Predictive value of transcranial evoked potentials during mechanical endovascular therapy for acute ischaemic stroke: a feasibility study.

BACKGROUND AND PURPOSE: Mechanical endovascular therapy (MET) is a promising adjuvant or stand-alone therapy for acute ischaemic stroke caused by occlusion of a large vessel. Real-time monitoring of recanalisation success with regard to functional outcome is usually not possible because these procedures are mainly performed under general anaesthesia. We present a novel application for evoked potential monitoring for real-time evaluation of reperfusion success with respect to functional outcome during MET for acute ischaemic stroke. METHODS: Prospective observational study from March 2012 to April 2013 of patients presenting with acute ischaemic stroke who were eligible for MET. Transcranial motor evoked potentials (MEPs) and somatosensory evoked potentials (SSEPs) were measured bilaterally during MET throughout the intervention. The electrophysiological data of the contralateral side served as control. Neurological outcome was assessed by the modified Rankin Scale and National Institutes of Health Stroke Scale at 0, 7 and 90 days following intervention. RESULTS: 20 patients were examined. MEPs and SSEPs were technically successful in 19 (95%) and 9 (45%) cases, respectively. Successful reperfusion was achieved in 16 cases. Functional recovery was observed in 14 patients. MEPs and SSEPs recovery status was a better predictor of functional recovery than successful reperfusion with a positive predictive value of 92%, 83% and 75% for MEPs, SSEPs and reperfusion, respectively. CONCLUSIONS: MEPs and SSEPs are safe and feasible methods of real-time monitoring of reperfusion success with respect to functional outcome during MET for acute ischaemic stroke.

Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner.

Rupture of a vulnerable atherosclerotic plaque causes thrombus formation and precipitates cardiovascular diseases. In addition to the thrombogenic content of a plaque, also the hemodynamic microenvironment plays a major role in thrombus formation. How the altered hemodynamics around a plaque promote pathological thrombus formation is not well understood. In this study, we provide evidence that plaque geometries result in fluid mechanical conditions that promote platelet aggregation and thrombus formation by increased accumulation and activity of von Willebrand factor (vWF) at poststenotic sites. Resonant-scanning multiphoton microscopy revealed that in vivo arterial stenosis of a damaged carotid artery markedly increased platelet aggregate formation in the stenotic outlet region. Complementary in vitro studies using microfluidic stenotic chambers, designed to mimic the flow conditions in a stenotic artery, showed enhanced platelet aggregation in the stenotic outlet region at 60-80% channel occlusion over a range of input wall shear rates. The poststenotic thrombus formation was critically dependent on bloodborne vWF and autocrine platelet stimulation. In stenotic chambers containing endothelial cells, flow provoked increased endothelial vWF secretion in the stenotic outlet region, contributing to exacerbated platelet aggregation. Taken together, this study identifies a role for the shear-sensitive protein vWF in transducing hemodynamic forces that are present around a stenosis to a prothrombogenic microenvironment resulting in spatially confined and exacerbated platelet aggregation in the stenosis outlet region. The developed stenotic microfluidic chamber offers a realistic platform for in vitro evaluation of shear-dependent thrombus formation in the setting of atherosclerosis.

Direct interaction of kindlin-3 with integrin αIIbß3 in platelets is required for supporting arterial thrombosis in mice.

