Odds Ratio; Polymorphism, Genetic; Research Design; Risk Factors; Systematic Reviews as Topic; Thrombomodulin; Venous Thromboembolism
PubMed: 33725974
DOI: 10.1097/MD.0000000000025001