Per-Pass Analysis of Thrombus Composition in Patients With Acute Ischemic Stroke Undergoing Mechanical Thrombectomy.

Background and Purpose- Mechanical thrombectomy may involve multiple attempts to retrieve the occluding thrombus. This study examined the composition of thrombus fragments retrieved with each pass of a device during the thrombectomy procedure. Second, the per-pass composition was compared with procedural and clinical data including angiographic outcome and stroke etiology. Methods- Thrombi were retrieved from 60 patients with acute ischemic stroke, where thrombus fragments retrieved in each pass were segregated as individual samples and maintained throughout the histological analysis as independent samples. All samples were stained with hematoxylin and eosin and Martius Scarlet Blue. The relative composition of red blood cells, fibrin, and white blood cells in thrombus fragments from each pass was quantified. Results- Over the 60 cases, thrombus material was retrieved in 106 of 138 passes. The number of passes required to complete the cases ranged from 1 to 6 passes. The analysis of thrombus fragments retrieved in each pass provided a greater insight into the thrombectomy procedure progression than the overall thrombus composition; the red blood cell content of thrombus fragments retrieved in passes 1 and 2 was significantly higher than that retrieved in passes 3 to 6. The removal of thrombus material in a total of 1, 2, or 3 passes was associated with the highest percentage of final modified Thrombolysis in Cerebral Infarction score of 2c-3. There was no association between modified Thrombolysis in Cerebral Infarction score and per-pass thrombus composition. Conclusions- The differentiation achieved through the per-pass analysis of acute ischemic stroke thrombi provides a greater insight into the thrombectomy procedure progression than the combined per-case thrombus analysis. Insights gained may be a useful consideration in determining the treatment strategy as a case evolves and may be useful for the development of new devices to increase rates of 1-pass recanalization.

Measuring the effect of thrombosis, thrombus maturation and thrombolysis on clot mechanical properties in an in-vitro model.

Changes in acute ischemic stroke thrombi structure and composition may result in significant differences in treatment responsiveness. Ischemic stroke patients are often treated with a thrombolytic agent to dissolve thrombi, however these patients may subsequently undergo mechanical thrombectomy to remove the occlusive clot. We set out to determine if rt-PA thrombolysis treatment of blood clots changes their mechanical properties, which in turn may impact mechanical thrombectomy. Using a design-of-experiment approach, ovine clot analogues were prepared with varying composition and further exposed to different levels of compaction force to simulate the effect of arterial blood pressure. Finally, clots were treated with three r-tPA doses for different durations. Clot mass and mechanical behaviour was analysed to assess changes due to (i) Platelet driven contraction (ii) Compaction force and (iii) Thrombolysis. Clots that were exposed to r-tPA for longer duration showed significant reduction in clot mass (p < 0.001). Exposure time to r-tPA (p < 0.001) was shown to be an independent predictor of lower clot stiffness. A decrease in energy dissipation ratio during mechanical compression was associated with longer exposure time in r-tPA (p = 0.001) and a higher platelet concentration ratio (p = 0.018). The dose of r-tPA was not a significant factor in reducing clot mass or changing mechanical properties of the clots. Fibrinolysis reduces clot stiffness which may explain increased distal clot migration observed in patients treated with r-tPA and should be considered as a potential clot modification factor before mechanical thrombectomy.

Applicability assessment of a stent-retriever thrombectomy finite-element model.

An acute ischaemic stroke appears when a blood clot blocks the blood flow in a cerebral artery. Intra-arterial thrombectomy, a mini-invasive procedure based on stent technology, is a mechanical available treatment to extract the clot and restore the blood circulation. After stent deployment, the clot, trapped in the stent struts, is pulled along with the stent towards a receiving catheter. Recent clinical trials have confirmed the effectiveness and safety of mechanical thrombectomy. However, the procedure requires further investigation. The aim of this study is the development of a numerical finite-element-based model of the thrombectomy procedure. In vitro thrombectomy tests are performed in different vessel geometries and one simulation for each test is carried out to verify the accuracy and reliability of the proposed numerical model. The results of the simulations confirm the efficacy of the model to replicate all the experimental setups. Clot stress and strain fields from the numerical analysis, which vary depending on the geometric features of the vessel, could be used to evaluate the possible fragmentation of the clot during the procedure. The proposed in vitro/in silico comparison aims at assessing the applicability of the numerical model and at providing validation evidence for the specific in vivo thrombectomy outcomes prediction.

Quantitative estimation of thrombus-erythrocytes using MRI. A phantom study with clot analogs and analysis by statistic regression models.

