The maintenance of hemostasis to ensure vascular integrity is dependent upon the rapid conversion of zymogen species of the coagulation cascade to their enzymatically active forms. This process culminates in the generation of the serine protease thrombin and polymerization of fibrin to prevent vascular leak at sites of endothelial cell injury or loss of cellular junctions. Thrombin generation can be initiated by the extrinsic pathway of coagulation through exposure of blood to tissue factor at sites of vascular damage, or alternatively by the coagulation factor (F) XII activated by foreign surfaces with negative charges, such as glass, through the contact activation pathway. Here, we used transient particle tracking microrheology to investigate the mechanical properties of fibrin in response to thrombin generation downstream of both coagulation pathways. We found that the structural heterogeneity of fibrin formation was dependent on the reaction kinetics of thrombin generation. Pharmacological inhibition of FXII activity prolonged the time to form fibrin and increased the degree of heterogeneity of fibrin, resulting in fibrin clots with reduced mechanical properties. Taken together, this study demonstrates a dependency of the physical biology of fibrin formation on activation of the contact pathway of coagulation.
Mathematical modeling of thrombosis typically involves modeling the coagulation cascade. Models of coagulation generally involve the reaction kinetics for dozens of proteins. The resulting system of equations is difficult to parameterize, and its numerical solution is challenging when coupled to blood flow or other physics important to clotting. Prior research suggests that essential aspects of coagulation may be reproduced by simpler models. This evidence motivates a systematic approach to model reduction. We herein introduce an automated framework to generate reduced‐order models of blood coagulation. The framework consists of nested optimizations, where an outer optimization selects the optimal species for the reduced‐order model and an inner optimization selects the optimal reaction rates for the new coagulation network. The framework was tested on an established 34‐species coagulation model to rigorously consider what level of model fidelity is necessary to capture essential coagulation dynamics. The results indicate that a nine‐species reduced‐order model is sufficient to reproduce the thrombin dynamics of the benchmark 34‐species model for a range of tissue factor concentrations, including those not included in the optimization process. Further model reduction begins to compromise the ability to capture the thrombin generation process. The framework proposed herein enables automated development of reduced‐order models of coagulation that maintain essential dynamics used to model thrombosis.
more » « less- NSF-PAR ID:
- 10453725
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- International Journal for Numerical Methods in Biomedical Engineering
- Volume:
- 35
- Issue:
- 10
- ISSN:
- 2040-7939
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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