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Background and Aims: Previous observational data indicate that young adults treated with intravenous thrombolysis (IVT) for acute ischemic stroke have more favorable outcomes and less complications when compared to older adults. Given the limited data on this topic, we aimed to provide more evidence on clinical outcomes and safety in such patients, using a large international thrombolysis registry., Methods: In this prospective multicenter study, we used data from the Thrombolysis in Ischemic Stroke Patients (TRISP) registry from 1998 to 2020. Patients who received endovascular treatment (EVT), as only treatment or in addition to IVT, were not included in this cohort. Using multivariable regression models, we compared thrombolysed young patients aged 18-49 years with those aged ⩾50 years with regards to the following outcomes: favorable outcome in stroke survivors (modified Rankin Scale ⩽2), symptomatic intracranial hemorrhage (sICH) according to European Cooperative Acute Stroke Study II (ECASS II) criteria, and three-months all-cause death., Results: Of the 16,651 IVT treated patients, 1346 (8.1%) were 18-49 years. Young adults in TRISP were more often male (59.6% vs 54.0%), had a lower median NIHSS score on admission, 7 (4-13) versus 8 (5-15), and had less cardiovascular risk factors except for smoking (42.0% vs 19.0%) when compared to older patients. When compared to thrombolysed patients aged ⩾50 years, a favorable functional outcome was more likely in young adults: 81.9% versus 56.4%, aOR 2.30 (1.80-2.95), whilst sICH 1.6% versus 4.6%, aOR 0.45 (0.23-0.90) and death 2.3% versus 14.2%, aOR 0.21 (0.11-0.39) were less likely., Conclusions: Intravenous thrombolysis in young adults is independently associated with higher rates of favorable outcomes and lower rates of complications., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Nicolas Martinez-Majander reports funding from the Finnish Medical Foundation.Jukka Putaala reports personal fees from Bayer, Boehringer-Ingelheim, BMS-Pfizer, Abbott; Advisory board: Portola, Novo Nordisk, and Herantis Pharma, outside the submitted work.Yannick Béjot reports personal fees from BMS, Pfizer, Medtronic, Amgen, Boehringer-Ingelheim, Servier, NovoNordisk, Novartis, outside the submitted work.Peter Ringleb received speaker and advisory board honoraria from Boehringer Ingelheim, Bayer, BMS and Pfizer paid to the institution.Christoph Gumbinger received Research support from the Gesellschaft für Internationale Zusammenarbeit (GIZ), European Stroke Research Foundation (paid to the institution) and Study compensation from AstraZeneca/Alexion/ (paid to the institution); all outside the submitted work.Matthias Ungerer has received research support from the European Stroke Research Foundation (paid to the institution), outside the submitted work.Marialuisa Zedde reports personal fees from Amicus, Sanofi Genzyme, Takeda, outside the submitted work.Christian H Nolte reports personal fees from AstraZeneca/Abbot, Alexion,/ (paid to the institution);, Astra-Zeneca, Bristol-Myers Squibb, Daiichi Sankyo, Novartis, Pfizer, Portola and Takeda, all outside the submitted work.Ronen R Leker reports personal fees from IschemaView, Filterlex, Bayer, Biogen, Boeringer-Ingelheim, Abott, all outside of the submitted work.Visnja Padjen reports travel or speaker honoraria from Boehringer Ingelheim; honoraria from scientific advisory board from Medtronic, outside the submitted work.Andrea Zini reports speaker honoraria from CSL Behring, Alexion-Astra Zeneca and Daiichi Sankyo and advisory board honoraria from Bayer, Astra Zeneca, all outside of the submitted work.Susanne Wegener reports speaker honoraria from Amgen, Springer, Teva Pharma, ADVISIS-AG, FOMF, Astra Zeneca, and a consultancy fee from Bayer and Novartis; all outside this work.Miriam Heldner reports grants from SITEM Research Support Funds and Swiss National Science Foundation, Swiss Heart Foundation, not directly related to this manuscript.Ivana Berisavac reports speaker honoraria from Medtronic.George Ntaios reports advisory boards/research support/speaker fees from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Javelin Medical, Novartis, and Sanofi; Clinical trial steering/executive committees for Janssen and Javelin Medical. All paid directly to the University of Thessaly. All outside of the submitted work.The other authors report nothing to disclose.

