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3.
Eur J Intern Med ; 105: 1-7, 2022 11.
Article in English | MEDLINE | ID: covidwho-2086143

ABSTRACT

Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome characterized by high-titer anti-platelet factor 4 (PF4) antibodies, thrombocytopenia and arterial and venous thrombosis in unusual sites, as cerebral venous sinuses and splanchnic veins. VITT has been described to occur almost exclusively after administration of ChAdOx1 nCoV-19 and Ad26.COV2.S adenovirus vector- based COVID-19 vaccines. Clinical and laboratory features of VITT resemble those of heparin-induced thrombocytopenia (HIT). It has been hypothesized that negatively charged polyadenylated hexone proteins of the AdV vectors could act as heparin to induce the conformational changes of PF4 molecule that lead to the formation of anti-PF4/polyanion antibodies. The anti-PF4 immune response in VITT is fostered by the presence of a proinflammatory milieu, elicited by some impurities found in ChAdOx1 nCoV-19 vaccine, as well as by soluble spike protein resulting from alternative splice events. Anti-PF4 antibodies bind PF4, forming immune complexes which activate platelets, monocytes and granulocytes, resulting in the VITT's immunothrombosis. The reason why only a tiny minority of patents receiving AdV-based COVID-19 vaccines develop VITT is still unknown. It has been hypothesized that individual intrinsic factors, either acquired (i.e., pre-priming of B cells to produce anti-PF4 antibodies by previous contacts with bacteria or viruses) or inherited (i.e., differences in platelet T-cell ubiquitin ligand-2 [TULA-2] expression) can predispose a few subjects to develop VITT. A better knowledge of the mechanistic basis of VITT is essential to improve the safety and the effectiveness of future vaccines and gene therapies using adenovirus vectors.


Subject(s)
COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombosis , Vaccines , Humans , Antigen-Antibody Complex , COVID-19 Vaccines/adverse effects , Ad26COVS1 , ChAdOx1 nCoV-19 , Ligands , Spike Glycoprotein, Coronavirus , COVID-19/prevention & control , Platelet Factor 4/genetics , Platelet Factor 4/metabolism , Heparin/adverse effects , Thrombocytopenia/chemically induced , Vaccines/adverse effects , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Ubiquitins
5.
Thromb Res ; 213 Suppl 1: S77-S83, 2022 05.
Article in English | MEDLINE | ID: covidwho-2061921

ABSTRACT

Vaccines to combat SARS-CoV-2 infection and the COVID-19 pandemic were quickly developed due to significant and combined efforts by the scientific community, government agencies, and private sector pharmaceutical and biotechnology companies. Following vaccine development, which took less than a year to accomplish, randomized placebo controlled clinical trials enrolled almost 100,000 people, demonstrating efficacy and no major safety signals. Vaccination programs were started, but shortly thereafter a small number of patients with a constellation of findings including thrombosis in unusual locations, thrombocytopenia, elevated D-dimer and often low fibrinogen led another intense and concentrated scientific effort to understand this syndrome. It was recognized that this occurred within a short time following administration of adenoviral vector SARS-CoV-2 vaccines. Critical to the rapid understanding of this syndrome was prompt communication among clinicians and scientists and exchange of knowledge. Now known as vaccine-induced immune thrombotic thrombocytopenia syndrome (VITT), progress has been made in understanding the pathophysiology of the syndrome, with the development of diagnostic criteria, and most importantly therapeutic strategies needed to effectively treat this rare complication of adenoviral vector vaccination. This review will focus on the current understanding of the pathophysiology of VITT, the findings that affected patients present with, and the rational for therapies, including for patients with cancer, as prompt recognition, diagnosis, and treatment of this syndrome has resulted in a dramatic decrease in associated mortality.


