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Introduction: COVID-19 has been responsible for millions of deaths and intensive care unit (ICU) admissions all over the world. Identifying the patients at risk of developing a severe form is crucial for an optimized orientation and allocation of resources. The main objective of our study was to identify among a selection of biomarkers, those predictive of short term worsening in COVID-19. Method(s): This is an ancillary study using clinical data and collected biobanking from the multicentric cohort study COVIDeF, which included prospectively from March 31th 2020 to March 30th 2021, patients admitted with a suspected Sars-CoV2 infection in the Assistance- Publique-Hopitaux de Paris network, France. Patients with confirmed COVID-19 were divided in 2 groups: a severe (ICU admission or invasive or non-invasive ventilation or ARDS or death) and a control group (no worsening). The routine blood tests and following biomarkers: troponin, C Reactive Protein (CRP), procalcitonin, Mild- Regional pro-Adrenomedulin (MR-proADM), pro-endothelin, SuPAR, NT-proBNP, calprotectin, PF4, D-dimers, were measured in plasma or serum and compared between both groups using a conditional logistic regression. Result(s): Among the 1040 first patients included in the COVIDEF cohort, we selected 512 patients having a blood sample drawn at admission before worsening, of which 60 secondarily worsened (severe group). The mean age was 59.5 (+/- 19.5) years and 50.2% were females. Among the biomarkers tested, three were independently associated with worsening: CRP (mg/l) OR 1.01 [IC 1.01-1.02], procalcitonin (ng/ml) OR 0.4428 [0.21-0.95] and MR-proADM (pg/ml) OR 3.012 [1.06-8.53]. Conclusion(s): Among a selection of biomarkers of interest, MRproADM appears to best identify at admission COVID-19 patients at risk of worsening. Future interventional studies should test the efficacy and security of this biomarker to rule-in and rule-out severe outcome and the usefulness for allocating resources.
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The common reported adverse impacts of COVID-19 vaccination include the injection site's local reaction followed by various non-specific flu-like symptoms. Nevertheless, uncommon cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) and cerebral venous sinus thrombosis (CVST) following viral vector vaccines (ChAdOx1 nCoV-19 vaccine, Ad26.COV2 vaccine) have been reported. This literature review was performed using PubMed and Google Scholar databases using appropriate keywords and their combinations: SARS-CoV-2, adenovirus, spike protein, thrombosis, thrombocytopenia, vaccine-induced immune thrombotic thrombocytopenia (VITT), NF-kappaB, adenoviral vector, platelet factor 4 (PF4), COVID-19 Vaccine, AstraZeneca COVID vaccine, ChAdOx1 nCoV-19 COVID vaccine, AZD1222 COVID vaccine, coagulopathy. The s and titles of each article were assessed by authors for screening and inclusion English reports about post-vaccine CVST and VITT in humans were also collected. Some SARS-CoV-2 vaccines based on viral vector, mRNA, or inactivated SARS-CoV-2 virus have been accepted and are being pragmatic global. Nevertheless, the recent augmented statistics of normally very infrequent types of thrombosis associated with thrombocytopenia have been stated, predominantly in the context of the adenoviral vector vaccine ChAdOx1 nCoV-19 from Astra Zeneca. The numerical prevalence of these side effects seems to associate with this particular vaccine type, i.e., adenoviral vector-based vaccines, but the meticulous molecular mechanisms are still not clear. The present review summarizes the latest data and hypotheses for molecular and cellular mechanisms into one integrated hypothesis demonstrating that coagulopathies, including thromboses, thrombocytopenia, and other associated side effects, are correlated to an interaction of the two components in the COVID-19 vaccine.Copyright © 2022, Iranian Pediatric Hematology and Oncology Society. All rights reserved.
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Case report Introduction: The COVID-19 pandemic has generated an inexorable cost to governments and a high mortality in general terms, the vaccination process is the only effective strategy to reduce morbidity and mortality in general, however, such administration is not without risks. Case presentation: Female patient of the seventh decade who is vaccinated against COVID-19 and 4 days after the second dose of vaccine against COVID-19 begins to present purpuric lesions that begin in the lower limbs and progressively ascend to the trunk associated with intense arthralgias, abdominal pain and nausea, presents macroscopic rectal bleeding, is admitted finding platelet counts lower than 10 thousand platelets, the diagnosis of a Henoch Scholein purpura associated with a vaccine against COVID-19 was confirmed no requiring specific immunosuppressive therapy with resolution at 21 days. The triggering mechanisms are being studied and described as similar to immunological thrombocytopenia due to heparins. Antibodies against platelet factor 4 have been reported so far. The test known as PIFPA (PF4-induced flow cytometry-based platelet activation) is a cytometric test with high sensitivity and specificity, only available in specialized laboratories, being described for the moment as the only test that allows the detection of immunological thrombocytopenic phenomena secondary to vaccination against COVID-19. Discussion(s): The present case constitutes the appearance of a Henoch Scholein Purpura, a rare pathology with a wide repertoire of triggering events, with infections and vaccine reactions among the main triggers. The present vaccine reaction is rare, being the specific anecdotal, until now there are very few descriptions in the literature about this type of vaccine reaction, which is why it is decided to publish it, mentioning the most recent scientific evidence available on this area. It is noteworthy that these are rare reactions that should not make us underestimate continuing with vaccination campaigns as the best strategy to prevent the advance of this pandemic.
