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(searched for: doi:10.1002/ana.26172)
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, Tristan Baumann, Christopher Werlein, Leonie Fingerhut, Rabea Imker, Marita Meurer, Friedrich Götz, Paul Bronzlik, Mark P. Kühnel, Danny D. Jonigk, et al.
Published: 10 May 2022
Frontiers in Immunology, Volume 13; https://doi.org/10.3389/fimmu.2022.879157

Abstract:
During the COVID-19 pandemic, vaccination is the most important countermeasure. Pharmacovigilance concerns however emerged with very rare, but potentially disastrous thrombotic complications following vaccination with ChAdOx1. Platelet factor-4 antibody mediated vaccine-induced immune thrombotic thrombocytopenia (VITT) was described as an underlying mechanism of these thrombotic events. Recent work moreover suggests that mechanisms of immunothrombosis including neutrophil extracellular trap (NET) formation might be critical for thrombogenesis during VITT. In this study, we investigated blood and thrombus specimens of a female patient who suffered severe stroke due to VITT after vaccination with ChAdOx1 in comparison to 13 control stroke patients with similar clinical characteristics. We analyzed cerebral thrombi using histological examination, staining of complement factors, NET-markers, DNase and LL-37. In blood samples at the hyper-acute phase of stroke and 7 days later, we determined cell-free DNA, myeloperoxidase-histone complexes, DNase activity, myeloperoxidase activity, LL-37 and inflammatory cytokines. NET markers were identified in thrombi of all patients. Interestingly, the thrombus of the VITT-patient exclusively revealed complement factors and high amounts of DNase and LL-37. High DNase activity was also measured in blood, implying a disturbed NET-regulation. Furthermore, serum of the VITT-patient inhibited reactive oxygen species-dependent NET-release by phorbol-myristate-acetate to a lesser degree compared to controls, indicating either less efficient NET-inhibition or enhanced NET-induction in the blood of the VITT-patient. Additionally, the changes in specific cytokines over time were emphasized in the VITT-patient as well. In conclusion, insufficient resolution of NETs, e.g. by endogenous DNases or protection of NETs against degradation by embedded factors like the antimicrobial peptide LL-37 might thus be an important factor in the pathology of VITT besides increased NET-formation. On the basis of these findings, we discuss the potential implications of the mechanisms of disturbed NETs-degradation for diagnostic and therapeutic approaches in VITT-related thrombogenesis, other auto-immune disorders and beyond.
, Betül Baykan, Ettore Beghi, Mohamed F Doheim, , Hasim Gezegen, Alla Guekht, Fan Kee Hoo, Michele Santacatterina, James Sejvar, et al.
Published: 6 May 2022
Abstract:
Background: Delayed-onset of headache seems a specific feature of cerebrovascular events after COVID-19 vaccines. Methods: All consecutive events reported to the United States Vaccine Adverse Reporting System following COVID-19 vaccines (1 January to 24 June 2021), were assessed. The timing of headache onset post-vaccination in subjects with and without concomitant cerebrovascular events, including cerebral venous thrombosis, ischemic stroke, and intracranial haemorrhage was analysed. The diagnostic accuracy in predicting concurrent cerebrovascular events of the guideline- proposed threshold of three-days from vaccination to headache onset was evaluated. Results: There were 314,610 events following 306,907,697 COVID-19 vaccine doses, including 41,700 headaches, and 178/41,700 (0.4%) cerebrovascular events. The median time between the vaccination and the headache onset was shorter in isolated headache (1 day vs. 4 (in cerebral venous thrombosis), 3 (in ischemic stroke), or 10 (in intracranial hemorrhage) days, all P < 0.001). Delayed onset of headache had an area under the curve of 0.83 (95% CI: 0.75–0.97) for cerebral venous thrombosis, 0.70 (95% CI: 0.63–76) for ischemic stroke and 0.76 (95% CI: 0.67–84) for intracranial hemorrhage, and >99% negative predictive value. Conclusion: Headache following COVID-19 vaccination occurs within 1 day and is rarely associated with cerebrovascular events. Delayed onset of headache 3 days post-vaccination was an accurate diagnostic biomarker for the occurrence of a concomitant cerebrovascular events.
Manuela De Michele, , Irene Berto, Oscar G. Schiavo, , ,
Circulation Research, Volume 130, pp 1187-1203; https://doi.org/10.1161/circresaha.122.319954

