Rationale: Fibrinolysis resistance in sepsis associates with thrombotic burden, multi-organ failure and death. The degrees and dynamics of resistance that associate with mortality in acute sepsis are unknown, and a simple tool to aid clinician interpretation of fibrinolysis measurements is lacking. Objectives: To establish a point of care grading tool of fibrinolysis resistance that aligns with scoring systems for disease acuity, is substantiated by plasma fibrinolysis markers and enables rapid investigation of the fibrinolysis state at the point of care. Methods: Prospective observational study of 116 adult sepsis/septic shock patients with sequential measurements of fibrinolysis resistance during Intensive Care Unit (ICU) admission using tissue plasminogen activator (tPA) enhanced viscoelastic testing (VET). The clot lysis time (TPA-LT) adjusted for fibrin clot amplitude (TPA-LT/FIBA10, sec/mm) underwent cluster analysis and was evaluated against disease severity scores, standard pathology, clinical outcomes and fibrinolysis markers. Measurements and Main Results: Three clusters of progressively increasing fibrinolysis resistance were identified (Grades 1-3). At admission, Grade 3 associated with the highest disease severity, organ failure, haematological and biochemical perturbations, fibrinolysis marker inhibitory profile and mortality (42% versus 24% and 15% in Grade 2 and Grade 1, respectively) with a 3.9-fold [95% CI 1.4-11] increased hazard ratio for death at 28 days compared to Grade 1. Transitions between grades were frequent over 7 days with a reduced Grade associated with decreased risk of death. Conclusions: Grading of fibrinolysis resistance in sepsis enables rapid identification of patients at greatest mortality risk with any dynamic improvement corresponding to favourable clinical outcomes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study received departmental funding only ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: South Western Sydney Local Health District Human Research Ethics Committee (2022/ETH02122). Consent was waived as permitted under the National Statement on Ethical Conduct in Human Research 2023 for low risk research in critically ill patients. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data interaction app links provided in manuscript For original data, please contact corresponding authors. [https://fortitude.shinyapps.io/TPA\_FIB\_CORREL][1] [1]: https://fortitude.shinyapps.io/TPA_FIB_CORREL

Abstract Background and aims Dornase-alpha, a recombinant human deoxyribonuclease-I, can potentiate alteplase-mediated clot lysis via breakdown of neutrophil extracellular traps in stroke clots. We aimed to determine if dornase potentiates clot lysis in combination with tenecteplase ex-vivo in thrombectomy clots retrieved from stroke patients. Methods Forty-two thrombectomy clots were divided and suspended in buffer, pooled citrated or heparinised plasma and incubated with 15nM tenecteplase or in combination with either 10U/ml or 100U/ml of dornase. Clot weight was measured over 120-minutes, and treated clots underwent immunofluorescence. Statistical significance was assessed using linear mixed-effects modelling. Results Addition of tenecteplase to retrieved clots in buffer resulted in a median percentage reduction to 40.7% (IQR:17.0-53.7%) of the initial clot weight after 120-minutes. The addition of 100U/ml of dornase led to significant clot weight reduction to 17.5% (IQR:8.8-27.2%) while the addition of 10U/ml of dornase led to a non-significant reduction to 28.0% (IQR:7.4-45.7%) compared to tenecteplase alone. Further, incubation in citrated and heparinised plasma resulted in a clot weight reduction to 55.7% (IQR:21.6-70.7) and 58.5% (IQR:45.3-73.2) in the presence of tenecteplase respectively, with a non-statistically significant reduction with addition of Dornase. However, there was a significant attenuation in clot weight reduction in plasma compared to buffer in clots treated with tenecteplase and Dornase. Conclusions 100U/ml dornase potentiated ex-vivo tenecteplase mediated clot lysis in buffer but was less effective at lower doses and in plasma. Further studies need to assess ex-vivo lytic activity in plasma to allow for greater clinical translation. Conflict of interest Oshi Swarup: nothing to disclose, Joanne Chia: nothing to disclose, Zikou Liu: nothing to disclose, Tammy Lam: nothing to disclose, Anna Balabanski: nothing to disclose, Geoffrey Cloud: nothing to disclose, Bruce Campbell: nothing to disclose, Robert Medcalf: nothing to disclose