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Introduction A subgroup of anti-platelet factor 4 (PF4) antibodies can activate platelets via Fcgamma RIIA and cause thrombotic and thrombocytopenic diseases such as heparin-induced thrombocytopenia and vaccine-induced immune thrombotic thrombocytopenia (VITT). Nonpathological anti-PF4 antibodies are detected in 1-7 % of healthy blood donors and in 2-8 % of SARS-CoV-2 vaccinated individuals. In this study, we investigated the long-term course of anti- PF4 antibodies detected after the first SARS-CoV-2 vaccination in healthy subjects and in patients with VITT. Method Five healthy subjects (all female, median age (range): 40 years (29-62) ) who had anti-PF4 antibodies after the first vaccination with ChadOx1 nCov19 (Vaxzevria, AstraZeneca-Oxford) were included. None of the subjects developed VITT. Blood samples were collected as part of a longitudinal study (TuSeRe:exact) evaluating the immune response to SARS-CoV-2 vaccines among employees of an University Hospital. In addition, data from 4 patients with VITT (3 female, median age (range): 44 years (22 -62 years)) were included for long-term follow-up of anti-PF4 antibodies. Anti-PF4/heparin antibodies were measured using a commercially available ELISA assay (Zymutest HIA IgG, Hyphen BioMed, France). Platelet activation was tested with a modified heparin- induced platelet aggregation assay (HIPA). Results In the non-VITT group, the median (range) OD for IgG anti-PF4/heparin antibodies was 0.69 (0.60-1.83) after the first vaccination. Blood samples were available up to 16 months after the first vaccination (range: 5-16 months). Anti-PF4 antibody levels decreased in all subjects despite further vaccination. However, antibody levels returned to pre-vaccination levels in only one subject. In one subject who had received two doses of ChadOx1 nCov19, anti-PF4 antibodies remained above OD 1.0 at the last follow-up. All samples were negative in the modified HIPA assay. Patients with VITT received mRNA-based vaccine as second vaccination against SARS CoV2. No significant drop in platelet count or new thromboembolic complication was observed. Conclusion Nonpathological anti-PF4 antibodies can be detected even several months after the first vaccination. The clinical significance of these antibodies in case of subsequent exposure to a vector vaccine or heparin is not yet clear. Furthermore, subsequent vaccination seems safe in VITT patietns.
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Introduction Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare, but severe side effect after vaccination with adenovirus vector-based vaccines (ChAdOx1 nCoV-19, AstraZeneca and Ad26.COV2.S, Johnson & Johnson/ Janssen) in which platelet activating anti-platelet factor 4 (PF4) antibodies cause thrombocytopenia and thrombosis at unusual sites. Patients and treating physicians are concerned about whether other vaccinations can also trigger thrombosis in patients with a history of VITT. We showed that VITT patients can safely receive their second and third vaccination against Covid-19 with an mRNA-based vaccine. [1] However, there is limited information on whether other vaccines than against Covid-19 could booster platelet activating anti-PF4 antibodies. Uncertainty increased after a report of VITT caused by human papilloma vaccination. [2] Method In our follow-up study of patients with laboratory confirmed VITT (EUPAS45098), an anti-PF4/heparin IgG enzyme immune assay (EIA) and a PF4-dependent platelet activation assay (PIPA) were performed at regular intervals and after each vaccination reported to us. Results Seventy-one VITT patients (43 female, median age at VITT diagnosis 48, range 18-80) were followed for a median of 56 weeks (range: 13-77 weeks). During the follow-up period, eight vaccinations other than against Covid-19 were reported: Six vaccinations against influenza (three Influvac, two Vaxigrip Tetra, one Influsplit Tetra) and two consecutive vaccinations against tick-borne encephalitis (TBE) in one patient. In six patients who received vaccination against influenza, all patients showed decreasing or stable EIA optical density (OD) levels. None of them showed a reactivation of platelet-activating anti- PF4-antibodies in the PIPA. The patient who was vaccinated against TBE twice showed stable EIA OD levels and remained negative in the PIPA throughout. No new thrombosis or recurrent thrombocytopenia were observed after any vac- cination. Five out of six patients still received therapeutic anticoagulation, one patient did not receive any anticoagulative drug (Fig. 1). Conclusion Similar to observations after consecutive mRNA-vaccinations against Covid-19 in VITT patients, vaccinations against influenza and TBE very unlikely reactivate platelet-activating anti-PF4-antibodies. Further follow up of the VITT patient cohort is performed to detect any new safety signal related to recurrence of VITT. (Table Presented).
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Introduction Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare, but severe side effect after Covid-19 and other vaccinations. First cases of VITT-mimicking antibodies in unvaccinated patients with recurrent thrombosis have been described. Differentiation between heparin-induced thrombocytopenia (HIT) and VITT is difficult in some patients. Widely used enzyme-linked immunoassays (EIA) cannot differentiate between the two, some of them even fail to detect VITT antibodies. So far, differentiation between HIT-like and VITT-like anti-PF4 antibodies can only be performed in specialized laboratories by functional tests using the heparin-induced platelet activation (HIPA) or PF4-induced platelet activation (PIPA) test. We have developed an assay, which can distinguish between HIT and VITT antibodies and can be used in any hospital laboratory. Method Confirming platelet-activation assays (HIPA and PIPA) were performed as described.[1] We defined 3 cohorts: 1) Negative controls (n = 112, including 35 healthy donors from before 2020, 46 clinical patients suspected for HIT but with negative EIA and HIPA and 31 non-thrombotic patients);2) classical HIT-patients with positive EIA and HIPA (n = 121);3) typical VITT patients (n = 63;presenting after vaccination with adenoviral vector-based Covid-19 vaccine and positive EIA and PIPA). Samples were analyzed by an automated coagulation analyzer ACL AcuStar (Werfen / IL Inc., Bedford, MA, USA) using HemosIL AcuStar HIT-IgG(PF4-H) and a prototype of VITT-IgG(PF4) assay according to the manufacturer's protocol. For both assays, raw data was analyzed as relative light units (RLU). Results All VITT samples were positive in the prototype VITT-assay (Fig. 1);only a few (n = 9;14.3 %) also showed weakly positive results in the HIT-assay. On the other hand, most of the HIT samples showed positive results in the HIT-assay (113;93.4 %), 34 of them (30.1 %) also reacted positive in the prototype VITT-assay (12 of them strongly;10.6 %), and three demonstrated an antibody pattern like autoimmune VITT. Negative control samples where all non-reactive in the HITassay and served to adjust the cutoff for the prototype VITT-assay. Conclusion The different reaction pattern of samples of HIT and VITT patients using HemosIL AcuStar HIT-IgG(PF4-H) and a VITT prototype assay was able to distinguish between the two antibody entities for the first time. The combination of assays can facilitate a rapid decision whether heparin may be used for treatment and also identify patients with autoimmune-VITT as a cause of recurrent thrombosis. (Table Presented).