OBJECTIVE: Kindlin-3 is a critical supporter of integrin function in platelets. Lack of expression of kindlin-3 protein in patients impairs integrin αIIbß3-mediated platelet aggregation. Although kindlin-3 has been categorized as an integrin-binding partner, the functional significance of the direct interaction of kindlin-3 with integrin αIIbß3 in platelets has not been established. Here, we evaluated the significance of the binding of kindlin-3 to integrin αIIbß3 in platelets in supporting integrin αIIbß3-mediated platelet functions. APPROACH AND RESULTS: We generated a strain of kindlin-3 knockin (K3KI) mice that express a kindlin-3 mutant that carries an integrin-interaction defective substitution. K3KI mice could survive normally and express integrin αIIbß3 on platelets similar to their wild-type counterparts. Functional analysis revealed that K3KI mice exhibited defective platelet function, including impaired integrin αIIbß3 activation, suppressed platelet spreading and platelet aggregation, prolonged tail bleeding time, and absence of platelet-mediated clot retraction. In addition, whole blood drawn from K3KI mice showed resistance to in vitro thrombus formation and, as a consequence, K3KI mice were protected from in vivo arterial thrombosis. CONCLUSIONS: These observations demonstrate that the direct binding of kindlin-3 to integrin αIIbß3 is involved in supporting integrin αIIbß3 activation and integrin αIIbß3-dependent responses of platelets and consequently contributes significantly to arterial thrombus formation.

α(1,3)-Fucosyltransferases FUT4 and FUT7 control murine susceptibility to thrombosis.

The α(1,3)-fucosyltransferases, types IV and VII (FUT4 and FUT7, respectively), are required for the synthesis of functional selectin-type leukocyte adhesion molecule ligands. The selectins and their ligands modulate leukocyte trafficking, and P-selectin and its ligand, P-selectin glycoprotein ligand-1, can modulate hemostasis and thrombosis. Regulation of thrombosis by FUT4 and/or FUT7 activity was examined in mouse models of carotid artery thrombosis and collagen/epinephrine-induced thromboembolism. Mice lacking both FUT4 and FUT7 (Fut(-/-) mice) had a shorter time to occlusive thrombus formation in the injured carotid artery and a higher mortality due to collagen/epinephrine-induced pulmonary thromboemboli. Mice lacking P-selectin or P-selectin glycoprotein ligand-1 did not have a prothrombotic phenotype. Whole blood platelet aggregation was enhanced, and plasma fibrinogen content, clot weight, and clot strength were increased in Fut(-/-) mice, and in vitro clot lysis was reduced compared with wild type. Fut4(-/-), but not Fut7(-/-), mice had increased pulmonary thromboembolism-induced mortality and decreased thromboemboli dissolution in vivo. These data show that FUT4 and FUT7 activity regulates thrombosis in a P-selectin- and P-selectin glycoprotein ligand-1-independent manner and suggest that FUT4 activity is important for thrombolysis.

Comparison of cognitive performance between two rat models of vascular dementia.

BACKGROUND AND PURPOSE: An ideal animal model to explore that pathogenesis and prevention of dementia is essential. The present study was designed to compare the difference of behavior and cerebral blood flow of the two vascular dementia rat models at different time intervals. METHODS: The rats were randomly allocated to three groups: bilateral common carotid artery occlusion (BCCAO) group, thromboembolism (TE) group and sham-operated (SHAM) group. The performance in the Morris water maze (MWM) was analyzed at 7, 14 and 28 d after operation and cerebral blood flow (CBF) was analyzed at 28 days after operation. RESULT: The results showed that the two models exhibited longer latency, less times to crossing platform in MWM and lower CBF than the SHAM rats. Compared with the TE rats, the BCCAO rats have a significant prolongation of escape latency at 7 days and 28 days. In the probe trial, the BCCAO rats showed less number of times across the platform. CONCLUSION: The BCCAO rats maybe provide a more useful model to study the physiopathological mechanisms of cognitive impairment related to chronic cerebral ischemia.

The cell motility modulator Slit2 is a potent inhibitor of platelet function.

