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 pathwayinhibitor
(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 GAGlike
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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:85863 |
| Date | 08 June 2023 |
| Creators | Kohli, Shrey, Shahzad, Khurrum, Jouppila, Annukka, Holthöfer, Harry, Isermann, Berend, Lassila, Riitta |
| Publisher | Frontiers Media S.A. |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 866751 |
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