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Objetivo: Relatar caso de paciente com Sindrome de Trombose com Trombocitopenia (TTS) identificado precocemente e com boa evolucao clinica. Relato do caso: Paciente de 21 anos, do sexo masculino, apresentou inicio dos sintomas sete dias apos terceira dose da vacina contra COVID-19, sendo esta a primeira dose de vacina de plataforma adenoviral (ChAdOx-1). Inicialmente com mal-estar e obstrucao nasal, procurou atendimento apos febre nao aferida e dor abdominal e lombalgia. Internado apos achado de trombocitopenia (13.500 plaquetas/mm3). Sorologia negativa para dengue e teste PCR para COVID-19 negativo. Tomografia computadorizada de abdome e pelve mostravam sinais de trombose de pequenos ramos tributarios das veias hepaticas direita e media, area compativel com infarto esplenico, nefrograma heterogeneo no rim esquerdo, predominando no polo superior, sugestivo de foco de infarto renal, e presenca de imagem sugestiva de trombo nao oclusivo na veia renal esquerda, ao nivel do hilo. Hemograma de admissao: Hb 15,3 Leucocitos 4.588 Plaquetas 13.370. TP e TTPa normais. Nadir plaquetario foi de 9.493. Fibrinogenio 178 mg/dL. Dimero D de 61,80 mg/L (VR <0,50). Paciente tratado com imunoglobulina humana (dose total de 2 g/kg) e dexametasona 40 mg /dia por 4 dias, apos quadro de cefaleia na vigencia de plaquetopenia grave, porem com TC de cranio contrastada sem sinais de sangramento ou de trombose venosa cerebral. Evoluiu com boa resposta plaquetaria, com contagem acima de 50.000 mm3 a partir de dois dias apos primeira dose de imunoglobulina. O paciente foi anticoagulado com fondaparinux e posteriormente rivaroxabana. Seguindo a norma tecnica ndegree 933/2021 do Ministerio da Saude, a amostra foi encaminhada para laboratorio de referencia, com resultado positivo para anticorpos anti-PF4 em altos titulos pelo metodo ELISA. Pesquisas de sorologias, anticorpos antifosfolipideos e para trombofilias hereditarias tambem resultaram negativas. Paciente seguiu estavel, com plaquetas de 160.000 mm3 e em anticoagulacao, quatro semanas apos a alta hospitalar. Discussao: A Sindrome de Trombose com Trombocitopenia (TTS) e uma rara complicacao da vacina de plataforma adenoviral nao-replicante, com uma incidencia de 0,5 a 6,8 casos a cada 100.000 vacinacoes. Sua mortalidade esta atualmente relatada em torno de 17%, mas chegando a 50% nos primeiros estudos, dependendo do tempo para diagnostico e inicio do tratamento. Manifesta-se entre 4 e 30 dias apos exposicao vacinal. Caso contempla todos os criterios para caso confirmado de TTS, alem de ser um caso provavel conforme o algoritmo de Naranjo para causalidade de reacao adversa. Apesar de complicacao potencialmente grave, nao compromete a seguranca vacinal, sendo evento clinico tratavel. Conclusao: A complicacao de TTS induzida por vacina com vetor adenoviral nao replicante, apesar de rara, e potencialmente fatal se nao identificada a tempo, alem de ter abordagem e tratamento que reduz de forma significativa a taxa de mortalidade. A divulgacao das informacoes para diagnostico precoce e manejo clinico devem ser ampliadas para melhoria dos desfechos. Copyright © 2022
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Purpose: Vaccine-induced thrombosis and thrombocytopenia (VITT) is a rare syndrome that has emerged since widespread vaccination against SARS-CoV-2. As a result of the high mortality, some patients have become deceased organ donors. Outcomes after kidney transplantation from donors with VITT are poorly described. Since the disease appears to be antibody-mediated, there is a theoretical risk of transmission from donor to recipient. Method(s): We examined the UK experience of kidney transplantation from donors with VITT, using data from the UK Transplant Registry. Our outcomes were early graft function, post-operative complications, 3-month estimated glomerular filtration rate (eGFR), patient and graft survival, and disease transmission. Result(s): Thirty patients (including two aged <18 years) received a single kidney transplant from 16 donors with VITT between 1st January and 30th June 2021. After a median follow-up of 5 months, patient and graft survival were 97% and 90%, respectively. Median 3-month eGFR was 51 mL/min/1.73m2. Two recipients had detectable anti-platelet factor 4 antibodies following transplantation, but no evidence of clinical disease. Major haemorrhagic or thrombotic complications occurred in three recipients, resulting in the loss of two grafts. Conclusion(s): The UK experience to date shows that favourable outcomes in kidney transplants from donors with VITT are possible. Ongoing vigilance for donor-related complications in these patients remains important. (Table Presented).