BACKGROUND: Vascular injury and atherothrombosis involve vessel infiltration by inflammatory leukocytes, migration of medial vascular smooth muscle cells to the intimal layer, and ultimately acute thrombosis. A strategy to simultaneously target these pathological processes has yet to be identified. The secreted protein, Slit2, and its transmembrane receptor, Robo-1, repel neuronal migration in the developing central nervous system. More recently, it has been appreciated that Slit2 impairs chemotaxis of leukocytes and vascular smooth muscle cells toward diverse inflammatory attractants. The effects of Slit2 on platelet function and thrombus formation have never been explored. METHODS AND RESULTS: We detected Robo-1 expression in human and murine platelets and megakaryocytes and confirmed its presence via immunofluorescence microscopy and flow cytometry. In both static and shear microfluidic assays, Slit2 impaired platelet adhesion and spreading on diverse extracellular matrix substrates by suppressing activation of Akt. Slit2 also prevented platelet activation on exposure to ADP. In in vivo studies, Slit2 prolonged bleeding times in murine tail bleeding assays. Using intravital microscopy, we found that after mesenteric arteriolar and carotid artery injury, Slit2 delayed vessel occlusion time and prevented the stable formation of occlusive arteriolar thrombi. CONCLUSIONS: These data demonstrate that Slit2 is a powerful negative regulator of platelet function and thrombus formation. The ability to simultaneously block multiple events in vascular injury may allow Slit2 to effectively prevent and treat thrombotic disorders such as myocardial infarction and stroke.

Vascular wall-produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through platelet EP3 receptors.

Prostanoids, bioactive lipids derived from arachidonic acid (AA), are important for vascular homeostasis. Among them, prostaglandin E2 (PGE2) enhances aggregation of platelets submaximally stimulated in vitro. This results from activation of EP3, one of the four PGE2 receptors, which decreases the threshold at which agonists activate platelets to aggregate. Although PGE2 altered venous thrombosis induced by administration of AA, its role in pathophysiopathological conditions has remained speculative. We report that arterial walls subjected to inflammatory stimuli produce PGE2. In several models, we show that PGE2 produced by the arterial wall facilitates arterial thrombosis. Next, we detected PGE2 in mouse atherosclerotic plaques. We demonstrate that this plaque-produced PGE2 is not altered and is still able to activate EP3. In addition, we present evidence that PGE2 can leave the plaque and activate EP3 on blood platelets. Consistent with these findings, we observed that atherothrombosis induced in vivo by mechanical rupture of the plaque was drastically decreased when platelets lacked EP3. In conclusion, PGE2 facilitates the initiation of arterial thrombosis and, hence, contributes to atherothrombosis. Inhibition of the platelet EP3 receptor should improve prevention of atherothrombosis.

Iridoid glycosides extracted from zhizi (fructus gardeniae) decrease collagen-induced platelet aggregation and reduce carotid artery thrombosis in an in vivo rat model.

OBJECTIVE: To investigate the anti-platelet aggregation and antithrombotic effects in rats of iridoid glycosides extracted from Zhizi (Fructus Gardeniae). METHODS: The present study evaluated the antithrombotic activity of iridoid glycosides (IGs) in a rat model of carotid artery thrombosis. The effects on coagulation, such as thromboplastin time (APTT), thrombin time (TT) and prothrombin time (PT), and the effect on collagen-induced platelet aggregation in vivo were investigated. Rats were intragastrically administered IGs (50, 100 or 200 mg/ kg) twice daily for 3 days. RESULTS: IGs were shown for the first time to have an antithrombotic action through the inhibition of platelet aggregation, with little effect on the coagulation time of peripheral blood. Our results also showed that IGs may significantly and dose-dependently reduce arterial thrombus load in a model of carotid artery thrombosis and inhibit collagen-induced platelet aggregation in rats. IGs (100 or 200 mg/kg) had no significant effect on APTT and PT, but did lengthen TT at a higher dose. CONCLUSION: These data, together with the previously reported neuroprotective effects of IGs in rats with cerebral ischemia, suggest that the antithrombotic action of IGs may potentially contribute to the treatment of cerebral ischemic diseases, including cerebral apoplexy.

A malignant case of acute promyelocytic leukemia with occlusion of carotid artery by tumor thrombus.

We report an unusual and malignant presentation of acute promyelocytic leukemia (APL) resulting in thrombosis of a cervicocephalic artery by tumor in a healthy 37-year-old woman. The patient's rapid decline and multiorgan involvement proved to be a diagnostic and therapeutic challenge, and despite the efforts of a coordinated multidisciplinary health care team, she suffered a cardiac arrest and died within 48 hours of presentation to the emergency department. Autopsy revealed an APL-related tumor thrombus obstructing the left internal carotid artery, which to the best of our knowledge has not yet been described as a cause of fatal stroke.

