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Background and purpose: First pass effect (FPE), the occurrence of complete reperfusion after one pass with no rescue attempt during endovascular therapy (EVT), is associated with the best clinical outcome after an acute ischemic stroke (AIS). Previous studies evaluating FPE occurrence according to EVT technical strategies, occlusion locations, or thrombus composition have provided controversial results. Here, we performed a correlation analysis between FPE occurrence and AIS thrombus cellular composition, as assessed using quantitative biochemical assays. Patients and methods: Homogenates of AIS thrombi from 250 patients were prepared by mechanical grinding. Platelet, red blood cell (RBC), and leukocyte contents of AIS thrombi were respectively estimated by quantification of GP (glycoprotein) VI, heme, and DNA in thrombus homogenates. FPE was defined as a modified Thrombolysis in Cerebral Infraction (mTICI) score of 2C or 3 after a single EVT device pass. Results: AIS thrombi successfully removed after a single pass were poorer in GPVI (0.098 ± 0.023 vs 0.111 ± 0.024 ng/mg, p Discussion and conclusion: Thrombus platelet content may hamper thrombus removal by EVT. This result suggests that adjunctive therapies or functionalization of retrieval devices targeting platelets may improve EVT efficacy.

Resistance to fibrinolysis, levels of procoagulant/antifibrinolytic neutrophil extracellular traps (NETs), and the severity of acute ischemic stroke (AIS) are increased by COVID-19. Whether NETs are components of AIS thrombi from COVID-19 patients and whether COVID-19 impacts the susceptibility of these thrombi to thrombolytic treatments remain unknown, however.We aimed to characterize AIS thrombi from COVID-19 patients by immunohistology and to compare their response to thrombolysis to that of AIS thrombi from non-COVID-19 patients.For this monocentric cohort study, 14 thrombi from COVID-19 AIS patients and 16 thrombi from non-COVID-19 patients, all recovered by endovascular therapy, were analyzed by immunohistology or subjected to ex vivo thrombolysis by tissue-type plasminogen (tPA)/plasminogen.COVID-19 AIS thrombi were rich in neutrophils and contained NETs, but not spike protein. Thrombolysis assays revealed a mean resistance profile to tPA/plasminogen of COVID-19 AIS thrombi similar to that of non-COVID-19 AIS thrombi. The addition of DNase 1 successfully improved thrombolysis by potentiating fibrinolysis irrespective of COVID-19 status. Levels of neutrophil, NETs, and platelet markers in lysis supernatants were comparable between AIS thrombi from non-COVID-19 and COVID-19 patients.These results show that COVID-19 does not impact NETs content or worsen fibrinolysis resistance of AIS thrombi, a therapeutic hurdle that could be overcome by DNase 1 even in the context of SARS-CoV-2 infection.

During the last decade, significant progress has been made in understanding thrombus composition and organization in the setting of acute ischemic stroke (AIS). In particular, thrombus organization is now described as highly heterogeneous but with 2 preserved characteristics: the presence of (1) two distinct main types of areas in the core—red blood cell (RBC)-rich and platelet-rich areas in variable proportions in each thrombus—and (2) an external shell surrounding the core composed exclusively of platelet-rich areas. In contrast to RBC-rich areas, platelet-rich areas are highly complex and are mainly responsible for the thrombolysis resistance of these thrombi for the following reasons: the presence of platelet-derived fibrinolysis inhibitors in large amounts, modifications of the fibrin network structure resistant to the tissue plasminogen activator (tPA)-induced fibrinolysis, and the presence of non-fibrin extracellular components, such as von Willebrand factor (vWF) multimers and neutrophil extracellular traps. From these studies, new therapeutic avenues are in development to increase the fibrinolytic efficacy of intravenous (IV) tPA-based therapy or to target non-fibrin thrombus components, such as platelet aggregates, vWF multimers, or the extracellular DNA network.