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SESSION TITLE: Cardiovascular Complications in Patients with COVID-19 SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: COVID-19 is associated with a hypercoagulable state and has been linked with Disseminated Intravascular Coagulation (DIC) [1]. DIC causes systemic thrombosis in micro- and macro- vasculature and in rare instances can involve coronary arteries [2]. In this case report, we present a patient who presented as an ST-segment elevation myocardial infarction (STEMI) and DIC in the setting of severe COVID-19 disease. CASE PRESENTATION: A 46-year-old lady with a history of hypertension presented with acute onset of typical chest pain. She tested positive for COVID-19 infection. Emergency room EKG showed anterior STEMI, and the patient underwent cardiac catheterization via a femoral approach which revealed a 99% stenosis in the proximal LAD, with filling defects consistent with a thrombus. Thrombectomy was performed and three drug-eluting stents were placed in the left anterior descending artery. Following stent placement, the patient went into ventricular fibrillation cardiac arrest followed by PEA. ROSC was attained after 3 rounds of CPR. Labs showed an acute drop in hemoglobin from 14 gm/dL to 5 gm/dL with CT evidence of extensive retroperitoneal bleed, extraperitoneal bleed, and large abdominal aorta thrombus proximal to the bifurcation. Labs were significant for prolonged INR (2.1), PT (23.4 seconds), PTT (106.7 seconds), elevated D-dimer (>4.0), decreased platelets (101K/μl), and increased fibrin split products (80uG/mL) consistent with DIC. The acute aortoiliac occlusive thrombus resulted in acute limb ischemia, rhabdomyolysis causing renal failure, and compartment syndrome requiring bedside fasciotomy. She was treated with triple therapy and demonstrated gradual clinical improvement. DISCUSSION: DIC was a possible precipitant of STEMI in this patient with evidence of thrombotic occlusion of LAD. DIC is a life-threatening coagulopathy characterized by mixed hypo- and hypercoagulation. This often leads to a systemic distribution of clots, evidenced by thrombi present in the coronary and aortoiliac arteries. Historically, bacterial sepsis was more strongly linked with DIC than viral causes;however, there has been an increasing amount of evidence linking COVID-19 with DIC, likely due to the severity of the illness. In this patient with recent stent placement, large aortic thrombus, and extensive retroperitoneal bleed, management was complicated by need for dual antiplatelet therapy for drug-eluting stents as well as anticoagulation for acute limb ischemia. Another diagnosis to keep in the differential includes heparin-induced thrombocytopenia, characterized by similar findings to DIC, but is associated with antibodies against platelet factor 4, which was not found in our patient. CONCLUSIONS: In this case, a young female patient without traditional cardiac risk factors was found to have an anterior STEMI, likely precipitated by DIC as a complication of COVID-19 infection. Reference #1: Asakura, Hidesaku, and Haruhiko Ogawa. "COVID-19-associated coagulopathy and disseminated intravascular coagulation.” International journal of hematology vol. 113,1 (2021): 45-57. doi:10.1007/s12185-020-03029-y Reference #2: M. Sugiura, K. Hiraoka, and S. Ohkawa, "A clinicopathological study on cardiac lesions in 64 cases of disseminated intravascular coagulation,” Japanese Heart Journal, vol. 18, no. 1, pp. 57–69, 1977. DISCLOSURES: No relevant relationships by radhika deshpande No relevant relationships by Shruti Hegde No relevant relationships by Robert Kropp No relevant relationships by Prashanth Singanallur
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The authors reported the clinical course of a 58-year-old female suffering from cerebral venous sinus thrombosis associated with hemorrhage after the ChAdOx1 nCov-19 vaccination. Emergent decompressive craniectomy was performed, and aggressive blood transfusion was given. Nevertheless, progressive intracerebral hemorrhage and thrombocytopenia developed. A delayed diagnosis was made on a rare complication of vaccine-induced immune thrombotic thrombocytopenia (VITT) with a positive result of anti-platelet factor 4 antibodies (PF4 Ab). The patient died 4 days postoperative due to brainstem failure.
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Introduction: In March 2021, a signal for embolic and thrombotic events with Vaxzevria (COVID-19 Vaccine AstraZeneca) was raised in Austria and Germany, and on 7 April 2021, the European Pharmacovigilance Risk Assessment Committee (PRAC) concluded that a causal relationship between Vaxzevria and thrombosis combined to thrombocytopenia (TTS) was at least a reasonable possibility [1]. TTS mechanism is close to heparin-induced thrombocytopenia [2,3]. We report two Luxembourg cases of TTS that occurred one before and one after this confirmed signal. Results: The first case is a 74-year-old woman, with no medical history, who received her first dose of Vaxzevria in March 2021. Fourteen days later, she was hospitalised for sudden loss of consciousness. On admission she had thrombocytopenia (18 G/L), D-Dimers >20 000 ng/mL, antithrombin III 79%, fibrinogen 0.69 g/dL. Brain CT scan showed cerebral and meningeal haemorrhages. She died three days later. Autopsy confirmed multiple intracranial haemorrhages and showed right transverse sinus organised thrombosis. Post-mortem analysis revealed positive heparin-Platelet Factor 4 (PF4) antibodies (HIPA and PIPA). The second case is a 31-year-old man with medical history of splenic infarction in 2017 during mononucleosis. He received his first dose of Vaxzevria in June 2021, and 12 days later was admitted for right lower limb and lumbar pain with severe thrombocytopenia (28 G/L), low fibrinogen and elevated D-Dimers. Angiography showed sub-occlusive cruoric impactions of the left carotid bifurcation, the sub-renal abdominal aorta and the right common femoral artery. PF4 antibody initially negative (Zymutest Hyphen) were positive with IMMUCOR technique. Management included clots removal, intravenous immunoglobulins started for 3 days and anticoagulation with sodium danaparoid. The patient recovered within one month without sequelae. Discussion/Conclusion: The quick communication about TTS signal and the rapid identification of its mechanism both allowed, as reported here for the second patient, adapted management (prohibiting heparin), with full recovery.
