Abstract
PurposeThis study establishes a multiphysics simulation platform for both conventional and targeted thrombolysis using tissue plasminogen activator (tPA). Based on our computational results, the effects of therapeutic parameters on the dynamics of thrombolysis and the risk of side effects are investigated.MethodsThe model extends our previously developed one-dimensional(1D) mathematical models for fibrinolysis by incorporating targeted thrombolysis. It consists of two parts: (i) a coupled mathematical model of systemic pharmacokinetics (PK) and pharmacodynamics (PD) and local PD in a 1D occluded artery, and (ii) a mechanistic model for a targeted thrombolytic system via activated platelet-targeted tPA-loaded nanovesicles (tPA-NV), with model parameters derived from our in vitro experiments. A total of 16 therapeutic scenarios are simulated by varying the clot location and composition as well as the dosing regimen with free tPA or tPA-NV.ResultsOur simulation results indicate that tPA-NV offers several advantages over free tPA for thrombolysis. It reduces systemic exposure of tPA, thereby minimising the risk of bleeding complications. Simulations with different tPA-NV doses reveal that tPA-NV at 10% of the recommended dose can be as effective as the standard regimen with the full recommended dose of free tPA, demonstrating the potential of our tPA-NV as a new thrombolytic strategy with a reduced tPA dose. Moreover, faster recanalisation can be achieved with tPA-NV, especially for platelet-rich(or fibrin-poor) clots.ConclusionsOur simulation platform for thrombolysis with well-tuned model parameters can be used to evaluate and optimise treatment regimens of existing and new thrombolytic therapies via benefit/risk assessment under various therapeutic scenarios.
Highlights
Thrombolytic therapy aims to restore blood flow by dissolving blood clots lodged in blood vessels
Our simulation results indicate that tissue plasminogen activator (tPA)-NV offers several advantages over free tPA for thrombolysis
Simulations with different tPA-loaded nanovesicles (tPA-NV) doses reveal that tPA-NV at 10% of the recommended dose can be as effective as the standard regimen with the full recommended dose of free tPA, demonstrating the potential of our tPA-NV as a new thrombolytic strategy with a reduced tPA dose
Summary
Thrombolytic therapy aims to restore blood flow by dissolving blood clots lodged in blood vessels. Blood clots can cause catastrophic cardiovascular events such as myocardial infarction, ischaemic stroke and pulmonary embolism [1, 2]. Conventional thrombolytic therapy involves intravenous administration of tissue plasminogen activator (tPA), which targets fibrin within blood clots [3, 4]. This thrombolytic therapy is known to be effective, it can cause severe bleeding complications due to systemic circulation of tPA and its influence on reducing fibrinogen levels. TPA has a short half-life, approximately 4 to 6 mins [5], which means high doses are needed to maintain therapeutic levels. The dosing regimen recommended by the US Food and Drug Administration (FDA) for the treatment of
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