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

De cellulaire en moleculaire architectuur van ischemische beroerte- en ECMO-klonters: Nieuwe inzichten in de pathofysiologie en therapie door middel van histologische studies.

Acute ischemic stroke is one of the leading causes for mortality and long-term disability worldwide. This is caused by blood thrombi that occlude cerebral blood arteries, leading to an impaired blood flow and irreversible damage of the associated brain tissue. The morbidity of ischemic stroke will continue to rise as age is one of the most substantiated risk factors. The socio-economic burden of stroke is in strong contrast with the limited treatment options. Currently, only one pharmacological/thrombolytic agent, tissue plasminogen activator (t-PA), has been approved. However, t-PA can only be administered in a limited time window of 4.5 hours after stroke onset due to the risk of intracranial hemorrhage when treatment is postponed. As a consequence, t-PA can only be used in less than half of the patients. Most remarkably, t-PA results in recanalization in less than half of the patients that are treated whereas factors contributing to this 't-PA resistance' are not well understood. Nowadays, thrombectomy can be used in patients that fail standard thrombolytic therapy to mechanically remove blood thrombi from the cerebral arteries. This technique presents itself with the possibility to analyze the retrieved thrombi ex vivo. Indeed, this project aims to unravel both clinical (e.g. functional outcome) and fundamental (e.g. clot composition) aspects of stroke by analyzing cerebral thrombi from patients.status: publishe

Thrombus heterogeneity in ischemic stroke

The structure of stroke thrombi has gained an increasing amount of interest in recent years. The advent of endovascular thrombectomy has offered the unique opportunity to provide and analyze thrombi removed from ischemic stroke patients. It has become clear that the composition of ischemic stroke thrombi is relatively heterogenous and various molecular and cellular patterns become apparent. Good understanding of the histopathologic characteristics of thrombi is important to lead future advancements in acute ischemic stroke treatment. In this review, we give a brief overview of the main stroke thrombus components that have been recently characterized in this rapidly evolving field. We also summarize how thrombus heterogeneity can affect stroke treatment

Thrombus heterogeneity in ischemic stroke

The structure of stroke thrombi has gained an increasing amount of interest in recent years. The advent of endovascular thrombectomy has offered the unique opportunity to provide and analyze thrombi removed from ischemic stroke patients. It has become clear that the composition of ischemic stroke thrombi is relatively heterogenous and various molecular and cellular patterns become apparent. Good understanding of the histopathologic characteristics of thrombi is important to lead future advancements in acute ischemic stroke treatment. In this review, we give a brief overview of the main stroke thrombus components that have been recently characterized in this rapidly evolving field. We also summarize how thrombus heterogeneity can affect stroke treatment.status: publishe

Studying stroke thrombus composition after thrombectomy: What can we learn?

The composition of ischemic stroke thrombi has gained an increasing amount of interest in recent years. The implementation of endovascular procedures in standard stroke care has granted researchers the unique opportunity to examine patient thrombus material. Increasing evidence indicates that stroke thrombi are complex and heterogenous, consisting of various biochemical (eg, fibrin, von Willebrand Factor, and neutrophil extracellular traps) and cellular (eg, red blood cells, platelets, leukocytes, and bacteria) components. This complex composition may explain therapeutic limitations and also offer novel insights in several aspects of stroke management. Better understanding of thrombus characteristics could, therefore, potentially lead to improvements in the management of patients with stroke. In this review, we provide a comprehensive overview of the lessons learned by examining stroke thrombus composition after endovascular thrombectomy and its potential relevance for thrombectomy success rates, thrombolysis, clinical outcomes, stroke etiology, and radiological imaging.This work was supported by research grants to S.F.D.M. from the Fonds voor Wetenschappelijk Onderzoek – Vlaanderen (FWO) (research grants G0A8613, G078517, 1509216N and G0E7620N), the KU Leuven (OT/14/099, ISP/14/02L2 and PDM/20/147), the Queen Elisabeth Medical Foundation and by the European Union's Horizon 2020 Research and Innovation Program INSIST under grant agreement No 777072. W.B received funding from the National Institutes of Health Grant 1R01NS105853-01. K.M.D. received funding from Science Foundation Ireland, funding from Cerenovus and funding from Sensome.peer-reviewe

Structural features of acute ischemic stroke thrombi

status: publishe

Histological analysis of a thrombectomy-resistant ischemic stroke thrombus: a case report

status: accepte