Thrombosis and Inflammation—A Dynamic Interplay and the Role of Glycosaminoglycans and Activated Protein C
Hemostasis, thrombosis, and inflammation are tightly interconnected processes which may give rise to thrombo-inflammation, involved in infectious and non-infectious acute and chronic diseases, including cardiovascular diseases (CVD). Traditionally, due to its hemostatic role, blood coagulation is is...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Cardiovascular Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcvm.2022.866751/full |
| _version_ | 1818308127783649280 |
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| author | Shrey Kohli Khurrum Shahzad Annukka Jouppila Annukka Jouppila Harry Holthöfer Berend Isermann Riitta Lassila Riitta Lassila Riitta Lassila |
| author_facet | Shrey Kohli Khurrum Shahzad Annukka Jouppila Annukka Jouppila Harry Holthöfer Berend Isermann Riitta Lassila Riitta Lassila Riitta Lassila |
| author_sort | Shrey Kohli |
| collection | DOAJ |
| description | Hemostasis, thrombosis, and inflammation are tightly interconnected processes which may give rise to thrombo-inflammation, involved in infectious and non-infectious acute and chronic diseases, including cardiovascular diseases (CVD). Traditionally, due to its hemostatic role, blood coagulation is isolated from the inflammation, and its critical contribution in the progressing CVD is underrated, until the full occlusion of a critical vessel occurs. Underlying vascular injury exposes extracellular matrix to deposit platelets and inflammatory cells. Platelets being key effector cells, bridge all the three key processes (hemostasis, thrombosis, and inflammation) associated with thrombo-inflammation. Under physiological conditions, platelets remain in an inert state despite the proximity to the endothelium and other cells which are decorated with glycosaminoglycan (GAG)-rich glycocalyx (GAGs). A pathological insult to the endothelium results in an imbalanced blood coagulation system hallmarked by increased thrombin generation due to losses of anticoagulant and cytoprotective mechanisms, i.e., the endothelial GAGs enhancing antithrombin, tissue factor pathway-inhibitor (TFPI) and thrombomodulin-protein C system. Moreover, the loss of GAGs promotes the release of mediators, such as von Willebrand factor (VWF), platelet factor 4 (PF4), and P-selectin, both locally on vascular surfaces and to circulation, further enhancing the adhesion of platelets to the affected sites. Platelet-neutrophil interaction and formation of neutrophil extracellular traps foster thrombo-inflammatory mechanisms exacerbating the cardiovascular disease course. Therefore, therapies which not only target the clotting mechanisms but simultaneously or independently convey potent cytoprotective effects hemming the inflammatory mechanisms are expected to provide clinical benefits. In this regard, we review the cytoprotective protease activated protein C (aPC) and its strong anti-inflammatory effects thereby preventing the ensuing thrombotic complications in CVD. Furthermore, restoring GAG-like vasculo-protection, such as providing heparin-proteoglycan mimetics to improve regulation of platelet and coagulation activity and to suppress of endothelial perturbance and leukocyte-derived pro-inflammatory cytokines, may provide a path to alleviate thrombo-inflammatory disorders in the future. The vascular tissue-modeled heparin proteoglycan mimic, antiplatelet and anticoagulant compound (APAC), dual antiplatelet and anticoagulant, is an injury-targeting and locally acting arterial antithrombotic which downplays collagen- and thrombin-induced and complement-induced activation and protects from organ injury. |
| first_indexed | 2024-12-13T07:09:20Z |
| format | Article |
| id | doaj.art-b61a50fdc41a4b93a12d28326398bda3 |
| institution | Directory Open Access Journal |
| issn | 2297-055X |
| language | English |
| last_indexed | 2024-12-13T07:09:20Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cardiovascular Medicine |
| spelling | doaj.art-b61a50fdc41a4b93a12d28326398bda32022-12-21T23:55:42ZengFrontiers Media S.A.Frontiers in Cardiovascular Medicine2297-055X2022-03-01910.3389/fcvm.2022.866751866751Thrombosis and Inflammation—A Dynamic Interplay and the Role of Glycosaminoglycans and Activated Protein CShrey Kohli0Khurrum Shahzad1Annukka Jouppila2Annukka Jouppila3Harry Holthöfer4Berend Isermann5Riitta Lassila6Riitta Lassila7Riitta Lassila8Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig University, Leipzig, GermanyInstitute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig University, Leipzig, GermanyClinical Research Institute HUCH, Helsinki, FinlandResearch Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, FinlandZentrum für Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, Hamburg, GermanyInstitute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig University, Leipzig, GermanyResearch Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, FinlandCoagulation Disorders Unit, Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, University of Helsinki, Helsinki, FinlandAplagon Ltd., Helsinki, FinlandHemostasis, thrombosis, and inflammation are tightly interconnected processes which may give rise to thrombo-inflammation, involved in infectious and non-infectious acute and chronic diseases, including cardiovascular diseases (CVD). Traditionally, due to its hemostatic role, blood coagulation is isolated from the inflammation, and its critical contribution in the progressing CVD is underrated, until the full occlusion of a critical vessel occurs. Underlying vascular injury exposes extracellular matrix to deposit platelets and inflammatory cells. Platelets being key effector cells, bridge all the three key processes (hemostasis, thrombosis, and inflammation) associated with thrombo-inflammation. Under physiological conditions, platelets remain in an inert state despite the proximity to the endothelium and other cells which are decorated with glycosaminoglycan (GAG)-rich glycocalyx (GAGs). A pathological insult to the endothelium results in an imbalanced blood coagulation system hallmarked by increased thrombin generation due to losses of anticoagulant and cytoprotective mechanisms, i.e., the endothelial GAGs enhancing antithrombin, tissue factor pathway-inhibitor (TFPI) and thrombomodulin-protein C system. Moreover, the loss of GAGs promotes the release of mediators, such as von Willebrand factor (VWF), platelet factor 4 (PF4), and P-selectin, both locally on vascular surfaces and to circulation, further enhancing the adhesion of platelets to the affected sites. Platelet-neutrophil interaction and formation of neutrophil extracellular traps foster thrombo-inflammatory mechanisms exacerbating the cardiovascular disease course. Therefore, therapies which not only target the clotting mechanisms but simultaneously or independently convey potent cytoprotective effects hemming the inflammatory mechanisms are expected to provide clinical benefits. In this regard, we review the cytoprotective protease activated protein C (aPC) and its strong anti-inflammatory effects thereby preventing the ensuing thrombotic complications in CVD. Furthermore, restoring GAG-like vasculo-protection, such as providing heparin-proteoglycan mimetics to improve regulation of platelet and coagulation activity and to suppress of endothelial perturbance and leukocyte-derived pro-inflammatory cytokines, may provide a path to alleviate thrombo-inflammatory disorders in the future. The vascular tissue-modeled heparin proteoglycan mimic, antiplatelet and anticoagulant compound (APAC), dual antiplatelet and anticoagulant, is an injury-targeting and locally acting arterial antithrombotic which downplays collagen- and thrombin-induced and complement-induced activation and protects from organ injury.https://www.frontiersin.org/articles/10.3389/fcvm.2022.866751/fullthrombo-inflammationneutrophil extracellular traps (NETs)activated protein C (aPC)glycosamine glycansplatelet-neutrophil complexesplatelet activation |
| spellingShingle | Shrey Kohli Khurrum Shahzad Annukka Jouppila Annukka Jouppila Harry Holthöfer Berend Isermann Riitta Lassila Riitta Lassila Riitta Lassila Thrombosis and Inflammation—A Dynamic Interplay and the Role of Glycosaminoglycans and Activated Protein C Frontiers in Cardiovascular Medicine thrombo-inflammation neutrophil extracellular traps (NETs) activated protein C (aPC) glycosamine glycans platelet-neutrophil complexes platelet activation |
| title | Thrombosis and Inflammation—A Dynamic Interplay and the Role of Glycosaminoglycans and Activated Protein C |
| title_full | Thrombosis and Inflammation—A Dynamic Interplay and the Role of Glycosaminoglycans and Activated Protein C |
| title_fullStr | Thrombosis and Inflammation—A Dynamic Interplay and the Role of Glycosaminoglycans and Activated Protein C |
| title_full_unstemmed | Thrombosis and Inflammation—A Dynamic Interplay and the Role of Glycosaminoglycans and Activated Protein C |
| title_short | Thrombosis and Inflammation—A Dynamic Interplay and the Role of Glycosaminoglycans and Activated Protein C |
| title_sort | thrombosis and inflammation a dynamic interplay and the role of glycosaminoglycans and activated protein c |
| topic | thrombo-inflammation neutrophil extracellular traps (NETs) activated protein C (aPC) glycosamine glycans platelet-neutrophil complexes platelet activation |
| url | https://www.frontiersin.org/articles/10.3389/fcvm.2022.866751/full |
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