Abstract:
The risk of stroke and cerebrovascular disease complicating infection with SARS-CoV-2 has been extensively reported since the onset of the pandemic. The striking efforts of many scientists in cooperation with regulators and governments worldwide have rapidly brought the development of a large landscape of vaccines against SARS-CoV-2. The novel DNA and mRNA vaccines have offered great flexibility in terms of antigen production and led to an unprecedented rapidity in effective and safe vaccine production. However, as mass vaccination has progressed, rare but catastrophic cases of thrombosis have occurred in association with thrombocytopenia and antibodies against PF4 (platelet factor 4). This catastrophic syndrome has been named vaccine-induced immune thrombotic thrombocytopenia. Rarely, ischemic stroke can be the symptom onset of vaccine-induced immune thrombotic thrombocytopenia or can complicate the course of the disease. In this review, we provide an overview of stroke and cerebrovascular disease as a complication of the SARS-CoV-2 infection and outline the main clinical and radiological characteristics of cerebrovascular complications of vaccinations, with a focus on vaccine-induced immune thrombotic thrombocytopenia. Based on the available data from the literature and from our experience, we propose a therapeutic protocol to manage this challenging condition. Finally, we highlight the overlapping pathophysiologic mechanisms of SARS-CoV-2 infection and vaccination leading to thrombosis.
Jan Heckelmann, Manuel Dafotakis,
Published: 12 April 2022
Der Nervenarzt, Volume 93, pp 413-421; https://doi.org/10.1007/s00115-022-01283-5

The publisher has not yet granted permission to display this abstract.
Lina Palaiodimou, Maria-Ioanna Stefanou, Diana Aguiar de Sousa, Jonathan M. Coutinho, Marianna Papadopoulou, Vasiliki Papaevangelou, Theodoros I. Vassilakopoulos, Sotirios Tsiodras, Dimitrios K. Filippou,
Published: 8 April 2022
Journal of Neurology pp 1-7; https://doi.org/10.1007/s00415-022-11101-2

The publisher has not yet granted permission to display this abstract.
Jiayue Ding, Baoying Song, Xiran Xie, XaingYu Li, Zhiying Chen, Zhongao Wang, Liqun Pan, Duo Lan,
Published: 4 April 2022
Frontiers in Immunology, Volume 13; https://doi.org/10.3389/fimmu.2022.833490

Abstract:
Cerebral venous thrombosis (CVT) is a rare form of cerebrovascular disease that impairs people’s wellbeing and quality of life. Inflammation is considered to play an important role in CVT initiation and progression. Several studies have reported the important role of leukocytes, proinflammatory cytokines, and adherence molecules in the CVT-related inflammatory process. Moreover, inflammatory factors exacerbate CVT-induced brain tissue injury leading to poor prognosis. Based on clinical observations, emerging evidence shows that peripheral blood inflammatory biomarkers—especially neutrophil-to-lymphocyte ratio (NLR) and lymphocyte count—are correlated with CVT [mean difference (MD) (95%CI), 0.74 (0.11, 1.38), p = 0.02 and −0.29 (−0.51, −0.06), p = 0.01, respectively]. Moreover, increased NLR and systemic immune-inflammation index (SII) portend poor patient outcomes. Evidence accumulated since the outbreak of coronavirus disease-19 (COVID-19) indicates that COVID-19 infection and COVID-19 vaccine can induce CVT through inflammatory reactions. Given the poor understanding of the association between inflammation and CVT, many conundrums remain unsolved. Further investigations are needed to elucidate the exact relationship between inflammation and CVT in the future.
Ah Young Kim, , , , Jae Won Yang, Ji Hong Kim, SeoYeon Park, , Min Seo Kim, , et al.
International Journal of Infectious Diseases, Volume 119, pp 130-139; https://doi.org/10.1016/j.ijid.2022.03.034

The publisher has not yet granted permission to display this abstract.
Giuseppe Famularo
Acta Neurologica Scandinavica, Volume 145, pp 787-788; https://doi.org/10.1111/ane.13608

Chengzi I. Kaku, Elizabeth R. Champney, Johan Normark, , Carl E. Johnson, , , Mrunal Sakharkar, , , et al.
Science, Volume 375, pp 1041-1047; https://doi.org/10.1126/science.abn2688

