It has become increasingly evident in recent years that, apart from the key role that thrombin plays in the blood coagulation cascade, thrombin also elicits cellular actions via the activation of proteinase-activated receptors, which are present in many cell types. These effects of thrombin are seen in a variety of physiological as well as pathological phenomena, including vascular development and physiology, tumor progression and metastasis, neuronal functions, inflammation, angiogenesis. Thrombin: Physiology and Disease, edited by Michael E. Maragoudakis and Nikos E. Tsopanoglou, emphasizes the new developments in this important field of research and provides the basis for translating these findings into therapeutic targets."
Table of contents
Table of contents
1. Thrombin: structure, functions and regulation
1.1. Introduction
1.2. Thrombin and Na+
1.3. Thrombin structure
1.4. Kinetics of Na+ activation
1.5. Structures of E*, E and E:Na+
1.6. Thrombin interaction with protein C
1.7. Thrombin interaction with the PARs
1.8. Dissociating procoagulant and anticoagulant activities
1.9. WE: a prototypic anticoagulant/antithrombotic thrombin
1.10. References
2. Thrombin: to PAR or not to PAR, and the regulation of inflammation
2.1. Introduction
2.2. Thrombin and the search for its receptor
2.3. Enzymes other than thrombin that are potential physiological regulators of PARs
2.3.1. Enzymes of the coagulation pathway
2.3.2. Proteinases of the gastrointestinal tract
2.3.3. PAR-regulating proteinases in the central nervous system
2.3.4. Immune cell-derived proteinases and PARs
2.3.5. Tumor-derived proteinases and a possible physiological role for kallikrein-related peptidases (KLKs) as PAR regulators
2.3.6. Pathogen-derived proteinases and PAR activation
2.4. Receptor dynamics and cell signaling: enzyme versus peptide-mediated activation
2.4.1. PAR-mediated signaling
2.4.2. PAR activation by enzyme versus peptide
2.5. PAR activation and the inflammation actions of thrombin
2.6. Non-PAR mechanisms of cell regulation mediated by thrombin and other proteinases
2.6.1. Signaling targets that are not "classical" receptors
2.6.2. Non-catalytic mechanisms for proteinase-mediated signaling
2.6.3. Thrombin-mediated generation of agonists from fibrin and other substrates
2.7. Therapeutic implications of thrombin action via PAR and non-PAR mechanisms
2.7.1. Targeting thrombin and other serine proteinases
2.7.2. Targeting the PARs
2.8. Summary
2.9. Acknowledgements
2.10. References
3. Regulation of thrombin receptor signaling
3.1. Introduction
3.2. Cell type specific expression of thrombin receptors
3.3. Thrombin receptor activation and signaling
3.3.1. Proteolytic mechanism of thrombin receptor activation
3.3.2. Thrombin receptor signaling to heterotrimeric G-proteins
3.3.3. Cell type specific thrombin receptor signaling
3.4. Regulation of thrombin receptor signaling
3.4.1. Thrombin receptor desensitization
3.4.2. Thrombin receptor internalization
3.4.3. Thrombin receptor down-regulation
3.5. PAR activation and signaling by other proteases
3.6. Conclusions
3.7. Acknowledgements
3.8. References
4. Thrombin-activated protein C: integrated to regulate vascular physiology
4.1. The protein C pathway is localized to the endothelial cell surface and limits thrombin generation through negative feedback