BACKGROUND: Thrombus composition has the potential to affect acute ischemic stroke (AIS) treatment. OBJECTIVE: To evaluate in an in vitro test the correlation of clot composition, especially erythrocytes (red blood cells (RBCs)), with the variation of signal intensity ratio (SIR) obtained with MRI sequences used for AIS, and qualification of the susceptibility vessel sign effect using clot analogs. MATERIALS AND METHODS: Nine ovine clots were fixed in a gelatin-manganese solution and studied by MRI (T2GE, T2-weighted gradient echo; SWI, susceptibility-weighted imaging; FLAIR, fluid attenuated inversion recovery). RBC concentration was estimated using regression models (SLR, single linear regression; MLR, multiple linear regression; RF, random Forest; and ANN, artificial neural networking), which combined the SIR-histology relationship of three MRI sequences. RESULTS: Negative correlation was found between SIR and RBC concentration. T2GE SWI could not statistically distinguish clots with RBC content >54% and <23%. SLR was applied only to FLAIR images since T2GE and SWI demonstrated signal saturation. All four regression models showed a correlation between MRI and histology: SLR=0.981; MLR=0.986; RF=0.994, and ANN=0.971. One unknown clot was studied and agreement between SIR and histological analyses was found in all models. CONCLUSIONS: We presented a method to quantify RBC concentration in clot analogs, combining SWI, T2GE, and FLAIR. This in vitro study has some limitations, so clot collection after thrombectomy with simultaneous imaging analysis is necessary to validate this model.

Characterization of strut indentation during mechanical thrombectomy in acute ischemic stroke clot analogs.

BACKGROUND: Although it is common practice to wait for an 'embedding time' during mechanical thrombectomy (MT) to allow strut integration of a stentriever device into an occluding thromboembolic clot, there is a scarcity of evidence demonstrating the value or optimal timing for the wide range of thrombus compositions. This work characterizes the behavior of clot analogs of varying fibrin and cellular compositions subject to indentation forces and embedding times representative of those imparted by a stentriever during MT. The purpose of this study is to quantify the effect of thrombus composition on device strut embedding, and to examine the precise nature of clot integration into a stentriever device at a microstructural level. METHOD: Clot analogs with 0% (varying densities), 5%, 40%, and 80% red blood cell (RBC) content were created using ovine blood. Clot indentation behavior during an initial load application (loading phase) followed by a 5-min embedding time (creep phase) was analyzed using a mechanical tester under physiologically relevant conditions. The mechanism of strut integration was examined using micro-computed tomography (µCT) with an EmboTrap MT device (Cerenovus, Galway, Ireland) deployed in each clot type. Microstructural clot characteristics were identified using scanning electron microscopy (SEM). RESULTS: Compressive clot stiffness measured during the initial loading phase was shown to be lowest in RBC-rich clots, with a corresponding greatest maximum indentation depth. Meanwhile, additional depth achieved during the simulated embedding time was most pronounced in fibrin-rich clots. SEM imaging identified variations in microstructural mechanisms (fibrin stretching vs rupturing) which was dependent on fibrin:cellular content, while µCT analysis demonstrated the mechanism of strut integration was predominantly the formation of surface undulations rather than clot penetration. CONCLUSIONS: Disparities in indentation behavior between clot analogs were attributed to varying microstructural features induced by the cellular:fibrin content. Greater indentation was identified in clots with higher RBC content, but with an increased level of fibrin rupture, suggesting an increased propensity for fragmentation. Additional embedding time improves strut integration, especially in fibrin-rich clots, through the mechanism of fibrin stretching with the majority of additional integration occurring after 3 mins. The level of thrombus incorporation into the EmboTrap MT device (Cerenovus, Galway, Ireland) was primarily influenced by the stentriever design, with increased integration in regions of open architecture.

Clot friction variation with fibrin content; implications for resistance to thrombectomy.

BACKGROUND: Despite significant advancements in the procedural efficacy of mechanical thrombectomy in patients with ischemic stroke in recent years, there still remains a portion of the population that does not achieve good recanalization. The reasons for this may be varied. We hypothesized that static friction between the clot and the vessel, or catheter wall might contribute to the difficulty in removing the clot. OBJECTIVE: To determine if there is a relationship between clot composition and the resistance to sliding (friction) which might contribute to resistance to clot removal. METHODS: As clot composition can vary significantly, we investigated five different types of clot in order to measure their respective frictional properties. To do this, a custom-made testing apparatus was created, consisting of various replaceable low-friction surfaces on which the clots could be placed. The surface was then gradually tilted until the clots began to slide; the angle at which this occurred is related to the coefficient of friction of the clots. The experiment was repeated on a bovine aortic surface in order to confirm the results. RESULTS: We found that fibrin-rich clots (<20% red blood cell content) have a significantly higher coefficient of friction than clots with a red blood cell content >20%. This result was confirmed by repeating the experiment on a bovine aortic surface as a representation of the interaction between clots and the arterial wall. CONCLUSIONS: The friction properties of clots were found to be related to the content ratio of fibrin to red blood cells. Future imaging techniques that could show fibrin and red blood cell content might help us to predict the 'stickiness' of a clot.