Abstract:
Heterologous prime-boost immunization strategies have the potential to augment COVID-19 vaccine efficacy. We longitudinally profiled severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)–specific serological and memory B cell (MBC) responses in individuals who received either homologous (ChAdOx1:ChAdOx1) or heterologous (ChAdOx1:mRNA-1273) prime-boost vaccination. Heterologous messenger RNA (mRNA) booster immunization induced higher serum neutralizing antibody and MBC responses against SARS-CoV-2 variants of concern (VOCs) compared with that of homologous ChAdOx1 boosting. Specificity mapping of circulating B cells revealed that mRNA-1273 boost immunofocused ChAdOx1-primed responses onto epitopes expressed on prefusion-stabilized S. Monoclonal antibodies isolated from mRNA-1273–boosted participants displayed overall higher binding affinities and increased breadth of reactivity against VOCs relative to those isolated from ChAdOx1-boosted individuals. Overall, the results provide molecular insight into the enhanced quality of the B cell response induced after heterologous mRNA booster vaccination.
Vinciguerra Luisa, Puglisi Valentina, Giossi Alessia, De Giuli Valeria, Caprioli Francesca, Costanzi Chiara, Pari Elisa, Tripodi Silvia Maria, Trapasso Maria Clauida,
Published: 27 February 2022
Journal of the Neurological Sciences, Volume 436; https://doi.org/10.1016/j.jns.2022.120209

The publisher has not yet granted permission to display this abstract.
, Uwe Walter, Erik Volmer, Alexander Storch, Marc-André Weber, Annette Großmann
Published: 19 February 2022
Neuroradiology, Volume 64, pp 865-874; https://doi.org/10.1007/s00234-022-02914-z

Abstract:
Cerebral venous and sinus thrombosis (CVST) after adenovirus-vectored COVID-19 ChAdOx1 nCov-19 (Oxford–AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson) is a rare complication, occurring mainly in individuals under 60 years of age and more frequently in women. It manifests 4–24 days after vaccination. In most cases, antibodies against platelet factor-4/polyanion complexes play a pathogenic role, leading to thrombosis with thrombocytopenia syndrome (TTS) and sometimes a severe clinical or even fatal course. The leading symptom is headache, which usually increases in intensity over a few days. Seizures, visual disturbances, focal neurological symptoms, and signs of increased intracranial pressure are also possible. These symptoms may be combined with clinical signs of disseminated intravascular coagulation such as petechiae or gastrointestinal bleeding. If TTS-CVST is suspected, checking d-dimers, platelet count, and screening for heparin-induced thrombocytopenia (HIT-2) are diagnostically and therapeutically guiding. The imaging method of choice for diagnosis or exclusion of CVST is magnetic resonance imaging (MRI) combined with contrast-enhanced venous MR angiography (MRA). On T2*-weighted or susceptibility weighted MR sequences, the thrombus causes susceptibility artefacts (blooming), that allow for the detection even of isolated cortical vein thromboses. The diagnosis of TTS-CVST can usually be made reliably in synopsis with the clinical and laboratory findings. A close collaboration between neurologists and neuroradiologists is mandatory. TTS-CVST requires specific regimens of anticoagulation and immunomodulation therapy if thrombocytopenia and/or pathogenic antibodies to PF4/polyanion complexes are present. In this review article, the diagnostic and therapeutic steps in cases of suspected TTS associated CSVT are presented.
Published: 17 February 2022
by MDPI
Abstract:
Two mRNA COVID-19 vaccines (mRNA-1273, Moderna; and BNT162b2, Pfizer-BioNTech) and one viral vector vaccine (JNJ-78436735, Janssen/Johnson and Johnson) are authorized in the US to hinder COVID-19 infections. We analyzed severe and common adverse events in response to COVID-19 vaccines using real-world, Vaccine Adverse Effect Reporting System (VAERS) data. From 14 December 2020 to 30 September 2021, 481,172 (50.7 ± 17.5 years, males 27.89%, 12.35 per 100,000 people) individuals reported adverse events (AEs). The median time to severe AEs was 2 days after injection. The risk of severe AEs following the one viral vector vaccine (OR = 1.044, 95% CI = 1.005–1.086) was significantly higher than that after the two mRNA vaccines, and the risk among males (OR = 1.374, 95% CI = 1.342–1.406) was higher than among females, except for anaphylaxis. For common AEs, however, the risk to males (OR = 0.621, 95% CI = 0.612–0.63) was lower than to females. In conclusion, we provided medical insight and clinical guidance about vaccine types by characterizing AEs using real-world data. In particular, COVID-19 mRNA vaccines are safer than viral vector vaccines with regard to coagulation disorders, whereas inflammation-related AEs are lower in the viral vaccine. The risk–benefit ratio of vaccines should be carefully considered, and close monitoring and management of severe AEs is needed.
Mostafa H. Elberry, , Aboalmagd Hamdallah, Walid Shaban Abdella, Ahmed Sayed Ahmed, Hazem S. Ghaith,
Journal of Thrombosis and Thrombolysis pp 1-26; https://doi.org/10.1007/s11239-021-02626-w

