Objective: We investigated the association between circulating biomarkers of inflammation and MRI markers of small vessel disease. Methods: We performed a cross-sectional study relating a panel of 15 biomarkers, representing systemic inflammation (high-sensitivity C-reactive protein, interleukin-6, monocyte chemotactic protein-1, tumor necrosis factor α, tumor necrosis factor receptor 2, osteoprotegerin, and fibrinogen), vascular inflammation (intercellular adhesion molecule 1, CD40 ligand, P-selectin, lipoprotein-associated phospholipase A₂ mass and activity, total homocysteine, and vascular endothelial growth factor), and oxidative stress (myeloperoxidase) to ischemic (white matter hyperintensities/silent cerebral infarcts) and hemorrhagic (cerebral microbleeds) markers of cerebral small vessel disease (CSVD) on MRI in 1,763 stroke-free Framingham offspring (mean age 60.2 ± 9.1 years, 53.7% women). Results: We observed higher levels of circulating tumor necrosis factor receptor 2 and myeloperoxidase in the presence of cerebral microbleed (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.1–4.1 and OR 1.5, 95% CI 1.1–2.0, respectively), higher levels of osteoprotegerin (OR 1.1, 95% CI 1.0–1.2), intercellular adhesion molecule 1 (OR 1.7, 95% CI 1.1–2.5), and lipoprotein-associated phospholipase A₂ mass (OR 1.5, 95% CI 1.1–2.1), and lower myeloperoxidase (OR 0.8, 95% CI 0.7–1.0) in participants with greater white matter hyperintensity volumes and silent cerebral infarcts. Conclusions: Our study supports a possible role for inflammation in the pathogenesis of CSVD, but suggests that differing inflammatory pathways may underlie ischemic and hemorrhagic subtypes. If validated in other samples, these biomarkers may improve stroke risk prognostication and point to novel therapeutic targets to combat CSVD.

Background: Intracerebral hemorrhage (ICH) is stroke caused by non-traumatic bleeding into the brain. Aim: This factsheet provides summary statistics for ICH from the 2021 Global of Burden of Diseases Study. Methods: Data were downloaded from the GBD results platform using “intracerebral hemorrhage” as a Level 4 cause of death or injury, extracting key metrics (number, percent, rate) for measures (incidence, disabilty adjusted life years [DALYs], deaths) described in this factsheet. Results: Globally, stroke was the third leading cause of death in 2021, and ICH accounted for 28.8% of incident strokes. There were estimated to be 7,252,678 deaths due to stroke in 2021 of which ICH accounted for 3,308,367 (45.6%). When considering the burden of ICH in terms of DALYs, ICH accounts for nearly half of the burden of stroke at 49.5%, compared to 43.8% caused by ischemic stroke. ICH must therefore be considered on an equal footing with ischemic stroke, so that efforts can be made to reduce its burden through public health, research, and healthcare provision. Although the overall age-standardized incidence of ICH has been decreasing since 1990, the rate of reduction has been much slower in regions with lower socio-demographic index (SDI). Most of the burden of ICH lies in areas with lower SDI, with 94.2% of DALYs lost to ICH outside areas of high SDI. Geographically, the majority of DALYs due to ICH occur in Southeast Asia, East Asia, and Oceania, with 53.3% of global DALYs lost in these regions alone. The risk factors for ICH are dominated by high systolic blood pressure, which accounts for at least 50% of the burden of ICH, regardless of SDI. Areas with middle or high-middle SDI have a greater proportion of the burden of ICH accounted for by ambient particulate pollution, smoking, and diets high in sodium, whereas household air pollution from solid fuels accounts for much more of the risk of ICH in low SDI regions. Conclusion: This World Stroke Organization (WSO) Global ICH Fact Sheet 2025 provides the most updated information on ICH that can be used to support communication with all internal and external stakeholders, inform healthcare policy, and raise public awareness. All statistics have been reviewed and approved for use by the WSO Executive Committee.

Background: Andexanet alfa is a modified recombinant inactive factor Xa (FXa) designed to reverse FXa inhibitors. ANNEXA-4 (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors) was a multicenter, prospective, phase-3b/4, single-group cohort study that evaluated andexanet alfa in patients with acute major bleeding. The results of the final analyses are presented. Methods: Patients with acute major bleeding within 18 hours of FXa inhibitor administration were enrolled. Co-primary end points were anti-FXa activity change from baseline during andexanet alfa treatment and excellent or good hemostatic efficacy, defined by a scale used in previous reversal studies, at 12 hours. The efficacy population included patients with baseline anti-FXa activity levels above predefined thresholds (≥75 ng/mL for apixaban and rivaroxaban, ≥40 ng/mL for edoxaban, and ≥0.25 IU/mL for enoxaparin; reported in the same units used for calibrators) who were adjudicated as meeting major bleeding criteria (modified International Society on Thrombosis and Haemostasis definition). The safety population included all patients. Major bleeding criteria, hemostatic efficacy, thrombotic events (stratified by occurring before or after restart of either prophylactic [ie, a lower dose, for prevention rather than treatment] or full-dose oral anticoagulation), and deaths were assessed by an independent adjudication committee. Median endogenous thrombin potential at baseline and across the follow-up period was a secondary outcome. Results: There were 479 patients enrolled (mean age, 78 years; 54% male; 86% White); 81% were anticoagulated for atrial fibrillation, and the median time was 11.4 hours since last dose, with 245 (51%) on apixaban, 176 (37%) on rivaroxaban, 36 (8%) on edoxaban, and 22 (5%) on enoxaparin. Bleeding was predominantly intracranial (n=331 [69%]) or gastrointestinal (n=109 [23%]). In evaluable apixaban patients (n=172), median anti-FXa activity decreased from 146.9 ng/mL to 10.0 ng/mL (reduction, 93% [95% CI, 94–93]); in rivaroxaban patients (n=132), it decreased from 214.6 ng/mL to 10.8 ng/mL (94% [95% CI, 95–93]); in edoxaban patients (n=28), it decreased from 121.1 ng/mL to 24.4 ng/mL (71% [95% CI, 82–65); and in enoxaparin patients (n=17), it decreased from 0.48 IU/mL to 0.11 IU/mL (75% [95% CI, 79–67]). Excellent or good hemostasis occurred in 274 of 342 evaluable patients (80% [95% CI, 75–84]). In the safety population, thrombotic events occurred in 50 (10%) patients; in 16 patients, these occurred during treatment with prophylactic anticoagulation that began after the bleeding event. No thrombotic episodes occurred after oral anticoagulation restart. Specific to certain populations, reduction of anti-FXa activity from baseline to nadir significantly predicted hemostatic efficacy in patients with intracranial hemorrhage (area under the receiver operating characteristic curve, 0.62 [95% CI, 0.54–0.70]) and correlated with lower mortality in patients <75 years of age (adjusted P =0.022; unadjusted P =0.003). Median endogenous thrombin potential was within the normal range by the end of andexanet alfa bolus through 24 hours for all FXa inhibitors. Conclusions: In patients with major bleeding associated with the use of FXa inhibitors, treatment with andexanet alfa reduced anti-FXa activity and was associated with good or excellent hemostatic efficacy in 80% of patients. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02329327.