fibrin and Ischemic-Stroke

Ischemic stroke is one of the most serious diseases today, and only a minority of patients are provided with effective clinical treatment. Importantly, leukocytes have gradually been discovered to play vital roles in stroke thrombosis, including promoting the activation of thrombin and the adhesion and aggregation of platelets. However, they have not received enough attention in the field of acute ischemic stroke. It is possible that we could not only prevent stroke-related thrombosis by inhibiting leukocyte activation, but also target leukocyte components to dissolve thrombi in the cerebral artery. In this review, we expound the mechanisms by which leukocytes are activated and participate in the formation of stroke thrombus, then describe the histopathology of leukocytes in thrombi of stroke patients and the influence of leukocyte composition on vascular recanalization effects and patient prognosis. Finally, we discuss the relevant antithrombotic strategies targeting leukocytes.

Topics: Extracellular Traps; Fibrin; Humans; Immune System; Ischemic Stroke; Leukocytes; Platelet Activation; Prognosis; Thrombosis; Tissue Plasminogen Activator

The thrombus enhancement sign (TES) is thought to be associated with the source of the stroke and thrombus composition. We investigated whether this imaging sign along with other thrombus characteristics could be used to predict the successful first pass effect (FPE) of mechanical thrombectomy.. 246 consecutive patients with acute ischemic stroke in the anterior circulation with large vessel occlusion who underwent thrombectomy with a stent retriever and clot collection were included. Patients were divided into FPE (modified Thrombolysis in Cerebral Infarction (mTICI) grade 2c or 3)/non-FPE (mTICI 0-2b) and modified FPE (mFPE) (mTICI 2b-3)/non-mFPE (mTICI 0-2a) groups based on flow restoration after the first pass. TES presence, thrombus density, thrombus length, clot burden score, and thrombus composition were compared. The association between FPE and imaging biomarkers, along with clinical and interventional parameters, was investigated by univariate and multivariate analysis.. FPE was achieved in 85 (34.6%) patients. TES presence was significantly lower in the FPE group (64.7% vs 80.7% in the non-FPE group, p=0.008) and mFPE group (69.1% vs 81.0% in the non-mFPE group, p=0.039). Histopathological examination revealed that TES (+) thrombi contained a higher fibrin/platelet proportion (50.9% vs 46.9% in TES (-) thrombi, p=0.029) and fewer erythrocytes (43.3% vs 47.3% in TES (-) thrombi, p=0.030). Thrombus characteristics, namely shorter thrombus length (p=0.032), higher erythrocyte proportions (p=0.026), and less fibrin/platelets (p=0.014), were confirmed in patients with FPE. In multivariable analysis, TES was the only independent predictor of FPE failure (OR 0.51, 95% CI 0.28 to 0.94; p=0.031).. TES was independently associated with first pass angiographic failure in patients treated with a stent retriever.

Topics: Brain Ischemia; Cerebral Angiography; Cerebral Infarction; Computed Tomography Angiography; Fibrin; Humans; Ischemic Stroke; Retrospective Studies; Stents; Stroke; Thrombectomy; Thrombosis; Treatment Outcome

To establish a nomogram incorporating pretreatment imaging parameters and clinical characteristics for predicting the thrombus composition of acute ischemic stroke (AIS) with large vessel occlusion (LVO).. We retrospectively enrolled patients with occlusion of the Middle Cerebral Artery (MCA) who underwent Mechanical Thrombectomy (MT). Retrieved thrombi were stained with Hematoxylin and Eosin (H&E) and Martius Scarlet Blue (MSB). Thrombi are assigned to the Fibrin-rich or RBC-rich group based on the relative fractions of Red Blood Cells (RBC), fibrin, and platelet. The independent risk factors for Fibrin-rich clots were determined via univariate and multivariate logistic regression analysis and were then integrated to establish a nomogram.. In total, 98 patients were included in this study. Patients with fibrin-rich clots had worse functional outcome [modified Rankin scale (mRS) 0-2, 34.7% vs 63.2%, p = 0.005], longer procedure time (76.8 min vs 50.8 min, p = 0.001), and increased maneuvers of MT (1.84 vs 1.46, p = 0.703) than those with RBC-rich clots. The independent risk factors for Fibrin-rich clots were lower perviousness measured by Non-Contrast Computer Tomography (NCCT) and CT Angiography (CTA), lower thrombus relative attenuation on NCCT, elevated Platelet-WBC ratio (PWR) of admission peripheral blood, and previous antithrombotic medication. The nomogram showed good discrimination with an area under the Receiver Operating Characteristic (ROC) curve (AUC) of 0.852 (95% CI: 0.778-0.926). The calibration curve and decision curve analysis also displayed satisfactory accuracy and clinical utility.. This study has developed and internally validated an easy-to-use nomogram which can help predict clot composition and optimize therapeutic strategies for thrombectomy.

Topics: Fibrin; Humans; Ischemic Stroke; Nomograms; Retrospective Studies; Stroke; Thrombectomy; Thrombosis

To develop a clot-based radiomics model using CT imaging radiomic features and machine learning to identify cardioembolic (CE) stroke before mechanical thrombectomy (MTB) in patients with acute ischemic stroke (AIS).. This retrospective four-center study consecutively included 403 patients with AIS who sequentially underwent CT and MTB between April 2016 and July 2021. These were grouped into training, testing, and external validation cohorts. Thrombus-extracted radiomic features and basic information were gathered to construct a machine learning model to predict CE stroke. The radiological characteristics and basic information were used to build a routine radiological model. A combined radiomics and radiological features model was also developed. The performances of all models were evaluated and compared in the validation cohort. A histological analysis helped further assess the proposed model in all patients.. The radiomics model yielded an area under the curve (AUC) of 0.838 (95% confidence interval [CI], 0.771-0.891) for predicting CE stroke in the validation cohort, significantly higher than the radiological model (AUC, 0.713; 95% CI, 0.636-0.781; p = 0.007) but similar to the combined model (AUC, 0.855; 95% CI, 0.791-0.906; p = 0.14). The thrombus radiomic features achieved stronger correlations with red blood cells (|r. The proposed CT-based radiomics model could reliably predict CE stroke in AIS, performing better than the routine radiological method.. • Admission CT imaging could offer valuable information to identify the acute ischemic stroke source by radiomics analysis. • The proposed CT imaging-based radiomics model yielded a higher area under the curve (0.838) than the routine radiological method (0.713; p = 0.007). • Several radiomic features showed significantly stronger correlations with two main thrombus constituents (red blood cells, |r