Aging induces endothelial dysfunction while sparing arterial thrombosis.

OBJECTIVE: To assess the effects of aging on arterial thrombus formation by comparing 2-year-old with 11-week-old C57Bl6 mice. METHODS AND RESULTS: Aging is a major risk factor for cardiovascular disease. In humans, assessing the direct effects of aging on vascular homeostasis is difficult because it occurs in the presence of other risk factors. Arterial thrombosis is the critical event in cardiovascular diseases; however, it is not known whether aging per se promotes its occurrence. Mice represent an interesting system to address this issue because they age without spontaneously developing other risk factors. Organ chamber experiments confirmed the advanced level of aging of old mice. As previously shown, old mice exhibited endothelial dysfunction; however, arterial thrombosis induced by photochemical injury was unchanged. Arterial tissue factor expression and activity; expressions of tissue factor pathway inhibitor, thrombomodulin, and plasminogen activator inhibitor 1; prothrombin time; partial thromboplastin time; thrombin-antithrombin complex; and platelet activation were comparable in both groups. CONCLUSIONS: Although these results cannot be directly extrapolated to humans, this study contributes novel important information on the direct effect of aging on arterial thrombosis and underscores the importance of controlling modifiable risk factors in aged individuals.

Predictive role of modified clinical diffusion mismatch in early neurological deterioration due to atherothrombotic ischemia in the anterior circulation.

BACKGROUND: Atherothrombotic ischemia is the most frequent cause of cerebral ischemia; however, few reports have addressed the prognostic factors predicting early neurological deterioration (END) when the occlusive lesion is limited to the anterior main trunk, middle cerebral artery (MCA) or internal cerebral artery (ICA). METHOD: Between 2006 and 2008, 122 atherothrombotic ischemia patients were diagnosed with MCA or ICA occlusive disease on magnetic resonance angiography. The National Institutes of Health Stroke Scale (NIHSS) score and the modified Alberta Stroke Program Early CT Score on diffusion-weighted imaging [ASPECTS-DW (modified)] were calculated. Clinical-DWI mismatch (CDM) was evaluated using NIHSS and the ASPECTS-DW (modified) to examine the predictive efficacy for early neurological deterioration. RESULTS: Eighteen of 122 (14.8%) patients fulfilled the definition of CDM. END was observed in 24 patients (19.7%) within 15 days after admission. CDM was observed in 14 cases in the END (+) group (14 of 24 cases, 58.3%) and 4 cases in the END (-) group (4 of 98 cases, 4.1%) (p = 0.001). Multivariate logistic regression analysis demonstrated that CDM was a significant predictive factor of END (odds ratio 26.68, p = 0.0001). CONCLUSIONS: CDM based on NIHSS and ASPECTS-DW (modified) could be a significant predictive factor for END of atherothrombotic ischemia in MCA/ICA.

The benefits of intravenous thrombolysis relate to the site of baseline arterial occlusion in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET).

BACKGROUND AND PURPOSE: In ischemic stroke, the site of arterial obstruction has been shown to influence recanalization and clinical outcomes. However, this has not been studied in randomized controlled trials, nor has the impact of arterial obstruction site on reperfusion and infarct growth been assessed. We studied the influence of site and degree of arterial obstruction patients enrolled in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). METHODS: EPITHET was a prospective, randomized, placebo-controlled trial of intravenous tissue plasminogen activator (tPA) in the 3- to 6-hour time window. Arterial obstruction site and degree were rated on magnetic resonance angiography blinded to treatment allocation and outcomes. RESULTS: In 101 EPITHET patients, 87 had adequate quality magnetic resonance angiography, of whom 54 had baseline arterial obstruction. Infarct growth attenuation was greater in those with tPA treatment compared to placebo among patients with middle cerebral artery (MCA) obstruction (P=0.037). The treatment benefit of tPA over placebo in attenuating infarct growth was greater for MCA than internal carotid artery (ICA) obstruction (P=0.060). With tPA treatment, good clinical outcome was more likely with MCA than with ICA obstruction (P=0.005). Most patients with ICA obstruction did not achieve good clinical outcome, whether treated with tPA (100%) or placebo (77%). The study was underpowered to prove any treatment benefit of tPA among patients with any or severe degree of arterial obstruction. CONCLUSIONS: Arterial obstruction site strongly predicts outcomes. ICA obstruction carries a uniformly poor prognosis, whereas good outcomes with MCA obstruction are associated with tPA therapy.

