Loss of protein C vs protein S results in discrepant thrombotic phenotypes
Abstract: Venous thrombosis is a leading cause of morbidity/mortality and associated with deficiencies of the anticoagulant protein C (PC; PROC) and its cofactor, protein S (PS; PROS1). Heterozygous mutations increase the risk of adult-onset thrombosis, whereas homozygous mutations result in pre/neo...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952924007171 |
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| author | Chia-Jui Ku Xinge Yu Queena Y. Zhao Steven J. Grzegorski Jeffrey G. Daniel Allison C. Ferguson Jordan A. Shavit |
| author_facet | Chia-Jui Ku Xinge Yu Queena Y. Zhao Steven J. Grzegorski Jeffrey G. Daniel Allison C. Ferguson Jordan A. Shavit |
| author_sort | Chia-Jui Ku |
| collection | DOAJ |
| description | Abstract: Venous thrombosis is a leading cause of morbidity/mortality and associated with deficiencies of the anticoagulant protein C (PC; PROC) and its cofactor, protein S (PS; PROS1). Heterozygous mutations increase the risk of adult-onset thrombosis, whereas homozygous mutations result in pre/neonatal lethal thrombosis. Phenotypes of patients with PC and PS deficiency are generally considered clinically indistinguishable. Here, we generate proc (zebrafish PROC ortholog) and pros1 knockouts through genome editing in zebrafish and uncover partially discordant phenotypes. proc−/− mutants exhibited ∼70% lethality at 1 year of age, whereas pros1−/− survival was unaffected. Induced venous endothelial injury in both mutants revealed reduced occlusive thrombus formation. This is consistent with the consumptive coagulopathy of zebrafish antithrombin 3 knockouts, which also results in spontaneous venous thrombosis. However, proc and pros1 mutants revealed a discrepancy. Although both mutants demonstrated spontaneous thrombosis, proc−/− was localized to the cardiac and venous systems, whereas pros1−/− was intracardiac. Aside from coagulation, PC has been shown to have PS-independent roles in inflammation. proc mutants displayed altered inflammatory markers and defects in neutrophil migration independent of pros1. Transcriptomic analysis and gene knockdown identified novel proc genetic interactions with adgrf7, a G protein-coupled receptor (GPCR) not previously known to be involved in coagulation. In summary, our data reveal differences between PC- and PS-deficient thrombosis, with cardiovascular tissue–specific phenotypes and survival differences, suggesting the possibility of underlying clinical differences in affected patients. This model of complete proc−/− deficiency in an accessible organism will facilitate further in vivo study of these distinctions, as well as PS-dependent and -independent functions of PC. |
| format | Article |
| id | doaj-art-3bdfcb10ba4c4ad187da66a88882423e |
| institution | Kabale University |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-3bdfcb10ba4c4ad187da66a88882423e2025-01-31T05:12:10ZengElsevierBlood Advances2473-95292025-02-0193545557Loss of protein C vs protein S results in discrepant thrombotic phenotypesChia-Jui Ku0Xinge Yu1Queena Y. Zhao2Steven J. Grzegorski3Jeffrey G. Daniel4Allison C. Ferguson5Jordan A. Shavit6Department of Pediatrics, University of Michigan, Ann Arbor, MIDepartment of Pediatrics, University of Michigan, Ann Arbor, MIDepartment of Pediatrics, University of Michigan, Ann Arbor, MIDepartment of Pediatrics, University of Michigan, Ann Arbor, MIDepartment of Pediatrics, University of Michigan, Ann Arbor, MIDepartment of Pediatrics, University of Michigan, Ann Arbor, MIDepartment of Pediatrics, University of Michigan, Ann Arbor, MI; Department of Human Genetics, University of Michigan, Ann Arbor, MI; Correspondence: Jordan A. Shavit, Department of Pediatrics, University of Michigan, Room 8301, Medical Science Research Building III, 1150 West Medical Center Dr, Ann Arbor, MI 48109;Abstract: Venous thrombosis is a leading cause of morbidity/mortality and associated with deficiencies of the anticoagulant protein C (PC; PROC) and its cofactor, protein S (PS; PROS1). Heterozygous mutations increase the risk of adult-onset thrombosis, whereas homozygous mutations result in pre/neonatal lethal thrombosis. Phenotypes of patients with PC and PS deficiency are generally considered clinically indistinguishable. Here, we generate proc (zebrafish PROC ortholog) and pros1 knockouts through genome editing in zebrafish and uncover partially discordant phenotypes. proc−/− mutants exhibited ∼70% lethality at 1 year of age, whereas pros1−/− survival was unaffected. Induced venous endothelial injury in both mutants revealed reduced occlusive thrombus formation. This is consistent with the consumptive coagulopathy of zebrafish antithrombin 3 knockouts, which also results in spontaneous venous thrombosis. However, proc and pros1 mutants revealed a discrepancy. Although both mutants demonstrated spontaneous thrombosis, proc−/− was localized to the cardiac and venous systems, whereas pros1−/− was intracardiac. Aside from coagulation, PC has been shown to have PS-independent roles in inflammation. proc mutants displayed altered inflammatory markers and defects in neutrophil migration independent of pros1. Transcriptomic analysis and gene knockdown identified novel proc genetic interactions with adgrf7, a G protein-coupled receptor (GPCR) not previously known to be involved in coagulation. In summary, our data reveal differences between PC- and PS-deficient thrombosis, with cardiovascular tissue–specific phenotypes and survival differences, suggesting the possibility of underlying clinical differences in affected patients. This model of complete proc−/− deficiency in an accessible organism will facilitate further in vivo study of these distinctions, as well as PS-dependent and -independent functions of PC.http://www.sciencedirect.com/science/article/pii/S2473952924007171 |
| spellingShingle | Chia-Jui Ku Xinge Yu Queena Y. Zhao Steven J. Grzegorski Jeffrey G. Daniel Allison C. Ferguson Jordan A. Shavit Loss of protein C vs protein S results in discrepant thrombotic phenotypes Blood Advances |
| title | Loss of protein C vs protein S results in discrepant thrombotic phenotypes |
| title_full | Loss of protein C vs protein S results in discrepant thrombotic phenotypes |
| title_fullStr | Loss of protein C vs protein S results in discrepant thrombotic phenotypes |
| title_full_unstemmed | Loss of protein C vs protein S results in discrepant thrombotic phenotypes |
| title_short | Loss of protein C vs protein S results in discrepant thrombotic phenotypes |
| title_sort | loss of protein c vs protein s results in discrepant thrombotic phenotypes |
| url | http://www.sciencedirect.com/science/article/pii/S2473952924007171 |
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