Abstract:
Reports of thrombotic response after receiving COVID-19 Adenoviral-Vector Based Vaccines raise concerns about vaccine-induced thrombotic thrombocytopenia (VITT); therefore, we conduct this systematic review to report susceptible demographics outcomes, commonalities, and prognosis of reporting cases. We identified published articles by searching PubMed, SCOPUS, and Web of Science from December 2020 till May 2021, with an updated search in September 2021. All case reports and case series reporting thrombotic response after receiving COVID-19 Adenoviral-Vector Based Vaccines were eligible for including. In addition, two authors independently extracted data and assessed the quality of the included studies. A total of 157 patients with thrombotic events after the ChAdOx1 nCoV-19 vaccine and 16 patients with thrombotic events after Ad26.COV2. S vaccine was included in our study. 72% of the ChAdOx1 nCoV-19 cases were females, while in Ad26.COV2.S subgroup, all reported patients were females. The commonest presentations were deep vein thrombosis 20 (12.7%) and cerebral venous sinus thrombosis 18 (11.5%) in the ChAdOx1 nCoV-19 subgroup while cerebral venous sinus thrombosis 14 (87.5%) and pulmonary embolism 2 (12.5%) in the Ad26.COV2. S subgroup. In this study, we described the certain demographics associated with VITT and the clinical presentations of those cases in the ChAdOx1 nCoV-19 and Ad26.COV2. S vaccines. Young individuals, particularly females, may be more susceptible to VITT, and future studies should seek to confirm this association. In addition, the clinical presentation of VITT commonly includes cerebral thrombi, pulmonary embolism, and deep venous thrombosis, but other presentations are also possible, highlighting the importance of clinical vigilance in recent vaccine recipients.
Maruan Saleh, , Nils C. Lehnen, Bernd Pötzsch,
Journal of Stroke and Cerebrovascular Diseases, Volume 31; https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106311

The publisher has not yet granted permission to display this abstract.
Published: 13 January 2022
Current Cardiology Reports, Volume 24, pp 43-50; https://doi.org/10.1007/s11886-021-01622-z

The publisher has not yet granted permission to display this abstract.
, Dario Luca Lauretti, Nadia Cecconi, Massimo Santini, Valentina Lami, Giovanni Orlandi, Sergio Casagli, Antonella Ghetta, Gaetano Liberti, Benini Maria Elena, et al.
Published: 13 January 2022
Neurological Sciences, Volume 43, pp 2085-2089; https://doi.org/10.1007/s10072-021-05800-3

The publisher has not yet granted permission to display this abstract.
, Viroj Wiwanitkit
The Egyptian Journal of Neurology, Psychiatry and Neurosurgery, Volume 58, pp 1-5; https://doi.org/10.1186/s41983-021-00442-w

Abstract:
COVID-19 is the present global public health problem. This respiratory viral infection can manifest atypical presentation including neurological presentations. An important neurological problem in COVID-19 is neurovascular thrombosis. The basic pathogenesis of thrombosis in neurological system is explainable by the basic principle of thrombohemostasis. A hypercoagulability is a possible problem seen in some COVID-19 cases. In this brief review, the authors summarize venous and arterial thrombosis of neurovascular system as a complication of COVID-19. The updated pathophysiology of COVID-associated blood coagulation disorder is discussed. In addition, consideration regarding new COVID-19 vaccine related thrombotic adverse event is also raised.
, Giulia Arena, Maria Pagliaro, Andrea Boghi, Andrea Naldi, Davide Castellano, Antonella Vaccarino, Daniela Silengo, Franco Aprà, Roberto Cavallo, et al.
Published: 10 January 2022
Neurological Sciences, Volume 43, pp 1499-1502; https://doi.org/10.1007/s10072-021-05805-y