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Background and aims: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare side effect of the ChAdOx1 nCoV-19 COVID- 19 vaccine (AstraZeneca/Oxford) and often manifests as cerebral venous thrombosis (CVT). So far, CVT-VITT has only been reported after a first ChAdOx1 nCoV-19 dose. Methods: We report cases (March-December 2021) of CVT-VITT after a second ChAdOx1 nCoV-19 vaccine dose from an international CVTVITT registry. We classified certainty of VITT diagnosis using criteria of the United Kingdom Expert Haematology Panel. Results: Out of 124 CVT cases that developed after ChAdOx1 nCoV- 19 vaccination, 120 were after a first dose (61 definite, 20 probable, 10 possible and 29 unlikely VITT), and 4 after a second dose (1 definite, 1 probable, 1 possible and 1 unlikely VITT). None of the four patients had any symptoms after the first ChAdOx1 nCoV-19 dose. All cases had symptom onset between 1 and 6 days after the second vaccination, thrombocytopenia, and increased D-dimer levels. Anti-PF4 antibodies were positive in 2/3 tested cases. Two patients presented in a coma and died during admission. Conclusion: CVT-VITT can occur after a second dose of ChAdOx1 nCoV-19 vaccine, but was reported substantially less often after a second than after a first vaccine dose. In some cases, symptom onset of VITT may be more rapid after a second than after the first dose, although the small number of cases precludes firm conclusions.
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Background and aims: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare syndrome of unclear aetiology occurring after 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. Serum levels of SP, soluble angiotensin-converting enzyme 2 (sACE2), and platelet response to VITT serum stimulation were studied. A thrombus retrieved from middle cerebral artery during mechanical thrombectomy of one VITT patient, was analysed by immunohistochemistry for SP and ACE2. Neutrophil extracellular traps (NETs) markers and coagulation parameters were also measured. Results: We detected SP and sACE2 in all VITT patients, and in two and three out of 7 HCs, respectively. VITT sera markedly activated platelets and this activation was inhibited by both anti-SP and anti-FcγRIIA blocking antibodies. The retrieved 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 VITT sera. Conclusions: The present data provide first evidence that DNA vaccineencoded Sars-cov-2 SP is detectable in VITT sera (up to several weeks post-vaccination) and in a platelet-rich thrombus, and suggest that SP may contribute to the initial platelet stimulation in VITT patients. Anti-PF4/ polyanion antibodies development could represent an epiphenomenon, which amplifies platelet aggregation, NETosis, and coagulation cascade.
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Objective: To report a rarely isolated central retinal artery occlusion (CRAO) following Coronavirus disease 2019 (COVID-19) Vaccine Moderna (mRNA-1273). Background: COVID-19 caused by severe acute respiratory syndrome coronavirus was firstly reported in Dec 2019 and became pandemic as of Mar 2020. Fortunately, novel rapidly developed COVID-19 vaccines are capable of lessening the pandemic effectively. As billions of people vaccinated, however, COVID-19 vaccine-induced thrombosis (VIT) are gradually emerging. Design/Methods: A previously healthy 70-year-old man presented with acute painless visual loss of the right eye five days after the first dose of Moderna vaccine. On examination of the right eye, visual acuity (VA) was counting finger at 15 cm. Fundoscopy revealed a diffuse whitened retina with cherry-red spot. Optical coherence tomography (OCT) showed hyperreflectivity. Screening tests for platelet and D-Dimer levels were unremarkable. CRAO was treated with clopidogrel and hyperbaric oxygen therapy. The serum level of anti-platelet factor-4 (PF4) antibody was 73.34 ng/ml (ref, 0-49.99 ng/ml).Two months later, VA was counting finger at 10 cm3 and OCT revealed hyperreflectivity and mild inner retina atrophy Results: COVID-19 vaccine-induced thrombosis and thrombocytopenia (VITT) based on the victims receiving AstraZeneca and Johnson & Johnson vaccines is through autoimmune antibody against PF4. VITT is typically manifested within 6-24 days post-vaccination;thrombotic sites are in the cerebral sinus, portal vein, splanchnic vein, and pulmonary emboli;as well as thrombocytopenia and increased level of D-Dimer. Our patient had isolated CRAO five days post-Moderna vaccination but normal platelet count and D-Dimer level. Moreover, VIT with isolated CRAO was not published on PubMed. Conclusions: VIT could occur in the unusual site such as CRAO in our case. Normal platelet and D-Dimer levels might not be sensitive tools to exclude VIT. Suspected patient with thrombotic event after COVID-19 vaccines should have anti-PF4 antibody test to assure an effective treatment.