Subject(s)
COVID-19 Vaccines , COVID-19 , Neoplasms , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombosis , Vaccines , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Fibrinogen , Humans , Neoplasms/complications , Pandemics , Pharmaceutical Preparations , SARS-CoV-2 , Syndrome , Thrombocytopenia/chemically induced
6.
Rinsho Ketsueki ; 63(9): 1233-1241, 2022.
Article in Japanese | MEDLINE | ID: covidwho-2056364

ABSTRACT

The levels of anti-platelet factor 4 (PF4) antibodies, also known as anti-PF4 or heparin complex antibodies, are used to diagnose heparin-induced thrombocytopenia (HIT). In HIT, anti-PF4 antibodies induced by heparin exposure cause thrombocytopenia and thrombosis. However, anti-PF4 antibodies were recently reported to be associated with the development of fatal vaccine-induced immune thrombotic thrombocytopenia (VITT) after adenoviral vector vaccination for coronavirus disease 2019. HIT and VITT are caused by anti-PF4 antibodies and have similar pathological conditions. However, the severity of these conditions differs and the detection sensitivity of their antibodies varies depending on the assays used. Herein, we review HIT and VITT associated with anti-PF4 antibodies.


Subject(s)
COVID-19 , Heparin , Platelet Factor 4 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombosis , Antibodies , Anticoagulants/adverse effects , COVID-19/prevention & control , Heparin/adverse effects , Humans , Immunologic Factors , Purpura, Thrombocytopenic, Idiopathic/complications , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Thrombosis/etiology , Thrombosis/pathology , Vaccines/adverse effects
7.
J Thromb Haemost ; 20(12): 2896-2908, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2052857

ABSTRACT

BACKGROUND: Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus-based vaccines aimed to prevent and minimize COVID-19 and related pathophysiology. OBJECTIVES: To describe patterns of testing for anti-platelet factor 4 (PF4) antibodies using various ELISA assays in a large Australian cohort and comparative functional platelet activation assays in a subset. PATIENTS/METHODS: Asserachrom HPIA IgG ELISA was performed in 1284 patients over a period of 12 months, supplemented in select cohorts by comparative ELISA using three other methods (n = 78-179), three different functional assays (flow cytometry, serotonin release assay, and/or Multiplate; n = 476), and rapid immunological chemiluminescence anti-PF4 assay (n = 460), in a multicenter study. RESULTS: For first episode presentations, 190/1284 (14.8%) ELISA tests were positive. Conversely, most (445/460; 96.7%) chemiluminescence anti-PF4 test results were negative. All functional assays showed associations of higher median ELISA optical density with functional positivity and with high rates of ELISA positivity (64.0% to 85.2%). Data also identified functional positivity in 14.8%-36.0% of ELISA negative samples, suggesting false negative VITT by HPIA IgG ELISA in upward of one third of assessable cases. CONCLUSION: To our knowledge, this is the largest multicenter evaluation of anti-PF4 testing for investigation of VITT. Discrepancies in test results (ELISA vs. ELISA or ELISA vs. functional assay) in some patients highlighted limitations in relying on single methods (ELISA and functional) for PF4 antibody detection in VITT, and also highlights the variability in phenotypic test presentation and pathomechanism of VITT.


Subject(s)
COVID-19 , Thrombocytopenia , Thrombosis , Vaccines , Humans , Platelet Factor 4 , Heparin/adverse effects , Australia , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Thrombosis/diagnosis , Immunologic Factors/adverse effects , Immunoglobulin G
8.
Sci Rep ; 12(1): 16406, 2022 09 30.
Article in English | MEDLINE | ID: covidwho-2050525

