Computational Simulations of Thrombolytic Therapy in Acute Ischaemic Stroke

Abstract

Ischaemic stroke can occur when an artery to the brain is blocked by a blood clot. The use of thrombolytic agents, such as tissue plasminogen activator (tPA), to dissolve the occluding clot is limited by the risk of intracerebral haemorrhage (ICH), a known side effect associated with tPA. We developed a computational thrombolysis model for a 3D patient-specific artery coupled with a compartmental model for temporal concentrations of tPA and lysis proteins during intravenous infusion of tPA, in order to evaluate the effects of tPA dose on the efficacy of thrombolytic therapy and the risk of ICH. The model was applied to a 3-mm-long fibrin clot with two different fibrin fibre radii in the middle cerebral artery (MCA) – a setting relevant to ischaemic stroke, and results for different tPA dose levels and fibrin fibre radii were compared. Our simulation results showed that clot lysis was accelerated at higher tPA doses at the expense of a substantial increase in the risk of ICH. It was also found that a fine clot with a smaller fibre radius dissolved much slowly than a coarse clot due to a slower tPA penetration into the clots.

Mathematical Modelling of Intravenous Thrombolysis in Acute Ischaemic stroke: Effects of Dose Regimens on Levels of Fibrinolytic Proteins and Clot Lysis Time

“…To the best of our knowledge, only two computational studies have attempted to include both the systemic effects of tPA via PK modelling and clot lysis dynamics [19,20]. Anand and Diamond [19], by combining a one-compartment model for the systemic circulation of tPA and a one-dimensional (1D) clot lysis model to simulate thrombolytic therapy for the treatment of AMI, developed a computational model.…”

“…Their model provides a good foundation for a computational study of fibrinolysis and it accounts for crucial fibrinolytic proteins, although the description of fibrinolysis as a continuous shrinkage of fibre diameter seems unrealistic as fibrin fibres are cut transversely during fibrinolysis [21]. A more recent three-dimensional (3D) patient-specific model has been developed by Piebalgs et al [20], which couples a one-compartment model and a fibrinolysis model that is based on the degradation of fibrin binding sites in the clot rather than fibre shrinkage. By using a multiscale modelling approach, the biochemical reactions of fibrinolysis are integrated with macroscale blood flow and drug transport in a 3D patient-specific model to assess the effects of different tPA doses on the outcome of thrombolytic therapy for AIS and the risk of ICH.…”

“…Our model includes (i) the systemic circulation and plasma reactions between fibrinolytic proteins (systemic PKPD) and (ii) clot lysis at the site of occlusion (local PD), whilst being computationally efficient for practical use. This model is developed upon the multiscale model of Piebalgs et al [20], with the following modifications: (i) adding a second compartment to allow for the delayed clearance of tPA in the late phase of drug distribution and (ii) replacing the 3D blood flow and drug transport model with a reduced-order one-dimensional (1D) model for fast computation. The new model has been used to evaluate 13 different administration regimens for tPA and to compare recanalisation times with the reference case.…”

In Silico Hemostasis Modeling and Prediction

“…Simulation of fibrinolysis in a 3D patient-specific artery during thrombolytic therapy showed that clot lysis was accelerated at higher tPA doses at the expense of a substantial increase in the risk of intracerebral hemorrhage, which was supposed to be associated with fibrinogen consumption. 104 Mathematical modeling in blood coagulation is a potent tool for investigation of mechanisms regulating different aspects of clotting, such as thrombin generation, clot dissolution, action of different drugs, used for hypo-and hypercoagulation correction, and for thrombolysis. Yet, the direct translation of in silico results to in vitro/ex vivo setups is apparently too premature and requires further investigations of clotting regulating parameters.…”

Endothelial Cell Activation in an Embolic Ischemia-Reperfusion Injury Microfluidic Model

“…The therapy involves the intravenous infusion of alteplase, to dissolve the clot. Although the treatment is critical it has a sever side effect, intracerebral hemorrhage (ICH) [27]. To simulate a thrombolytic treatment in our model, a blood clot was inserted, and occlusion of the vascular compartment was confirmed.…”