Introduction: Increased levels of extracellular vesicles (EVs) are associated with haemostatic disturbances in various clinical settings. However, their role in COVID‐19 patients is still not fully clear. In the present study we investigated EVs in plasma from patients with COVID‐19 and neurological symptoms in relation to the activation of coagulation.Methods: Nineteen COVID‐19 patients with neurological symptoms and twenty‐three aged‐matched healthy individuals were included. Global coagulation assays were performed and levels of EVs were determined by flow‐cytometry in plasma and cerebrospinal fluid (CSF).Results: A procoagulant state characterized by significantly increased overall coagulation‐ (OCP) and overall haemostatic potential (OHP), diminished overall fibrinolytic potential (OFP) together with a denser fibrin structure was found in patients with COVID‐19. Flow cytometry revealed elevated levels of plasma circulating EVs derived from neutrophils (MPO+) and platelets (CD61+), as well as EVs expressing phosphatidylserine (PS+) and complement component C5b‐9 (TCC+) in patients with COVID‐19 compared with controls. The concentrations of PS+, CD61+ and TCC+ EVs were positively correlated with OCP and OHP in COVID‐19 patients. Moreover, we identified CD61+, MPO+ and endothelial cell‐derived EVs, as well as EVs exposing PS and TCC in the CSF of patients suffering from neurological symptoms during COVID‐19.Conclusion: The unique finding in this study was the presence of EVs in the CSF of COVID‐19 patients with neurologic manifestations as well as higher expression of complement protein on circulating plasma EVs. EVs may indicate blood–brain barrier damage during SARS‐COV‐2 infection.

Complement and extracellular vesicles (EVs) association with thrombogenic tendencies is acknowledged, but limited evidence exists for their link to COVID-19 venous thromboembolism. This study aims to examine the relationship between pulmonary embolism and the expression of complement and other proteins related to thrombogenesis in severe Covid-19 patients. We included prospectively 207 severe COVID-19 patients and retrospectively screened for pulmonary embolism (PE). This analysis comprises 20 confirmed PE cases and 20 matched patients without PE. Blood samples taken at the admission in the intensive care unit were analyzed for complement using ELISA. EVs derived from neutrophils, endothelium, or platelets, as well carrying complement or tissue factor were analyzed using flow cytometry. Complement levels were markedly elevated, with a notable increase in C3a and Terminal Complement Complex. The most prevalent EV population was identified as tissue factor (TF)-carrying EVs which peaked in patients with PE during ICU days 4–9. However, for both the complement and analyzed EV populations, no statistically significant differences were found between the patients who developed pulmonary embolism and those who did not. In conclusion, complement factors and EVs expressing tissue factor, along with EVs derived from endothelial cells and platelets, are elevated in severe COVID-19 patients, regardless of the presence of pulmonary embolism. However, the involvement of complement and procoagulant EVs in peripheral plasma in the development of pulmonary embolism is still unclear and requires further investigation.

Purpose of review: SARS-CoV-2 disease (COVID-19) is increasingly recognized as a thromboinflammatory vascular disorder characterized by dysregulated complement activation, endothelial injury, and sustained hypercoagulability. This review examines emerging evidence that extracellular vesicles act as key intermediaries linking complement activation to coagulation in acute and postacute COVID-19 infection. Recent findings: Recent studies demonstrate that extracellular vesicles released from platelets, endothelial cells, and neutrophils are markedly increased in COVID-19 and exhibit a combined procoagulant and complement-active phenotype. Sub-lytic complement attack, particularly membrane attack complex (MAC) deposition, triggers phosphatidylserine exposure and extracellular vesicle shedding, generating vesicles that support thrombin generation and propagate complement activity in the circulation. Extracellular vesicle-associated complement components, including C1q, C3 fragments, MASP2, and preassembled MACs, promote tissue factor decryption, platelet activation, and assembly of the prothrombinase complex, establishing a self-amplifying thromboinflammatory loop. Proteomic profiling further reveals compartment-specific extracellular vesicle signatures, with systemic extracellular vesicles enriched in complement and coagulation pathways. Importantly, complement-bearing and tissue factor-bearing extracellular vesicles persist beyond acute infection and are increasingly implicated in postacute sequelae of COVID-19. Summary: Extracellular vesicles serve as mobile platforms integrating complement activation with coagulation, providing a mechanistic framework for acute and chronic immunothrombosis in COVID-19. Targeting extracellular vesicle-mediated complement-coagulation crosstalk may offer novel diagnostic and therapeutic opportunities.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, marked by progressive degeneration of upper and lower motor neurons. Clinically, genetically, and pathologically heterogeneous, ALS poses a major challenge for disease modeling and therapeutic translation. Over the past two decades, induced pluripotent stem cells (iPSCs) have reshaped our understanding of ALS pathogenesis and emerged as a promising translational platform for therapy development. ALS modeling has further expanded with the advent of three-dimensional systems, including ALS-on-chip platforms and organoid models, which better capture cell–cell interactions and tissue-level phenotypes. Despite these advances, effective disease-modifying therapies remain elusive. Recent clinical trial setbacks highlight the need for improved trial design alongside robust, translational iPSC models that can better predict therapeutic response. Nonetheless, the outlook is promising as large iPSC patient cohorts, quantitative phenotyping combined with genetically informed patient stratification, and reverse translational research are beginning to close the gap between in vitro discovery and clinical testing. In this review, we summarize the major advances in iPSC technology and highlight key iPSC-based studies of sporadic ALS. We further discuss emerging examples of iPSC-informed therapeutic strategies and outline the challenges associated with translating iPSC-derived mechanistic insights and pharmacological findings into successful clinical therapies.