BACKGROUND:Early transfusion improves survival of traumatic hemorrhage. We hypothesized that increased ratios of prehospital to total blood (red blood cell or whole blood) transfusion within 24 hours would be associated with improved outcomes. METHODS:A retrospective cohort study using a harmonized database of six hemorrhagic shock trials was conducted. Decedents within 4 hours and those not transfused within 24 hours were excluded. The primary outcome was 24-hour mortality; secondary outcomes included 28-day mortality, intensive care unit (ICU)-free and ventilator-free days, and incidence of acute lung injury (ALI). Prehospital blood ratio was calculated as volume prehospital transfusion:volume 24-hour total transfusion (prehospital plus 24-h total at the admitting facility). Multivariable analyses adjusted for age, sex, mechanism, Injury Severity Score (ISS), inter-facility transfer, transport mode, arrival systolic blood pressure and Glasgow Coma Scale, treatment group, trial, and transfusion volume were conducted. Sensitivity analyses (prehospital-only recipients, excluding traumatic brain injury) were conducted. RESULTS:Overall, 2,340 subjects were eligible, and 1,024 (43.8%) received prehospital blood. Prehospital recipients were older (median age 41 vs. 38 y, P =0.013), more likely blunt mechanism (81.6% vs. 66.0%; P <0.001), more likely transferred (13.3% vs. 4.3%; P <0.001), more likely transported by air (77.4% vs. 47.1%; P <0.001), and had higher ISS (median 29 vs. 25, P <0.001) compared with in-hospital only recipients. For every 10% increase in prehospital (PH):total blood ratio, there was an 8.8% decrease in odds of ALI (95% CI: 1.8-15.4%; P =0.015) and no significant association with mortality, ICU-free or ventilator-free days. Among prehospital recipients, for every 10% increase in PH:total blood ratio, there was a 16.7% decrease in odds of ALI (95% CI: 5.3-26.6%; P =0.005; n=375) and 0.21 (95% CI: 0.01-0.41; P =0.036; n=909) more ICU-free days. CONCLUSIONS:An increased proportion of resuscitation in the prehospital phase of care was associated with improved secondary clinical outcomes for select subjects. These data support initiating transfusion for hemorrhage as early as feasible. ( J Trauma Acute Care Surg . 2026;101: 39-47. Copyright © 2026 Wolters Kluwer Health, Inc. All rights reserved.). LEVEL OF EVIDENCE:Therapeutic/Care Management; Level III.

BACKGROUND:Thrombotic and thromboembolic events are a common and potentially preventable complication in multitrauma patients, and substantial quality improvement efforts are directed at prevention. The results of several randomized controlled trials (RCTs) related to the association between tranexamic acid (TXA) and thrombotic/thromboembolic events have demonstrated conflicting results. We aimed to address this by examining whether prehospital TXA was associated with higher rates of thrombotic/thromboembolic events in a harmonized data set from three large multicenter RCTs. METHODS:We analyzed data using a harmonized data set from three RCTs examining the effects of prehospital TXA: The Pre-Hospital Anti-fibrinolytics for Traumatic Coagulopathy and Hemorrhage Study (PATCH trial), Study of Tranexamic Acid During Air and Ground Medical Prehospital Transport Trial (STAAMP trial) and the Prehospital TXA for TBI trial, part of the Resuscitation Outcomes Consortium (ROC trial). Outcomes included deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, stroke, combined venous thrombotic/thromboembolic events (VTE), and combined arterial thrombotic/thromboembolic events. Multivariable regression was used to adjust for TXA administration, sex, age, injury severity score, Glasgow Coma Scale, shock index, and 24-hour red cell transfusion. RESULTS:There were no differences in myocardial infarction, stroke, arterial thrombotic/thromboembolic events, DVT, PE, or VTE in patients who were randomized to TXA compared with those who were not. On univariate analysis, rates of PE, DVT and VTE were significantly higher in the PATCH cohort compared with STAAMP and ROC cohorts, but patients in PATCH had significantly higher injury severity scores and chest trauma when compared with those in ROC and STAAMP. CONCLUSION:This multicenter database combining three large RCTs showed that randomization to TXA was not associated with higher rates of arterial and VTE. The higher rates of thrombotic/thromboembolic events observed in the PATCH trial may be explained by higher injury severity as well as protocolized screening. ( J Trauma Acute Care Surg. 2026;101: 48-56. Copyright © 2026 Wolters Kluwer Health, Inc. All rights reserved.). LEVEL OF EVIDENCE:Sub-analysis of randomized controlled trials; Level II.

