Internal fibrinolysis of fibrin clots is driven by pore expansion
Abstract Blood clots, which are composed of blood cells and a stabilizing mesh of fibrin fibers, are critical in cessation of bleeding following injury. However, their action is transient and after performing their physiological function they must be resolved through a process known as fibrinolysis....
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-52844-4 |
| _version_ | 1797275232384319488 |
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| author | Rebecca A. Risman Bradley Paynter Victoria Percoco Mitali Shroff Brittany E. Bannish Valerie Tutwiler |
| author_facet | Rebecca A. Risman Bradley Paynter Victoria Percoco Mitali Shroff Brittany E. Bannish Valerie Tutwiler |
| author_sort | Rebecca A. Risman |
| collection | DOAJ |
| description | Abstract Blood clots, which are composed of blood cells and a stabilizing mesh of fibrin fibers, are critical in cessation of bleeding following injury. However, their action is transient and after performing their physiological function they must be resolved through a process known as fibrinolysis. Internal fibrinolysis is the degradation of fibrin by the endogenous or innate presence of lytic enzymes in the bloodstream; under healthy conditions, this process regulates hemostasis and prevents bleeding or clotting. Fibrin-bound tissue plasminogen activator (tPA) converts nearby plasminogen into active plasmin, which is bound to the fibrin network, breaking it down into fibrin degradation products and releasing the entrapped blood cells. It is poorly understood how changes in the fibrin structure and lytic protein ratios influence the biochemical regulation and behavior of internal fibrinolysis. We used turbidity kinetic tracking and microscopy paired with mathematical modeling to study fibrin structure and lytic protein ratios that restrict internal fibrinolysis. Analysis of simulations and experiments indicate that fibrinolysis is driven by pore expansion of the fibrin network. We show that this effect is strongly influenced by the ratio of fibrin:tPAwhen compared to absolute tPA concentration. Thus, it is essential to consider relative protein concentrations when studying internal fibrinolysis both experimentally and in the clinic. An improved understanding of effective internal lysis can aid in development of better therapeutics for the treatment of bleeding and thrombosis. |
| first_indexed | 2024-03-07T15:11:24Z |
| format | Article |
| id | doaj.art-be496e226fa14300a0de8d9e2d3646dc |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-07T15:11:24Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-be496e226fa14300a0de8d9e2d3646dc2024-03-05T18:39:00ZengNature PortfolioScientific Reports2045-23222024-02-0114111610.1038/s41598-024-52844-4Internal fibrinolysis of fibrin clots is driven by pore expansionRebecca A. Risman0Bradley Paynter1Victoria Percoco2Mitali Shroff3Brittany E. Bannish4Valerie Tutwiler5Department of Biomedical Engineering, Rutgers UniversityDepartment of Mathematics and Statistics, University of Central OklahomaDepartment of Biomedical Engineering, Rutgers UniversityDepartment of Cell Biology and Neuroscience, Rutgers UniversityDepartment of Mathematics and Statistics, University of Central OklahomaDepartment of Biomedical Engineering, Rutgers UniversityAbstract Blood clots, which are composed of blood cells and a stabilizing mesh of fibrin fibers, are critical in cessation of bleeding following injury. However, their action is transient and after performing their physiological function they must be resolved through a process known as fibrinolysis. Internal fibrinolysis is the degradation of fibrin by the endogenous or innate presence of lytic enzymes in the bloodstream; under healthy conditions, this process regulates hemostasis and prevents bleeding or clotting. Fibrin-bound tissue plasminogen activator (tPA) converts nearby plasminogen into active plasmin, which is bound to the fibrin network, breaking it down into fibrin degradation products and releasing the entrapped blood cells. It is poorly understood how changes in the fibrin structure and lytic protein ratios influence the biochemical regulation and behavior of internal fibrinolysis. We used turbidity kinetic tracking and microscopy paired with mathematical modeling to study fibrin structure and lytic protein ratios that restrict internal fibrinolysis. Analysis of simulations and experiments indicate that fibrinolysis is driven by pore expansion of the fibrin network. We show that this effect is strongly influenced by the ratio of fibrin:tPAwhen compared to absolute tPA concentration. Thus, it is essential to consider relative protein concentrations when studying internal fibrinolysis both experimentally and in the clinic. An improved understanding of effective internal lysis can aid in development of better therapeutics for the treatment of bleeding and thrombosis.https://doi.org/10.1038/s41598-024-52844-4 |
| spellingShingle | Rebecca A. Risman Bradley Paynter Victoria Percoco Mitali Shroff Brittany E. Bannish Valerie Tutwiler Internal fibrinolysis of fibrin clots is driven by pore expansion Scientific Reports |
| title | Internal fibrinolysis of fibrin clots is driven by pore expansion |
| title_full | Internal fibrinolysis of fibrin clots is driven by pore expansion |
| title_fullStr | Internal fibrinolysis of fibrin clots is driven by pore expansion |
| title_full_unstemmed | Internal fibrinolysis of fibrin clots is driven by pore expansion |
| title_short | Internal fibrinolysis of fibrin clots is driven by pore expansion |
| title_sort | internal fibrinolysis of fibrin clots is driven by pore expansion |
| url | https://doi.org/10.1038/s41598-024-52844-4 |
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