BackgroundAccumulating evidence indicates that neutrophil activation (NA) contributes to microvascular thromboinflammation in acute ischemic stroke (AIS) due to a large vessel occlusion. Preclinical data have suggested that intravenous thrombolysis (IVT) before endovascular therapy (EVT) could dampen microvascular thromboinflammation. In this study we investigated the association between NA dynamics and stroke outcome, and the impact of IVT on NA in patients with AIS treated with EVT.MethodsA single-center prospective study was carried out, including patients treated with EVT for whom three blood samples (before, within 1 hour, 24 hours post-EVT) were drawn to measure plasma myeloperoxidase (MPO) concentration as a marker of NA. Unfavorable outcome was defined as a modified Rankin score of 3–6 at 3 months.ResultsBetween 2016 and 2020, 179 patients were included. The plasma MPO concentration peaked significantly 1 hour post-EVT (median increase 21.0 ng/mL (IQR −2.1–150)) and returned to pre-EVT baseline values 24 hours after EVT (median change from baseline −0.8 ng/mL (IQR −7.6–6.7)). This peak was strongly associated with unfavorable outcomes at 3 months (aOR 0.53 (95% CI 0.34 to 0.84), P=0.007). IVT before EVT abolished this 1 hour post-EVT MPO peak. Changes in plasma MPO concentration (baseline to 1 hour post-EVT) were associated with unfavorable outcomes only in patients not treated with IVT before EVT (aOR 0.54 (95% CI 0.33 to 0.88, P=0.013). However, we found no significant heterogeneity in the associations between changes in plasma MPO concentration and outcomes.ConclusionsA peak in plasma MPO concentration occurs early after EVT and is associated with unfavorable outcomes. IVT abolished the post-EVT MPO peak and may modulate the association between NA and outcomes.

More than 40% of endovascular therapy (EVT) fail to achieve complete reperfusion of the territory of the occluded artery in patients with acute ischemic stroke (AIS). Understanding factors influencing EVT could help overcome its limitations. Our objective was to study the impact of thrombus cell composition on EVT procedures, using a simulation system for modeling thrombus-induced large vessel occlusion (LVO) in flow conditions. In an open comparative trial, we analyzed the behavior of size-standardized platelet-rich and red blood cells (RBC)-rich thrombi during simulated stent retriever-mediated EVT procedures. Sixteen simulated EVT procedures were performed (8 RBC- vs. 8 platelet-rich thrombi). Platelet-rich thrombi were associated with a higher number of stent retriever passes (p = 0.03) and a longer procedure duration (p = 0.02) compared to RBC-rich thrombi. Conversely, RBC-rich thrombi released more embolic fragments than platelet-rich thrombi (p = 0.004). Both RBC-rich and platelet-rich thrombi underwent drastic compaction after being injected into the in vitro circulation model, and histologic analyses showed that these EVT-retrieved thrombi displayed features comparable to those previously observed in thrombi from patients with AIS patients having LVO, including a marked structural dichotomy between RBC- and platelet-rich areas. Our results show that the injection of in vitro-produced thrombi in artificial cerebrovascular arterial networks is suitable for testing recanalization efficacy and the risk of embolization of EVT devices and strategies in association with thrombus cell composition.

Immediate reocclusion after mechanical thrombectomy (MT) for acute ischemic stroke (AIS) is a rare but devastating condition associated with poor functional outcome. The aim of this study was to gain insights into the mechanisms underlying immediate reocclusion, and to evaluate the efficacy and safety of the glycoprotein IIb/IIIa antagonist abciximab, for its treatment. Clinical data were collected from April 2015 to April 2019 in a monocentric prospective registry of AIS patients treated by MT. All patients with immediate reocclusion were retrospectively selected and subdivided into 2 groups according to abciximab treatment status.

Background Carotid webs are an under-recognized embolic source in patients with cryptogenic stroke. Limited resources currently exist to assist clinicians in stroke prevention for patients with symptomatic carotid webs (SCW). We aimed at analysing the clinical, radiological and procedural features of stroke patients with SCW undergoing endovascular thrombectomy (EVT), and to describe the histopathological composition of their occlusive thrombi. Methods In a single-center observational study on consecutive patients with ischemic stroke treated by EVT, carotid web was defined symptomatic when it was ipsilateral to the ischemic lesion in a patient classified with stroke of otherwise undetermined etiology. Clinical, radiological and procedural data of patients with SCW were evaluated. Histopathological examination of the retrieved thrombi was performed. Results Out of 1430 patients with large vessel occlusion stroke treated by EVT, 11(0.7%) were found to have a SCW. Patients with SCW had a median age of 47 years old (IQR 38–50), they were prevalently women (55%), mostly of African ethnicity (91%). Each of the 11 patients achieved successful angiographic reperfusion (mTICI 2b-3) after EVT. For secondary prevention, elective endovascular carotid stenting was performed in 5 (55%) patients, while 1 (9%) was treated by surgical endoarterectomy. Histological analysis of the retrieved thrombi performed in 4 patients showed a mixed composition with variable red blood cell content. Conclusions EVT is feasible in large vessel occlusion stroke related to SCW. Procedures of carotid revascularization appear to be feasible therapeutic options for secondary prevention. The histopathological analysis of cerebral thrombi may provide new insights on stroke pathogenesis in patients with SCW.