Background: Severe traumatic brain injury (TBI) can disrupt blood-brain barrier permeability and increase transfer of albumin from the serum to the cerebrospinal fluid (CSF). A high CSF/serum albumin quotient (QAlb) is a biomarker for blood brain barrier (BBB) permeability and may be a measure of the severity of TBI. The aim of this study was to determine if the QAlb was abnormal in patients with severe TBI and whether an abnormal QAlb was associated with long-term outcomes. Methods: For this prospective cohort study, the eligible TBI population had extra-ventricular drains inserted. Uninjured patients underwent lumbar puncture for non-trauma indications, with patients who had abnormal CSF samples excluded. The primary outcome was the Glasgow Outcome Scale- Extended (GOSE) at 6 months. Results: There were 24 patients with TBI and 5 control subjects included. Among patients with TBI, the median initial GCS was 3.5 (IQR 3-6.5). A high QAlb was observed in 10 (41.7 %) patients with TBI and no uninjured patient had high QAlb. Among TBI patients with high QAlb, the median 6-month GOSE was 3 (IQR 2-4) compared to median GOSE of 6.5 (IQR 3-7) among patients with normal QAlb (p = 0.06). The association between high QAlb and unfavourable GOSE at 6 months (OR 5.3; 95 %CI: 0.82-34.8; p = 0.08) did not reach statistical significance. Conclusions: A high QAlb was observed among a subgroup of patients with severe TBI and may be associated with worse long-term outcomes. Further evaluation of this biomarker as a prognostic tool after severe TBI is indicated.

Personalized medicine is nowadays increasingly being used to tailor therapies to the individual needs of patients [1]. We recently demonstrated, that various fibrinolytic parameters, including the plasma-based inducible plasmin-antiplasmin (plap) complex, as well as viscoelastic parameters, predict the individual treatment response in patients with intermediate- or high-risk pulmonary embolism (PE), treated with ultrasound-assisted catheter-directed thrombolysis (USAT) [2]. Markers of fibrinolysis and coagulation were assessed before the start of treatment (t0) and during the 10 - 15-hour infusion of recombinant tissue-type plasminogen activator (rt-PA) (t6). While we have already provided evidence of the predictive value of the assessed parameters for efficacy outcomes, in this article we present data on the correlation between these predictive markers and the endogenous fibrinolytic response during USAT. These data confirm the predictive value of the identified pre-treatment parameters for the endogenous treatment response, which may be important for their potential usefulness in modulating treatment decisions and dose adjustments in USAT for PE in the future.

Background: Fibrinolysis is essential for dissolving blood clots and maintaining hemostasis. This process is primarily mediated by tissue-type plasminogen activator, which converts plasminogen into plasmin, thereby breaking down fibrin clots. Traditional amidolytic assays often measure plasmin generation without directly assessing fibrin degradation, while thromboelastography frequently overlooks clot maturation, which significantly influences fibrinolysis resistance. Objectives: To address these limitations, we present a novel quantitative assay for analyzing fibrinolysis on established clots, termed the halo fluorescence fibrinolysis (HoFF) test. Methods: The HoFF test used fluorophore-conjugated fibrinogen to form halo-shaped plasma clots. Fibrinolysis was induced with tissue-type plasminogen activator or its variant tenecteplase, and clot breakdown was monitored via real-time fluorescence detection by a microplate reader. The fluorescence signal was analyzed to calculate a fibrinolysis index, indicating fibrinolytic capacity. Its specificity for fibrinolysis over plasmin generation was validated against traditional amidolytic assays using a plasmin substrate. Results: Fluorescence-labeled fibrinogen was confirmed as a reliable marker of fibrin degradation. The HoFF test exhibited strong linear correlations between the fibrinolysis index and plasminogen activator concentrations, with robust reproducibility. It also effectively evaluated tenecteplase-induced fibrinolysis and demonstrated versatility across clot types, including mouse plasma and human whole-blood models. Furthermore, the test distinguished fibrinolysis from plasmin generation, demonstrated by the differential effects of tranexamic acid inhibition. Conclusion: The HoFF test offers a sensitive, reliable, and high-throughput tool for quantitatively evaluating fibrinolysis on established human and mouse plasma and whole blood clots.

