Plasminogen activator inhibitor-1 (PAI-1), a central fibrinolytic regulator encoded by the SERPINE1 gene, is increasingly recognized as a context-dependent molecular hub in tumor biology. Despite its canonical protease-inhibitory role, elevated PAI-1 levels are associated with metastasis and poor prognosis in many malignancies, creating an apparent functional paradox. This review examines how reactive-center-loop conformational transitions, binding partners, cellular source, and anatomical compartment can alter SERPINE1 output. We compare tissue-specific circuits across lung, breast, colorectal, and neural tumors and incorporate recent evidence that SERPINE1 loss can engage distinct p53/SMAD3-MCM3, uPAR-ERK/p38, and HSP90α-p38-MMP-1 modules. We also evaluate a testable convergence model linking GDNF-GFRα1-RET signaling to SERPINE1 regulation and downstream PAI-1-associated pathways in neural tumors, while emphasizing that a direct causal connection has not yet been demonstrated. Finally, we frame the concentration-dependent inflammation-invasion switch as a working hypothesis and assess therapeutic strategies, including TM5614 and ACT001, in relation to tumor context and hemostatic safety.

Ischemic stroke is a leading cause of mortality and long-term disability worldwide, with complex pathophysiological mechanisms and limited therapeutic options. The identification of key molecular targets that can effectively modulate the multifaceted pathological and reparative processes underlying ischemic stroke is urgently needed. Low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional receptor widely expressed in the central nervous system (CNS), where it regulates lipid and bioenergetic metabolism, preserves blood‒brain barrier (BBB) function, modulates synaptic signaling, and supports neural stem/progenitor cell homeostasis. During cerebral ischemia, LRP1 undergoes a stage-dependent functional shift. In the acute phase, LRP1 promotes BBB disruption, tissue-type plasminogen activator (tPA)-associated hemorrhagic transformation, and early neuroinflammation, while also conferring neuroprotection by restraining inflammasome-mediated inflammatory responses and facilitating astrocyte-to-neuron mitochondrial transfer. In the recovery phase, LRP1 is involved in white matter injury and remodeling, including demyelination, remyelination, and white matter restoration. These effects are highly cell type-specific, reflecting distinct functions of LRP1 in endothelial cells, astrocytes, microglia, neutrophils, and oligodendrocyte-lineage cells. This context-dependent complexity underscores the need for a systematic review of the role of LRP1 in stroke. Here, we summarize the structural features and physiological functions of LRP1 in the CNS, discuss its roles and underlying mechanisms in ischemic stroke, and highlight the therapeutic potential and challenges of LRP1-targeted strategies for stroke intervention.

Acute ischemic stroke is the second leading cause of death worldwide, and the benefit of intravenous thrombolysis decays steeply with time while its hemorrhagic risk does not. That asymmetry makes the door-to-needle interval, measured from emergency department arrival to administration of the thrombolytic bolus, one of the few determinants of stroke outcome that can be improved without new technology or additional resources. This review synthesizes the evidence underlying door-to-needle optimization. It begins with the quantified biology of delay, in which roughly 1.9 million neurons are lost for every minute of untreated large-vessel ischemia, and with the pooled randomized data showing that the number needed to treat for one additional good outcome rises from approximately five within ninety minutes to approximately fifteen at the outer edge of the 4.5-hour window. It then examines how the interval should be measured, arguing that the mean and the minimum door-to-needle time must both be reported because they describe different properties of the same system. Prehospital determinants of delay, including field triage instruments, dispatcher and paramedic education, prenotification, and ambulance-based thrombolysis, are reviewed alongside the in-hospital Helsinki protocol, whose parallelization of imaging, clinical assessment, and drug preparation reduced median in-hospital delay to twenty minutes and was reproduced in Melbourne within four months. National registry data from the Target: Stroke initiative confirm that these gains scale across a hospital network with concurrent reductions in mortality and symptomatic hemorrhage. The review closes with the trade-off between speed and diagnostic certainty, the reassuring safety profile of thrombolysis in stroke mimics, and the way tenecteplase, imaging-based patient selection, and endovascular thrombectomy are reshaping what the metric measures.