The publisher has not yet granted permission to display this abstract.
, , Patricia Dijamco, Angela Ishak, Mehak Dagar, , Nishat Shama, , Kriti Lnu, Saloni Mitra, et al.
Journal of Primary Care & Community Health, Volume 13; https://doi.org/10.1177/21501319221074450

Abstract:
Introduction: COVID-19 vaccines became available after being carefully monitored in clinical trials with safety and efficacy on the human body. However, a few recipients developed unusual side effects, including cerebral venous sinus thrombosis (CVST). We aim to systematically review the baseline features, clinical characteristics, treatment, and outcomes in patients developing CVST post-COVID-19 vaccination. Methods: This study was conducted according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) 2020 guideline. Investigators independently searched PubMed, Embase, and Google Scholar for English language articles published from inception up until September 10, 2021, reporting the incidence of CVST post-COVID-19 vaccines. We analyzed CVST patients’ baseline data, type of vaccines, clinical findings, treatment, and outcomes. Our systematic review process yielded patient-level data. Result: The final analysis included 25 studies that identified 80 patients who developed CVST after the COVID-19 vaccination. Of the 80 CVST cases, 31 (39.24%) patients died. There was no significant relationship between mortality and age ( P = .733), sex ( P = .095), vaccine type ( P = .798), platelet count ( P = .93), and comorbidities such as hypertension ( P = .734) and diabetes mellitus ( P = .758). However, mortality was associated with the duration of onset of CVST symptoms after vaccination ( P = .022). Patients with CVST post-COVID-19 vaccination were more likely to survive if treated with an anticoagulant ( P = .039). Patients who developed intracranial hemorrhage ( P = .012) or thrombosis in the cortical vein ( P = .021) were more likely to die. Conclusion: COVID-19 vaccine-associated CVST is associated with high mortality rate. Timely diagnosis and management can be lifesaving for patients.
, Sinda Zarrouk
The Egyptian Journal of Neurology, Psychiatry and Neurosurgery, Volume 57, pp 1-6; https://doi.org/10.1186/s41983-021-00431-z

