Abstract
Sepsis results in the concurrent activation of inflammatory and procoagulant pathways. Bacterial products and proinflammatory cytokines trigger the coagulation system primarily via induction of tissue factor. During sepsis, activation of coagulation is accompanied by impaired function of major anticoagulant mechanisms, including antithrombin, the protein C system and fibrinolysis. Protease activated receptors (PARs) form the molecular connection between coagulation and inflammation, and especially PAR1 seems to play an eminent role in sepsis pathogenesis. Activated protein C (APC) can cleave PAR1 when associated with either the endothelial protein C receptor (EPCR) or CD11b/CD18, resulting in broad cytoprotective effects mediated by sphingosine 1 phosphate (S1P) receptor 1 (S1P1). In contrast, activation of PAR1 by high dose thrombin results in barrier disruptive effects in endothelial cells via an S1P3 dependent mechanism. Recombinant APC protects against mortality in experimental endotoxemia and sepsis by effects that can be mediated by either EPCR - PAR1 dependent (endothelial cells, dendritic cells) or CD11b/CD18 – PAR1 dependent (macrophages) mechanisms. These protective APC effects do not rely on the anticoagulant properties of this protein. APC mutants that lack anticoagulant properties but retain the capacity to activate PAR1 are promising new drugs for sepsis treatment.
Keywords: Activated protein C, coagulation, inflammation, protease activated receptors, sepsis, TF, endothelial cells, dendritic cells, Toll-like receptors, endotoxemia
Current Vascular Pharmacology
Title:Crosstalk between Inflammation and Coagulation: The Lessons of Sepsis
Volume: 10 Issue: 5
Author(s): Tom van der Poll and Marcel Levi
Affiliation:
Keywords: Activated protein C, coagulation, inflammation, protease activated receptors, sepsis, TF, endothelial cells, dendritic cells, Toll-like receptors, endotoxemia
Abstract: Sepsis results in the concurrent activation of inflammatory and procoagulant pathways. Bacterial products and proinflammatory cytokines trigger the coagulation system primarily via induction of tissue factor. During sepsis, activation of coagulation is accompanied by impaired function of major anticoagulant mechanisms, including antithrombin, the protein C system and fibrinolysis. Protease activated receptors (PARs) form the molecular connection between coagulation and inflammation, and especially PAR1 seems to play an eminent role in sepsis pathogenesis. Activated protein C (APC) can cleave PAR1 when associated with either the endothelial protein C receptor (EPCR) or CD11b/CD18, resulting in broad cytoprotective effects mediated by sphingosine 1 phosphate (S1P) receptor 1 (S1P1). In contrast, activation of PAR1 by high dose thrombin results in barrier disruptive effects in endothelial cells via an S1P3 dependent mechanism. Recombinant APC protects against mortality in experimental endotoxemia and sepsis by effects that can be mediated by either EPCR - PAR1 dependent (endothelial cells, dendritic cells) or CD11b/CD18 – PAR1 dependent (macrophages) mechanisms. These protective APC effects do not rely on the anticoagulant properties of this protein. APC mutants that lack anticoagulant properties but retain the capacity to activate PAR1 are promising new drugs for sepsis treatment.
Export Options
About this article
Cite this article as:
van der Poll Tom and Levi Marcel, Crosstalk between Inflammation and Coagulation: The Lessons of Sepsis, Current Vascular Pharmacology 2012; 10 (5) . https://dx.doi.org/10.2174/157016112801784549
DOI https://dx.doi.org/10.2174/157016112801784549 |
Print ISSN 1570-1611 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6212 |
Call for Papers in Thematic Issues
Advancements in Arterial Stiffness: Novel Therapeutic Frontiers
Arterial stiffness, a hallmark of cardiovascular disease, poses significant challenges in contemporary healthcare. This thematic issue delves into the multifaceted landscape of arterial stiffness and explores cutting-edge therapeutic interventions aimed at mitigating its adverse effects. Within these pages, readers will find a comprehensive overview of the mechanisms underlying arterial stiffness, ...read more
TREATMENT OF CARDIOVASCULAR DISEASE IN CHRONIC AND END STAGE KIDNEY DISEASE
Cardiovascular disease still remains the leading cause of death in Chronic and End Stage Kidney Disease, accounting for more than half of all deaths in dialysis patients. During the past decade, research has been focused on novel therapeutic agents that might delay or even reverse cardiovascular disease and vascular calcification, ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Anabolic Androgenic Steroids Abuse and Liver Toxicity
Mini-Reviews in Medicinal Chemistry The Clinics and Etiology of Preeclampsia
Current Women`s Health Reviews Von Willebrand Factor and Cardiovascular Disease: From a Biochemical Marker to an Attractive Therapeutic Target
Current Vascular Pharmacology Action of Nanoparticles on Platelet Activation and Plasmatic Coagulation
Current Medicinal Chemistry Discovery of Chromen-7-yl Furan-2-Carboxylate as a Potent and Selective Factor XIa Inhibitor
Cardiovascular & Hematological Agents in Medicinal Chemistry Red Cell Membrane Lipids in Hemoglobinopathies
Current Molecular Medicine Candidate Circulating Biomarkers for the Cardiovascular Disease Continuum
Current Pharmaceutical Design Subject Index to Volume 4
Current Drug Targets - Cardiovascular & Hematological Disorders Pigment Epithelium-derived Factor (PEDF) and Cardiometabolic Disorders
Current Pharmaceutical Design Hematoma Expansion: Clinical and Molecular Predictors and Corresponding Pharmacological Treatment
Current Drug Targets Antithrombin, an Important Inhibitor in Blood Clots
Current Topics in Medicinal Chemistry Schizophrenia and Liver Dysfunction Caused by Portacaval Shunting
Current Psychiatry Reviews Interaction Between Platelets and Cytokines - A Possible Role in the Pathogenesis of Preeclampsia
Vascular Disease Prevention (Discontinued) Scientific and Clinical Challenges in Sepsis
Current Pharmaceutical Design Omega-3 Fatty Acids Supplementation in Psychiatric Disorders: A Systematic Review
Current Psychopharmacology Protrhombotic Effects of Contraceptives
Current Pharmaceutical Design Subclinical Hypothyroidism and Homeostatic Disturbances: Case Report and Literature Review
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Role of Platelet Signaling in Thrombus Stabilization: Potential Therapeutic Implications
Current Signal Transduction Therapy Recommendations for Severe Hypertriglyceridemia Treatment, are there New Strategies?
Current Vascular Pharmacology Sepsis, Coagulation and Anticoagulants
Endocrine, Metabolic & Immune Disorders - Drug Targets