Injury to the vascular endothelium occurs in up to 34

INTRODUCTION:Traumatic brain injury (TBI) is a leading cause of trauma-related death. A pre-hospital 2-gram bolus of tranexamic acid (TXA) has shown mortality benefit but no reduction in brain bleed size on cross-sectional imaging, suggesting an alternative mechanism may explain its effect. Plasmin activates complement proteins C3 and C5, and complement activation is linked to worse outcomes in animal TBI models. METHODS:40 adult trauma patients with imaging-confirmed TBI, randomized to TXA (2-gram bolus) or placebo in a pre-hospital trial. Plasma was analyzed at presentation (ED), 6 hours, and 24 hours. Complement activation and regulatory markers, coagulation/fibrinolysis parameters, and plasmin generation were assessed using complement multiplex, ELISA, and clinical laboratory testing. Pairwise comparisons were made using ANOVA with significance set at p<0.05. RESULTS:Patients were mostly male (85%) and white (72.5%), with a median age of 36.5 years. TXA significantly reduced sC5b-9 levels at ED arrival (191.5±143.4 ng/mL TXA vs. 333.9±404.4 ng/mL placebo, p=0.04) and C5a at 24 hours. Factor H levels were higher in the TXA group at ED arrival (226.2±103.6 ng/mL TXA vs. 186.0±38.0 ng/mL placebo, p=0.03). D-dimer levels were significantly lower in the TXA group at 6 hours (4.8±5.1 µg/mL TXA vs. 8.4±7.5 µg/mL placebo, p=0.04). Plasmin-antiplasmin levels and thromboelastography LY30 showed no differences. CONCLUSIONS:A pre-hospital 2-gram TXA bolus appears to significantly reduce complement activation and preserve Factor H, a key complement regulatory protein, suggesting TXA's benefit may involve complement modulation. TXA reduced D-dimer, a downstream product of plasmin activation, indicating complement modulation could be due to a plasmin-mediated process. Further studies are needed to determine if this mechanism is plasmin-mediated and applicable to other dosing regimens and non-TBI trauma populations.

BACKGROUND:Ultrasound-assisted catheter-directed thrombolysis (USAT) is nowadays available as an alternative reperfusion approach for acute pulmonary embolism (PE). The lytic agent recombinant tissue-type plasminogen activator (rt-PA) activates the effector protease plasmin to induce fibrinolysis. OBJECTIVES:The aim of this study was to identify predictive markers for the efficacy of USAT in patients with acute PE. METHODS:In a single-center cohort study of USAT for intermediate-high or high-risk PE, pulmonary-arterial hemodynamic measurements were performed, and plasma samples were obtained from 35 patients before treatment start, at 6 hours (during infusion of rt-PA), and at 24 hours after treatment start (postlysis). The hemostatic properties were evaluated with thromboelastometry, and fibrinolytic markers and the ex vivo capacity of rt-PA-spiked plasma to generate the plasmin-antiplasmin complex were assessed. RESULTS:Patients presented with an elevated mean pulmonary artery pressure (32.9 ± 7.6 mm Hg), with an average postlysis reduction of 9.4 ± 8.3 mm Hg, yet the treatment response varied markedly across individuals. The endogenous fibrinolytic capacity, as represented by the plasmin-antiplasmin complex and D-dimer, as well as consumption of the endogenous fibrinolysis inhibitor α2-antiplasmin at 6 hours, predicted the individual treatment efficacy, indicated by the reduction in mean pulmonary artery pressure (all P < .05). Furthermore, ex vivo assessment of the fibrinolytic potential before the start of USAT also predicted efficacy. Both maximum clot lysis INTEM and the novel parameter fibrin-sensitivity ratio were identified as predictors of USAT responsiveness (both P < .05). CONCLUSION:Markers of fibrinolysis may be harnessed to predict treatment responsiveness to USAT in patients with acute PE.