Abstract:
There is accumulating evidence that SARS-CoV-2 vaccinations can be complicated by venous sinus thrombosis (VST). This review aimed at summarising and discussing previous and recent advances regarding the diagnosis, pathogenesis, treatment, and outcome of post-SARS-CoV-2 vaccination VST. At least 308 patients with post-SARS-CoV-2 vaccination VST have been reported as per the end of July 2021. Ages among these 308 patients ranged between 22 and 81 years, 69 were male and 197 were female. Post-SARS-CoV-2 vaccination VST most commonly occurred with the ChAdOx1-S vaccine followed by the BNT126b2 vaccine. In the vast majority of cases, VST occurred after the first dose. Only in six patients did VST occur after the second dose. Latency between vaccination and onset of VST ranged between 0 and 24 days. Regarding treatment, most patients received heparin followed by oral anticoagulants. Seven patients received IVIGs and six patients received steroids because of concomitant vaccine-induced immune thrombotic thrombocytopenia. Complete recovery was reported in 5 patients. Partial recovery was reported in 9 patients. Eight patients were alive or discharged. Sixty-two patients died. The outcome was not specified in the remainder. In conclusion, SARS-CoV-2 vaccinations can be complicated by VST. There is female preponderance and the outcome is frequently poor.
Katarzyna Krzywicka, Anita van de Munckhof, Mayte Sánchez van Kammen, , Katarina Jood, , Turgut Tatlisumak, , , Saskia Middeldorp, et al.
Abstract:
Background and Objectives: Cerebral venous sinus thrombosis (CVST) as a part of the thrombosis and thrombocytopenia syndrome is a rare adverse drug reaction of severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) vaccination. Estimated background rate of CVST with thrombocytopenia is 0.1 per million per month. We assessed the age-stratified risk of CVST with and without thrombocytopenia after SARS-CoV-2 vaccination.Methods: We estimated the absolute risk of CVST with and without thrombocytopenia within 28 days of a first dose of 4 SARS-CoV-2 vaccinations using data from the European Medicines Agency's EudraVigilance database (until June 13, 2021). As a denominator, we used data on vaccine delivery from 31 European countries. For 22.8 million adults from 25 countries, we estimated the absolute risk of CVST after the first dose of ChAdOx1 nCov-19 per age category.Results: The absolute risk of CVST within 28 days of first-dose vaccination was 7.5 (95% confidence interval [CI] 6.9–8.3), 0.7 (95% CI 0.2–2.4), 0.6 (95% CI 0.5–0.7), and 0.6 (95% CI 0.3–1.1) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2, and mRNA-1273, respectively. The absolute risk of CVST with thrombocytopenia within 28 days of first dose vaccination was 4.4 (95% CI 3.9–4.9), 0.7 (95% CI 0.2–2.4), 0.0 (95% CI 0.0–0.1), and 0.0 (95% CI 0.0–0.2) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2, and mRNA-1273, respectively. In recipients of ChAdOx1 nCov-19, the absolute risk of CVST, both with and without thrombocytopenia, was the highest in the 18- to 24-year-old group (7.3 per million, 95% CI 2.8–18.8 and 3.7 per million, 95% CI 1.0–13.3, respectively). The risk of CVST with thrombocytopenia in ChAdOx1 nCov-19 recipients was the lowest in the age group ≥70 years (0.2, 95% CI 0.0–1.3). Age <60 years compared to ≥60 years was a predictor for CVST with thrombocytopenia (incidence rate ratio 5.79, 95% CI 2.98–11.24, p < 0.001).Discussion: The risk of CVST with thrombocytopenia within 28 days of first-dose vaccination with ChAdOx1 nCov-19 was higher in younger age groups. The risk of CVST with thrombocytopenia was slightly increased in patients receiving Ad26.COV2.S compared with the estimated background risk. The risk of CVST with thrombocytopenia was not increased in recipients of SARS-CoV-2 mRNA vaccines.
Chengzi I. Kaku, Elizabeth R. Champney, Johan Normark, Carl E. Johnson, , Mrunal Sakharkar, , ,
Published: 14 December 2021
Abstract:
Heterologous prime-boost immunization strategies have the potential to augment COVID-19 vaccine efficacy and address ongoing vaccine supply challenges. Here, we longitudinally profiled SARS-CoV-2 spike (S)-specific serological and memory B cell (MBC) responses in individuals receiving either homologous (ChAdOx1:ChAdOx1) or heterologous (ChAdOx1:mRNA-1273) prime-boost vaccination. Heterologous mRNA booster immunization induced significantly higher serum neutralizing antibody and MBC responses compared to homologous ChAdOx1 boosting. Specificity mapping of circulating S-specific B cells revealed that mRNA-1273 booster immunization dramatically immunofocused ChAdOx1-primed responses onto epitopes expressed on prefusion-stabilized S. Monoclonal antibodies isolated from mRNA-1273-boosted participants displayed higher binding affinities and increased breadth of reactivity against variants of concern (VOCs) relative to those isolated from ChAdOx1-boosted participants. Overall, the results provide fundamental insights into the B cell response induced by ChAdOx1 and a molecular basis for the enhanced immunogenicity observed following heterologous mRNA booster vaccination.
, Menaka Pai, Menno V Huisman, Michael Makris
Published: 11 November 2021
The Lancet Haematology, Volume 9; https://doi.org/10.1016/s2352-3026(21)00306-9

The publisher has not yet granted permission to display this abstract.
Seminars in Thrombosis and Hemostasis, Volume 48, pp 008-014; https://doi.org/10.1055/s-0041-1736168