ObjectivesThrombi responsible for large vessel occlusion (LVO) in the setting of acute ischemic stroke (AIS) are characterized by a low recanalization rate after IV thrombolysis. To test whether AIS thrombi have inherent common features that limit their susceptibility to thrombolysis, we analyzed the composition and ultrastructural organization of AIS thrombi causing LVO.MethodsA total of 199 endovascular thrombectomy-retrieved thrombi were analyzed by immunohistology and scanning electron microscopy (SEM) and subjected to ex vivo thrombolysis assay. The relationship between thrombus organization and thrombolysis resistance was further investigated in vitro using thrombus produced by recalcification of citrated whole blood.ResultsSEM and immunohistology analyses revealed that, although AIS thrombus composition and organization was highly heterogeneous, AIS thrombi shared a common remarkable structural feature in the form of an outer shell made of densely compacted thrombus components including fibrin, von Willebrand factor, and aggregated platelets. In vitro thrombosis experiments using human blood indicated that platelets were essential to the formation of the thrombus outer shell. Finally, in both AIS and in vitro thrombi, the thrombus outer shell showed a decreased susceptibility to tissue plasminogen activator–mediated thrombolysis as compared to the thrombus inner core.InterpretationIrrespective of their etiology and despite their heterogeneity, intracranial thrombi causing LVO have a core shell structure that influences their susceptibility to thrombolysis.

Cerebral venous sinus thrombosis (CVST) is an uncommon cause of stroke resulting in parenchymal injuries associated with heterogeneous clinical symptoms and prognosis. Therefore, an experimental animal model is required to further study underlying mechanisms involved in CVST. This study is aimed at developing a novel murine model suitable and relevant for evaluating injury patterns during CVST and studying its clinical aspects. CVST was achieved in C57BL/6J mice by autologous clot injection into the superior sagittal sinus (SSS) combined with bilateral ligation of external jugular veins. Clot was prepared ex vivo using thrombin before injection. On days 1 and 7 after CVST, SSS occlusion and associated-parenchymal lesions were monitored using different modalities: in vivo real-time intravital microscopy, magnetic resonance imaging (MRI), and immuno-histology. In addition, mice were subjected to a neurological sensory-motor evaluation. Thrombin-induced clot provided fibrin- and erythrocyte-rich thrombi that lead to reproducible SSS occlusion at day 1 after CVST induction. On day 7 post-CVST, venous occlusion monitoring (MRI, intravital microscopy) showed that initial injected-thrombus size did not significantly change demonstrating no early spontaneous recanalization. Microscopic histological analysis revealed that SSS occlusion resulted in brain edema, extensive fibrin-rich venular thrombotic occlusion, and ischemic and hemorrhagic lesions. Mice with CVST showed a significant lower neurological score on post-operative days 1 and 7, compared to the sham-operated group. We established a novel clinically CVST-relevant model with a persistent and reproducible SSS occlusion responsible for symptomatic ischemic and hemorrhagic lesions. This method provides a reliable model to study CVST physiopathology and evaluation of therapeutic new regimens.

Background and Purpose: Identification of acute ischemic stroke (AIS) cause is crucial for guidance of secondary prevention. Previous studies have yielded inconsistent results regarding possible correlations between AIS cause and thrombus composition, as assessed by semiquantitative histological analysis. Here, we performed a correlation analysis between AIS cause and AIS thrombus cellular composition and content, as assessed using quantitative biochemical assays. Methods: Homogenates of 250 patients with AIS thrombi were prepared by mechanical grinding. Platelet, red blood cell, and leukocyte content of AIS thrombi were estimated by quantification of GP (glycoprotein) VI, heme, and DNA in thrombus homogenates. AIS cause was defined as cardioembolic, noncardioembolic, or embolic stroke of undetermined source, according to the TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment). Results: Cardioembolic thrombi were richer in DNA (35.8 versus 13.8 ng/mg, P P =0.045) than noncardioembolic ones. The area under the receiver operating characteristic curve of DNA content to discriminate cardioembolic thrombi from noncardioembolic was 0.72 (95% CI, 0.63–0.81). With a threshold of 44.7 ng DNA/mg thrombus, 47% of thrombi from undetermined cause would be classified as cardioembolic with a specificity of 90%. Conclusions: Thrombus DNA content may provide an accurate biomarker for identification of cardioembolic thrombi in patients with AIS with embolic stroke of undetermined source. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03268668.