Expanding the role of stent-retriever endovascular thrombectomy: a case series of free-floating thrombus.

Carotid artery free-floating thrombus (FFT) is a rare but clinically significant cause of embolic stroke. Treatment has historically been confined to carotid surgery or best medical therapy, with neither option proved to be superior. However, recent advancements in endovascular interventions have heralded a new age of innovative management strategies for vascular disease. We present three distinct cases of stroke secondary to carotid artery FFT, successfully treated with stent retriever endovascular thrombectomy.

Utility of single-energy and dual-energy computed tomography in clot characterization: An in-vitro study.

Background and purpose Because computed tomography (CT) is the most commonly used imaging modality for the evaluation of acute ischemic stroke patients, developing CT-based techniques for improving clot characterization could prove useful. The purpose of this in-vitro study was to determine which single-energy or dual-energy CT techniques provided optimum discrimination between red blood cell (RBC) and fibrin-rich clots. Materials and methods Seven clot types with varying fibrin and RBC densities were made (90% RBC, 99% RBC, 63% RBC, 36% RBC, 18% RBC and 0% RBC with high and low fibrin density) and their composition was verified histologically. Ten of each clot type were created and scanned with a second generation dual source scanner using three single (80 kV, 100 kV, 120 kV) and two dual-energy protocols (80/Sn 140 kV and 100/Sn 140 kV). A region of interest (ROI) was placed over each clot and mean attenuation was measured. Receiver operating characteristic curves were calculated at each energy level to determine the accuracy at differentiating RBC-rich clots from fibrin-rich clots. Results Clot attenuation increased with RBC content at all energy levels. Single-energy at 80 kV and 120 kV and dual-energy 80/Sn 140 kV protocols allowed for distinguishing between all clot types, with the exception of 36% RBC and 18% RBC. On receiver operating characteristic curve analysis, the 80/Sn 140 kV dual-energy protocol had the highest area under the curve for distinguishing between fibrin-rich and RBC-rich clots (area under the curve 0.99). Conclusions Dual-energy CT with 80/Sn 140 kV had the highest accuracy for differentiating RBC-rich and fibrin-rich in-vitro thrombi. Further studies are needed to study the utility of non-contrast dual-energy CT in thrombus characterization in acute ischemic stroke.

Novel methodology to replicate clot analogs with diverse composition in acute ischemic stroke.

BACKGROUND: Translational research on clot composition may be advanced by the use of clot analogs for the preclinical evaluation of mechanical thrombectomy devices. This work describes a novel set of clot analogs to represent a diverse range of fibrin and red blood cell (RBC) compositions for use in acute ischemic stroke (AIS) occlusion models. METHOD: Fresh whole blood obtained from ovine species was used to create seven different clot analog types. Five replicates were formed for each clot type. Varying amounts of whole blood constituents were mixed with thrombotic factors to create clots of varying compositions. Following histological processing, five sections from each clot were stained with H&E and Martius Scarlet Blue. Fibrin, RBC and white blood cell compositions were quantified. RESULTS: Histological examination demonstrated that the clot types had a distinct RBC and fibrin composition. No significant difference in composition was shown between replicates (p>0.05), indicating that the method of clot formation was reproducible. Percentage fibrin composition of the clot types was 1%, 8%, 31%, 38%, 64%, 79%, and 100%. A significant difference in fibrin and RBC composition between clot types was observed (p<0.05). CONCLUSIONS: Seven different clot types were developed to replicate common AIS thrombi. These clot analogs may be beneficial for the preclinical evaluation of endovascular therapies, and may be applied to interventional technique training.

Correlation of imaging and histopathology of thrombi in acute ischemic stroke with etiology and outcome: a systematic review.

