A simplified mesoscale 3D model for characterizing fibrinolysis under flow conditions

One of the routine clinical treatments to eliminate ischemic stroke thrombi is injecting a biochemical product into the patient’s bloodstream, which breaks down the thrombi’s fibrin fibers: intravenous or intravascular thrombolysis. However, this procedure is not without risk for the patient; the worst circumstances can cause a brain hemorrhage or embolism that can be fatal. Improvement in patient management drastically reduced these risks, and patients who benefited from thrombolysis soon after the onset of the stroke have a significantly better 3-month prognosis, but treatment success is highly variable. The causes of this variability remain unclear, and it is likely that some fundamental aspects still require thorough investigations. For that reason, we conducted in vitro flow-driven fibrinolysis experiments to study pure fibrin thrombi breakdown in controlled conditions and observed that the lysis front evolved non-linearly in time. To understand these results, we developed an analytical 1D lysis model in which the thrombus is considered a porous medium. The lytic cascade is reduced to a second-order reaction involving fibrin and a surrogate pro-fibrinolytic agent. The model was able to reproduce the observed lysis evolution under the assumptions of constant fluid velocity and lysis occurring only at the front. For adding complexity, such as clot heterogeneity or complex flow conditions, we propose a 3-dimensional mesoscopic numerical model of blood flow and fibrinolysis, which validates the analytical model’s results. Such a numerical model could help us better understand the spatial evolution of the thrombi breakdown, extract the most relevant physiological parameters to lysis efficiency, and possibly explain the failure of the clinical treatment. These findings suggest that even though real-world fibrinolysis is a complex biological process, a simplified model can recover the main features of lysis evolution.</p

Impact of the Internal Carotid Artery Morphology on in silico Stent-Retriever Thrombectomy Outcome

The aim of this work is to propose a methodology for identifying relationships between morphological features of the cerebral vasculature and the outcome of in silico simulations of thrombectomy, the mechanical treatment for acute ischemic stroke. Fourteen patient-specific cerebral vasculature segmentations were collected and used for geometric characterization of the intracranial arteries mostly affected by large vessel occlusions, i.e., internal carotid artery (ICA), middle cerebral artery (MCA) and anterior cerebral artery (ACA). First, a set of global parameters was created, including the geometrical information commonly provided in the clinical context, namely the total length, the average diameter and the tortuosity (length over head-tail distance) of the intracranial ICA. Then, a more exhaustive geometrical analysis was performed to collect a set of local parameters. A total of 27 parameters was measured from each patient-specific vascular configuration. Fourteen virtual thrombectomy simulations were performed with a blood clot with the same length and composition placed in the middle of the MCA. The model of TREVO ProVue stent-retriever was used for all the simulations. Results from simulations produced five unsuccessful outcomes, i.e., the clot was not removed from the vessels. The geometric parameters of the successful and unsuccessful simulations were compared to find relations between the vascular geometry and the outcome. None of the global parameters alone or combined proved able to discriminate between positive and negative outcome, while a combination of local parameters allowed to correctly identify the successful from the unsuccessful simulations. Although these results are limited by the number of patients considered, this study indicates a promising methodology to relate patient-specific geometry to virtual thrombectomy outcome, which might eventually guide decision making in the treatment of acute ischemic stroke

Modelling the leptomeningeal collateral circulation during acute ischaemic stroke

A novel model of the leptomeningeal collateral circulation is created by combining data from multiple sources with statistical scaling laws. The extent of the collateral circulation is varied by defining a collateral vessel probability. Blood flow and pressure are simulated using a one-dimensional steady state blood flow model. The leptomeningeal collateral vessels provide significant flow during a stroke. The pressure drop over an occlusion predicted by the model ranges between 60 and 85 mmHg depending on the extent of the collateral circulation. The linear transport of contrast material was simulated in the circulatory network. The time delay of peak contrast over an occlusion is 3.3 s in the model, and 2.1 s (IQR 0.8–4.0 s) when measured in dynamic CTA data of acute ischaemic stroke patients. Modelling the leptomeningeal collateral circulation could lead to better estimates of infarct volume and patient outcome

Modelling collateral flow and thrombus permeability during acute ischaemic stroke

The presence of collaterals and high thrombus permeability are associated with good functional outcomes after an acute ischaemic stroke. We aim to understand the combined effect of the collaterals and thrombus permeability on cerebral blood flow during an acute ischaemic stroke. A cerebral blood flow model including the leptomeningeal collateral circulation is used to simulate cerebral blood flow during an acute ischaemic stroke. The collateral circulation is varied to capture the collateral scores: absent, poor, moderate and good. Measurements of the transit time, void fraction and thrombus length in acute ischaemic stroke patients are used to estimate thrombus permeability. Estimated thrombus permeability ranges between 10-7 and 10-4 mm2. Measured flow rates through the thrombus are small and the effect of a permeable thrombus on brain perfusion during stroke is small compared with the effect of collaterals. Our simulations suggest that the collaterals are a dominant factor in the resulting infarct volume after a stroke

Modelling collateral flow and thrombus permeability during acute ischaemic stroke

The presence of collaterals and high thrombus permeability are associated with good functional outcomes after an acute ischaemic stroke. We aim to understand the combined effect of the collaterals and thrombus permeability on cerebral blood flow during an acute ischaemic stroke. A cerebral blood flow model including the leptomeningeal collateral circulation is used to simulate cerebral blood flow during an acute ischaemic stroke. The collateral circulation is varied to capture the collateral scores: absent, poor, moderate and good. Measurements of the transit time, void fraction and thrombus length in acute ischaemic stroke patients are used to estimate thrombus permeability. Estimated thrombus permeability ranges between 10-7 and 10-4 mm2. Measured flow rates through the thrombus are small and the effect of a permeable thrombus on brain perfusion during stroke is small compared with the effect of collaterals. Our simulations suggest that the collaterals are a dominant factor in the resulting infarct volume after a stroke