Background and Purpose— Previous experimental studies found that the infusion of human purified nascent HDL (high-density lipoprotein) significantly reduced infarct volume and hemorrhagic transformation rate by decreasing neutrophil recruitment. ApoA1-M (apolipoprotein A1-Milano) is a natural variant of human ApoA1 that confers protection against atherosclerosis. Recombinant ApoA1-M has been formulated as a complex with phospholipids to mimic the properties of nascent HDL. The aim of this study was to assess the impact of intravenous ApoA1-M in a transient middle cerebral artery occlusion stroke model in rats. Methods— In a first experiment, rats were subjected to 120-minute transient middle cerebral artery occlusion and intravenous ApoA1-M was infused immediately or 4 hours after occlusion. In a second experiment, rats were subjected to 240-minute transient middle cerebral artery occlusion and intravenous ApoA1-M was infused with or without recombinant tPA (tissue-type plasminogen activator) immediately after recanalization. Primary outcome criteria were the infarct volume and hemorrhagic transformation rate measured at 24 hours. Platelets, coagulation, and neutrophil activation biomarkers were measured in brain homogenates and plasma. Additional in vitro experiments studied the effects of ApoA1-M on platelet aggregation and platelet-neutrophil interactions. Results— The infusion of ApoA1-M immediately or 4 hours after 120-minute transient middle cerebral artery occlusion significantly reduced the infarct volume compared with saline ( P =0.034 and P =0.036, respectively). Compared with tPA alone, co-administration of ApoA1-M and tPA showed similar rates of hemorrhagic transformation. ApoA1-M had no significant inhibition effect on neutrophil activation biomarkers. Platelet activation was slightly decreased in rats treated with ApoA1-M compared with saline. In vitro, the incubation of human and rat platelet-rich plasma with ApoA1-M significantly reduced ADP-induced platelet aggregation ( P =0.001 and P =0.02, respectively). Conclusions— ApoA1-Milano significantly decreased the infarct volume through an inhibition of platelet aggregation but did not reduce hemorrhagic transformation and neutrophils activation as expected after previous experimental studies with nascent HDL. Visual Overview— An online visual overview is available for this article.

Introduction L’amylose a transthyretine (ATTR) est une pathologie genetique rare entrainant l’accumulation de proteines amyloides notamment au niveau du systeme nerveux peripherique. Objectifs Notre objectif etait d’evaluer les connaissances sur l’ATTR chez des neurologues en formation. Patients et methodes 22 questions sur les thematiques suivantes : – orientation diagnostique devant une neuropathie des petites fibres ; – manifestations cliniques et biologiques a rechercher devant une suspicion d’amylose ; – modalites du suivi et des traitements de l’ATTR ont ete adressees par e-mail a 890 membres de l’Association Nationale des Assistants et Internes de Neurologie de France (ANAINF). Resultats 124 membres de l’ANAINF ont complete l’enquete, dont 75 % d’internes. 64 % des jeunes neurologues interroges rencontrent moins de 10 cas mensuels de neuropathie peripherique. Devant un tableau de neuropathie des petites fibres 68 % ont evoque ce diagnostic. 98 % proposaient le test genetique comme outil diagnostic de l’ATTR. 30 % considerent qu’il n’y aura pas d’apparition de deficit moteur ni de handicap a 6 ans. 7 % ne connaissent pas l’existence de traitements efficaces. Discussion Chez les jeunes neurologues, la neuropathie des petites fibres est mal connue. L’ATTR est une des premieres etiologies evoquees malgre sa faible incidence. La gravite du pronostic de l’ATTR est sous-estimee, et les traitements disponibles restent mal connus. Conclusion Une sensibilisation des jeunes neurologues sur l’ATTR, son diagnostic, son pronostic et les traitements disponibles pourrait permettre d’eviter les errances diagnostiques et le retard de prise en charge.