Background: Symptomatic intracerebral hemorrhage (sICH) and major bleeding can be fatal complications of intravenous thrombolysis (IVT) for acute ischemic stroke. We investigated the impact of early fibrinogen depletion after IVT on major bleeding events., Methods: This multicenter observational prospective cohort study enrolled 1678 consecutive patients receiving IVT for acute ischemic stroke at 6 Italian centers, undergoing fibrinogen concentration assessment at baseline, 2 hours and 6 hours after IVT. Fibrinogen depletion was defined as a reduction below 200 mg/dL after 2 hours from IVT, or as a reduction below 50% of baseline fibrinogen levels after 2 hours from IVT. Main outcomes were (1) sICH (National Institute of Neurological Disorders and Stroke criteria) and (2) major bleeding defined as fatal bleeding, decrease in the hemoglobin level>2 g/dL/>1 unit transfusion, or bleeding at critical site. Additional outcomes were (1) any ICH, (2) any bleeding, (3) fatal ICH, and (4) sICH according to ECASSII definition. Good functional recovery was defined as modified Rankin Scale score 0 to 2 at 3 months., Results: Overall, 1678 patients were included (mean age 72 years, 46% female). sICH (n=116) and major bleeding (n=297) were associated with lower rate of good functional recovery ( P <0.001). Despite similar fibrinogen levels at admission, fibrinogen depletion after 2 hours from IVT was more common in people with sICH, major bleeding and all additional bleeding outcomes. In the backward stepwise multivariable logistic regression model, fibrinogen depletion remained a significant predictor of sICH (OR, 1.55 [95% CI, 1.04-2.32]) and major bleeding (OR, 1.36 [95% CI, 1.03-1.8]). Thirty-one percent of sICH could be attributable to fibrinogen depletion. The association between fibrinogen depletion and worse clinical outcome at 3 months after stroke ( P =0.012) was attributable to the higher risk of major bleeding/sICH., Conclusions: Fibrinogen depletion significantly increases the risk of sICH and major bleeding after IVT for acute ischemic stroke. Fibrinogen depletion represents an independent risk factor for bleeding, and routine assessment could be considered to stratify the risk of ICH. Trials on early fibrinogen repletion are needed to investigate mitigation of bleeding risk.

Background: Ischemic stroke is a known complication of COVID-19. It may have a different pathogenesis and worse outcome compared to stroke in patients without COVID-19. Furthermore, patients with COVID-19 and out-of-hospital stroke onset might have different characteristics compared to patients with COVID-19 and in-hospital stroke onset. The aim of our study was to analyze the characteristics of patients with stroke with and without COVID-19 and of patients with COVID-19 with in-hospital and out-of-hospital stroke., Methods: We performed a retrospective study of all consecutive patients admitted to our hospital with ischemic stroke between October 2020 and February 2021. We compared functional outcome, lab test, demographic, and clinical characteristics between patients with or without COVID-19. We performed a sub-analysis comparing patients with COVID-19 and in-hospital and out-of-hospital stroke onset., Results: We included in the final analysis 137 patients of whom 26 with COVID-19. Half (13) had out-of-hospital stroke and half in-hospital stroke onset. Overall, patients with COVID-19 had higher mortality compared to the control group (27% vs 9%, p: 0.02), and non-significantly lower rate of good functional outcome (50% vs 63%, p: 0.22). Patients with COVID-19 and out-of-hospital stroke had higher rate of good functional outcome (69% vs 39%, p: 0.05), higher lymphocyte count, and lower D-dimer compared with patients with in-hospital stroke onset., Conclusions: Patients with stroke and COVID-19 had higher mortality compared to patients without COVID-19. Among patients with COVID-19 those with out-of-hospital stroke had better outcome and fewer blood test abnormalities compared to patients with in-hospital stroke., (© 2021. Fondazione Società Italiana di Neurologia.)

Objectives: Many studies showed that platelet reactivity testing can predict ischemic events after carotid stenting or ischemic stroke. The aim of our study was to assess the role of early platelet function monitoring in predicting 90-days functional outcome, stent thrombosis and hemorrhagic transformation in patients with ischemic stroke treated with endovascular procedures requiring emergent extracranial stenting., Materials and Methods: We performed a retrospective study on consecutive patients with acute anterior circulation stroke admitted to our hospital between January 2015 and March 2020, in whom platelet reactivity testing was performed within 10 days from stenting. Patients were divided according to validated cutoffs in acetylsalicylic acid and Clopidogrel responders and not responders. Group comparison and regression analyses were performed to identify differences between groups and outcome predictors., Results: We included in the final analysis 54 patients. Acetylsalicylic acid resistance was an independent predictor of poor 90 days outcome (OR for modified Rankin scale (mRS) ≤ 2: 0.10 95% CI: 0.02 - 0.69) whereas Clopidogrel resistance was an independent predictor of good outcome (OR for mRS ≤ 2: 7.09 95%CI: 1.33 - 37.72). Acetylsalicylic acid resistance was also associated with increased 90-days mortality (OR: 18.42; 95% CI: 1.67 - 203.14)., Conclusion: We found a significant association between resistance to acetylsalicylic acid and poor 90-days functional outcome and between resistance to Clopidogrel and good 90-days functional outcome. If confirmed, our results might improve pharmacological management after acute carotid stenting., Competing Interests: Declaration of Competing Interest Andrea Zini has received consultancy and speaker fees from Boehringer-Ingelheim, Medtronic, Stryker, Daiichi Sankyo, Johnson&Johnson. The other authors have no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

We present a clinical case of a patient with SARS-CoV-2 infection and respiratory symptoms, complicated with a pro-thrombotic state involving multiple vascular territories and concomitant interleukin-6 increase. This case underlines the possibility to develop a COVID-19-related coagulopathy.