Topics: Embolic Stroke; Fibrin; Humans; Ischemic Stroke; Retrospective Studies; Thrombosis; Tomography, X-Ray Computed

Radiomics features (RFs) extracted from CT images may provide valuable information on the biological structure of ischemic stroke blood clots and mechanical thrombectomy outcome. Here, we aimed to identify RFs predictive of thrombectomy outcomes and use clot histomics to explore the biology and structure related to these RFs.. We extracted 293 RFs from co-registered non-contrast CT and CTA. RFs predictive of revascularization outcomes defined by first-pass effect (FPE, near to complete clot removal in one thrombectomy pass), were selected. We then trained and cross-validated a balanced logistic regression model fivefold, to assess the RFs in outcome prediction. On a subset of cases, we performed digital histopathology on the clots and computed 227 histomic features from their whole slide images as a means to interpret the biology behind significant RF.. We identified 6 significantly-associated RFs. RFs reflective of continuity in lower intensities, scattered higher intensities, and intensities with abrupt changes in texture were associated with successful revascularization outcome. For FPE prediction, the multi-variate model had high performance, with AUC = 0.832 ± 0.031 and accuracy = 0.760 ± 0.059 in training, and AUC = 0.787 ± 0.115 and accuracy = 0.787 ± 0.127 in cross-validation testing. Each of the 6 RFs was related to clot component organization in terms of red blood cell and fibrin/platelet distribution. Clots with more diversity of components, with varying sizes of red blood cells and fibrin/platelet regions in the section, were associated with RFs predictive of FPE.. Upon future validation in larger datasets, clot RFs on CT imaging are potential candidate markers for FPE prediction.

Topics: Brain Ischemia; Fibrin; Humans; Ischemic Stroke; Stroke; Thrombectomy; Thrombosis; Treatment Outcome

Thrombi in cerebral large vessel occlusion associated with active cancer are often fibrin and platelet-rich white thrombi. However, evaluating the thrombus composition in a short time before thrombectomy is often ineffective. We sought to determine factors related to white thrombi in acute ischemic stroke due to large vessel occlusion in cancer patients.. Consecutive cancer patients undergoing thrombectomy for acute ischemic stroke due to large vessel occlusion between January 2018 and May 2022 were retrospectively reviewed. The patients were classified into white thrombus and red thrombus groups on the basis of the pathological findings of retrieved thrombi. Patient characteristics and laboratory findings were compared between the two groups.. In acute ischemic stroke in cancer patients, active cancer, no internal carotid artery occlusion, and higher D-dimer levels (≥3.5 μg/mL) may be associated with occlusion with fibrin and platelet-rich white thrombi.

Topics: Arterial Occlusive Diseases; Brain Ischemia; Fibrin; Humans; Ischemic Stroke; Neoplasms; Retrospective Studies; Stroke; Thrombectomy; Thrombosis

In cases of acute ischemic stroke (AIS), mechanical thrombectomy (MT) can be used to directly remove lodged thromboemboli. Despite improvements in patient outcomes, one of the key factors affecting MT success is the mechanical properties of the occlusive thrombus. Therefore, the goal of this study was to investigate the viscoelastic properties of embolus analogs (EAs) and determine the influence of EA hematocrit and loading frequency. Bovine blood EAs were created over a range of physiological hematocrits (0-60%) and cyclic uniaxial compression testing was performed at three loading frequencies to mimic in vivo loading conditions, followed by stress-relaxation testing. It was found that EAs exhibited behaviors typical of hyper-viscoelastic materials and that EA hematocrit played a large role in both EA stiffness and relaxation, with both parameters decreasing as hematocrit increased from 0 to 60%. The viscoelastic behavior of the EAs was also affected by the frequency at which they were loaded, with significant increases in peak stresses between the 0.5 and 2 Hz loaded EAs. Lower hematocrit EAs had very dense fibrin networks while the higher hematocrit EAs consisted of closely packed RBCs with little fibrin present. These results suggest that fibrin contributes to EA stiffness and relaxation behaviors while RBCs play a role in decreasing the overall viscous response and strain-rate dependency. An Ogden hyperelastic model was found to best reproduce the EA loading data while a 3-term Prony series was fit to the stress relaxation data. A hyper-viscoelastic modeling framework was then implemented combining the loading and stress-relaxation fits and the results could match the full cyclic loading data for EAs of varying hematocrit and loading frequency. The results of the experimental mechanical characterization and hyper-viscoelastic curve fitting can be incorporated in future modeling efforts to optimize mechanical thrombectomy for AIS patients.