ABSTRACT

There is a need for better understanding of the risk of thrombocytopenic, haemorrhagic, thromboembolic disorders following first, second and booster vaccination doses and testing positive for SARS-CoV-2. Self-controlled cases series analysis of 2.1 million linked patient records in Wales between 7th December 2020 and 31st December 2021. Outcomes were the first diagnosis of thrombocytopenic, haemorrhagic and thromboembolic events in primary or secondary care datasets, exposure was defined as 0-28 days post-vaccination or a positive reverse transcription polymerase chain reaction test for SARS-CoV-2. 36,136 individuals experienced either a thrombocytopenic, haemorrhagic or thromboembolic event during the study period. Relative to baseline, our observations show greater risk of outcomes in the periods post-first dose of BNT162b2 for haemorrhagic (IRR 1.47, 95%CI: 1.04-2.08) and idiopathic thrombocytopenic purpura (IRR 2.80, 95%CI: 1.21-6.49) events; post-second dose of ChAdOx1 for arterial thrombosis (IRR 1.14, 95%CI: 1.01-1.29); post-booster greater risk of venous thromboembolic (VTE) (IRR-Moderna 3.62, 95%CI: 0.99-13.17) (IRR-BNT162b2 1.39, 95%CI: 1.04-1.87) and arterial thrombosis (IRR-Moderna 3.14, 95%CI: 1.14-8.64) (IRR-BNT162b2 1.34, 95%CI: 1.15-1.58). Similarly, post SARS-CoV-2 infection the risk was increased for haemorrhagic (IRR 1.49, 95%CI: 1.15-1.92), VTE (IRR 5.63, 95%CI: 4.91, 6.4), arterial thrombosis (IRR 2.46, 95%CI: 2.22-2.71). We found that there was a measurable risk of thrombocytopenic, haemorrhagic, thromboembolic events after COVID-19 vaccination and infection.


Subject(s)
COVID-19 Vaccines , COVID-19 , Thrombocytopenia , Venous Thromboembolism , BNT162 Vaccine , COVID-19/complications , COVID-19/epidemiology , COVID-19 Vaccines/adverse effects , Hemorrhage , Humans , SARS-CoV-2 , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology , Vaccination/adverse effects , Venous Thromboembolism/chemically induced , Wales/epidemiology
9.
Clin Adv Hematol Oncol ; 20(9): 572-578, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-2033774

ABSTRACT

BACKGROUND: The COVID-19 pandemic gave rise to rapid development of anti-SARS-CoV-2 vaccines using established and new technologies. Immune thrombocytopenia (ITP) is a bleeding disorder that has been associated with COVID-19 vaccine products that are currently in use. We reviewed the available evidence regarding the most commonly used vaccines against SARS-CoV-2 in North America and Europe and their association with ITP. We found that population-based studies suggested a small increase in the incidence of ITP in persons receiving the ChAdOx1 nCoV-19 vaccine from Oxford-AstraZeneca, on the order of 6 cases per million doses administered. Severe bleeding was an even rarer event. Both messenger RNA-based and adenovirus-based vaccines have been associated with exacerbation of preexisting ITP in 6% to 20% of patients. ITP exacerbation is readily treatable with standard approaches when needed. Severe bleeding events are rare both in the general population and in persons with preexisting ITP, and overall, the benefits of vaccination outweigh the risks. Further identification of persons at the highest risk for complications (including those with ITP, vaccine-induced immune thrombotic thrombocytopenia, and myocarditis) and clear communication of both risks and benefits of immunization will continue to be paramount in the global campaign against COVID-19.


Subject(s)
COVID-19 Vaccines , COVID-19 , Thrombocytopenia , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , ChAdOx1 nCoV-19 , Humans , Pandemics , SARS-CoV-2 , Thrombocytopenia/chemically induced
11.
Intern Med ; 61(18): 2797-2801, 2022 Sep 15.
Article in English | MEDLINE | ID: covidwho-2029870

ABSTRACT

A 53-year-old woman with severe coronavirus disease 2019 (COVID-19) pneumonia was admitted and treated with intravenous unfractionated heparin for thromboprophylaxis under general anesthesia with mechanical ventilation. She developed right hemiparesis after hospitalization due to a large hemorrhagic infarction. Her platelet count decreased from 243,000/µL at administration to 121,000/µL. Anti-platelet factor 4-heparin antibody testing was positive according to a latex immunoturbidimetric assay. She was therefore diagnosed with heparin-induced thrombocytopenia. We immediately stopped the heparin and started argatroban; the platelet count recovered, and thrombosis did not relapse. Physicians should consider heparin-induced thrombocytopenia as a cause of ischemic stroke in patients with COVID-19 infection.