Functional activity of rabbit salivary glands in reduced and restored regional arterial blood supply conditions.

BACKGROUND: Although the vascular pathology of carotid arteries is widespread, the function of salivary glands in reduced arterial flow conditions is not much investigated clinically and in experiments. At the same time blood supply is a keystone to normal functioning of every organ and especially of salivary secretion. The aim of this study was to estimate functional activity of salivary glands in reduced and restored blood supply conditions in experiment by sialoscintigraphy which is an approved method for functional assessment of salivary glands. METHODS: The ligature of a. carotis communis dextra was performed on 20 Californian rabbits. After 28 days sialoscintigraphy with Tc99 pertechnetate and revascularization through resection of the occluded part of a. carotis communis and reconstruction with venous autograft was performed. One month later sialoscintigraphy was done. RESULTS: The functional activity of rabbit salivary glands after the ligature of a. carotis communis is strongly depressed. The revascularized glands accumulated isotope slowly, but the level of accumulation was higher than on the control side. CONCLUSION: The ligature and reconstruction of a common carotid artery on rabbits confirm the important role of the arterial blood supply in functional activity of salivary glands and may be an appropriate experimental model for investigation of ischemic disease of salivary glands.

Increased dipeptidyl peptidase-4 accelerates chronic stress-related thrombosis in a mouse carotid artery model.

OBJECTIVE: Exposure to chronic psychosocial stress is a risk factor for metabolic cardiovascular disorders. Given that dipeptidyl peptidase-4 (DPP-4) has an important role in human pathobiology, we investigated the role of DPP-4 in stress-related thrombosis in mice, focusing on oxidative stress and the von Willebrand factor (vWF)-cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13). METHODS AND RESULTS: Male mice randomly assigned to nonstress and 2-week immobilized-stress groups underwent iron chloride3 (FeCl3)-induced carotid artery thrombosis surgery for morphological and biochemical studies at specific times. On day 14 post-stress/surgery, stress had enhanced the lengths and weights of arterial thrombi, with alterations of plasma DPP-4, plasminogen activation inhibitor-1 and ADAMTS13. The stressed mice had increased levels of vascular cell adhesion molecule-1, intracellular adhesion molecule-1, monocyte chemoattractant protein-1, gp91phox, p22phox, matrix metalloproteinase-2 (MMP-2), MMP-9, cathepsins S and K mRNAs and/or proteins, and reduced levels of endothelial nitric oxide synthase, catalase and superoxide dismutase-1 mRNAs and/or proteins. Stress also accelerated arterial endothelial cell damage. The DPP-4 inhibitor anagliptin ameliorated the stress-induced targeted molecular and morphological changes and thrombosis. In vitro, DPP-4 inhibition also mitigated the alterations in the targeted ADAMTS13 and other oxidative and inflammatory molecules in human umbilical vein endothelial cells in response to H2O2. CONCLUSION: DPP-4 inhibition appeared to improve the FeCl3-induced thrombosis in mice that received stress, possibly via the improvement of ADAMTS13 and oxidative stress, suggesting that DPP-4 could become a novel therapeutic target for chronic psychological stress-related thrombotic events in metabolic cardiovascular disorders.