ObjectivesAdmission lactate carries prognostic information in acute pulmonary embolism (PE), but the value of its early change in patients receiving systemic thrombolysis is unclear. We examined the association between 24-h lactate dynamics and an adverse in-hospital clinical course.MethodsIn this retrospective single-centre cohort, 40 consecutive adults who received systemic alteplase for acute PE (2024-2025) were analysed. In 35 patients the 24-h sample followed thrombolysis. The primary outcome was a composite adverse event (complicated or fatal clinical course). Admission (T0) and 24-h (T24) lactate, absolute Δ lactate and percentage clearance were assessed by ROC analysis and Firth-penalised logistic regression with 2000-resample bootstrap internal validation.ResultsThe composite event occurred in 12 patients (30%). Admission lactate did not discriminate the outcome (AUC 0.56), whereas Δ lactate and percentage clearance did (AUC 0.88 for both; 95% CI 0.76-0.99 and 0.77-0.99, respectively; DeLong p = 0.84, the two AUCs did not differ). A Δ ≥ 0 mmol/L identified an adverse course with a sensitivity of 0.75 and a specificity of 0.82, and a T24 ≥ 4 mmol/L gave a specificity of 1.00. The association of Δ lactate persisted after adjustment for age and showed minimal optimism on bootstrap internal validation.ConclusionsIn this selected cohort receiving systemic thrombolysis, admission lactate did not reproduce the discrimination reported in broader PE populations, whereas 24-h lactate dynamics showed a stronger association with the adverse in-hospital course. Δ lactate should be regarded as a marker of concurrent severity rather than a predictor of treatment response; the candidate thresholds are hypothesis-generating and require prospective validation.

This retrospective observational study evaluated the incidence, subtypes, and risk factors for hemorrhagic transformation (HT) after tenecteplase-tissue plasminogen activator (TNK-tPA) therapy in patients with acute ischemic stroke. Adults with acute ischemic stroke who received intravenous TNK-tPA between June 2022 and June 2025 and had complete baseline data and follow-up neuroimaging were included. All patients underwent routine follow-up computed tomography or magnetic resonance imaging at 24 ± 6 hours after thrombolysis, with additional earlier imaging when neurological deterioration occurred. Demographic characteristics, vascular risk factors, baseline neurological severity assessed by the National Institutes of Health Stroke Scale, blood pressure, pre-stroke antiplatelet use, onset-to-needle time, Alberta Stroke Program Early CT Score, and admission laboratory parameters - including white blood cell count, hemoglobin, platelet count, international normalized ratio, fibrinogen, and D-dimer (mg/L fibrinogen-equivalent units) - were collected. HT was classified as hemorrhagic infarction (HI-1, HI-2) or parenchymal hematoma (PH-1, PH-2) according to European Cooperative Acute Stroke Study criteria. Among 181 TNK-tPA-treated patients, 28 (15.5%) developed HT, including 17 cases of HI and 11 of PH. In an exploratory multivariable logistic regression model, older age, higher baseline National Institutes of Health Stroke Scale, lower Alberta Stroke Program Early CT Score, higher systolic blood pressure, and increased international normalized ratio and D-dimer levels were associated with HT. The model showed acceptable apparent calibration and discrimination (area under the receiver operating characteristic curve = 0.86); however, 14 candidate variables were evaluated for only 28 events (approximately 2 events per variable), creating a substantial risk of overfitting. These findings are hypothesis-generating and require validation in larger independent cohorts.