Subject(s)
COVID-19 , Ischemic Stroke , Thrombocytopenia , Venous Thromboembolism , Anticoagulants/adverse effects , COVID-19/complications , Female , Heparin/adverse effects , Humans , Ischemic Stroke/etiology , Middle Aged , Thrombocytopenia/chemically induced , Thrombocytopenia/drug therapy , Venous Thromboembolism/drug therapy
12.
J Thromb Haemost ; 20(11): 2579-2586, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2019525

ABSTRACT

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a prothrombotic, heparin-induced thrombocytopenia (HIT)-mimicking, adverse reaction caused by platelet-activating anti-platelet factor 4 (PF4) antibodies that occurs rarely after adenovirus vector-based COVID-19 vaccination. Strength of PF4-dependent enzyme immunoassay (EIA) reactivity-judged by optical density (OD) measurements-strongly predicts platelet-activating properties of HIT antibodies in a functional test. Whether a similar relationship holds for VITT antibodies is unknown. OBJECTIVES: To evaluate probability for positive platelet activation testing for VITT antibodies based upon EIA OD reactivity; and to investigate simple approaches to minimize false-negative platelet activation testing for VITT. METHODS: All samples referred for VITT testing were systematically evaluated by semiquantitative in-house PF4/heparin-EIA (OD readings) and PF4-induced platelet activation (PIPA) testing within a cohort study. EIA-positive sera testing PIPA-negative were retested following 1/4 to 1/10 dilution. Logistic regression was performed to predict the probability of a positive PIPA per magnitude of EIA reactivity. RESULTS: Greater EIA ODs in sera from patients with suspected VITT correlated strongly with greater likelihood of PIPA reactivity. Of 61 sera (with OD values >1.0) testing negative in the PIPA, a high proportion (27/61, 44.3%) became PIPA positive when tested at 1/4 to 1/10 dilution. CONCLUSIONS: VITT serology resembles HIT in that greater EIA OD reactivity predicts higher probability of positive testing for platelet-activating antibodies. Unlike the situation with HIT antibodies, however, diluting putative VITT serum increases probability of a positive platelet activation assay, suggesting that optimal complex formation depends on the stoichiometric ratio of PF4 and anti-PF4 VITT antibodies.


Subject(s)
COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombosis , Vaccines , Humans , Heparin/adverse effects , Cohort Studies , COVID-19 Vaccines , Platelet Factor 4 , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Immunoenzyme Techniques , Antibodies , Thrombosis/diagnosis , Thrombosis/chemically induced , Purpura, Thrombocytopenic, Idiopathic/chemically induced
15.
Nat Commun ; 13(1): 5206, 2022 09 05.
Article in English | MEDLINE | ID: covidwho-2008281

ABSTRACT

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare yet serious adverse effect of the adenoviral vector vaccines ChAdOx1 nCoV-19 (AstraZeneca) and Ad26.COV2.S (Janssen) against COVID-19. The mechanisms involved in clot formation and thrombocytopenia in VITT are yet to be fully determined. Here we show neutrophils undergoing NETosis and confirm expression markers of NETs in VITT patients. VITT antibodies directly stimulate neutrophils to release NETs and induce thrombus formation containing abundant platelets, neutrophils, fibrin, extracellular DNA and citrullinated histone H3 in a flow microfluidics system and in vivo. Inhibition of NETosis prevents VITT-induced thrombosis in mice but not thrombocytopenia. In contrast, in vivo blockage of FcγRIIa abrogates both thrombosis and thrombocytopenia suggesting these are distinct processes. Our findings indicate that anti-PF4 antibodies activate blood cells via FcγRIIa and are responsible for thrombosis and thrombocytopenia in VITT. Future development of NETosis and FcγRIIa inhibitors are needed to treat VITT and similar immune thrombotic thrombocytopenia conditions more effectively, leading to better patient outcomes.