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Background: Vaccines have been an important strategy to control the SARS-CoV-2 pandemic. In The Netherlands two mRNA vaccines (BTN162b2, Pfizer-BioNTech;mRNA-1273, Moderna), and two adenovirus vector-based vaccines (ChAdOx1 nCoV-19, AstraZeneca;Ad26. COV2.S, Johnson & Johnson/Janssen) have been administered. In 2021, vaccination with the ChAdOx1 nCoV-19 was ceased in The Netherlands and other European countries due to the occurrence of thrombocytopenia and thromboembolic events. This new phenomenon was termed vaccine-induced thrombotic thrombocytopenia (VITT) and was clinically associated with thrombocytopenia and thrombosis at unusual sites, in particular cerebral venous sinus thrombosis (CVST). In addition, VITT was characterized by the presence of IgG-antibodies directed against platelet factor 4 (PF4). As PF4 appears to play a central role in the pathophysiology of VITT, it is recommended that the role of PF4 should be taken into account for VITT diagnostic testing. Aims: To characterize and define the patient population of clinically suspected VITT cases in The Netherlands from a diagnostics perspective. Methods: We describe a cohort of 283 clinically suspected VITT patients. We assessed these patients based on their clinical presentation and using an anti-PF4 IgG ELISA and a functional PF4-dependent platelet activation assay. Results: We found that when the 283 clinically suspected VITT patients were analysed in the anti-PF4 IgG ELISA: 24 (8.5%) tested positive, 248 (87.6%) tested negative, and 11 (3.9%) tested weak positive. Out of the 24 patients that tested positive in the anti-PF4 IgG ELISA, 19 (79.2%) patients also demonstrated increased PF4-dependent platelet activation. Furthermore, we observed that platelet activation was inhibited by excess levels of heparin and by a FcγRIIa-blocking antibody, indicating a role for platelet-FcγRIIa in the pathophysiology of VITT. Remarkably, we found that patients vaccinated with mRNA vaccines BTN162b2 (N = 84) and mRNA-1273 (N = 36), did not test positive in the anti-PF4 IgG ELISA. Based on these test results 19 patients (11 women) were eventually diagnosed with probable VITT, of which 13 presented with both thrombocytopenia and thrombosis and three suffered from CVST. Strikingly, discrepancies in test results were also present, including nine patients with low levels of anti-PF4 IgG but with increased PF4-dependent platelet activation, and two patients with high levels of anti-PF4 IgG but without any PF4-dependent platelet activation. Summary/Conclusions: VITT is a rare but serious complication of SARS-CoV-2 virus vaccination, particularly due to adenovirus vectorbased vaccines. Our results underline the importance of using the clinical presentation, in combination with the anti-PF4 IgG ELISA and the PF4-dependent platelet activation assay for VITT diagnostics. Discrepancies in test results, however, proved it difficult to unequivocally diagnose VITT. Therefore, it will be essential to obtain more insights into the pathophysiology of VITT in order to improve the diagnostic accuracy and identify preventive and therapeutic approaches.
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We present the case of a 39-year-old female who presented to University Hospitals of Leicester 14 days after the second dose of ChAdOx1 nCov-19 vaccine. Her presenting symptoms included skin rash, nausea, intermittent abdominal pain and occasional episodes of dizziness. Her past medical history included Type 2 Diabetes Mellitus and hidradenitis suppurativa. The first dose of ChAdOx1 nCov-19 vaccine had been administered on 27th February 2021, following which the patient reported flu like symptoms that resolved after four days and did not require further medical input. Following this, a preplanned surgical procedure to incise and drain a vulval abscess was performed on 17th May 2021. Preoperative testing performed on 13th May 2021 showed a normal platelet count of 219 × 10 9 /l. The second dose of ChAdOx1 nCov-19 vaccine was subsequently administered on 23rd May 2021. On presentation, examination revealed mild epigastric tenderness and features of classical thrombocytopenic rash affecting all limbs with no other associated bleeding. Initial blood results confirmed thrombocytopenia of 11 × 10 9 /l, with D-Dimer 14.26 μg/ml and fibrinogen 2.1 g/l. Blood film microscopy revealed an occasional schistocyte and microangiopathic haemolysis was considered. Treatment with plasmapheresis of 1.5 x plasma volume using Octaplas was administered. Subsequent abdominal computed topography imaging identified extensive thrombotic events. This included bilateral pulmonary embolism, superior mesenteric vein non-occlusive thrombus and multiple soft atheromas lining the abdominal aorta causing moderate infrarenal stenosis. In view of the recent history, vaccine associated thrombosis and thrombocytopenia (VITT) was considered. Subsequent testing showed a normal ADAMTS13 level. Treatment for VITT with intravenous immunoglobulin along with oral steroids and anticoagulation using Argatroban was commenced in line with national guidance. Anti-PF4 antibody, tested using the Asserachrom HPIA ELISA assay, was positive at a level of 1.298 OD units confirming the diagnosis of VITT;the first case we are aware of in the UK following second dose administration. Given high-risk presentation, Rituximab therapy was given as an inpatient with good clinical response. Prior to discharge, anticoagulation was switched to oral apixaban with a platelet count on discharge of 170 × 10 9 /l. Subsequent follow-up has shown ongoing clinical remission with consistently negative Anti-PF4 antibody titres. This report outlines the first known definite case of VITT identified following administration of the second dose of ChAdOx1 nCov-19 vaccine in the United Kingdom. The subsequent clinical course was similar to those of patients presenting after their first dose but the atypical presentation mimicking that of Thrombotic Thrombocytopenia is noted..