Neutrophil extracellular trap formation (NETosis) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome assembly are associated with a similar spectrum of disorders. We hypothesized that NLRP3 inflammasome may participate in NETosis. Using confocal microscopy, we observed the formation of ASC speck in stimulated neutrophils in the absence of infection, as well as the association of ASC speck with the released NETs. Peptidylarginine deiminase (PAD) 4, a mediator of NETosis, was needed for optimal NLRP3 inflammasome assembly in neutrophils and rendered bone marrow–derived macrophages more susceptible to inflammasome formation, possibly by increasing NLRP3 and ASC protein levels. NLRP3 deficiency or specific inhibition by MCC950 resulted in significantly impaired NETosis, and time-lapse visualization revealed defects in nuclear envelope and plasma membrane breakdown. Our results reveal PAD-dependent formation of NLRP3 inflammasome in neutrophils and macrophages and implicate the NLRP3 inflammasome in NETosis.

Background Previous experimental studies have shown that downstream microvascular thromboinflammation is involved in brain damage from acute ischemic stroke. Using intravital microscopy, we investigated and characterized the sequence of downstream microvascular thromboinflammation in an ischemia/reperfusion acute ischemic stroke model. Methods and Results Rats underwent transient monofilament middle cerebral artery (MCA) occlusion. Cerebral microcirculation in the MCA territory was exposed through a craniotomy and analyzed using real‐time intravital imaging coupled with laser Doppler interferometry. Leukocytes, platelets, fibrinogen, and blood–brain barrier permeability were analyzed by intravenous injection of fluorescent antibodies and bovine serum albumin. MCA occlusion induced a sudden and profound drop in downstream microvascular blood flow associated with leukocyte margination in the venous compartment. Leukocyte margination fostered fibrinogen deposition and thrombosis in postcapillary venules. Either in venules or arterioles, blood flow was not fully restored after MCA recanalization. Furthermore, venular thrombi persisted despite MCA recanalization, and leukocyte extravasation continued to develop in venules in association with blood–brain barrier disruption. Finally, microhemorrhages were occasionally observed, colocalizing with thrombosed venules characterized by marked leukocyte margination. Conclusions We showed that microvascular thrombosis in transient monofilament MCA occlusion and blood–brain barrier disruption are initiated immediately after occlusion and are propagated through the venous compartment in close association with marginating leukocytes. MCA occlusion–induced downstream microvascular thromboinflammation response was responsible for incomplete reperfusion after MCA recanalization and delayed microhemorrhages.

Background Hemorrhagic transformation (HT) is a complication of stroke [1] that can occur spontaneously or after treatment. We aimed to assess the interrater and intrarater reliability of HT diagnosis. Methods Studies assessing the reliability of the European Cooperative Acute Stroke Study (ECASS) classification [2] of HT or of the presence (yes/no) of HT were systematically reviewed. Eighteen raters independently examined 30 post-thrombectomy [3] computed tomography scans selected from the Aspiration versus Stentriever (ASTER) trial [4] . They were asked whether there was HT (yes/no), what the ECASS classification of the particular scan (0/HI1/HI2/PH1/PH2) was, and whether they would prescribe an antiplatelet agent if it was otherwise indicated. Agreement [5] was measured with Fleiss’ and Cohen's kappa statistics. Results The systematic review yielded 4 studies involving few (≤ 3) raters with heterogeneous results. In our 18-rater study, agreement for the presence of HT was moderate (κ=0.55, 95%CI [0.41–0.68]). Agreement for ECASS classification was only fair for all 5 categories, but agreement improved to substantial (k = 0.72, 95%CI [0.69-0.75]) after dichotomizing ECASS into 0/HI1/HI2/PH1 versus PH2. The interrater agreement for the decision to reintroduce antiplatelet therapy was moderate for all raters, but substantial among vascular neurologists (κ=0.70 [0.57–0.84]). Conclusion The ECASS classification may involve too many categories and the diagnosis of HT may not be easily replicable, except in the presence of a large parenchymal hematoma. Clinical Trial Registration URL: http://www.clinicaltrials.gov Unique identifier: NCT02523261 .