From perviousness to permeability, modelling and measuring intra-thrombus flow in acute ischemic stroke

Thrombus permeability determines blood flow through the occluding thrombus in acute ischemic stroke (AIS) patients. The quantification of thrombus permeability is challenging since it cannot be directly measured nor derived from radiological imaging data. As a proxy of thrombus permeability, thrombus perviousness has been introduced, which assesses the amount of contrast agent that has penetrated the thrombus on single-phase computed tomography angiography (CTA). We present a method to assess thrombus permeability rather than perviousness. We follow a three-step approach: (1) we propose a theoretical channel-like structure model describing the thrombus morphology. Using Darcy's law, we provide an analytical description of the permeability for this model. According to the channel-like model, permeability depends on the number of channels in the thrombus, the radius of the occluded artery, and the void fraction representing the volume available for the blood to flow; (2) we measure intra-thrombus blood flow and velocity on dynamic CTA; and (3) we combine the analytical model with the dynamic CTA measurements to estimate thrombus permeability. Analysis of dynamic CTA data from 49 AIS patients showed that the median blood velocity in the thrombus was 0.58 (IQR 0.26–1.35) cm/s. The median flow within the thrombus was 3.48 · 10−3 (IQR 1.71 · 10−3–9.21 · 10−3) ml/s. Thrombus permeability was of the order of 10−3–10−5 mm2, depending on the number of channels in the thrombus. The channel-like thrombus model offers an intuitive way of modelling thrombus permeability, which can be of interest when studying the effect of thrombolytic drugs

Associations of thrombus perviousness derived from entire thrombus segmentation with functional outcome in patients with acute ischemic stroke

Thrombus perviousness is strongly associated with functional outcome and intravenous alteplase treatment success in patients with acute ischemic stroke. Accuracy of thrombus attenuation increase (TAI) assessment may be compromised by a heterogeneous thrombus composition and interobserver variations of currently used manual measurements. We hypothesized that TAI is more strongly associated with clinical outcomes when evaluated on the entire thrombus. In 195 patients, five TAI measures were performed: one manual by placing three regions of interest (TAImanual) and four automated ones assessing densities from the entire thrombus. The automated TAI measures were calculated by comparing quartiles; Q1, Q2, and Q3 of the non-contrast and contrast enhanced thrombus density distribution and using the lag of the maximum of the cross correlations (MCC). Associations with functional outcome (mRS at 90 days) were assessed with univariate and multivariable analyses. All entire TAI measures were significantly associated with functional outcome with odd ratios (OR) of 1.63(95 %CI:1.19–2.25, p = 0.003) for Q1, 1.56(95 %CI:1.16–2.10, p = 0.003) for Q2, 1.24(95 %CI:1.00–1.54, p = 0.045) for Q3, and 1.70(95 %CI:1.24–2.34, p = 0.001) for MCC per 10 HU increase in univariate models. TAImanual was not significantly associated with functional outcome (p = 0.055). In the multivariable logistic regression models including age, NIHSS, and recanalization, only TAI measures derived from the entire thrombus were independently associated with favorable outcome; OR of 1.64(95 %CI:1.01–2.66, p = 0.048) for Q2 and 1.82(1.13–2.95, p = 0.014) for MCC per 10 HU increase of thrombus attenuation. The novel perviousness measures of the entire thrombus are more strongly associated with functional outcome than the traditional manual perviousness assessments.</p

Modelling collateral flow and thrombus permeability during acute ischaemic stroke

The presence of collaterals and high thrombus permeability are associated with good functional outcomes after an acute ischaemic stroke. We aim to understand the combined effect of the collaterals and thrombus permeability on cerebral blood flow during an acute ischaemic stroke. A cerebral blood flow model including the leptomeningeal collateral circulation is used to simulate cerebral blood flow during an acute ischaemic stroke. The collateral circulation is varied to capture the collateral scores: absent, poor, moderate and good. Measurements of the transit time, void fraction and thrombus length in acute ischaemic stroke patients are used to estimate thrombus permeability. Estimated thrombus permeability ranges between 10-7 and 10-4 mm2. Measured flow rates through the thrombus are small and the effect of a permeable thrombus on brain perfusion during stroke is small compared with the effect of collaterals. Our simulations suggest that the collaterals are a dominant factor in the resulting infarct volume after a stroke.Computational Design and Mechanic

Generation of a Virtual Cohort of Patients for in Silico Trials of Acute Ischemic Stroke Treatments

The development of in silico trials based on high-fidelity simulations of clinical procedures requires the availability of large cohorts of three-dimensional (3D) patient-specific anatomy models, which are often hard to collect due to limited availability and/or accessibility and imaging quality. Statistical shape modeling (SSM) allows one to identify the main modes of shape variation and to generate new samples based on the variability observed in a training dataset. In this work, a method for the automatic 3D reconstruction of vascular anatomies based on SSM is used for the generation of a virtual cohort of cerebrovascular models suitable for computational simulations, useful for in silico stroke trials. Starting from 88 cerebrovascular anatomies segmented from stroke patients’ images, an SSM algorithm was developed to generate a virtual population of 100 vascular anatomies, defined by centerlines and diameters. An acceptance criterion was defined based on geometric parameters, resulting in the acceptance of 83 generated anatomies. The 3D reconstruction method was validated by reconstructing a cerebrovascular phantom lumen and comparing the result with an STL geometry obtained from a computed tomography scan. In conclusion, the final 3D models of the generated anatomies show that the proposed methodology can produce a reliable cohort of cerebral arteries