Characteristics and Outcomes of Patients With Cerebral Venous Sinus Thrombosis in SARS-CoV-2 Vaccine–Induced Immune Thrombotic Thrombocytopenia

Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson). Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS. Design, setting, and participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination. Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria. Main outcomes and measures: Clinical characteristics and mortality rate. Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later. Conclusions and relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination.info:eu-repo/semantics/publishedVersio

Management of Cerebral Venous Thrombosis Due to Adenoviral COVID-19 Vaccination

Objective Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality. Methods We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis. Results Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74-6.54). Conclusions In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022Peer reviewe

Advance directives and end-of-life decisions in Switzerland: role of patients, relatives and health professionals.

Little is known in Europe about end-of-life (EOL) decisions and advance directives (AD), particularly in patients with severe advanced disease. Switzerland is a multicultural and multilingual federal country and has the particularity of being divided into four linguistic and cultural regions OBJECTIVE: To understand better in different regions of Switzerland which specific patient's characteristics could have an impact on their decision to complete AD or not. Prospective study conducted in four palliative care units. Patients with an advanced oncological disease, fluent in French, German or Italian and with a Mini-Mental State Examination &gt;20 were included. Demographic data, symptom burden (Edmonton Symptom Assessment System, ESAS; Hospital Anxiety and Depression Scale, HADS) and spiritual well-being (Functional Assessment of Chronic Illness Therapy-Spiritual well-being, FACIT-sp) have been assessed. A structured questionnaire has been completed by patients, their relatives and health professionals. 143 patients were included (mean age 68.3 years; 62 male). 41 completed ADs. No particular features were associated with the completion of ADs. Most patients were satisfied with the medical information received. A third of them were not worrying about their future, especially those living in the German-speaking part. Should they become unable to communicate, 87 expected their relative to transmit their own wishes, but only 38 had spoken recently with them about what they wanted. 23 of the 69 included relatives would like to play a more active role in decision-making. These results illustrate the fact that terminally ill patients wish to be active in decision-making, but only seldom transmit their wishes to their relative or complete a written document. The discussion about ACP should be defined according to the particularity of each region and the role of healthcare professionals' attitudes towards ADs, but we should also be creative and find other ways to promote shared decision-making

5B9, a monoclonal anti-platelet factor 4 /heparin IgG with a human Fc fragment that mimics heparin-induced thrombocytopenia antibodies

International audienceThe diagnosis of heparin-induced thrombocytopenia (HIT) is based on clinical and biological criteria, but a standard is lacking for laboratory assays. Moreover, no humanized HIT antibody is available for pathophysiological studies.To characterise 5B9, a chimeric monoclonal antibody, which fully mimics the effects of human HIT antibodies. 5B9, a chimeric anti-PF4/H IgG1 antibody was obtained after immunizing specific transgenic mice. 5B9 induced heparin FcγRIIA-dependent platelet aggregation and tissue factor mRNA synthesis in monocytes. It also induced significant thrombocytopenia and thrombin generation in mice expressing human PF4 and FcγRIIA receptors. The binding of 5B9 to PF4/H complexes was inhibited by 15 of 25 HIT plasma samples and only 3 of 25 samples containing non-pathogenic anti-PF4/H antibodies. KKO, a murine IgG2b HIT antibody, also inhibited the binding of 5B9 to PF4/H, suggesting that epitopes recognized by both antibodies are close. A docking analysis based on VH and VL sequences of 5B9 showed that binding of 5B9 Fab to PF4 involved 12 and 12 residues in B and D monomers, respectively, including 7 previously identified as critical to the formation of a PF4/KKO complex. Two regions (Asp-7 to Thr-15 and Ala-32 to Thr-38) therefore appeared important for the binding of 5B9 and KKO on PF4 modified by heparin.5B9 is the first anti-PF4/H monoclonal antibody with a human Fc fragment, which induces similar cellular activation as HIT antibodies. Moreover, 5B9 binds epitopes within PF4 that are likely critical for the pathogenicity of HIT antibodies

Effect of topical morphine (mouthwash) on oral pain due to chemotherapy- and/or radiotherapy-induced mucositis: a randomized double-blinded study

PURPOSE: The objective of the study was to determine if mouthwashes with a morphine-containing solution decrease oral pain associated with radiotherapy- and/or chemotherapy-induced oral mucositis (OM). METHODS: Randomized double-blinded crossover study to evaluate the effect of topical oral application of 2 per thousand morphine solution in patients suffering from radiotherapy- and/or chemotherapy-induced OM. Participants assigned to either the morphine solution or a placebo mouthwash received one of the solutions days 1-3 and were then switched over to the other treatment for days 4-6. RESULTS: Nine patients were randomized in both groups. All patients (mean age, 55.1 +/- 3.0) except one had head and neck cancers. Mean intensity of pain associated with mucosal injury (World Health Organization [WHO] mucositis ≥ 2) was on a 10-point visual analogue scale: 6.0 +/- 2.7). The analysis of variance (ANOVA) model that included morphine or placebo, day and time of mouthwash, and mouthwash effect shows that pain alleviation 1 hour after mouthwash was significantly influenced by the gesture of the mouthwash (p < 0.001 with either morphine or placebo) and almost by the efficiency of morphine (p = 0.020). Duration of pain relief was 123.7 (standard deviation [SD] +/- 98.2) minutes for morphine. Most other reported symptoms were present at the baseline and were probably associated with the main disease and not secondary to the morphine mouthwash. CONCLUSIONS: Our results suggest a possible analgesic effect of topical morphine in line with previous studies. However, more efforts must be made for the adjustment of systemic analgesics and the development of new alternatives to treat locally OM-associated pain

Multicentre evaluation of 5B9, a monoclonal anti-PF4/heparin IgG mimicking human HIT antibodies, as an internal quality control in HIT functional assays: Communication from the ISTH SSC Subcommittee on Platelet Immunology.

Functional tests for the diagnosis of heparin-induced thrombocytopenia (HIT) exhibit variable performance. We evaluated in a multicenter study whether 5B9, a monoclonal anti-PF4/heparin IgG mimicking human HIT antibodies, could be used as an internal quality control. 5B9 was sent to 11 laboratories in seven countries, and six initial concentrations ranging from 10 to 400 μg/mL were tested by heparin-induced platelet activation assay (HIPA), serotonin release assay (SRA), platelet aggregation test (PAT), flow cytometry (FC), or heparin-induced multiple-electrode aggregometry (HIMEA). Each method was evaluated in three different laboratories using experimental procedures identical to those usually applied for the diagnosis of HIT by testing platelets from 10 different healthy donors. The procedures used varied among the laboratories, particularly when platelet-rich plasma and whole blood were used. Nevertheless, positive results were obtained with at least 100 μg/ml of 5B9 for most donors tested by all centers (except one) performing HIPA, SRA, or HIMEA. FC and PAT results were more heterogeneous. FC results from one center that used washed platelets preincubated with PF4 were positive with all donors at 50 µg/ml 5B9, but at least 200 μg/ml of 5B9 were required to activate cells with most donors tested using PAT. This study confirms that HIT functional tests are not well standardized and exhibit variable sensitivity for the detection of platelet-activating antibodies. However, 5B9 is a potentially useful tool to standardize functional tests, to select responding platelet donors, and consequently to improve the performance of these assays and comparability between laboratories