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Background. Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare syndrome of unclear aetiology occurring after DNA-based vaccinations against COVID-19. The aim of this study was to investigate the DNA vaccine-encoded Sars-cov-2 soluble spike protein (SP). as a potential trigger of platelet activation in VITT. Methods. We studied three VITT patients and seven healthy controls (HCs) within 3 weeks from the first dose of ChAdOx1 nCoV-19, and one non vaccinated HC. Serum levels of SP and soluble angiotensin-converting enzyme 2 (sACE2), ACE2 expression in platelets and platelet response to VITT serum stimulation were studied. A thrombus retrieved during mechanical thrombectomy from one VITT patients, was analysed by immunohistochemistry for SP and ACE2. Neutrophil extracellular traps (NETs) markers and coagulation parameters were also measured. Results. We detected serum SP (up to 35 days post-vaccination) and sACE2 in all VITT patients, and respectively in two and three out of 7 vaccinated HCs. Only platelets from one non-vaccinated HC expressed ACE2. VITT sera markedly activated platelets and this activation was inhibited by both anti-SP and anti-FcγRIIA blocking antibodies. The thrombus showed positive immunohistochemical labelling of platelets using an anti-SP antibody with reduced ACE2 expression, compared to a thrombus from a pre-pandemic stroke patient. Markers of endothelial dysfunction, NETs and hypercoagulability state were present in all VITT sera. Conclusions. The present data provides first evidence that DNA vaccine-encoded Sars-cov-2 SP is detectable in VITT sera (several weeks post-vaccination) and in a platelet-rich thrombus, and that may contribute to the initial platelet stimulation in VITT patients.

Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%. OBJECTIVES: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients. METHODS: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations. RESULTS: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively. CONCLUSIONS: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Background: For many conditions causing transient ischemic attack or minor stroke, secondary prevention with early initiation of oral anticoagulation is indicated. The individual response to coumarins is known to vary widely and is not well predicted by clinical variables. Patients’ discharge from hospital care is often delayed only because the therapeutic target range has not been reached yet. A feasible tool to guide coumarin dosing and thereby safely shortening time in hospital is required. Methods: We established a polymerase chain reaction technique for rapid genotyping of the vitamin K epoxide reductase complex (VKORC1), which is the pharmaceutical target of the coumarins. C283 + 837C –> T (rs2359612) genotypes were determined in 49 patients who underwent de novo oral anticoagulation with phenprocoumon for cerebrovascular disease. Other variables potentially affecting phenprocoumon sensitivity were systematically evaluated. Results: Of 49 genotyped patients, 47 were treated in hospital until an international normalized ratio (INR) of 2–3 was reached. The time and the cumulative dose of phenprocoumon necessary to achieve the target INR both were strongly dependent on the individual C283 + 837C –> T genotype (Kruskal-Wallis test p = 0.0002, and p < 0.0001, respectively). Carriers of the TT genotype reached an INR of 2–3 after a mean time of 3.2 days (n = 5), CT carriers after 4.4 days (n = 27), and CC carriers after 6.5 days (n = 15). No other variable, including body weight, was significantly correlated with the treatment response. Conclusion: In patients with cerebrovascular disease, genotyping for VKORC1 alone can strongly predict the individual response to de novo phenprocoumon treatment. The size of the pharmacogenetic test’s potential effect on a more efficient use of hospital capacities remains to be shown by a controlled interventional study.

Aim: In order to define the clinical and instrumental profile of patients with Obstructive Sleep Apnea/Hypopnea (OSAH) and to compare them with that of cases with Central Sleep Apnea/Hypopnea (CSAH), a series of stable strokes were studied. Methods: Thirty four patients were submitted to both clinical and polisomnographyc study (PSG) after 4 months of stroke. A Sleep Disordered Breathing (SDB) was diagnosed in all cases with an AHI>5. Patients were classified as affected by predominantly OSAH (pOSAH), predominantly CSAH (pCSAH), or normal patients. Comparisons were made among the groups and correlation analyses were done in each group. Significance was set at p30. In CSAH, Δt was inversely related to SE Index (p 0.021), and directly related to both the number of arrhythmias/h sleep (p 0.016) and ODI (p 0.033). No correlations were found between the number of arrhythmias/h sleep and causes of stroke both in pOSAH and in pCSAH groups. Conclusions: Our data suggest a direct effect of stroke on the peripheral breathing system with subsequent alteration of loop gain and CSAH phenotype, at least in a subgroup of cases. To confirm this hypothesis multicenter clinical sleep studied are needed.