Topics: Animals; Cattle; Elasticity; Embolism; Fibrin; Humans; Ischemic Stroke; Stress, Mechanical; Thromboembolism; Viscosity

Recombinant tissue-type plasminogen activator (rtPA, or Alteplase) is the first approved thrombolytic drug for acute ischemic stroke, but suffers from a short half-life and poor resistance to plasminogen activator inhibitor (PAI-1), limiting its clinical use. The development of novel thrombolytic agents with improved benefit/risk balance has always been of great significance. In this study, we identified a mutant of serine protease domain of tPA (named ΔtPA

Topics: Animals; Embolism; Fibrin; Fibrinolytic Agents; Ischemic Stroke; Mice; Plasminogen Activator Inhibitor 1; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator

Acute ischemic stroke (AIS) is associated with enhanced oxidative stress and unfavorably altered fibrin clot properties. We investigated determinants of plasma protein carbonylation (PC) in AIS, its impact on the prothrombotic state, and prognostic value during follow-up.. We included 98 consecutive AIS patients aged 74±12 years (male:female ratio, 50:48 [51%:49%]) at the Neurology Center in Warsaw, Poland, between January and December 2014. As many as 74 (75.5%) patients underwent thrombolysis, and 24 were unsuitable for thrombolysis. We determined plasma PC, along with thrombin generation, fibrin clot permeability, and clot lysis time on admission, at 24 hours, and 3 months. Stroke severity was assessed using the National Institutes of Health Stroke Scale and stroke outcome with the modified Rankin Scale. Hemorrhagic transformation was assessed on the computed tomography scan within 48 hours from the symptom onset, while stroke-related mortality was evaluated at 3 months.. On admission, PC levels (median, 4.61 [3.81-5.70] nM/mg protein) were associated with the time since symptom onset (r=0.41;. Elevated plasma PC levels in patients with AIS, related to prothrombotic fibrin clot properties, are associated with stroke severity. Thrombolysis reduces the extent of PC. The current study suggests a prognostic value of PC in AIS.

Topics: Female; Fibrin; Fibrin Clot Lysis Time; Humans; Ischemic Stroke; Male; Phenotype; Protein Carbonylation; Stroke; Thrombin; Thrombosis

Magnetic resonance imaging quantitative T2* mapping has shown reliable identification of thrombus red blood cell content in vitro. The thrombus composition has been in vivo, associated with outcomes after endovascular therapy for acute ischemic stroke. We aim to analyze the red blood cell content of thrombi retrieved from patients with large vessel occlusions in relation to the thrombus-T2* relaxation time in magnetic resonance imaging.. Consecutive acute ischemic stroke patients treated by endovascular therapy were scanned with an magnetic resonance imaging quantitative T2* mapping sequence. Quantitative histologic evaluations of red blood cell content were performed. A linear regression assessed the association between vascular risk factors, comorbidities, antithrombotic drugs intake, baseline National Institutes of Health Stroke Scale (NIHSS), intravenous thrombolysis before endovascular therapy, time between onset and groin puncture, patient's outcome at 3 months, magnetic resonance imaging quantitative T2* mapping results, and the red blood cell content of thrombi. The correlation between the mean thrombus-T2* relaxation time and red blood cell content was assessed by calculating the Pearson correlation coefficient.. Our study shows that a shorter thrombus-T2* relaxation time is related to a higher red blood cell content within in vivo thrombi.

Topics: Erythrocytes; Fibrin; Fibrinolytic Agents; Humans; Ischemic Stroke; Magnetic Resonance Imaging; Stroke; Thrombectomy; Thrombosis

Advances in our understanding of ADAMTS13 structure, and the conformation changes required for full activity, have rejuvenated the possibility of its use as a thrombolytic therapy. We have tested a novel Ala1144Val ADAMTS13 variant (constitutively active [ca] ADAMTS13) that exhibits constitutive activity, characterized using in vitro assays of ADAMTS13 activity, and greatly enhanced thrombolytic activity in 2 murine models of ischemic stroke, the distal FeCl3 middle cerebral artery occlusion (MCAo) model and transient middle cerebral artery occlusion (tMCAO) with systemic inflammation and ischemia/reperfusion injury. The primary measure of efficacy in both models was restoration of regional cerebral blood flow (rCBF) to the MCA territory, which was determined using laser speckle contrast imaging. The caADAMTS13 variant exhibited a constitutively active conformation and a fivefold enhanced activity against fluorescence resonance energy transfer substrate von Willebrand factor 73 (FRETS-VWF73) compared with wild-type (wt) ADAMTS13. Moreover, caADAMTS13 inhibited VWF-mediated platelet capture at subphysiological concentrations and enhanced t-PA/plasmin lysis of fibrin(ogen), neither of which were observed with wtADAMTS13. Significant restoration of rCBF and reduced lesion volume was observed in animals treated with caADAMTS13. When administered 1 hour after FeCl3 MCAo, the caADAMTS13 variant significantly reduced residual VWF and fibrin deposits in the MCA, platelet aggregate formation, and neutrophil recruitment. When administered 4 hours after reperfusion in the tMCAo model, the caADAMTS13 variant induced a significant dissolution of platelet aggregates and a reduction in the resulting tissue hypoperfusion. The caADAMTS13 variant represents a potentially viable therapeutic option for the treatment of acute ischemic stroke, among other thrombotic indications, due to its enhanced in vitro and in vivo activities that result from its constitutively active conformation.

Topics: ADAMTS13 Protein; Animals; Anti-Inflammatory Agents; Fibrin; Fibrinolytic Agents; Infarction, Middle Cerebral Artery; Ischemic Stroke; Mice; Stroke; von Willebrand Factor

As a first line option in the treatment of acute ischemic stroke (AIS), direct aspiration is a fast and effective technique with promising outcomes. In silico models are widely used for design and preclinical assessment of new developed devices and therapeutic methods. Accurate modelling of the mechanical behaviour of blood clot is a key factor in the design and simulation of aspiration devices. In this study we develop a new constitutive model which incorporates the unrecoverable plastic deformation of clots. The model is developed based on the deformation-induced microstructural changes in fibrin network, including the formation and dissociation of the cross-links between fibrin fibres. The model is calibrated using previously reported experimentally measured permanent clot deformation following uniaxial stretching. The calibrated plasticity model is then used to simulate aspiration thrombectomy. Results reveal that inclusion of permanent plastic deformation results in ∼ 15 % increase in clot aspiration length at an applied aspiration pressure of 100 mmHg. The constitutive law developed in this study provides a basis for improved design and evaluation of novel aspiration catheters leading to increased first-pass revascularization rate.

