This review provides an updated analysis of the main aspects involving the diagnosis and the management of children with acute ischemic stroke. Acute ischemic stroke is an emergency of rare occurrence in children (rate of incidence of 1/3500 live birth in newborns and 1–2/100,000 per year during childhood with peaks of incidence during the perinatal period, under the age of 5 and in adolescence). The management of ischemic stroke in the paediatric age is often challenging because of pleomorphic age-dependent risk factors and aetiologies, high frequency of subtle or atypical clinical presentation, and lacking evidence-based data about acute recanalization therapies. Each pediatric tertiary centre should activate adequate institutional protocols for the optimization of diagnostic work-up and treatments.Conclusion: The implementation of institutional standard operating procedures, summarizing the steps for the selection of candidate for neuroimaging among the ones presenting with acute neurological symptoms, may contribute to shorten the times for thrombolysis and/or endovascular treatments and to improve the long-term outcome. What is Known:•Acute ischemic stroke has a higher incidence in newborns than in older children (1/3500 live birth versus 1–2/100,000 per year).•Randomized clinical trial assessing safety and efficacy of thrombolysis and/or endovascular treatment were never performed in children What is New:•Recent studies evidenced a low risk (2.1% of the cases) of intracranial haemorrhages in children treated with thrombolysis.•A faster access to neuroimaging and hyper-acute therapies was associated with the implementation of institutional protocols for the emergency management of pediatric stroke.

Vaccine-induced thrombotic thrombocytopenia with cerebral venous thrombosis is a syndrome recently described in young adults within two weeks from the first dose of the ChAdOx1 nCoV-19 vaccine. Here we report two cases of malignant middle cerebral artery (MCA) infarct and thrombocytopenia 9-10 days following ChAdOx1 nCoV-19 vaccination. The two cases arrived in our facility around the same time but from different geographical areas, potentially excluding epidemiological links; meanwhile, no abnormality was found in the respective vaccine batches. Patient 1 was a 57-year-old woman who underwent decompressive craniectomy despite two prior, successful mechanical thrombectomies. Patient 2 was a 55-year-old woman who developed a fatal bilateral malignant MCA infarct. Both patients manifested pulmonary and portal vein thrombosis and high level of antibodies to platelet factor 4-polyanion complexes. None of the patients had ever received heparin in the past before stroke onset. Our observations of rare arterial thrombosis may contribute to assessment of possible adverse effects associated with COVID-19 vaccination.

Neurofilament light chain (NfL) is a specific biomarker of neuro-axonal damage. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in blood–brain barrier (BBB) integrity. We explored neuro-axonal damage, alteration of BBB integrity and SARS-CoV-2 RNA presence in COVID-19 patients with severe neurological symptoms (neuro-COVID) as well as neuro-axonal damage in COVID-19 patients without severe neurological symptoms according to disease severity and after recovery, comparing the obtained findings with healthy donors (HD). Overall, COVID-19 patients (n = 55) showed higher plasma NfL levels compared to HD (n = 31) (p < 0.0001), especially those who developed ARDS (n = 28) (p = 0.0005). After recovery, plasma NfL levels were still higher in ARDS patients compared to HD (p = 0.0037). In neuro-COVID patients (n = 12), higher CSF and plasma NfL, and CSF MMP-2 levels in ARDS than non-ARDS group were observed (p = 0.0357, p = 0.0346 and p = 0.0303, respectively). SARS-CoV-2 RNA was detected in four CSF and two plasma samples. SARS-CoV-2 RNA detection was not associated to increased CSF NfL and MMP levels. During COVID-19, ARDS could be associated to CNS damage and alteration of BBB integrity in the absence of SARS-CoV-2 RNA detection in CSF or blood. CNS damage was still detectable after discharge in blood of COVID-19 patients who developed ARDS during hospitalization.

The pathophysiology of COVID-19-associated coagulopathy is complex and not fully understood. SARS-CoV-2 spike protein (SP) may activate platelets and interact with fibrin(ogen). We aimed to investigate whether isolated SP can be present in clots retrieved in COVID-19 patients with acute ischemic stroke (by mechanical thrombectomy) and myocardial infarction. In this pilot study, we could detect SP, but not nucleocapsid protein, on platelets of COVID-19 patients’ thrombi. In addition, in all three COVID-19 thrombi analyzed for molecular biology, no SARS-CoV-2 RNA could be detected by real-time polymerase chain reaction. These data could support the hypothesis that free SP, besides the whole virus, may be the trigger of platelet activation and clot formation in COVID-19.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare syndrome characterized by platelet anti-PF4 (platelet-activating antiplatelet factor 4)–related thrombosis. Platelet-neutrophil interaction has been suggested to play a role, but the underlying mechanism has not been fully elucidated. METHODS: The study included 10 patients with VITT after ChAdOx1 (chimpanzee adenovirus Oxford 1) nCoV-19 (Oxford-AstraZeneca) vaccine administration, 10 patients with ischemic stroke (IS), 10 patients with acute deep vein thrombosis, and 10 control subjects in whom blood levels of neutrophil extracellular traps (NETs), soluble TF (tissue factor), and thrombin generation were examined. Furthermore, we performed in vitro studies comparing the effect of serum from patients and controls on NETs formation. Finally, immunohistochemistry was performed in cerebral thrombi retrieved from a patients with VITT and 3 patients with IS. RESULTS: Compared with patients with IS, patients with deep vein thrombosis, controls, and patients with VITT had significantly higher blood values of CitH3 (citrullinated histone H3), soluble TF, D-dimer, and prothrombin fragment 1+2 ( P <0.0001). Blood CitH3 significantly correlated with blood soluble TF (Spearman rank correlation coefficient=0.7295; P =0.0206) and prothrombin fragment 1+2 (Spearman rank correlation coefficient=0.6809; P <0.0350) in patients with VITT. Platelet-neutrophil mixture added with VITT plasma resulted in higher NETs formation, soluble TF and thrombin generation, and platelet-dependent thrombus growth under laminar flow compared with IS and deep vein thrombosis plasma; these effects were blunted by PAD4 (protein arginine deiminase 4) and cathepsin G inhibitors, anti-FcγRIIa (Fc receptor for IgG class IIa), and high doses of heparin. Immunohistochemistry analysis showed a more marked expression of PAD4 along with more diffuse neutrophil infiltration and NETs formation as well as TF and cathepsin expression in VITT thrombus compared with thrombi from patients with IS. CONCLUSIONS: Patients with VITT display enhanced thrombogenesis by PAD4-mediated NETs formation via cathepsin G–mediated platelet/neutrophil interaction.