Predicting Clinical Outcome After Mechanical Thrombectomy: The GADIS (Gender, Age, Diabetes Mellitus History, Infarct Volume, and Current Smoker [corrected]) Score.

OBJECTIVE: To investigate predictive factors and develop an outcome assessment tool to determine clinical outcome after endovascular mechanical thrombectomy (EMT) in patients presenting with large vessel occlusion (LVO). METHODS: A retrospective analysis was carried out of a prospective cohort of patients presenting with LVO who underwent EMT after adoption of an expanded time window of ≤24 hours. Final cerebral infarction volume (CIV) after EMT was estimated using magnetic resonance imaging segmentation software. Stepwise linear regression models were used to identify factors that determined clinical outcome and to develop a predictive scale. RESULTS: Ninety patients underwent EMT over 19 months (68 within 6 hours and 22 between 6 and 24 hours). Clinical outcome determined using modified Rankin Scale (mRS) score at discharge and 3 months was no different among these subcohorts. A threshold of 16.99 mL of CIV, using the Youden index, resulted in a sensitivity of 90.5% and specificity of 58.1% for predicting mRS score of 0-2. A regression model identified gender, age, diabetes mellitus status, CIV, and smoking status as outcome determinants, which were used to develop the GADIS (Gender, Age, Diabetes Mellitus History, Infarct Volume, and Sex) scoring system to predict good clinical outcome. Using the GADIS score, <6 predicted mRS score 0-2 at discharge with a sensitivity of 83.3% and specificity of 80.6%. CONCLUSIONS: The GADIS score for patients with LVO-related acute ischemic stroke includes CIV after EMT and helps in early short-term prognostication. It is not intended to predict preintervention patient selection or outcome prediction.

Interventional recanalization as a treatment of carotid stump syndrome caused by right internal carotid artery occlusion: A case report.

RATIONALE: Carotid stump syndrome is a cerebral infarction caused by an embolus formed subsequent to the vortex of blood flow from the occluded stump, which then moves through the collateral vessels into the brain. The covered stent and stent-assisted coil embolization stump are the effective interventions for the carotid artery stump. PATIENT CONCERNS: A 71-year-old man twice experienced left limb weakness; diffusion weighted imaging confirmed the diagnosis of cerebral infarction. Cervical computed tomography angiography, intracranial magnetic resonance angiography, and digital subtraction angiography were conducted to evaluate collateral circulation, intraluminal composition, and shape of the carotid stump. DIAGNOSES: The patient was diagnosed with cerebral infarction and right carotid stump syndrome. INTERVENTION: The patient underwent interventional recanalization of the occluded internal carotid artery, which relieved his symptoms and led to satisfactory therapeutic outcomes during the clinical follow-up. OUTCOMES: A 9-month clinical follow-up revealed no stroke recurrence. LESSONS: Interventional recanalization for the carotid artery stump syndrome is feasible. Accurate preoperative evaluation including collateral circulation, intraluminal composition, and shape of the carotid stump can assure a successful vascularization and guided management.

Use of Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS) and Ischemic Core Volume to Determine the Malignant Profile in Acute Stroke.

Background Malignant profiles were identified by imaging profiles and unfavorable outcomes that have poor response to reperfusion therapy. Many trials have used this profile in their inclusion criteria including large-vessel occlusion acute ischemic stroke trials. We aimed to redefine the cutoff values for malignant profile in acute ischemic stroke patients with large-vessel occlusion regardless of reperfusion therapy. Methods and Results Consecutive acute ischemic stroke patients with anterior large-vessel occlusion were prospectively extracted from the National Cerebral and Cardiovascular Center Stroke Registry between March 2014 and December 2017. Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECTS) and diffusion-weighted imaging lesion ischemic core volume (VolDWI) were measured in acute ischemic stroke patients with large-vessel occlusion with or without treatment. Unfavorable outcome was defined as a modified Rankin Scale score 5 to 6 at 3 months, and optimal DWI-ASPECTS and VolDWI for unfavorable outcome were assessed. In total, 198 patients (111 men, 77±13 years old) were enrolled. Median DWI-ASPECTS was 7 (5-9), and median VolDWI was 55 (6-134) mL. Among the patients, 72 (36%) patients underwent reperfusion therapy, and 83 (42%) had unfavorable outcomes. The threshold values for a malignant profile on receiver operating characteristic curve analysis for DWI-ASPECTS and VolDWI were 4 (area under the curve 0.78, P<0.01; sensitivity 0.71, specificity 0.75) and 71 mL (area under the curve 0.80, P<0.01; sensitivity 0.76, specificity 0.77), respectively. Conclusions The cutoff values for our redefined malignant profile were DWI-ASPECTS 4 and VolDWI 71 mL with no selection bias for reperfusion therapy in the real-world clinical practice. Clinical Trial Registration URL: http://www.clinicaltrials.gov Unique identifier: NCT02251665.