Introduction: Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder due to heterozygous pathogenic variants in transforming growth factor beta (TGFβ) signaling-related genes. LDS types 1-6 are distinguished depending on the involved gene. LDS is characterized by multiple arterial aneurysms and dissections in addition to variable neurological and systemic manifestations. Patient 1: a 68-year-old man was admitted due to an aphasic transient ischemic attack (TIA). Brain CT-scan and CT angiography revealed a chronic and asymptomatic right vertebral artery dissection. Stroke diagnostic panel was unremarkable. His history showed mild stroke familiarity. At age of 49, he was treated for dissecting-aneurysm of the ascending aorta and started anticoagulation therapy. Seven years later, he underwent surgery for dissecting aneurysm involving aortic arch, descending-thoracic aorta, left subclavian artery, and both iliac arteries. Patient 2: a 47-year-old man presented a left hemiparesis due to right middle cerebral artery (MCA) and anterior cerebral artery (ACA) occlusion caused by right internal carotid artery (ICA) dissection after sport activity. Despite i.v. thrombolysis and mechanical thrombectomy, he developed malignant cerebral infarction and underwent decompressive hemicraniectomy. Digital subtraction angiography showed bilateral carotid and vertebral kinking, aneurysmatic dilatation on both common iliac arteries and proximal ectasia of the descending aorta. His father and his uncle died because of an ischemic stroke and a cerebral aneurysm rupture with a subarachnoid hemorrhage (SAH), respectively., Discussion: in both cases, considering the family history and the multiple dissections and aneurysms, LDS molecular analysis was performed. In patient 1, the novel NM&#95;005902.3 (SMAD3): c.840T > G; p.(Asn280Lys) likely pathogenic variant was identified, thus leading to a diagnosis of LDS type 3. In patient 2, the novel NM&#95;004612.2 (TGFBR1): c.1225T > G; p.(Trp409Gly) likely pathogenic variant was found, allowing for a diagnosis of LDS type 1., Conclusion: LDS is characterized by genetic and clinical variability. Our report suggests that this genetically-determined connective tissue disorder is probably underestimated, as it might firstly show up with cerebrovascular events, although mild systemic manifestations. These findings could lead to identify people at risk of severe vascular complications (i.e., through genetic consult on asymptomatic relatives), in order to perform adequate vascular assessments and follow-up to prevent complications such as stroke., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Background: Post-thrombotic intracerebral hemorrhage (ICH) is experienced by 6-8% of stroke patients and is associated with multiple factors, including acquired coagulopathy induced by the thrombolytic drug., Objectives: The objective of this study was to assess the outcome of the intravenous (IV) administration of fibrinogen concentrate in a series of acute stroke patients who developed iatrogenic fibrinogen critical depletion after IV thrombolysis., Material and Methods: Of the 39 ischemic stroke patients treated with IV thrombolysis with a severe hypofibrinogenemia requiring infusion with IV fibrinogen concentrate, 30 patients were treated with 2 g of IV recombinant tissue plasminogen activator (rt-PA), followed by further doses until the fibrinogen level reached 200 mg/dL in hemorrhagic patients or 100 mg/dL in non-hemorrhagic patients, and 9 were treated with IV rt-PA followed by endovascular thrombectomy., Results: Preand post-thrombolysis National Institutes of Health Stroke Scale (NIHSS) scores were statistically different for the Cochran-Mantel-Haenszel test overall (p = 0.0002), at 24-hour evaluation (p = 0.0455) and at 7-day assessment (p = 0.0006). Within the first 7 days post-thrombolysis, the brain computed tomography (CT) scans showed that 20/39 (51.28%) patients had ICH. Of the whole sample, 25.6% of the ICH patients had symptomatic intracerebral hemorrhage (SICH), according to National Institute of Neurological Disorders and Stroke (NINDS) classification. After rt-PA treatment, the median pre-thrombolysis fibrinogenemia of 332 mg/dL significantly dropped to 133 mg/dL (p < 0.0001). After the fibrinogen concentrate infusion, the median level of fibrinogenemia rose to 160 mg/dL, which was significantly higher than the median postthrombolysis levels (p < 0.0001). Recanalization was observed in 25/28 patients (89.29%): complete in 18 and partial in 7 patients. After fibrinogen IV infusion, no thrombotic complications were seen in 37 out of 39 patients (94.77%); 2/39 (0.05%) patients experienced a pulmonary embolism, 1 of them a segmental one., Conclusions: This study showed the clinical safety of administering IV fibrinogen concentrate in order to increase plasma fibrinogen levels in a series of acute stroke patients with iatrogenic fibrinogen depletion after IV thrombolysis.