Topics: Computer Simulation; Fibrin; Humans; Ischemic Stroke; Thrombectomy; Thrombosis; Treatment Outcome

It has been hypothesized that circulating neutrophils have a direct correlation with the composition of emboli in acute ischemic stroke (AIS). The aim of this study is to evaluate the association between neutrophil-lymphocyte ratio (NLR) in peripheral blood and the expression of neutrophil extracellular traps (NETs) within stroke emboli.. Consecutive patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) that underwent mechanical thrombectomy (MT) were included. Patients were divided into two groups based on NLR median value. Retrieved thrombi were histologically analyzed using Martius Scarlett Blue (MSB) for main thrombus components including red blood cells (RBCs), white blood cells (WBCs), fibrin and platelet. Immunohistochemistry staining for von Willebrand Factor (vWF) and anti-citrullinated H3 (H3Cit; NETs marker) was also performed.. Samples from a total of 84 patients were included. The average percentage of RBCs, WBCs, fibrin, platelet, H3Cit, and vWF components in thrombi were 45.1%, 3.5%, 21.8%, 29.6%, 19.7% and 14.8% respectively. When stratifying by NLR group [low (≤3.94) versus high (>3.95)], high NLR group had significantly more WBCs (4.5%), fibrin (24.2%), H3Cit (22.7%) and vWF (17.1%) thrombus fractions compared to low NLR group. Additionally, RBC content (38.8%) was lower in the high NLR group.. NLR is correlated with the amounts of WBCs, fibrin, NETs and vWF within the thrombi retrieved from AIS patients due to LVO.

Topics: Brain Ischemia; Extracellular Traps; Fibrin; Humans; Ischemic Stroke; Lymphocytes; Neutrophils; Stroke; Thrombectomy; Thrombosis; von Willebrand Factor

To investigate the relationship between fibrin deposition and "no-reflow" within microcirculation after thrombolysis in acute ischemic stroke (AIS).. Experiments were approved by the institutional animal care and use committee. An experimental AIS model was induced in C57BL/6 mice by middle cerebral artery occlusion (MCAO) via the photothrombotic method. Mice were randomly assigned to non-thrombolytic or thrombolytic treated groups (n = 12 per group). The modified Neurological Severity Score and Fast Beam Balance Test were performed by a researcher blinded to the treatment method. MRI was utilized to evaluate all of the mice. An FXIIIa-targeted probe was applied to detect fibrin deposition in acute ischemic brain regions by fluorescence imaging. Necrosis and pathological changes of brain tissue were estimated via Hematoxylin and eosin staining while fibrin deposition was observed by immunohistochemistry.. Thrombolytic therapy improved AIS clinical symptoms. The infarct area of non-thrombolytic treated mice was significantly greater than that of the thrombolytic treated mice (p < .0001). Fluorescent imaging indicated fibrin deposition in ischemic brain tissue in both groups, with less fibrin in non-thrombolytic treated mice than thrombolytic treated mice, though the difference was not significant. Brain cells with abnormal morphology, necrosis, and liquefication were observed in the infarcted area for both groups. Clotted red blood cells (RBCs) and fibrin build-up in capillaries were found near the ischemic area in both non-thrombolytic and thrombolytic treated groups of mice.. Fibrin deposition and stacked RBCs contribute to microcirculation no-reflow in AIS after thrombolytic therapy.

Topics: Animals; Brain Ischemia; Fibrin; Fibrinolytic Agents; Infarction, Middle Cerebral Artery; Ischemic Stroke; Mice; Mice, Inbred C57BL; Molecular Imaging; Stroke; Tissue Plasminogen Activator

Thrombus computed tomography (CT) characteristics might be used to assess histopathologic thrombus composition in patients treated with endovascular thrombectomy (EVT) for acute ischemic stroke (AIS). We aimed to assess the variability in thrombus composition that could be predicted with combined thrombus CT characteristics.. Thrombi of patients enrolled in the MR CLEAN Registry between March 2014 and June 2016 were histologically analyzed with hematoxylin-eosin staining and quantified for percentages of red blood cells (RBCs) and fibrin/platelets. We estimated the association between general qualitative characteristics (hyperdense artery sign [HAS], occlusion location, clot burden score [CBS]) and thrombus composition with linear regression, and quantified RBC variability that could be explained with individual and combined characteristics with R. In 332 included patients, the presence of HAS (aβ 7.8 [95% CI 3.9-11.7]) and shift towards a more proximal occlusion location (aβ 3.9 [95% CI 0.6-7.1]) were independently associated with increased RBC and decreased fibrin/platelet content. With general characteristics, 12% of RBC variability could be explained; HAS was the strongest predictor. In 94 patients with available thin-slice imaging, 30% of RBC variability could be explained; thrombus density and thrombus length were the strongest predictors.. Quantitative thrombus CT characteristics on thin-slice admission CT improve prediction of thrombus composition and might be used to further guide clinical decision-making in patients treated with EVT for AIS in the future.. • With hyperdense artery sign and occlusion location, 12% of variability in thrombus RBC content can be explained. • With hyperdense artery sign, occlusion location, and quantitative thrombus characteristics on thin-slice (≤ 2.5 mm) non-contrast CT and CTA, 30% of variability in thrombus RBC content can be explained. • Absolute thrombus density and thrombus length were the strongest predictors for thrombus composition.

