Advanced in vitro and in silico models to explore mechanisms of deep vein thrombosis

Baksamawi, Hosam Alden (2024). Advanced in vitro and in silico models to explore mechanisms of deep vein thrombosis. University of Birmingham. Ph.D.

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Abstract

Deep vein thrombosis is a significant global medical issue associated with high levels of illness and death. Investigating DVT mechanisms and discovering innovative approaches for its prevention and treatment rely extensively on animal models; however, using animals in research is associated with technical and ethical challenges, which raise the critical need to create in vitro and in silico models that mimic the formation of thrombi in deep veins without relying on animals. Here, a microfluidics in-vitro method allows for the investigation of valve flexibility through an in-situ fabrication process, which provides independent control over the rigidity of valve leaflets and enables testing under pulsatile flow conditions. Symmetrical valves exhibit platelet accumulation on valve tips, while asymmetrical valves show platelet accumulation within the valve pocket. This model has been further developed by incorporating moving valve leaflets to replicate venous hydrodynamics alongside an endothelial cell monolayer. Employing a pulsatile flow, typical of veins, these experiments reveal that unstimulated human platelets, reconstituted with whole blood, accumulate on the luminal side of leaflet tips in proportion to leaflet flexibility. Thrombin-induced platelet activation results in robust accrual at leaflet tips. GPIbα-vWF interaction blockade abolishes platelet deposition. Histamine-induced endothelial stimulation prompts platelet accrual at the basal side of leaflets, illustrating human thrombi location and indicating a dependence on leaflet flexibility and GPIbα-vWF interaction. An in-silico model has also been developed to simulate particle agglomeration within elastic valves, replicating venous valve geometry and fluid dynamics. The findings support the hypothesis that fluid dynamics near the valve leaflets primarily drive clot formation.

These approaches combine experimental and numerical models to increase our understanding of DVT initiation phenomena, highlighting crucial aspects of thrombus formation. Also, It offers a feasible alternative to animal models in research.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):