BACKGROUND AND PURPOSE: Studying the imaging and histopathologic characteristics of thrombi in ischemic stroke could provide insights into stroke etiology and ideal treatment strategies. We conducted a systematic review of imaging and histologic characteristics of thrombi in acute ischemic stroke. MATERIALS AND METHODS: We identified all studies published between January 2005 and December 2015 that reported findings related to histologic and/or imaging characteristics of thrombi in acute ischemic stroke secondary to large vessel occlusion. The five outcomes examined in this study were (1) association between histologic composition of thrombi and stroke etiology; (2) association between histologic composition of thrombi and angiographic outcomes; (3) association between thrombi imaging and histologic characteristics; (4) association between thrombi imaging characteristics and angiographic outcomes; and (5) association between imaging characteristics of thrombi and stroke etiology. A meta-analysis was performed using a random effects model. RESULTS: There was no significant difference in the proportion of red blood cell (RBC)-rich thrombi between cardioembolic and large artery atherosclerosis etiologies (OR 1.62, 95% CI 0.1 to 28.0, p=0.63). Patients with a hyperdense artery sign had a higher odds of having RBC-rich thrombi than those without a hyperdense artery sign (OR 9.0, 95% CI 2.6 to 31.2, p<0.01). Patients with a good angiographic outcome had a mean thrombus Hounsfield unit (HU) of 55.1±3.1 compared with a mean HU of 48.4±1.9 for patients with a poor angiographic outcome (mean standard difference 6.5, 95% CI 2.7 to 10.2, p<0.001). There was no association between imaging characteristics and stroke etiology (OR 1.13, 95% CI 0.32 to 4.00, p=0.85). CONCLUSIONS: The hyperdense artery sign is associated with RBC-rich thrombi and improved recanalization rates. However, there was no association between the histopathological characteristics of thrombi and stroke etiology and angiographic outcomes.

Development and Standardization of the Diagnostic Adaptive Behavior Scale: Application of Item Response Theory to the Assessment of Adaptive Behavior.

The Diagnostic Adaptive Behavior Scale (DABS) was developed using item response theory (IRT) methods and was constructed to provide the most precise and valid adaptive behavior information at or near the cutoff point of making a decision regarding a diagnosis of intellectual disability. The DABS initial item pool consisted of 260 items. Using IRT modeling and a nationally representative standardization sample, the item set was reduced to 75 items that provide the most precise adaptive behavior information at the cutoff area determining the presence or not of significant adaptive behavior deficits across conceptual, social, and practical skills. The standardization of the DABS is described and discussed.

The diagnostic adaptive behavior scale: evaluating its diagnostic sensitivity and specificity.

The Diagnostic Adaptive Behavior Scale (DABS) was constructed with items across three domains--conceptual, social, and practical adaptive skills--and normed on a representative sample of American individuals from 4 to 21 years of age. The DABS was developed to focus its assessment around the decision point for determining the presence or absence of significant limitations of adaptive behavior for the diagnosis of Intellectual Disability (ID). The purpose of this study, which was composed of 125 individuals with and 933 without an ID-related diagnosis, was to determine the ability of the DABS to correctly identify the individuals with and without ID (i.e., sensitivity and specificity). The results indicate that the DABS sensitivity coefficients ranged from 81% to 98%, specificity coefficients ranged from 89% to 91%, and that the Area Under the Receiver Operating Characteristic Curve were excellent or good. These results indicate that the DABS has very good levels of diagnostic efficiency.

The construct of adaptive behavior: its conceptualization, measurement, and use in the field of intellectual disability.

This article updates the current conceptualization, measurement, and use of the adaptive behavior construct. Major sections of the article address an understanding of the construct, the current approaches to its measurement, four assessment issues and challenges related to the use of adaptive behavior information for the diagnosis of intellectual disability, and two future issues regarding the relations of adaptive behavior to multidimensional models of personal competence and the distribution of adaptive behavior scores. An understanding of the construct of adaptive behavior and its measurement is critical to clinicians and practitioners in the field because of its role in understanding the phenomenon of intellectual disability, diagnosing a person with intellectual disability, providing a framework for person-referenced education and habilitation goals, and focusing on an essential dimension of human functioning.

Economic stress, parenting, and child adjustment in Mexican American and European American families.

To assess the impact of economic hardship on 111 European American and 167 Mexican American families and their 5th-grade (M age=11.4 years) children, a family stress model was evaluated. Structural equation analyses revealed that economic hardship was linked to indexes of economic pressure that were related to depressive symptoms for mothers and fathers of both ethnicities. Depressive symptoms were linked to marital problems and hostile parenting. Paternal hostile parenting was related to child adjustment problems for European Americans, whereas marital problems were linked to child adjustment problems for Mexican Americans. Maternal acculturation was associated with both higher marital problems and lower hostile parenting. The utility of the model for describing the effects of economic hardship in Mexican Americans is noted.