Abstract:
Despite the huge efforts globally underway for preventing or limiting the spread of severe acute respiratory coronavirus disease 2 (SARS-CoV-2), the coronavirus disease 2019 (COVID-19) pandemic outbreak appears still virtually unstoppable. As for many other infectious diseases, COVID-19 vaccination has now become crucial for limiting viral spread, especially for averting hospitalizations, need for intensive care, and fatal outcome. Nonetheless, as for other vaccines, COVID-19 vaccination is not completely free from side effects. Among the adverse events that have been reported after receiving COVID-19 vaccination, special emphasis has been given to an unexpected number of thrombocytopenic episodes with or without thrombotic complications, especially in recipients of adenovirus-based COVID-19 vaccines. Along with a specific clinical presentation, encompassing “atypical” thrombosis (especially cerebral venous [sinus] thrombosis, CVT) more prevalent in young female subjects, this new syndrome called vaccine-induced thrombocytopenia and thrombosis (VITT) is characterized by, and thereby diagnosed for, the presence of three paradigmatic laboratory abnormalities, i.e., low platelet count (0.5 mg/L), accompanied by a positive test for anti-PF4 (platelet factor 4) antibodies assayed with ELISA (enzyme-linked immunosorbent assay) techniques. Timely identification of these important abnormalities by both clinicians and laboratory professional is essential for early diagnosis and management of VITT, since the outcome of this condition may be fatal in half or even more of effected patients with severe disease. Therefore, this narrative review aims to review here the epidemiology, pathogenesis, clinical, and laboratory characteristics of VITT and other COVID-19 vaccine-associated thrombocytopenias.
, Sofia Doubrovinskaia, Christoph Mooshage, Berit Jordan, , Carmen Haubner, , Hanns‐Martin Lorenz, , Brigitte Wildemann, et al.
Published: 19 October 2021
European Journal of Neurology, Volume 29, pp 555-563; https://doi.org/10.1111/ene.15147

The publisher has not yet granted permission to display this abstract.
Published: 14 October 2021
Abstract:
W present a rare case of cerebral venous sinus thrombosis after the BNT162b2 mRNA COVID-19 vaccine. A 61-year-old Japanese man developed a headache 10 days after the first dose of the vaccine. Magnetic resonance venography and contrast-enhanced brain MRI showed thrombosis in the superior sagittal sinus and the right transverse sinus. Anticoagulation with intravenous unfractionated heparin followed by oral warfarin was started. His headache improved, and brain MRI on day 22 showed resolution of thrombus. He was maintained on anticoagulation with warfarin and discharged without any neurological sequelae. This case is presented in the context of the relevant literature.
, David Schub, Fatma Merzou, Klaus Fassbender, Martina Sester, Michael Kettner, Piergiorgio Lochner, Tina Schmidt, João Reinoldo Goi Júnior
Published: 5 October 2021
Journal of Neurology, Volume 269, pp 583-586; https://doi.org/10.1007/s00415-021-10731-2

Abstract:
SARS-CoV-2 infection is associated with an increased rate of thromboembolic events and mortality. Different vaccines are globally used to limit the pandemic. In this report, we present the case of two young female patients with newly diagnosed cerebral sinus vein thrombosis occurring after injection of the vector-based ChAdOx1 vaccine. Both patients presented with unusual headache only. The two of them used an estrogen-containing contraception, had had a history of deep venous thrombosis, and both had MTHFR mutations. Both patients developed SARS-CoV-2 specific humoral and cellular immunity including both CD4 and CD8 T cells. This rare, but serious complication needs to be considered after vaccination of young females, even if there is no evidence of heparin-induced thrombocytopenia.
Lina Palaiodimou, Maria-Ioanna Stefanou, Aristeidis H. Katsanos, , Jonathan M. Coutinho, Pagona Lagiou, Ioannis Michopoulos, Androniki Naska, , Konstantinos Vadikolias, et al.
Abstract:
Background and Objectives: There is accumulating evidence supporting an association between the thrombosis and thrombocytopenia syndrome (TTS) and adenovirus vector-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Yet TTS and TTS-associated cerebral venous sinus thrombosis (CVST) remain poorly characterized. We aim to systematically evaluate the proportion of CVST among TTS cases and assess its characteristics and outcomes.Methods: We performed a systematic review and meta-analysis of clinical trials, cohorts, case series, and registry-based studies with the aim to assess (1) the pooled mortality rate of CVST, TTS-associated CVST, and TTS and (2) the pooled proportion of patients with CVST among patients with any thrombotic event and TTS. Secondary outcomes comprised clinical characteristics of patients with postvaccination thrombotic event. This meta-analysis is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was written according to the Meta-analysis of Observational Studies in Epidemiology proposal.Results: Sixty-nine studies were included in the qualitative analysis comprising 370 patients with CVST out of 4,182 patients with any thrombotic event associated with SARS-CoV-2 vector-based vaccine administration. Twenty-three studies were included further in quantitative meta-analysis. Among TTS cases, the pooled proportion of CVST was 51% (95% confidence interval [CI] 36%–66%; I2 = 61%). TTS was independently associated with a higher likelihood of CVST when compared to patients without TTS with thrombotic events after vaccination (odds ratio 13.8; 95% CI 2.0–97.3; I2 = 78%). The pooled mortality rates of TTS and TTS-associated CVST were 28% (95% CI 21%–36%) and 38% (95% CI 27%–49%), respectively. Thrombotic complications developed within 2 weeks of exposure to vector-based SARS-CoV-2 vaccines (mean interval 10 days; 95% CI 8–12) and affected predominantly women (69%; 95% CI 60%–77%) under age 45, even in the absence of prothrombotic risk factors.Discussion: Approximately half of patients with TTS present with CVST; almost one-third of patients with TTS do not survive. Further research is required to identify independent predictors of TTS following adenovirus vector-based vaccination.Registration Information: The prespecified study protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (CRD42021250709).
David García-Azorín, Thien Phu Do, Andreas R. Gantenbein, Jakob Møller Hansen, Marcio Nattan P. Souza, Mark Obermann, Heiko Pohl, Christoph J. Schankin, Henrik Winther Schytz, Alexandra Sinclair, et al.
Published: 17 September 2021
The Journal of Headache and Pain, Volume 22, pp 1-5; https://doi.org/10.1186/s10194-021-01324-5