Background and Objectives: Biological correlates of baseline clinical responsiveness remain incompletely characterized in older adults with acute ischemic stroke treated with intravenous thrombolysis. We evaluated associations between admission Glasgow Coma Scale (GCS) and pre-thrombolysis hematologic, inflammatory, iron-status, and micronutrient parameters. Materials and Methods: This retrospective single-center cohort included 95 unique patients aged ≥65 years, all treated with intravenous alteplase between 2020 and 2024. Admission GCS ranged from 11 to 14. Spearman correlations used original GCS scores. Principal proportional odds models used ordered GCS categories of 11-12, 13, and 14, and were adjusted for age, sex, and admission National Institutes of Health Stroke Scale (NIHSS), with false discovery rate corrections. Sensitivity analyses additionally considered clinician-documented aphasia, congestive heart failure, atrial fibrillation, and reperfusion status for 24 h GCS change. Results: Admission GCS correlated most strongly with RDW-CV (rho = -0.843; 95% bootstrap CI, -0.892 to -0.774) and MCV (rho = 0.779; 95% CI, 0.668 to 0.866). Principal adjusted odds ratios per one-SD increase were 5.68 for hemoglobin, 3.01 for log-transformed ferritin, 4.71 for serum iron, 4.71 for log-transformed vitamin B12, 0.20 for C-reactive protein, and 0.019 for RDW-CV (all FDR-adjusted p < 0.001). Association directions remained consistent in sensitivity analyses. MCV showed an exploratory nonlinear association. No biomarker was associated with the direction of 24 h GCS change after FDR correction, including reperfusion-adjusted models. Conclusions: Pre-thrombolysis biological parameters were concurrently associated with baseline GCS within this single-center cohort and restricted GCS range. These associations do not establish causality, independence from unmeasured lesion location or infarct volume, predictive utility, or early neurological recovery. Prospective external validation is required.

Background: Dedicated pulmonary embolism (PE) thrombectomy devices are not universally available. We evaluated the early outcomes and safety of catheter-directed bolus thrombolysis plus manual aspiration thrombectomy (BT-MAT) using conventional catheters for intermediate-high- or high-risk acute PE. Methods: This retrospective, single-center, historical control study included adults with acute intermediate-high- or high-risk PE involving the main pulmonary artery. Patients who underwent BT-MAT from November 2023 to October 2025 were compared with historical controls who received conventional management such as anticoagulation or systemic thrombolysis before BT-MAT implementation (November 2022 to October 2023). BT-MAT comprised catheter-directed bolus alteplase injection followed by manual aspiration using conventional 7- to 8-Fr catheters or sheaths. Results: Twenty-three patients were included (BT-MAT, n = 11; historical control, n = 12). BT-MAT patients were younger (65.3 ± 16.5 vs. 78.2 ± 11.4 years; p = 0.040) and more frequently had bilateral main pulmonary artery involvement (82% vs. 33%; p = 0.036). Technical success was achieved in all BT-MAT procedures. Clinical success occurred in 11/11 BT-MAT patients and 10/12 conventional-treatment patients (100.0% vs. 83.3%; p = 0.478). No treatment-related complications occurred in the BT- MAT group, whereas two patients in the historical control group developed blood-tinged sputum and hematuria. Estimated right ventricular systolic pressure decreased from 47.1 ± 8.6 to 36.2 ± 10.1 mmHg after BT-MAT. Hospital stay did not differ significantly between groups. Conclusions: BT-MAT was technically feasible and showed favorable early clinical outcomes in this small series. Further prospective studies are warranted to evaluate its efficacy and safety.

Background/Objectives: The mortality rate for acute high-risk and intermediate-high-risk pulmonary embolism (PE) was high despite treatment with heparin anticoagulation alone. Although adjunctive systemic thrombolysis can significantly reduce mortality, it still increases the incidence of major bleeding. Ultrasound-facilitated catheter-directed thrombolysis (USCDT) has been shown to reduce the incidence of major bleeding; however, the optimal treatment duration remains uncertain. Methods: This retrospective cohort study included 155 hospitalized patients with acute PE who underwent USCDT between January 2017 and June 2025 in the intensive care unit at China Medical University Hospital, Taichung, Taiwan. Patients were categorized into four groups based on average usage time: <20, 20-29, 30-39, and ≥40 h. The primary endpoints were 30-day all-cause mortality rate and major bleeding. Covariates associated with 30-day all-cause mortality were estimated and adjusted using logistic regression modeling. Results: Across all treatment groups, USCDT significantly reduced systolic pulmonary artery (PA) pressure (26.9%), mean PA pressure (21.0%), fibrinogen levels (25.2%), and right ventricle-to-left ventricle diameter ratio (21.5%) (all p < 0.001). Compared with the group with a USCDT ≥ 40 h, the group with a USCDT < 20 h had a lower odds ratio for 30-day all-cause mortality (OR: 0.36, 95% CI: 0.07-1.81). A similar benefit was observed for a USCDT 20-29 h. Conclusions: USCDT < 20 or 20-29 h (mean 15-20 mg alteplase) may provide an optimal balance between efficacy and safety by reducing 30-day all-cause mortality and major bleeding in patients with acute PE.