4.2. APC has protective effects in systemic inflammation that are independent of its anticoagulant function
4.3. The thrombin receptor PAR1 mediates APC signaling in tissues culture
4.4. APC and thrombin can mediate opposite cellular responses in endothelial cells through PAR1 activation
4.4.1. Barrier integrity
4.4.2. Adhesion molecule expression
4.4.3. Apoptosis
4.5. Role of the sphingosine-1 phosphate pathway in mediating protective signaling by PAR1.
4.6. Protective PAR1 signaling by APC is mechanistically coupled to PC activation by thrombin
4.7. Not PAR1- or EPCR-dependent mechanisms for signaling by the PC pathway?
4.8. Thrombin-PAR1 and APC-PAR1 signaling in in vivo models of inflammation
4.9. How can activation of the thrombin receptor PAR1 by the PC pathway be of physiological relevance?
4.9.1. PAR1 cleavage by APC is very inefficient compared with thrombin
4.9.2. What are physiological relevant concentrations of thrombin and APC?
4.9.3. Are dual roles of PAR1 dependent on kinetics of receptor activation?
4.9.4. What is the role of membrane compartmentalization of PAR1?
4.9.5. Surface-retention of APC- but not thrombin-cleaved PAR-1?
4.10. Conclusion
4.11. References
5. The role of thrombin in vascular development
5.1. Introduction
5.2. The coagulation cascade
5.3. Intrinsic pathway
5.4. Extrinsic pathway
5.4.1. Tissue factor
5.4.2. Factor VII
5.5. Common pathway
5.6. FII
5.7. Blood coagulation and vasculogenesis
5.8. Thrombin recaptors
5.9. Diversity of thrombin signaling
5.10. Conclusion
5.11. References
6. The role of thrombin in angiogenesis
6.1. Angiogenesis in health and disease
6.2. Angiogenesis and the coagulation system
6.3. Thrombin-induced angiogenesis: Involvement of coagulation-dependent pathways
6.4. Thrombin-induced angiogenesis: Involvement of coagulation-independent mechanisms
6.5. Thrombin is a protection factor for endothelial cells
6.6. Thrombin and PAR1 as targets for inhibiting angiogenesis
6.7. Conclusion
6.8. References
7. Thrombin and thrombin peptides in wound healing and tissue repair
7.1. Introduction
7.2. Proteolytic and non-proteolytic cell signaling
7.3. Biological activity of thrombin peptides
7.4. Cellular effects of TP508
7.4.1. Chemotaxis
7.4.2. Angiogenesis
7.4.3. Gene expression
7.5. Animal models of wound healing
7.6. Clinical studies
7.6.1. Diabetic foot ulcers
7.6.2. Distal radius fracture repair
7.7. Conclusions
7.8. References
8. The role of thrombin and thrombin receptors in the brain
8.1. Introduction
8.2. Thrombin in neural development and plasticity
8.3. Thrombin in neyroinflammation
8.4. Thrombin in neurodegenerative disorders
8.4.1. Thrombin in stroke
8.4.2. Thrombin and Alzheimer’s disease
8.4.3. Thrombin and Parkinson’s disease
8.4.4. Thrombin and multiple sclerosis
8.4.5. Thrombin and HIV
8.5. Conclusions
8.6. References
9. The role of thrombin in tumor biology
9.1. Introduction
9.2. Thrombin can stimulate tumor growth in vivo
9.2.1. Supporting evidence
9.2.2. Mechanisms of thrombin-tumor interactions
9.3. Thrombin and metastases
9.3.1. Supporting evidence
9.3.2. Mechanisms of thrombin promoting metastases
9.3.3. Thrombin and metastases: a proposed mechanism
9.4. Thrombin and tumor cell dormancy
9.4.1. Evidence for dormancy
9.4.2. The possible role of thrombin
9.5. References
10. The role of thrombin and its receptors in epithelial malignancies: lessons from a transgenic mouse model and transcriptional regulation
10.1. Morphogenesis of epithelia sheets
10.2. PAR1 over-expression directly correlates with metastatic potential: lessons from malignant and physiological invasion processes
10.3. Placenta physiological invasion
10.4. Transgenic mice of hPar1 targeted to over-express in the mammary gland tissue
10.5. Wnt-4 and wnt-7b are over-expressed in hPar1-tg mammary glands
10.6. Catenin stabilization by hPar1
10.7. hPar1 acts as a survival factor while promoting tumor progression
10.8. Transcriptional regulation of human Par1
10.9. Concluding remarks
10.10. References
11. Anti-thrombotic therapy in cancer patients
11.1. Introduction
11.2. Clinical challenges and epidemiology
11.3. Thromboprophylaxis
11.3.1. Primary surgical thromboprophylaxis
11.3.2. Prevention of VTE in non-surgical patients
11.4. Treatment of venous thromboembolism
11.5. Prevention of secondary recurrence
11.6. Anti-thrombotic and cancer survival
11.7. Conclusion
11.8. References
12. Thrombin receptor modulators: medicinal chemistry, biological evaluation and clinical application
12.1. Introduction
12.2. Proteinase-activated receptor-1 (PAR1) modulators
12.2.1. Peptide agonists and antagonists
12.2.2. Peptidomimetic antagonists
12.2.3. Non-peptide antagonists
12.2.4. Cell-penetrating pepducins
12.3. Proteinase-activated receptor-4 (PAR4) modulators
12.3.1. Peptide agonists
12.3.2. Peptide and non-peptide antagonists
12.3.3. Cell-penetrating pepducins
12.4. Potential therapeutic applications
12.4.1. Anti-thrombotic agents
12.4.2. Treatment of atherosclerosis and restenosis
12.4.3. Anticancer therapeutics
12.5. Conclusion
12.6. References
13. Novel anticoagulant therapy: principle and practice
13.1. Introduction
13.2. Anticoagulant targets that inhibit the initiation phase
13.2.1. Tissue factor/Factor VIIa complex inhibitors
13.3. Inhibitors of coagulation propagation
13.3.1. Indirect Factor Xa inhibitors
13.3.2. Selective direct Factor Xa inhibitors
13.3.3. Selective, direct Factor IXa inhibitors
13.3.4. Factor XIa inhibitors
13.4. Inhibitors of thrombin activity
13.4.1. Indirect thrombin inhibitors
13.4.2. Direct thrombin inhibitors
13.4.3. Selective oral direct thrombin inhibitors
13.5. Expert opinion and conclusions
13.6. References