BACKGROUND:Uncertainty about optimal tranexamic acid (TXA) dosage has led to significant practice variation in hip arthroplasty. We aimed to identify the optimal intravenous dosage of TXA using a population pharmacokinetic/pharmacodynamic (PK/PD) approach in adults undergoing primary elective hip arthroplasty. METHODS:Participants received an i.v. TXA bolus dose of 15 mg kg-1 of total body weight, 30 min before skin incision (maximum dose 1500 mg). Blood samples were collected at baseline, 5 min post-TXA, skin incision, skin closure, and 3, 6, and 24 h post-TXA administration. TXA activity was measured ex vivo using a tissue plasminogen activator-induced clot lysis assay, targeted to achieve 90% maximal antifibrinolysis, based on maximum lysis rate. A nonlinear mixed-effects population PK/PD model was developed. Monte Carlo simulations (n=1000) identified the dosing regimens to achieve the PK/PD target over 24 h. RESULTS:There were 24 participants (18 females, 6 males), with a median (range) age of 62 (56.5-72) yr and BMI of 31.1 (23.0-41.8) kg m-2. A three-compartment model best described the 24-h data. The 15 mg kg-1 i.v. bolus maintained TXA concentrations above the PK/PD target of 10 mg L-1 for a median duration of 4.94 h (IQR: 3.76-8.21 h). Of the various simulated regimens, only 30 mg kg-1 i.v. TXA infusion after this bolus achieved the 24-h PK/PD target in 76-100% of patients, varying with their estimated glomerular function rates. CONCLUSIONS:The PK/PD modelling indicated that a 15 mg kg-1 i.v. TXA bolus followed by a continuous i.v. infusion achieved the 24-h antifibrinolytic target. CLINICAL TRIAL REGISTRATION:https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377339&isClinicalTrial=False (ACTRN12619000670178); registered on May 6, 2019.

Tranexamic acid (TXA) has proven mortality benefit if used early after traumatic injury, likely related to a combination of bleeding reduction and other non-bleeding effects. If TXA is given more than 3 h after traumatic injury, there is a significant and paradoxical increased risk of death due to bleeding. TXA has level 1 evidence for use as a bleeding reduction agent in isolated orthopedic operations, but in polytrauma patients undergoing orthopedic operations, it is not clear if and when TXA is safe or effective once outside the 3-h window of proven trauma efficacy.

Cannabidiol is a major component of cannabis but without known psychoactive properties. A wide range of properties have been attributed to it, such as anti-inflammatory, analgesic, anti-cancer, anti-seizure and anxiolytic. However, being a fairly new compound in its purified form, little is known about cannabidiol brain entry, especially during development. Sprague Dawley rats at four developmental ages: embryonic day E19, postnatal day P4 and P12 and non-pregnant adult females were administered intraperitoneal cannabidiol at 10 mg/kg with [ 3 H] labelled cannabidiol. To investigate the extent of placental transfer, the drug was injected intravenously into E19 pregnant dams. Levels of [ 3 H]-cannabidiol in blood plasma, cerebrospinal fluid and brain were estimated by liquid scintillation counting. Plasma protein binding of cannabidiol was identified by polyacrylamide gel electrophoresis and its bound and unbound fractions measured by ultrafiltration. Using available RNA-sequencing datasets of E19 rat brain, choroid plexus and placenta, as well as P5 and adult brain and choroid plexus, expression of 13 main cannabidiol receptors was analysed. Results showed that cannabidiol rapidly entered both the developing and adult brains. Entry into CSF was more limited. Its transfer across the placenta was substantially restricted as only about 50% of maternal blood plasma cannabidiol concentration was detected in fetal plasma. Albumin was the main, but not exclusive, cannabidiol binding protein at all ages. Several transcripts for cannabidiol receptors were expressed in age- and tissue-specific manner indicating that cannabidiol may have different functional effects in the fetal compared to adult brain.