Topics: Brain Ischemia; Fibrin; Humans; Ischemic Stroke; Registries; Stroke; Thrombectomy; Thrombosis; Tomography, X-Ray Computed

Recombinant human tissue plasminogen activator (rh-tPA) is an important thrombolytic agent for treatment of acute ischemic stroke. It requires fibrin binding for plasminogen activation. In contrast, Microlyse, a novel thrombolytic agent, requires von Willebrand factor (VWF) binding for plasminogen activation. We compared rh-tPA with Microlyse, administered 20 minutes after inducing thrombosis, in 2 randomized blinded acute ischemic stroke mouse models. Thrombosis was induced in the middle cerebral artery with different experimental triggers. Where thrombin infusion generates fibrin-rich thrombi, topical FeCl3 application generates platelet-rich thrombi. In the fibrin-rich model, both rh-tPA and Microlyse increased cortical reperfusion (determined by laser speckle imaging) 10 minutes after therapy administration (35.8 ± 17.1%; P = .001 39.3 ± 13.1%; P < .0001; 15.6 ± 7.5%, respectively, vs vehicle). In addition, both thrombolytic agents reduced cerebral lesion volume (determined by magnetic resonance imaging) after 24 hours (18.9 ± 11.2 mm3; P = .033; 16.1 ± 13.9 mm3; P = .018; 26.6 ± 5.6 mm3, respectively, vs vehicle). In the platelet-rich model, neither rh-tPA nor Microlyse increased cortical reperfusion 10 minutes after therapy (7.6 ± 8.8%; P = .216; 16.3 ± 13.9%; P = .151; 10.1 ± 7.9%, respectively, vs vehicle). However, Microlyse, but not rh-tPA, decreased cerebral lesion volumes (13.9 ± 11.4 mm3; P < .001; 23.6 ± 11.1 mm3; P = .188; 30.3 ± 10.9 mm3, respectively, vs vehicle). These findings support broad applicability of Microlyse in ischemic stroke, irrespective of the thrombus composition.

Topics: Animals; Fibrin; Fibrinolytic Agents; Humans; Ischemic Stroke; Mice; Plasminogen; Stroke; Thromboembolism; Thrombolytic Therapy; Thrombosis; Tissue Plasminogen Activator; von Willebrand Factor

Mechanical thrombectomy (MT) treatment of acute ischemic stroke (AIS) patients typically involves use of stent retrievers or aspiration catheters alone or in combination. For in silico trials of AIS patients, it is crucial to incorporate the possibility of thrombus fragmentation during the intervention. This study focuses on two aspects of the thrombectomy simulation: i) Thrombus fragmentation on the basis of a failure model calibrated with experimental tests on clot analogs; ii) the combined stent-retriever and aspiration catheter MT procedure is modeled by adding both the proximal balloon guide catheter and the distal access catheter. The adopted failure criterion is based on maximum principal stress threshold value. If elements of the thrombus exceed this criterion during the retrieval simulation, then they are deleted from the calculation. Comparison with in-vitro tests indicates that the simulation correctly reproduces the procedures predicting thrombus fragmentation in the case of red blood cells rich thrombi, whereas non-fragmentation is predicted for fibrin-rich thrombi. Modeling of balloon guide catheter prevents clot fragments' embolization to further distal territories during MT procedure.

Topics: Fibrin; Humans; Ischemic Stroke; Stents; Thrombectomy; Thrombosis; Treatment Outcome

Understanding the composition of stroke thrombi retrieved by mechanical thrombectomy is essential to clarify the pathogenesis of stroke. However, it is difficult to evaluate thrombus composition precisely and objectively. Immunohistochemical staining was used to evaluate thrombus composition and age.. Consecutive thrombi (n = 108) retrieved from patients who underwent mechanical thrombectomy for acute large-vessel ischemic stroke were retrospectively analyzed. Lytic features of granulocytes and CD163 were estimated as indicators of the age of the cardioembolic (CE) thrombus.. The stroke subtypes were as follows: CE, 74 cases; large artery atherosclerosis, 11; undetermined etiology, 12; and other determined etiology, 11. There were no statistical differences in thrombi composition according to stroke subtypes. The fibrin area was positively correlated with the red blood cell (RBC) and platelet areas. The following analysis was performed using CE only. Regarding age, the thrombus was judged as fresh in 30.0 % and older in 70.0 % based on the lytic features. The RBC areas of older thrombi were smaller than those of fresh thrombi. The puncture-to-reperfusion time of older thrombi was longer than that of fresh thrombi. Platelet-rich thrombi were associated with a greater number of maneuvers, a smaller prevalence of TICI 3, and unfavorable functional outcomes compared to platelet-poor thrombi. The number of CD163 positive cells in thrombi with anticoagulants was higher than in those without anticoagulants.. Thrombus composition correlated with revascularization and clinical outcomes. The composition of an acute ischemic thrombus may reflect the pathophysiology of stroke and influence treatment efficacy.

Topics: Anticoagulants; Brain Ischemia; Fibrin; Humans; Ischemic Stroke; Retrospective Studies; Stroke; Thrombectomy; Thrombosis

Ischemic stroke is characterized by the loss of cerebral blood flow, which frequently leads to neurological deficits. Tissue plasminogen activator is the only therapeutic agent approved to treat ischemic stroke but increases the risk of intracranial hemorrhage and mortality. The fibrinogen-depleting agent lumbrokinase has been used to improve myocardial perfusion in symptomatic stable angina and to prevent secondary ischemic stroke. Lumbrokinase is highly fibrin-specific and only active in the presence of fibrin. Therefore, lumbrokinase has a low risk of hemorrhage due to excessive fibrinolysis. In this study, we aimed to clarify the neuroprotection of lumbrokinase in mice subjected to permanent middle cerebral artery occlusion. Lumbrokinase significantly attenuated infarct volume and improved neurological dysfunction. Lumbrokinase dramatically decreased the expressions of the endoplasmic reticulum (ER) transmembrane receptor protein inositol-requiring enzyme-1 (IRE1) and its downstream transcription factor, XBP-1, caspase-12, and NF-κB activity, thereby significantly inhibiting apoptosis and autophagy and decreasing the NLRP3 inflammasome. Our evidence indicates that post-stroke treatment with lumbrokinase protects against ischemic stroke, thereby regulating ER stress through the collective inhibitory effect of the IRE1 signaling pathways to decrease apoptosis, autophagy, and inflammatory responses. We suggest that lumbrokinase is potential as an adjuvant treatment for ischemic stroke.

