Towards a multi-physics modelling framework for thrombolysis under the influence of blood flow

Thrombolytic therapy is an effective means of treating thromboembolic diseases but can also give rise to life-threatening side-effects. The infusion of a high drug concentration can provoke internal bleeding while an insufficient dose can lead to artery reocclusion. It is hoped that mathematical modelling of the process of clot lysis can lead to a better understanding and improvement of thrombolytic therapy. To this end, a multi-physics continuum model has been developed to simulate the dissolution of clot over time upon the addition of tissue plasminogen activator (tPA). The transport of tPA and other lytic proteins is modelled by a set of reaction-diffusion-convection equations, while blood flow is described by volume-averaged continuity and momentum equations. The clot is modelled as a fibrous porous medium with its properties being determined as a function of the fibrin fibre radius and voidage of the clot. A unique feature of the model is that it is capable of simulating the entire lytic process from the initial phase of lysis of an occlusive thrombus (diffusion-limited transport), the process of recanalization, to post-canalization thrombolysis under the influence of convective blood flow. The model has been used to examine the dissolution of a fully occluding clot in a simplified artery at different pressure drops. Our predicted lytic front velocities during the initial stage of lysis agree well with experimental and computational results reported by others. Following canalisation, clot lysis patterns are strongly influenced by local flow patterns which are symmetric at low pressure drops, but asymmetric at higher pressure drops which give rise to larger recirculation regions and extended areas of intense drug accumulation

Computational simulations of thrombolytic therapy in acute ischaemic stroke

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

Methane regulation in the EU: Stakeholder perspectives on MRV and emissions reductions

Published online 19 September 2022Methane is potent greenhouse gas (GHG) accounting for 11% of all EU emissions, but in contrast to CO2 it has received relatively little attention. Although methane is regulated under the EU Effort Sharing framework, this policy lacks methane-specific regulations or targets, leaving the Member States considerable discretion over whether to prioritize methane reduction or not. The European Commission presented a proposal for EU methane regulation on 15 December 2021. However, our understanding of how to design measurement, reporting and verification (MRV) regulation for methane is limited. MRV involves many stakeholders at different steps in the process (policymakers, industry, civil society, MRV service providers, etc.), whose perspectives may differ, and our study aims to gain an insight into what constitutes an effective MRV by garnering the different stakeholders’ perspectives. The study reveals that: (1) the limits of voluntary MRV initiatives justify regulatory intervention, (2) the major barrier to the implementation of methane-specific MRV is not economic, but relates to an incomplete understanding of methane sources and available measurement technologies, (3) verification is likely to be the most challenging MRV element to implement, partly due to the limited number of accredited verifiers and overlapping tasks (4) MRV needs to be accompanied by methane mitigation policies incentivising continuous improvement of companies’ performance. The study recommends enhancing the proposed regulation by: introducing equal requirements for operated and non-operated assets; an obligation to report measurement uncertainties; a closer integration of MRV and LDAR; clear verification rules; and an introduction of minimum and optimum methane control standards

Computational simulations of thrombolysis in acute stroke: Effect of clot size and location on recanalisation

Acute ischaemic stroke can be treated by intravenous thrombolysis whereby tissue plasminogen activator (tPA) is infused to dissolve clots that block blood supply to the brain. In this study, we aim to examine the influence of clot location and size on lysis pattern and recanalisation by using a recently developed computational modelling framework for thrombolysis under physiological flow conditions. An image-based patient-specific model is reconstructed which consists of the internal carotid bifurcation with the A1 segment of anterior cerebral arteries and M1 segment of middle cerebral arteries, and the M1 bifurcation containing the M2 segments. By varying the clot size and location, 7 scenarios are simulated mimicking thrombolysis of M1 and M2 occlusions. Our results show that initial breakthrough always occurs along the inner curvature of the occluded cerebral artery, due to prolonged tPA residence time in the recirculation zone. For a given occlusion site, lysis completion time appears to increase almost quadratically with the initial clot volume; whereas for a given clot volume, the simulated M2 occlusions take up to 30% longer for complete lysis compared to the corresponding M1 occlusions

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

Thrombolytic therapy is one of the medical procedures in the treatment of acute ischaemic stroke (AIS), whereby the tissue plasminogen activator (tPA) is intravenously administered to dissolve the obstructive blood clot. The treatment of AIS by thrombolysis can sometimes be ineffective and it can cause serious complications, such as intracranial haemorrhage (ICH). In this study, we propose an efficient mathematical modelling approach that can be used to evaluate the therapeutic efficacy and safety of thrombolysis in various clinically relevant scenarios. Our model combines the pharmacokinetics and pharmacodynamics of tPA with local clot lysis dynamics. By varying the drug dose, bolus-infusion delay time, and bolus-infusion ratio, with the FDA approved dosing protocol serving as a reference, we have used the model to simulate 13 dose regimens. Simulation results are compared for temporal concentrations of fibrinolytic proteins in plasma and the time that is taken to achieve recanalisation. Our results show that high infusion rates can cause the rapid degradation of plasma fibrinogen, indicative of increased risk for ICH, but they do not necessarily lead to fast recanalisation. In addition, a bolus-infusion delay results in an immediate drop in plasma tPA concentration, which prolongs the time to achieve recanalisation. Therefore, an optimal administration regimen should be sought by keeping the tPA level sufficiently high throughout the treatment and maximising the lysis rate while also limiting the degradation of fibrinogen in systemic plasma. This can be achieved through model-based optimisation in the future

EU-Russia Energy Relations: Aggregation and Aggravation

Reliance on energy resources is inextricably linked to energy security. Whether dependent upon energy imports or exports, all states, regions and companies strive to reduce the risks associated with resource dependence by linking energy with their own security. Ensuring access to energy resources involves negotiating with a variety of external actors. As a result, energy is deeply connected to the external affairs of political and commercial actors alike. Within this terrain Russia and the EU emerge as very different energy actors. Indeed, the two are polar opposites in their ability to tackle the geo-economic asymmetry of importers and exporters, the structural unevenness in market versus governmental authority over energy resources and the geopolitical imbalances arising from differing perceptions of energy's role in foreign and security policy. This article examines the rise and fall of the EU–Russia Energy Dialogue. Launched in 2000 as a sector-specific forum with the capacity to engineer change in a host of other areas, the dialogue is now all but defunct, the victim of increased diplomatic fallout between the EU and Russia over political and energy issues. An overview of the key policy papers of the EU–Russia Energy Dialogue illustrates that the generic demands of energy security take on particularist orientations depending on the geo-economic and geopolitical circumstances of a given energy actor. Dialogue documents illustrate that the two sides ultimately understand energy security in very different ways. Now a viable component part of Russian national and foreign policy in its post-Cold War reconstruction, energy security is perceived by the EU in a rather more holistic way, and remains an unwieldy policy instrument