Subject(s)
COVID-19 , Extracellular Traps , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Thrombosis , Vaccines , Ad26COVS1 , Animals , ChAdOx1 nCoV-19 , Extracellular Traps/metabolism , Humans , Mice , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Thrombocytopenia/chemically induced , Thrombosis/prevention & control , Vaccines/metabolism
16.
Vaccine ; 40(38): 5585-5593, 2022 09 09.
Article in English | MEDLINE | ID: covidwho-1996602

ABSTRACT

BACKGROUND: Post-marketing surveillance for COVID-19 vaccines during the pandemic identified an extremely rare thrombosis with thrombocytopenia syndrome (TTS) reported post-vaccination, requiring further characterisation to improve diagnosis and management. METHODS: We searched the AstraZeneca Global Safety Database (through April 26, 2021) for cases with co-reported thrombocytopenia and thrombosis (using standardised MedDRA queries/high-level terms) following AZD1222 (ChAdOx1 nCoV-19). Cases were adjudicated by experts as 'typical','possible', 'no' or 'unknown' according to available TTS criteria. Additional confirmatory datasets (May 20-June 20, October 1-December 28) were evaluated. FINDINGS: We identified 573 reports, including 273 (47.6 %) 'typical' and 171 (29.8 %) 'possible' TTS cases. Of these 444 cases, 275 (61.9 %) were female, median age was 50.0 years (IQR: 38.0-60.0). Cerebral venous sinus thrombosis was reported in 196 (44.1 %) cases, splanchnic venous thrombosis in 65 (14.6 %) and thromboses at multiple sites in 119 (26.8 %). Median time to onset was 12.0 days (IQR: 9.0-15.0). Comparison with a pre-pandemic reference population indicated higher rates of autoimmune disorders (13.8 %, 4.4 %), previous heparin therapy (7.4 %, 1.2 %), history of thrombosis (5.5 %, 1.4 %), and immune thrombocytopenia (6.1 %, 0.2 %). Fatality rate was 22.2 % (127/573) overall and 23.6 % (105/444) in 'typical'/'possible' TTS, which decreased from 39.0 % (60/154) in February/March to 15.5 % (45/290) in April. Overall patterns were similar in confirmatory datasets. CONCLUSIONS: The reporting rate of 'typical'/'possible' TTS post first-dose vaccination in this dataset is 7.5 per million vaccinated persons; few cases were reported after subsequent doses, including booster doses. Peak reporting coincided with media-driven attention. Medical history differences versus a reference population indicate potentially unidentified risk factors. The decreasing fatality rate correlates with increasing awareness and publication of diagnostic/treatment guidelines. Adjudication was hindered by unreported parameters, and an algorithm was developed to classify potential TTS cases; comprehensive reporting could help further improve definition and management of this extremely rare syndrome.


Subject(s)
COVID-19 Vaccines , COVID-19 , Thrombocytopenia , Thrombosis , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , ChAdOx1 nCoV-19 , Female , Humans , Male , Middle Aged , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology , Thrombosis/chemically induced , Thrombosis/epidemiology , Vaccination/adverse effects
17.
J Neuroimmunol ; 368: 577883, 2022 07 15.
Article in English | MEDLINE | ID: covidwho-1991160

ABSTRACT

INTRODUCTION: Large-scale vaccination is considered one of the most effective strategies to control the pandemic of COVID-19. Since its start, different complications have been described thought to be related to vaccination. Here, we present a rare case where encephalopathy, myocarditis, and thrombocytopenia developed simultaneously following the second dose of Pfizer-BioNTech mRNA vaccine (BNT162b2). CASE PRESENTATION: A 15-years-old female presented with fever, altered consciousness, and convulsions after taking the second shot of the vaccine. Clinical and laboratory workup was notable for the presence of thrombocytopenia and myocarditis. No alternative causes of encephalitis were found. The patient responded significantly to methylprednisolone suggesting underlying immune pathogenesis responsible for the clinical features. The diagnostic criteria for possible autoimmune encephalitis were also fulfilled. CONCLUSION: Although rare, the clinician should be aware of the possible adverse events following COVID-19 vaccination. Further research with large pooled data is needed to get more insight into its pathogenesis and causal relationship.


