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The APC-EPCR-PAR1 axis in sickle cell disease

Sickle Cell Disease (SCD) is a group of inherited hemoglobinopathies. Sickle cell anemia (SCA) is caused by a homozygous mutation in the β-globin generating sickle hemoglobin (HbS). Deoxygenation leads to pathologic polymerization of HbS and sickling of erythrocytes. The two predominant pathologies...

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Autores principales: Ramadas, Nirupama, Sparkenbaugh, Erica M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10366386/
https://www.ncbi.nlm.nih.gov/pubmed/37497271
http://dx.doi.org/10.3389/fmed.2023.1141020
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author Ramadas, Nirupama
Sparkenbaugh, Erica M.
author_facet Ramadas, Nirupama
Sparkenbaugh, Erica M.
author_sort Ramadas, Nirupama
collection PubMed
description Sickle Cell Disease (SCD) is a group of inherited hemoglobinopathies. Sickle cell anemia (SCA) is caused by a homozygous mutation in the β-globin generating sickle hemoglobin (HbS). Deoxygenation leads to pathologic polymerization of HbS and sickling of erythrocytes. The two predominant pathologies of SCD are hemolytic anemia and vaso-occlusive episodes (VOE), along with sequelae of complications including acute chest syndrome, hepatopathy, nephropathy, pulmonary hypertension, venous thromboembolism, and stroke. SCD is associated with endothelial activation due to the release of danger-associated molecular patterns (DAMPs) such as heme, recurrent ischemia–reperfusion injury, and chronic thrombin generation and inflammation. Endothelial cell activation is mediated, in part, by thrombin-dependent activation of protease-activated receptor 1 (PAR1), a G protein coupled receptor that plays a role in platelet activation, endothelial permeability, inflammation, and cytotoxicity. PAR1 can also be activated by activated protein C (APC), which promotes endothelial barrier protection and cytoprotective signaling. Notably, the APC system is dysregulated in SCD. This mini-review will discuss activation of PAR1 by APC and thrombin, the APC-EPCR-PAR1 axis, and their potential roles in SCD.
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spelling pubmed-103663862023-07-26 The APC-EPCR-PAR1 axis in sickle cell disease Ramadas, Nirupama Sparkenbaugh, Erica M. Front Med (Lausanne) Medicine Sickle Cell Disease (SCD) is a group of inherited hemoglobinopathies. Sickle cell anemia (SCA) is caused by a homozygous mutation in the β-globin generating sickle hemoglobin (HbS). Deoxygenation leads to pathologic polymerization of HbS and sickling of erythrocytes. The two predominant pathologies of SCD are hemolytic anemia and vaso-occlusive episodes (VOE), along with sequelae of complications including acute chest syndrome, hepatopathy, nephropathy, pulmonary hypertension, venous thromboembolism, and stroke. SCD is associated with endothelial activation due to the release of danger-associated molecular patterns (DAMPs) such as heme, recurrent ischemia–reperfusion injury, and chronic thrombin generation and inflammation. Endothelial cell activation is mediated, in part, by thrombin-dependent activation of protease-activated receptor 1 (PAR1), a G protein coupled receptor that plays a role in platelet activation, endothelial permeability, inflammation, and cytotoxicity. PAR1 can also be activated by activated protein C (APC), which promotes endothelial barrier protection and cytoprotective signaling. Notably, the APC system is dysregulated in SCD. This mini-review will discuss activation of PAR1 by APC and thrombin, the APC-EPCR-PAR1 axis, and their potential roles in SCD. Frontiers Media S.A. 2023-07-11 /pmc/articles/PMC10366386/ /pubmed/37497271 http://dx.doi.org/10.3389/fmed.2023.1141020 Text en Copyright © 2023 Ramadas and Sparkenbaugh. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Ramadas, Nirupama
Sparkenbaugh, Erica M.
The APC-EPCR-PAR1 axis in sickle cell disease
title The APC-EPCR-PAR1 axis in sickle cell disease
title_full The APC-EPCR-PAR1 axis in sickle cell disease
title_fullStr The APC-EPCR-PAR1 axis in sickle cell disease
title_full_unstemmed The APC-EPCR-PAR1 axis in sickle cell disease
title_short The APC-EPCR-PAR1 axis in sickle cell disease
title_sort apc-epcr-par1 axis in sickle cell disease
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10366386/
https://www.ncbi.nlm.nih.gov/pubmed/37497271
http://dx.doi.org/10.3389/fmed.2023.1141020
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