Topics: Animals; Apoptosis; Brain Ischemia; Endoplasmic Reticulum Stress; Fibrin; Infarction, Middle Cerebral Artery; Ischemic Stroke; Membrane Proteins; Mice; Protein Serine-Threonine Kinases; Tissue Plasminogen Activator

Histological structure of thrombi is a strong determinant of the outcome of vascular recanalization therapy, the only treatment option for acute ischemic stroke (AIS) patients. A total of 21 AIS patients from this study after undergoing non-enhanced CT scan and multimodal MRI were treated with mechanical stent-based and manual aspiration thrombectomy, and thromboembolic retrieved from a cerebral artery. Complementary histopathological and imaging analyses were performed to understand their composition with a specific focus on fibrin, von Willebrand factor, and neutrophil extracellular traps (NETs). Though distinct RBC-rich and platelet-rich areas were found, AIS patient thrombi were overwhelmingly platelet-rich, with 90% of thrombi containing <40% total RBC-rich contents (1.5 to 37%). Structurally, RBC-rich areas were simple, consisting of tightly packed RBCs in thin fibrin meshwork with sparsely populated nucleated cells and lacked any substantial von Willebrand factor (VWF). Platelet-rich areas were structurally more complex with thick fibrin meshwork associated with VWF. Plenty of leukocytes populated the platelet-rich areas, particularly in the periphery and border areas between platelet-rich and RBC-rich areas. Platelet-rich areas showed abundant activated neutrophils (myeloperoxidase+ and neutrophil-elastase+) containing citrullinated histone-decorated DNA. Citrullinated histone-decorated DNA also accumulated extracellularly, pointing to NETosis by the activated neutrophils. Notably, NETs-containing areas showed strong reactivity to VWF, platelets, and high-mobility group box 1 (HMGB1), signifying a close interplay between these components.

Topics: DNA; Extracellular Traps; Fibrin; Histones; Humans; Ischemic Stroke; Neutrophils; Stroke; Thrombosis; von Willebrand Factor

Endovascular thrombectomy has revolutionized the management of acute ischemic stroke and proven superior to stand-alone intravenous thrombolysis for large vessel occlusions. However, failed or delayed revascularization may occur as a result of a mismatch between removal technique and clot composition. Determination of clot composition before thrombectomy provides the possibility to adapt the technique to improve clot removal efficacy. We evaluated the application of diffuse reflectance spectroscopy (DRS) for intravascular determination of clot composition in vivo.. Three clot types, enriched in red blood cells or fibrin or with a mixed content, were prepared from porcine blood and injected into the external carotids of a domestic pig. A guidewire-like DRS probe was used to investigate the optical spectra of clots, blood and vessel wall. Measurement positions were confirmed with angiography. Spectra were analyzed by fitting an optical model to derive physiological parameters. To evaluate the method's accuracy, photon scattering and blood and methemoglobin contents were included in a decision tree model and a random forest classification.. DRS could differentiate between the three different clot types, blood and vessel wall in vivo (p<0.0001). The sensitivity and specificity for detection was 73.8% and 98.8% for red blood cell clots, 80.6% and 97.8% for fibrin clots, and 100% and 100% for mixed clots, respectively.. Intravascular DRS applied via a custom guidewire can be used for reliable determination of clot composition in vivo. This novel approach has the potential to increase efficacy of thrombectomy procedures in ischemic stroke.

Topics: Animals; Brain Ischemia; Fibrin; Ischemic Stroke; Spectrum Analysis; Stroke; Swine; Thrombectomy; Thrombosis

The procoagulant state in cancer increases the thrombotic risk, and underlying cancer could affect treatment strategies and outcomes in patients with ischemic stroke. However, the histopathological characteristics of retrieved thrombi in patients with cancer have not been well studied. This study aimed to assess the histopathological difference between thrombi in patients with and without cancer.. We studied consecutive patients with acute major cerebral artery occlusion who were treated with endovascular therapy between October 2010 and December 2016 in our single-center registry. The retrieved thrombi were histopathologically investigated with hematoxylin and eosin and Masson's trichrome staining. The organization and proportions of erythrocyte and fibrin/platelet components were studied using a lattice composed of 10×10 squares.. Of the 180 patients studied, 17 (8 women, age 76.5±11.5 years) had cancer and 163 (69 women, age 74.1±11.2 years) did not. Those with cancer had a higher proportion of fibrin/platelets (56.6±27.4% vs 40.1±23.9%, p=0.008), a smaller proportion of erythrocytes (42.1±28.3% vs 57.5±25.1%, p=0.019), and higher serum D-dimer levels (5.9±8.2 vs 2.4±4.3 mg/dL, p=0.005) compared with the non-cancer cases. Receiver operating characteristic curve analysis showed the cut-off ratio of fibrin/platelet components related to cancer was 55.7% with a sensitivity of 74.8%, specificity 58.8% and area under the curve (AUC) value of 0.67 (95% CI 0.53 to 0.81), and the cut-off ratio of erythrocyte components was 44.7% with a sensitivity of 71.2%, specificity 58.9% and AUC value of 0.66 (95% CI 0.51 to 0.80).. Thromboemboli of major cerebral arteries in patients with cancer were mainly composed of fibrin/platelet-rich components.