Protective effects of gelsolin in acute pulmonary thromboembolism and thrombosis in the carotid artery of mice.

The present study provides first evidence on the role of plasma gelsolin in protecting pulmonary thromboembolism and thrombosis in a mouse model. Gelsolin is the most abundant actin depolymerizing protein in plasma and its significantly depleted values have been reported in metabolic disorders including cardiovascular diseases and myocardial infarction. Though gelsolin replacement therapy (GRT) has been shown to be effective in some animal models, no such study has been reported for thrombotic diseases that are acutely in need of bio-therapeutics for immediate and lasting relief. Here, using mice model and recombinant human gelsolin (rhuGSN), we demonstrate the antithrombotic effect of gelsolin in ferric chloride induced thrombosis in carotid artery and thrombin induced acute pulmonary thromboembolism. In thrombosis model, arterial occlusion time was significantly enhanced upon subcutaneous (SC) treatment with 8 mg of gelsolin per mice viz. 15.83 minutes vs. 8 minutes in the placebo group. Pertinently, histopathological examination showed channel formation within the thrombi in the carotid artery following injection of gelsolin. Fluorescence molecular tomography imaging further confirmed that administration of gelsolin reduced thrombus formation following carotid artery injury. In thrombin-induced acute pulmonary thromboembolism, mice pretreated with aspirin or gelsolin showed 100 and 83.33% recovery, respectively. In contrast, complete mortality of mice was observed in vehicle treated group within 5 minutes of thrombin injection. Overall, our studies provide conclusive evidence on the thrombo-protective role of plasma gelsolin in mice model of pulmonary thromboembolism and thrombosis.

Optimizing in-hospital triage for large vessel occlusion using a novel clinical scale (GAI2AA).

OBJECTIVE: To identify a proximal anterior circulation occlusion for effectively administering immediate mechanical thrombectomy by developing a novel, simple diagnostic scale to predict the occlusion, to compare its validity with available scales, and to assess its utility. METHODS: To develop a novel clinical scale, we retrospectively analyzed a cohort of 429 patients with acute ischemic stroke from a single center. The novel scale GAI2AA was applied to a prospective cohort of 259 patients from 3 stroke centers for external validation. The utility of the scale as an in-hospital triage was compared for the temporal factors of 158 patients with the occlusion. RESULTS: In a scale-developmental phase, those with a proximal anterior circulation occlusion had significantly more frequent signs of hemispheric symptoms, including gaze palsy, aphasia, inattention, arm paresis, and atrial fibrillation. The GAI2AA scale was developed using consolidated hemispheric symptoms and was scored as follows: score = 2, arm paresis score = 1, and atrial fibrillation score = 1. A cutoff value ≥3 was optimal for the correlation between sensitivity (88%) and specificity (81%), with a C statistic of 0.90 (95% confidence interval 0.87-0.93). External validation indicated that discrimination was significantly better than or not different from that of available complex scales. Door-to-puncture time was significantly reduced (91 [82-111] vs 52 [32-75] minutes, p < 0.001). CONCLUSION: The GAI2AA scale showed high sensitivity and specificity when an optimal cutoff score was used and was useful as an in-hospital triage tool.