Le diaphragme des arteres cervicales est une lesion de la paroi arterielle le plus souvent situee a la face posterieure du bulbe carotidien. C’est une cause rare d’infarctus cerebral du sujet jeune par embolie d’artere a artere. Son diagnostic est essentiel car il expose a un risque eleve de recidive dans le meme territoire vasculaire. Sa mise en evidence repose sur un angioscanner des troncs supra-aortiques de bonne qualite avec reconstruction en coupe sagittale. En cas d’infarctus cerebral recidivant avec imagerie non invasive normale, une arteriographie conventionnelle permet d’obtenir une meilleure resolution et de mettre en evidence une stagnation du produit de contraste caracteristique. La simple anti-agregation plaquettaire semble insuffisante pour prevenir la recidive. Ses alternatives sont l’anticoagulation curative, le stenting endovasculaire et l’endarteriectomie.

Background and Purpose— Neutrophil Extracellular Traps (NETs) are DNA extracellular networks decorated with histones and granular proteins produced by activated neutrophils. NETs have been identified as major triggers and structural factors of thrombosis. A recent study designated extracellular DNA threads from NETs as a potential therapeutic target for improving tissue-type plasminogen activator (tPA)-induced thrombolysis in acute coronary syndrome. The aim of this study was to assess the presence of NETs in thrombi retrieved during endovascular therapy in patients with acute ischemic stroke (AIS) and their impact on tPA-induced thrombolysis. Methods— We analyzed thrombi from 108 AIS patients treated with endovascular therapy. Thrombi were characterized by hematoxylin/eosin staining, immunostaining, and ex vivo enzymatic assay. Additionally, we assessed ex vivo the impact of deoxyribonuclease 1 (DNAse 1) on thrombolysis of AIS thrombi. Results— Histological analysis revealed that NETs contributed to the composition of all AIS thrombi especially in their outer layers. Quantitative measurement of thrombus NETs content was not associated with clinical outcome or AIS pathogenesis but correlated significantly with endovascular therapy procedure length and device number of passes. Ex vivo, recombinant DNAse 1 accelerated tPA-induced thrombolysis, whereas DNAse 1 alone was ineffective. Conclusions— This study suggests that thrombus NETs content may be responsible for reperfusion resistance, including mechanical or pharmacological approaches with intravenous tPA, irrespectively of their etiology. The efficacy of a strategy involving an administration of DNAse 1 in addition to tPA should be explored in the setting of AIS. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT02907736.

Background and Purpose— Admission hyperglycemia is associated with a poor outcome in acute ischemic stroke. How hyperglycemia impacts the pathophysiology of acute ischemic stroke remains largely unknown. We investigated how preexisting hyperglycemia increases ischemia/reperfusion cerebral injury. Methods— Normoglycemic and streptozotocin-treated hyperglycemic rats were subjected to transient middle cerebral artery occlusion. Infarct growth and brain perfusion were assessed by magnetic resonance imaging. Markers of platelet, coagulation, and neutrophil activation were measured in brain homogenates and plasma. Downstream microvascular thromboinflammation (DMT) was investigated by intravital microscopy. Results— Hyperglycemic rats had an increased infarct volume with an increased blood–brain barrier disruption and hemorrhagic transformation rate compared with normoglycemic rats. Magnetic resonance imaging scans revealed that hyperglycemia enhanced and accelerated lesion growth and was associated with hemorrhagic transformation originating from territories that were still not completely reperfused at 1 hour after middle cerebral artery recanalization. Intravital microscopy and analysis of brain homogenates showed that DMT began immediately after middle cerebral artery occlusion and was exacerbated by hyperglycemia. Measurement of plasma serotonin and matrix metalloproteinase-9 indicated that platelets and neutrophils were preactivated in hyperglycemic rats. Neutrophils from hyperglycemic diabetic patients showed increased adhesion to endothelial cells as compared with neutrophils from normoglycemic donors in flow chamber experiments. Conclusions— We show that hyperglycemia primes the thromboinflammatory cascade, thus, amplifying middle cerebral artery occlusion–induced DMT. DMT exacerbation in hyperglycemic rats impaired reperfusion and precipitated neurovascular damage, blood–brain barrier disruption, and hemorrhagic transformation. Our results designate DMT as a possible target for reduction of the deleterious impact of hyperglycemia in acute ischemic stroke.