Background Risk profiles for stroke recurrence are poorly characterized. Aims We determined the variation in the risk and type of recurrent stroke among index ischemic stroke subtypes, and whether index stroke subtype and conventional stroke risk factors were predictors of stroke recurrence. Methods Patients enrolled in the Prevention Regimen for Effectively Avoiding Second Strokes trial were included in this study. Results In 1794 patients' recurrent stroke subtypes were the same as the index stroke in: 48·3% of patients with large artery atherothrombosis stroke; 50% of patients with cardioembolic stroke; 48·7% of patients with small artery occlusion stroke; 8·1% of patients with stroke of other etiology, and 45·3% of patients with undetermined etiology stroke. Patients with cardioembolic stroke, who were unwilling or unable to take oral anticoagulants, had the greatest risk of stroke recurrence. Predictors of stroke recurrence in multivariable analysis were: older age and previous stroke among large artery atherothrombosis strokes; older age, male sex, previous stroke, previous transient ischemic attack, hypertension, diabetes, and tobacco use among small artery occlusion strokes; older age among cardioembolic strokes; atrial fibrillation and anti-diabetic medications among other etiology strokes; older age, previous stroke and atrial fibrillation among undetermined etiology strokes. Predictors of brain hemorrhage as recurrent stroke were index small artery occlusion stroke, older age, previous stroke, and antiplatelet treatment with aspirin plus extended-release dipyridamole. Conclusions Risk predictors for stroke recurrence and for brain hemorrhage differ by index ischemic stroke subtype, information that is important when initiating secondary prevention therapy.

To the Editor: We read with great interest the article by Mosley et al1 as well as the letter by Chiti et al2 on the role of information campaigns in improving people awareness about stroke, and we wish to enter the debate by briefly reporting some of our unpublished data. In order to evaluate whether having experienced a stroke improves the recognition of stroke warning signs and symptoms, a pilot case-control study was performed on a selected sample of subjects who had previously had a stroke and unmatched controls. Aims of the study …

Aim of the study: In order to characterise sleep disordered breathing (SDB) in patients with stable stroke, a prospective observational study is ongoing in Rome. We report the results of the first 55 cases studied.Methods: A consecutive series of patients with acute stroke, admitted to the stroke unit of two different Roman University Hospitals, were screened. Participants were submitted to both clinical and instrumental evaluations at stroke onset and then at 4 months. The diagnostic tests included polisomnographyc (PSG) study and brain MRI. SDB, either central or obstructive, was diagnosed in presence of an apnoea/hypopnoea index (AHI) value ≥5. Statistical analysis was performed with SPSS version 18.0 for Windows. Comparisons were done by ϰ2 tests or via Fisher’s exact test depending on which was more appropriate. Correlations were done with non-parametric tests (Spearman’s rho). Statistical significance was set at pResults: Fifty-five PSG studies were performed. Forty-two cases (76.4 %) had a SDB. Twenty-eight out of the 42 (67 %) cases with an AHI ≥5 had an obstructive sleep apnoea-hypopnoea (OSAH) and 12 (29 %) cases had a central sleep apnoea-hypopnoea (CSAH). Patients affected by CSAH were significantly older than those affected by OSAH (p=0.052). In the group of patients affected by predominantly OSAH, the longer the time interval from stroke to PSG, the shorter both the total sleep period and the total sleep time. Patients with predominantly CSAH were more frequently arrhythmic and more frequently affected by increase in pharyngeal tissue and referred significantly more frequently inattention or unrefreshing sleep.Discussion and Conclusions: The hypothesis we postulate is that, in a subgroup of patients with stroke, stroke moves to worsen patients’ pre-existing breathing condition, causing ventilatory instability. In these cases, central apnoea may take precedence over the obstructive one, in a loop gain circuit over than one, that gives rise to alternating obstructive and central events (possible complex-sleep apnoeas). Multicentre studies, capable of enrolling larger cohorts, are needed to confirm this hypothesis.