Abstract:
Background Headache is a frequent symptom following COVID-19 immunization with a typical onset within days post-vaccination. Cases of cerebral venous thrombosis (CVT) have been reported in adenovirus vector-based COVID-19 vaccine recipients. Findings We reviewed all vaccine related CVT published cases by April 30, 2021. We assessed demographic, clinical variables and the interval between the vaccination and onset of headache. We assessed whether the presence of headache was associated with higher probability of death or intracranial hemorrhage. We identified 77 cases of CVT after COVID-19 vaccination. Patients’ age was below 60 years in 74/77 (95.8%) cases and 61/68 (89.7%) were women. Headache was described in 38/77 (49.4%) cases, and in 35/38 (92.1%) was associated with other symptoms. Multiple organ thrombosis was reported in 19/77 (24.7%) cases, intracranial hemorrhage in 33/77 (42.9%) cases and 19/77 (24.7%) patients died. The median time between vaccination and CVT-related headache onset was 8 (interquartile range 7.0–9.7) days. The presence of headache was associated with a higher odd of intracranial hemorrhage (OR 7.4; 95% CI: 2.7–20.8, p < 0.001), but not with death (OR: 0.51, 95% CI: 0.18–1.47, p = 0.213). Conclusion Delayed onset of headache following an adenovirus vector-based COVID-19 vaccine is associated with development of CVT. Patients with new-onset headache, 1 week after vaccination with an adenovirus vector-based vaccine, should receive a thorough clinical evaluation and CVT must be ruled out.
Xin Le Ng, , Ilaria Testi, Su Ling Ho, Melissa Tien, Wei Kiong Ngo, Manfred Zierhut, , , Carlos E Pavesio, et al.
Ocular Immunology and Inflammation, Volume 29, pp 1216-1224; https://doi.org/10.1080/09273948.2021.1976221

Abstract:
The COVID-19 pandemic has galvanized the development of new vaccines at an unprecedented pace. Since the widespread implementation of vaccination campaigns, reports of ocular adverse effects after COVID-19 vaccinations have emerged. This review summarizes ocular adverse effects possibly associated with COVID-19 vaccination, and discusses their clinical characteristics and management. Narrative Literature Review. Ocular adverse effects of COVID-19 vaccinations include facial nerve palsy, abducens nerve palsy, acute macular neuroretinopathy, central serous retinopathy, thrombosis, uveitis, multiple evanescent white dot syndrome, Vogt-Koyanagi-Harada disease reactivation, and new-onset Graves’ Disease. Studies in current literature are primarily retrospective case series or isolated case reports – these are inherently weak in establishing association or causality. Nevertheless, the described presentations resemble the reported ocular manifestations of the COVID-19 disease itself. Hence, we hypothesize that the human body’s immune response to COVID-19 vaccinations may be involved in the pathogenesis of the ocular adverse effects post-COVID-19 vaccination. Ophthalmologists and generalists should be aware of the possible, albeit rare, ocular adverse effects after COVID-19 vaccination.
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