Thrombolytic therapies for acute ischemic stroke are widely available but only result in recanalization early enough, to be therapeutically useful, in 10% to 30% of cases. This large gap in treatment effectiveness could be filled by novel therapies that can increase the effectiveness of thrombus clearance without significantly increasing the risk of harm. This focused update will describe the current state of emerging adjuvant treatments for acute ischemic stroke reperfusion. We focus on new treatments that are designed to (1) target different components that make up a stroke thrombus, (2) enhance endogenous fibrinolytic systems, (3) reduce stagnant blood flow, and (4) improve recanalization of distal thrombi and postendovascular thrombectomy.

Self-assembly of misfolded proteins can lead to the formation of amyloids, which are implicated in the onset of many pathologies including Alzheimer's disease and Parkinson's disease. The facile detection and discrimination of different amyloids are crucial for early diagnosis of amyloid-related pathologies. Here, we report the development of a fluorescent coumarin-based two-sensor array that is able to correctly discriminate between four different amyloids implicated in amyloid-related pathologies with 100% classification. The array was also applied to mouse models of Alzheimer's disease and was able to discriminate between samples from mice corresponding to early (6 months) and advanced (12 months) stages of Alzheimer's disease. Finally, the flexibility of the array was assessed by expanding the analytes to include functional amyloids. The same two-sensor array was able to correctly discriminate between eight different disease-associated and functional amyloids with 100% classification.

Cerebrovascular injuries leading to edema and hemorrhage after ischemic stroke are common. The mechanisms underlying these events and how they are connected to known risk factors for poor outcome, like obesity and diabetes, is relatively unknown. Herein we demonstrate that increased adipose tissue lipolysis is a dominating risk factor for the development of a compromised cerebrovasculature in ischemic stroke. Reducing adipose lipolysis by VEGF-B antagonism improved vascular integrity by reducing ectopic cerebrovascular lipid deposition. Thrombolytic therapy in ischemic stroke using tissue plasminogen activator (tPA) leads to increased risk of hemorrhagic complications, substantially limiting the use of thrombolytic therapy. We provide evidence that thrombolysis with tPA promotes adipose tissue lipolysis, leading to a rise in plasma fatty acids and lipid accumulation in the ischemic cerebrovasculature after stroke. VEGF-B blockade improved the efficacy and safety of thrombolysis suggesting the potential use of anti-VEGF-B therapy to extend the therapeutic window for stroke management.

BACKGROUND:Ischemic stroke is characterized by a necrotic lesion in the brain surrounded by an area of dying cells termed the penumbra. Salvaging the penumbra either with thrombolysis or mechanical retrieval is the cornerstone of stroke management. At-risk neuronal cells release extracellular adenosine triphosphate, triggering microglial activation and causing a thromboinflammatory response, culminating in endothelial activation and vascular disruption. This is further aggravated by ischemia-reperfusion injury that follows all reperfusion therapies. The ecto-enzyme CD39 regulates extracellular adenosine triphosphate by hydrolyzing it to adenosine, which has antithrombotic and anti-inflammatory properties and reverses ischemia-reperfusion injury. OBJECTIVES:The objective off the study was to determine the efficacy of our therapeutic, anti-VCAM-CD39 in ischaemic stroke. METHODS:We developed anti-VCAM-CD39 that targets the antithrombotic and anti-inflammatory properties of recombinant CD39 to the activated endothelium of the penumbra by binding to vascular cell adhesion molecule (VCAM)-1. Mice were subjected to 30 minutes of middle cerebral artery occlusion and analyzed at 24 hours. Anti-VCAM-CD39 or control agents (saline, nontargeted CD39, or anti-VCAM-inactive CD39) were given at 3 hours after middle cerebral artery occlusion. RESULTS:Anti-VCAM-CD39 treatment reduced neurologic deficit; magnetic resonance imaging confirmed significantly smaller infarcts together with an increase in cerebrovascular perfusion. Anti-VCAM-CD39 also restored blood-brain barrier integrity and reduced microglial activation. Coadministration of anti-VCAM-CD39 with thrombolytics (tissue plasminogen activator [tPA]) further reduced infarct volumes and attenuated blood-brain barrier permeability with no associated increase in intracranial hemorrhage. CONCLUSION:Anti-VCAM-CD39, uniquely targeted to endothelial cells, could be a new stroke therapy even when administered 3 hours postischemia and may further synergize with thrombolytic therapy to improve stroke outcomes.