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Instituição: Hospital Felício Rocho (HFR). Objetivos: Descrever o caso de uma paciente jovem que desenvolveu trombocitemia-trombotica induzida por vacina pós uso de Ad26.COV2.S, popularmente conhecida como vacina Janssen. Material e métodos: Estudo de prontuário médico. Discussão: Trata-se de paciente, 37 anos, atendida pela cardiologia no pronto atendimento (PA) do Hospital Felicio Rocho (HFR) em Belo Horizonte-MG, na noite do dia 03/08/2021, com queixa de cefaleia intensa, holocraniana, associada a náuseas e vômitos, sem melhora ao uso de analgésicos simples ou anti-inflamatórios não estereoidais, que evoluiu com dor torácica ventilatório-dependente, sem dispneia, dessaturação, ou sintomas gripais. Não apresentava ao exame físico déficits neurológicos. Como história pregressa afirmava quadro de tromboembolismo pulmonar (TEP) ocorrido em 2014, quando fez uso de Marevan® por três anos (abandonou tratamento sem orientação médica) e vacinação recente, em 27/07/2021, contra COVID19, com Ad26.COV2.S, popularmente conhecida como vacina Janssen. Foi acompanhada por hematologista após ocorrência do primeiro TEP para investigação de trombofilias quando foi constatado presença de mutação heterozigota de gene da metilenotetrahidrofolato redutase. Como fator de risco prévio apresentava apenas o uso de contraceptivo hormonal combinado. Ainda no PA foram realizadas tomografia (TC) e angiotomografia (ATC) de crânio e tórax, além de exames laboratoriais. Ao hemograma, paciente apresentava plaquetopenia (50 × 10³mm³). Os exames de imagem mostraram ausência de trombose cerebral, e falha de enchimento luminal em ramos lobar e segmentar para o lobo pulmonar inferior direito, compatível com TEP. Paciente foi internada para anticoagulação terapêutica com Enoxaparina 1 mg/Kg BID, que posteriormente foi substituído por Apixabana 10mg BID. Foi solicitado anticorpo anti-heparina(PF4) sob a hipótese de trombocitemia-trombotica induzida por vacina, já descrita em literatura como evento adverso grave e raro, secundário ao uso de vacina anti-COVID 19, mais comum ao uso de ChAdOx1 n CoV-19 (Astrazenica), mas também relatada após o uso de Ad26.COV2.S (Janssen). Paciente evoluiu diariamente com piora da plaquetopenia, chegando a 22 × 10³mm³no segundo dia de internação, quando optou-se por suspensão da anticoagulação e tratamento empírico com imunoglobulina humana IgG, na dose de 1 mg/Kg/dose 24/24h, duas doses. Após administração da primeira dose, houve ainda queda do nível de plaquetas, 10x10³mm³. Horas após a administração da segunda dose, paciente evoluiu com novo episódio de cefaleia, seguido de déficits motores focais. TC de crânio realizada mostrou áreas de hemorragia parenquimatosa, e ATC de crânio mostrou presença de extensa trombose de seio sagital superior e do seio transverso. Nas 24h que se seguiram, evoluiu com herniação de uncos, pupilas midriáticas fixas e ausência de reflexos neurológicos. Foi suspensa sedação e instituído protocolo de morte encefálica, confirmado 48h após. Aguardamos resultado do Anti-PF4 com previsão de resultado no dia 30/08/2021.
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Objetivos: Relatar caso fatal de hemorragia cerebral e complicações tromboembólicas após realização de vacina ChAdOx1 nCoV-19. Relato de caso: Mulher, 22 anos, obesa, é encaminhada ao serviço de urgência por quadro súbito de alteração na fala e perda de força em hemicorpo esquerdo 10 dias após receber a primeira dose da vacina ChAdOx1 nCoV-19 (Astrazeneca). Há 3 dias com cefaleia holocraniana persistente refratária ao uso domiciliar de analgésicos. Sem história prévia de doenças crônicas, uso de medicações ou hospitalizações. Na admissão, Escala de Coma de Glasgow de 11 pontos, disartria e hemiplegia de membro superior esquerdo. Foram realizados angiotomografia de crânio e tórax com sinais de trombose do seio sagital, coleções hemorrágicas intraparenquimatosas nos lobos parietal e occipital à direita, compatíveis com evento vascular hemorrágico recente, além de tromboembolismo pulmonar agudo em ambas as artérias pulmonares principais e seus ramos. Exames laboratoriais: plaquetopenia (34.000/mm³), hemoglobina de 13,2 g/dL, INR de 1,31, tempo de tromboplastina parcial ativada (TTPa) de 39,1 segundos (TTPa controle: 32,5 segundos), fibrinogênio de 54 mg/dL (VR: 200 a 400 mg/dL), d-dímeros 35,20 ug/mL (VR: até 0,5 ug/mL). Também foi realizada dosagem de anticorpos anti fator plaquetário 4 (Anti-PF4), mas sem resultado imediato do teste. Após 4 horas da admissão hospitalar, nova imagem de crânio foi realizada e mostrou aumento da hemorragia intracraniana. Mesmo após o manejo terapêutico inicial com suporte de terapia intensiva, imunoglobulina intravenosa 1 g/kg e dexametasona 40 mg, cerca de 12 horas da admissão, não houve resposta neurológica satisfatória, evoluindo para morte encefálica. Alguns dias após o óbito, resultado detectável de anticorpos anti-PF4. Discussão: As vacinas são as principais ferramentas para controle da pandemia da COVID-19. Consequentemente, com a vacinação de grande parte da população mundial, vários casos de eventos tromboembólicos e plaquetopenia foram reportados em indivíduos que receberam a vacina ChAdOx1 nCoV-19 (Astrazeneca) e, mais recentemente, nos que receberam a Ad26.COV2.S vaccine (Janssen), em um intervalo de 5 a 30 dias da aplicação. Esta síndrome recebeu o nome de trombocitopenia trombótica imune induzida por vacinas (VITT), que apesar da incidência ainda ser desconhecida, é considerada rara. Os achados clínicos são muito semelhantes aos encontrados na trombocitopenia imune induzida por heparina (HIT): plaquetopenia (mediana de 20.000 a 30.000/mm3), elevação de d-dímeros, níveis reduzidos de fibrinogênio e evidência de trombose, principalmente trombose de seio venoso cerebral. Além disto, ocorre presença de altos níveis de anticorpo anti-PF4, mesmo na ausência de exposição à heparina. O manejo terapêutico deve ser realizado com uso de imunoglobulina intravenosa, corticoides em altas doses e anticoagulação (preferencialmente por agentes não-heparina), minimizando as transfusões de plaquetas (apenas para casos com sangramento crítico). A despeito da síndrome ser potencialmente fatal, os benefícios da vacinação superam os riscos. Conclusão: Apesar da VITT ser uma síndrome rara, a crescente vacinação da população exige que a comunidade médica saiba identificar e manejar esta condição.