Patients with congenital heart disease (CHD) have a propensity towards thrombotic events (TE) that can carry significant hemodynamic impact, morbidity, and mortality. Tissue plasminogen activator (tPA), a fibrinolytic agent, can be used in the acute treatment of thrombotic conditions but its use in pediatric patients with heart disease is not well described. We present our single-center experience of tPA infusion use in pediatric patients with congenital and acquired heart disease. This was a retrospective cohort study conducted between January 2008 and January 2024. Chart review was conducted to collect variables of interest. The primary outcome was thrombus resolution; secondary outcomes included major and minor bleeding events and in-hospital mortality. We identified 33 patients with 40 TE instances. 70% of patients had single ventricle circulation with cavopulmonary circulation being the most common thrombus location (39% of TE). The overall mortality among all patients was 39%; all patients with a major bleed experienced mortality. Major bleeding occurred in 12.5% of TE, associated with higher maximum tPA dose administered (0.2 vs. 0.1 mg/kg/hr, p = 0.036) and with recent surgery within 14 days of tPA administration (p = 0.0058). Fibrinogen nadir (< 150 mg/dL) and INR > 2 were associated with major bleeding (fibrinogen OR 13.5, CI 1.3-138.6, p = 0.02; INR OR 11.6, CI 1.5-92.1, p = 0.03). In our single-center experience, we demonstrated TE resolution of 58% and overall major bleeding rate of 12.5%. We also demonstrated the importance of tPA dosing, considering recent surgical intervention when determining tPA candidacy, and possible biomarkers to predict bleeding risk. Further investigation with a larger cohort is necessary.

Streptokinase (SK) is an effective plasminogen-activating fibrinolytic protein, but its lack of intrinsic fibrin specificity limits thrombus-directed fibrinolysis. We computationally evaluated an engineered SK-K2 fusion in which the fibrin-interacting Kringle 2 (K2) domain of human tissue-type plasminogen activator was appended to the SK C-terminus. Structural modeling showed high K2 confidence (mean pLDDT = 85.67), and all 22 K2 residues at the predicted fibrin interface had pLDDT values ≥70 (mean = 89.88). HDOCK ranked SK-K2-fibrin more favorably than native SK-fibrin (-276.71 vs. -249.24), while PRODIGY predicted a more favorable binding free energy (-14.9 vs. -13.3 kcal/mol). Although native SK showed a more favorable HDOCK score toward plasminogen, both plasminogen complexes had identical PRODIGY-predicted binding free energies (-11.2 kcal/mol) and closely comparable dissociation constants, indicating no marked computational loss in predicted plasminogen-binding characteristics after K2 fusion. PDBePISA showed direct K2 participation and a larger chain-matched fibrin interface for SK-K2 than native SK, with six hydrogen bonds and an Asp291-Arg515 salt bridge (2.966 Å) in the HDOCK-derived complex. An independent MOE workflow reproduced the fibrin-directed ranking, with SK-K2 showing a more favorable S score than native SK (-101.8501 vs. -93.9472). PDBePISA analysis of the independent MOE complex identified Arg515 in a second salt bridge, Arg515-Glu220 (3.369 Å), providing residue-level convergence across both docking models. These findings support the structural rationale for C-terminal K2 engineering of SK and prioritize SK-K2, particularly Arg515, for experimental evaluation of fibrin association, plasminogen activation, and clot-directed fibrinolysis.