Background: The measurement of platelet reactivity in patients with stroke undergoing antiplatelet therapies is not commonly performed in clinical practice. We assessed the prevalence of therapy responsiveness in patients with stroke and further investigated differences between patients on prevention therapy at stroke onset and patients naive to antiplatelet medications. We also sought differences in responsiveness between etiological subtypes and correlations between Clopidogrel responsiveness and genetic polymorphisms., Methods: A total of 624 stroke patients on antiplatelet therapy were included. Two different groups were identified: "non-naive patients", and "naive patients". Platelet function was measured with multiple electrode aggregometry, and genotyping assays were used to determine CYP2C19 polymorphisms., Results: Aspirin (ASA) responsiveness was significantly more frequent in naive patients compared with non-naive patients (94.9% versus 82.6%, P < .0010). A better responsiveness to ASA compared with Clopidogrel or combination therapy was found in the entire population (P < .0010), in non-naive patients (P < .0253), and in naive patients (P < .0010). Multivariate analysis revealed a strong effect of Clopidogrel as a possible "risk factor" for unresponsiveness (odds ratio 3.652, P < .0001). No difference between etiological subgroups and no correlations between responsiveness and CYP2C19 polymorphisms were found., Conclusion: In our opinion, platelet function testing could be potentially useful in monitoring the biological effect of antiplatelet agents. A substantial proportion of patients with stroke on ASA were "resistant", and the treatment with Clopidogrel was accompanied by even higher rates of unresponsiveness. Longitudinal studies are needed to assess whether aggregometry might supply individualized prognostic information and whether it can be considered a valid tool for future prevention strategies., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Rotation thromboelastometry is a viscoelastometric method that provides a rapid assessment of a patient's hemostatic processes in emergency settings, allowing prompt identification of specific coagulation abnormalities. Its results thus might guide targeted replacement therapy in hemorrhagic conditions, in case of platelet or coagulation factor deficiency, or hyperfibrinolysis, which is difficult to identify otherwise. Although currently used in emergency and traumatic surgery, there are limited data about thromboelastometry in ischemic stroke, particularly in monitoring the coagulative response to recombinant tissue plasminogen activator after intravenous thrombolysis (IVT). Here we report a case of ischemic stroke complicated by a remote asymptomatic intracranial hemorrhage after IVT and additional endovascular therapy that has been successfully treated with intravenous infusion of tranexamic acid after the detection of the status of hyperfibrinolysis provided by thromboelastometry. Further studies are needed to provide the potential usefulness of thromboelastometry and tranexamic acid in ischemic stroke complicated by intracranial bleeding., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Cerebrotendinous xanthomatosis (CTX) is an autosomal-recessive disorder of lipid storage caused by mutations in the CYP27A1 gene, coding for a sterol 27-hydroxylase, leading to increased deposition of cholesterol in multiple tissues. CTX is characterized by the association of early non-neurological manifestations and adult-onset neurological dysfunctions (spastic ataxia, dementia, psychiatric disorders, peripheral neuropathy). Early and long-term treatment with chenodeoxycholic acid (CDCA) can slow down neurological symptoms progression, but diagnosis usually has a delay of several years. We report two Italian siblings having quite different phenotypes associated to a G-to-A transition in the c-1263 terminal causing a splicing alteration. This mutation has not been described before in Italy, and has been reported once in Japan. This case widens the clinical and genetic spectrum of Cerebrotendinous Xantomatosis in Italy and would like to suggest the importance of genetic testing in patients with autosomal recessive spastic paraparesis associated with typical non-neurological symptoms., (Copyright © 2016 Elsevier B.V. All rights reserved.)