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Abstract Thromboembolic diseases are a significant cause of mortality and are clinically treated enzymatically with tissue plasminogen activator (tPA). Interestingly, prior studies in fibrin fibers and fibrin gels have demonstrated that thrombolysis may be mechanically sensitive. This study aims to expand mechano‐lytic studies to whole blood clots. Furthermore, this study investigates not only how mechanics impacts lysis but also how lysis impacts mechanics. Therefore, clots made from whole human blood are exposed to tPA while the clots are either stretched or unstretched. After, the resulting degree of clot lysis is measured by weighing the clots and by measuring the concentration of D‐dimer in the surrounding bath. Additionally, each clot's mechanical properties are measured. This study finds that mechanical stretch accelerates loss in clot weight but does not impact the lysis rate as measured by D‐dimer. Moreover, lysis not only removes clot volume but also reduces the remaining clot's stiffness and toughness. In summary, tPA‐induced lysis of whole clot appears mechanically insensitive, but stretch reduces clot weight. Furthermore, results show that thrombolysis weakens clot. This suggests that thrombolysis may increase the risk of secondary embolizations but may also ease clot removal during thrombectomy, for example.
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A mathematical model of plasmin-mediated fibrinolysis of single fibrin fibers
Fibrinolysis, the plasmin-mediated degradation of the fibrin mesh that stabilizes blood clots, is an important physiological process, and understanding mechanisms underlying lysis is critical for improved stroke treatment. Experimentalists are now able to study lysis on the scale of single fibrin fibers, but mathematical models of lysis continue to focus mostly on fibrin network degradation. Experiments have shown that while some degradation occurs along the length of a fiber, ultimately the fiber is cleaved at a single location. We built a 2-dimensional stochastic model of a fibrin fiber cross-section that uses the Gillespie algorithm to study single fiber lysis initiated by plasmin. We simulated the model over a range of parameter values to learn about patterns and rates of single fiber lysis in various physiological conditions. We also used epifluorescent microscopy to measure the cleavage times of fibrin fibers with different apparent diameters. By comparing our model results to the laboratory experiments, we were able to: 1) suggest value ranges for unknown rate constants(namely that the degradation rate of fibrin by plasmin should be ≤ 10 s−1and that if plasmin crawls, the rate of crawling should be between 10 s−1and 60 s−1); 2) estimate the fraction of fibrin within a fiber cross-section that must be degraded for the fiber to cleave in two; and 3) propose that that fraction is higher in thinner fibers and lower in thicker fibers. Collectively, this information provides more details about how fibrin fibers degrade, which can be leveraged in the future for a better understanding of why fibrinolysis is impaired in certain disease states, and could inform intervention strategies.
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- PAR ID:
- 10582247
- Publisher / Repository:
- Public Library of Science
- Date Published:
- Journal Name:
- PLOS Computational Biology
- Volume:
- 20
- Issue:
- 12
- ISSN:
- 1553-7358
- Page Range / eLocation ID:
- e1012684
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1371/journal.pcbi.1012684