Subject(s)
Brain Diseases , COVID-19 , Encephalitis , Myocarditis , Thrombocytopenia , Adolescent , BNT162 Vaccine , COVID-19 Vaccines/adverse effects , Encephalitis/complications , Female , Humans , Methylprednisolone/therapeutic use , Myocarditis/diagnosis , Myocarditis/etiology , Thrombocytopenia/chemically induced , Vaccines, Synthetic , mRNA Vaccines
18.
J Infect Chemother ; 28(8): 1208-1211, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1983457

ABSTRACT

A 53-year-old male Japanese patient with COVID-19 was admitted to our hospital after his respiratory condition worsened on day 9 of the disease. With the diagnosis of severe COVID-19, treatment with remdesivir, dexamethasone, and unfractionated heparin was started for the prevention of thrombosis. Although the patient's respiratory status data improved after treatment, severe respiratory failure persisted. Thrombocytopenia and D-dimer elevation were observed on day 8 after heparin therapy initiation. Heparin-induced thrombocytopenia (HIT) antibody measured by immunological assay was positive, and contrast computed tomography showed pulmonary artery thrombus. The patient was diagnosed with HIT because the pre-test probability score (4Ts score) for HIT was 7 points. Heparin was changed to apixaban, a direct oral anticoagulant, which resulted in a reduction of the pulmonary thrombus and improvement of the respiratory failure. In patients with COVID-19, anticoagulant therapy with heparin requires careful monitoring of thrombocytopenia and elevated D-dimer as possible complications related to HIT. (151/250 words).


Subject(s)
COVID-19 , Pulmonary Embolism , Respiratory Insufficiency , Thrombocytopenia , Thrombosis , Anticoagulants/adverse effects , COVID-19/drug therapy , Heparin/adverse effects , Humans , Male , Middle Aged , Pulmonary Embolism/drug therapy , Respiratory Insufficiency/chemically induced , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Thrombocytopenia/drug therapy , Thrombosis/drug therapy
20.
Bioconjug Chem ; 33(8): 1574-1583, 2022 08 17.
Article in English | MEDLINE | ID: covidwho-1977960

ABSTRACT

The pentasaccharide Fondaparinux, a synthetic selective factor Xa inhibitor, is one of the safest anticoagulants in the heparin family that is recommended as an alternative drug for patients with hypersensitivity to other drugs such as heparin-induced thrombocytopenia (HIT). However, some observations of Fondaparinux-induced thrombocytopenia (FIT) have been reported while others claimed that FIT does not occur in patients with fondaparinux therapy, indicating that the mechanism of FIT remains controversial. Here, we utilized different methodologies including dynamic light scattering, immunosorbent and platelet aggregation assays, confocal laser scanning microscopy, and flow cytometry to gain insights into FIT. We found that at a certain concentration, Fondaparinux formed sufficient large and stable complexes with PF4 that facilitated binding of the HIT-like monoclonal KKO antibody and enhanced platelet aggregation and activation. We proposed a model to describe the role of Fondaparinux concentration in the formation of complexes with platelet factor 4 and how it promotes the binding of KKO. Our results clarify controversial observations of FIT in patients as each contains a dissimilar PF4:Fondaparinux concentration ratio.


Subject(s)
Thrombocytopenia , Antibodies, Monoclonal/therapeutic use , Anticoagulants/adverse effects , Fondaparinux/adverse effects , Heparin/adverse effects , Humans , Platelet Factor 4/metabolism , Platelet Factor 4/therapeutic use , Polysaccharides , Thrombocytopenia/chemically induced , Thrombocytopenia/drug therapy
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