Topics: Aged; Aged, 80 and over; Female; Fibrin; Humans; Ischemic Stroke; Male; Middle Aged; Neoplasms; Thrombectomy

CT is the most commonly used imaging modality for acute ischemic stroke evaluation. There is growing interest to use pre-operative imaging to characterize clot composition in stroke. We performed an in-vitro study examining the ability of various CT techniques in differentiation between different clot types.. Five clot types with varying fibrin and red blood cells (RBCs) densities (5% RBC and 95% fibrin; 25% RBC and 75% fibrin; 50% RBC and 50% fibrin; 75% RBC and 25% fibrin; 95% RBC and 5% fibrin) were prepared and scanned using various CT scanning protocols (single-energy, dual-energy, photon-counting detector CT, mixed images, and virtual monoenergetic images). Martius Scarlett Blue trichrome staining was performed to confirm the composition of each clot. Mean CT values of each type of clot under different scanning protocol were calculated and compared.. Mean CT values of the CT numbers in the five clot specimens for 5%, 25%, and 50% RBC clot were similar across modalities, and increased significantly for 75% and 95% RBC clots (P<0.0001). Mean CT values are highest in the Mono +50 keV images in each type of clot, and they were also significantly higher than all other imaging protocols (P<0.001). Dual-energy CT with Mono +50 keV images showed the greatest difference between attenuation in each type of clot.. Mono +50 keV dual-energy CT scan may be helpful for differentiating between RBC-rich and fibrin-rich thrombi seen in large-vessel occlusion patients.

Topics: Erythrocytes; Fibrin; Humans; Ischemic Stroke; Multimodal Imaging; Preoperative Care; Radiography, Dual-Energy Scanned Projection; Research Design; Staining and Labeling; Thrombosis; Tomography, X-Ray Computed

The Coronavirus disease 2019 (COVID)-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications. The increasing incidence of large vessel ischemic strokes as well as intracranial hemorrhages, frequently in younger individuals, and associated with increased morbidity and mortality, has raised questions as to why the brain is a major target of the disease. COVID-19 is characterized by hypercoagulability with alterations in hemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.

Topics: Angiotensin-Converting Enzyme 2; Blood Coagulation; Brain; Brain Ischemia; COVID-19; Cytokines; Endothelial Cells; Fibrin; Fibrin Fibrinogen Degradation Products; Hemostasis; Humans; Hypoxia; Incidence; Inflammation; Ischemic Stroke; Myocardial Infarction; Pandemics; Prognosis

Mechanical thrombectomy can be significantly affected by the mechanical properties of the occluding thrombus. In this study, we provide the first characterisation of the volumetric behaviour of blood clots. We propose a new hyperelastic model for the volumetric and isochoric deformation of clot. We demonstrate that the proposed model provides significant improvements over established models in terms of accurate prediction of nonlinear stress-strain and volumetric behaviours of clots with low and high red blood cell compositions. We perform a rigorous investigation of the factors that govern clot occlusion of a tapered vessel. The motivation for such an analysis is twofold: (i) the role of clot composition on the in vivo occlusion location is an open clinical question that has significant implications for thrombectomy procedures; (ii) in vitro measurement of occlusion location in an engineered tapered tube can be used as a quick and simple methodology to assess the mechanical properties/compositions of clots. Simulations demonstrate that both isochoric and volumetric behaviours of clots are key determinants of clot lodgement location, in addition to clot-vessel friction. The proposed formulation is shown to provide accurate predictions of in vitro measurement of clot occlusion location in a silicone tapered vessel, in addition to accurately predicting the deformed shape of the clot.

Topics: Compressive Strength; Computer Simulation; Elasticity; Erythrocytes; Fibrin; Finite Element Analysis; Friction; Humans; In Vitro Techniques; Ischemic Stroke; Shear Strength; Silicon; Silicones; Stress, Mechanical; Stroke; Thrombectomy; Thromboembolism; Thrombosis

Previous studies have successfully created blood clot analogs for in vitro endovascular device testing using animal blood of various species. Blood components vary greatly among species; therefore, creating clot analogs from human blood is likely a more accurate representation of thrombi formed in the human vasculature.. Following approval from the Mayo Clinic institutional review board, human whole-blood and platelet donations were obtained from the blood transfusion service. Twelve clot analogs were created by combining different ratios of red blood cells + buffy coat, plasma, and platelets. Thrombin and calcium chloride were added to stimulate coagulation. Clot composition was assessed using histologic and immunohistochemical staining. To assess the similarities of mechanical properties to patient clots, 3 types of clot analogs (soft, elastic, and stiff) were selected for in vitro thrombectomy testing.. The range of histopathologic compositions produced is representative of clots removed during thrombectomy procedures. The red blood cell composition ranged from 8.9% to 91.4%, and fibrin composition ranged from 3.1% to 53.4%. Platelets (CD42b) and von Willebrand Factor ranged from 0.5% to 47.1% and 1.0% to 63.4%, respectively. The soft clots had the highest first-pass effect and successful revascularization rates followed by the elastic and stiff clots. Distal embolization events were observed when clot ingestion could not be achieved, requiring device pullback. The incidence rate of distal embolization was the highest for the stiff clots due to the weak clot/device integration.. Red blood cell-rich, fibrin-rich, and platelet-rich clot analogs that mimic clots retrieved from patients with acute ischemic stroke were created in vitro. Differing retrieval outcomes were confirmed using in vitro thrombectomy testing in a subset of clots.

Topics: Blood Platelets; Erythrocytes; Fibrin; Humans; In Vitro Techniques; Ischemic Stroke; Models, Biological; Thrombectomy; Thrombosis

The aim of the present study was to determine whether there is a correlation between thrombotic pathology and prognosis of endovascular treatment (EVT) for acute ischemic stroke (AIS).. Thrombi were taken from 58 patients with cerebral ischemic thrombosis who were consecutively selected for EVT for AIS. The collected thrombi then underwent hematoxylin-eosin staining for pathological examinations to determine the red blood cell (RBC) ratio and fibrin/platelet components. The patients were divided into the following three groups according to their proportions of RBCs in thrombi: RBC-rich group (RBC ratio ≥ 70%), mixed group (RBC ratio at 31-69%), and fibrin/platelet-rich group (RBC ratio ≤ 30%). Prognosis was classified into good (0-2 points on modified Rankin scale [mRS] at postoperative 90 days) and poor (3-6 points on mRS at postoperative 90 days). Correlational analysis was performed between thrombotic pathology and prognosis of EVT for AIS.. Among all patients, the distributions were as follows: 18.96% (11/58) patients in the RBC-rich group, 63.79% (37/58) patients in the mixed group, and 17.24% (10/58) patients in the fibrin/platelet-rich group. In addition, 43.10% (25/58) of the patients had good prognosis and 56.90% (33/58) had poor prognosis.There was no statistically significant difference between the good prognosis and the poor prognosis in the RBC-rich group, the mixed group, and the fibrin/platelet-rich group (P=0.713, 0.829, 0.748).Multivariate logistic regression analysis to explored the association between RBC-rich group and good prognosis while adjusting for other baseline prognostic factors (age, ASPECTS, NIHSS score, and PRT and intravenous alteplase-bridging therapy). Compared to the fibrin/platelet-rich group, the odds ratio(OR) of achieving good prognosis was 0.60 (P = 0.592) for the mixed group and OR = 0.74 (P = 0.793) for the RBC-rich group.Notably, age was found to be negatively associated with good prognosis (OR = 0.91, P = 0.013). The ASPECTS score was found to be positively associated with good prognosis (OR = 2.01, P = 0.002). Alteplase bridging was associated with a marginally significant positive association with good prognosis (OR = 4.23, P = 0.083).. No correlation was found between thrombotic pathology and prognosis of EVT for AIS. Good prognosis after endovascular treatment was associated with low age, high ASPECTS at admission, and alteplase bridging.

Topics: Age Factors; Aged; Blood Platelets; Disability Evaluation; Endovascular Procedures; Erythrocytes; Female; Fibrin; Fibrinolytic Agents; Humans; Intracranial Thrombosis; Ischemic Stroke; Male; Middle Aged; Risk Assessment; Risk Factors; Stents; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome

This study's purpose was to improve understanding of the forces driving the complex mechanical interaction between embolic material and current stroke thrombectomy devices by analyzing the histological composition and strength of emboli retrieved from patients and by evaluating the mechanical forces necessary for retrieval of such emboli in a middle cerebral artery (MCA) bifurcation model.. Embolus analogs (EAs) were generated and embolized under physiological pressure and flow conditions in a glass tube model of the MCA. The forces involved in EA removal using conventional endovascular techniques were described, analyzed, and categorized. Then, 16 embolic specimens were retrieved from 11 stroke patients with large-vessel occlusions, and the tensile strength and response to stress were measured with a quasi-static uniaxial tensile test using a custom-made platform. Embolus compositions were analyzed and quantified by histology.. Uniaxial tension on the EAs led to deformation, elongation, thinning, fracture, and embolization. Uniaxial tensile testing of patients' emboli revealed similar soft-material behavior, including elongation under tension and differential fracture patterns. At the final fracture of the embolus (or dissociation), the amount of elongation, quantified as strain, ranged from 1.05 to 4.89 (2.41 ± 1.04 [mean ± SD]) and the embolus-generated force, quantified as stress, ranged from 63 to 2396 kPa (569 ± 695 kPa). The ultimate tensile strain of the emboli increased with a higher platelet percentage, and the ultimate tensile stress increased with a higher fibrin percentage and decreased with a higher red blood cell percentage.. Current thrombectomy devices remove emboli mostly by applying linear tensile forces, under which emboli elongate until dissociation. Embolus resistance to dissociation is determined by embolus strength, which significantly correlates with composition and varies within and among patients and within the same thrombus. The dynamic intravascular weakening of emboli during removal may lead to iatrogenic embolization.

Topics: Arterial Occlusive Diseases; Carotid Arteries; Erythrocyte Count; Fibrin; Hemodynamics; Humans; Intracranial Embolism; Ischemic Stroke; Mechanical Phenomena; Middle Cerebral Artery; Models, Biological; Platelet Count; Pressure; Tensile Strength; Thrombectomy

The purpose was to assess quantitatively and qualitatively the composition and structure of cerebral thrombi and correlate them with the signs of intravital clot contraction (retraction), as well as with etiology, severity, duration, and outcomes of acute ischemic stroke.. We quantified high-resolution scanning electron micrographs of 41 cerebral thrombi for their detailed cellular and noncellular composition and analyzed histological images for the overall structure with the emphasis on red blood cell compression, fibrin age, and the signs of inflammation.. Cerebral thrombi were quite compact and had extremely low porosity. The prevailing cell type was polyhedral compressed erythrocytes (polyhedrocytes) in the core, and fibrin-platelet aggregates were concentrated at the periphery; both findings are indicative of intravital contraction of the thrombi. The content of polyhedrocytes directly correlated with the stroke severity. The prevalence of fibrin bundles was typical for more severe cases, while the content of fibrin sponge prevailed in cases with a more favorable course. The overall platelet content in cerebral thrombi was surprisingly small, while the higher content of platelet aggregates was a marker of stroke severity. Fibrillar types of fibrin prevailed in atherothrombogenic thrombi. Older fibrin prevailed in thrombi from the patients who received thrombolytics, and younger fibrin dominated in cardioembolic thrombi. Alternating layers of erythrocytes and fibrin mixed with platelets were common for thrombi from the patients with more favorable outcomes. Thrombi with a higher number of leukocytes were associated with fatal cases.. Most cerebral thrombi undergo intravital clot contraction (retraction) that may be of underestimated clinical importance. Despite the high variability of the composition and structure of cerebral thrombi, the content of certain types of blood cells and fibrin structures combined with the morphological signs of intravital contraction correlate with the clinical course and outcomes of acute ischemic stroke.

Topics: Aged; Blood Platelets; Cell Shape; Clot Retraction; Embolic Stroke; Erythrocytes; Female; Fibrin; Fibrinolytic Agents; Humans; Inflammation; Ischemic Stroke; Male; Microscopy, Electron, Scanning; Severity of Illness Index; Thrombectomy; Thrombotic Stroke