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Objetivos: Revisão sistemática da literatura sobre os possíveis eventos tromboembólicos após a administração da vacina ChAdOx1 nCov-19/AZD1222 (Astrazeneca®). Materiais e métodos: A questão foi estruturada pelo sistema PICO, acrômio de Paciente/Problema (P), Intervenção (I), Comparação (C) e Resultado/Outcome (O). Estabelecemos que o P seria população vacinada, I seria vacina Astrazeneca, C seria nenhuma intervenção e O como efeitos tromboembólicos. Dessa forma, evidências foram pesquisadas nas principais bases científicas (MEDLINE/PubMed), utilizando os seguintes termos: ChAdOx1 nCov-19 AND thromboembolism. Foram incluídos estudos na língua inglesa sem limite no período consultado. Inicialmente, os estudos foram selecionados pelo título, sequencialmente pelo resumo, e por fim, pelo texto completo, o qual foi submetido a avaliação crítica. Recuperou-se 19 trabalhos, sendo acessados 4 textos completos que se relacionaram aos componentes PICO. Os principais motivos de exclusão foram os não relacionados aos componentes PICO. Resultados: Dados pela European Medical Association identificaram em 5,5 milhões de vacinados a ocorrência de 202 casos graves de eventos tromboembólicos. Destes, 122 em mulheres, observando os primeiros episódios alguns dias após a vacinação, que duraram de 2 a 3 dias, com agravamento do 6°ao 12°dia. Em outro estudo no Reino Unido, 3 pacientes (2 mulheres e 1 homem) após o 10°e 16°dia da 1°dose da vacina ChAdOx1 nCov-19 apresentaram reações tromboembólicas graves, como trombose extensa, aumento de dímero D e fibrinogênio limítrofe baixo. Dois desses pacientes foram diagnosticados com trombose do seio venoso cerebral (CVST), fatal em ambos os casos, enquanto o 3°paciente apresentou embolia pulmonar. GREINACH, A. et al avaliando 11 pacientes, sendo 9 do sexo feminino, descreveram presença de trombocitopenias e trombose venosa cerebral e esplênica após a vacinação com ChAdOx1 nCov-19. Ademais, pesquisas na Alemanha notaram o desenvolvimento de CVST em 3 mulheres vacinadas com a Astrazeneca®, em média de 15 dias entre a vacinação e os eventos. Discussão: As vacinas contra a COVID-19 tornaram-se ferramentas fundamentais para o controle da pandemia, todavia eventos trombolíticos foram identificados após a vacinação com a vacina Astrazeneca®, levantando preocupações. A Trombocitopenia trombótica induzida por vacina (VITT) é uma síndrome relatada entre 5 e 28 dias após a vacinação. Seus eventos tromboembólicos ocorrem devido às interações eletrostáticas entre o PF4 e a superfície do adenovírus, que, consequentemente, quando polarizados, ligam-se por meio do receptor FC às plaquetas, ativando os trombócitos e levando à VITT. O SARS-CoV-2 é um vírus de RNA de fita simples que apresenta proteínas spike (S) na superfície viral. A sua ligação com a enzima conversora de angiotensina 2 configura a entrada viral. A vacina ChAdOx1 é do tipo vetor viral não replicante, adenovírus, que codifica a proteína S com um peptídeo sinal do ativador do plasminogênio tecidual, podendo desencadear VITT. Todavia, embora seja raro ocorrer eventos trombolíticos na população vacinada, foram analisados casos de VITT após a 1°dose da vacina Astrazeneca®. Conclusão: Diante do exposto, conclui-se que os eventos tromboembólicos são raros, porém quando encontrados, foi observado que são mais frequentes na população vacinada com a Astrazeneca®, sendo a sua maioria mulheres. Contudo, constatou-se que os benefícios da vacina superam seus riscos.
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A Trombocitopenia Trombótica induzida por vacina (VITT) tem sido relatada como um efeito adverso raro e grave após a administração de vacinas contra o COVID-19 que usam adenovírus não replicante como vetor. A VITT caracteriza-se pela presença de: (1) trombose em sítios não usuais (e.g., seio venoso sagital, veias esplênicas e renais), (2) plaquetopenia, (3) aumento importante dos valores de D-dímero e (4) elevação do Fator anti-plaquetário 4. Ocorre geralmente cerca de 3 a 30 dias após a vacinação. Segundo a Organização Mundial de Saúde, sua incidência é de 0,5 a 6,8 casos/100.000 vacinados. A fisiopatologia da VITT ainda não é bem esclarecida, porém existe relação com mecanismos relacionados a Trombocitopenia induzida pela Heparina. A maioria dos relatos de reação estão associados a primeira dose da vacina, porém também há casos na segunda dose. Devido a potencial gravidade na evolução, o tratamento não deve ser retardado. A terapia inicial inclui o uso de Imunoglobulina 2 g/kg (em 2 dias). O uso de corticoide em alguns casos pode ser feito como adjuvante, porém ainda não há comprovação de sua eficácia. A plasmaférese deve ser feita de imediato em pacientes com Trombose em Seio Venoso Sagital ou em casos refratários a Imunoglobulina. Não deve ser realizado transfusão de plaquetas e o uso de heparina como anticoagulante deve ser evitado. Faremos o relato de 2 casos em que a plasmaférese foi utilizada como terapia auxiliar ao tratamento: Paciente 1: Paciente mulher, jovem, 24 anos, foi admitida no Hospital 10 dias após a primeira dose da vacina Astrazeneca com quadro de cefaleia persistente refratária a analgésicos e petéquias em face e tronco iniciado 3 dias da internação. Admitida com plaquetopenia 2000, fibrinogênio 190 e D dímero 12000. Iniciado Imunoglobulina 2 g/kg (dois dias seguidos). Foi associado corticoide 1 mg/kg/dia. No nono dia de tratamento, evoluiu com 50 mil plaquetas, D dímero 7400 e PF4 3,34 U/mL. Evoluiu com Crise Convulsiva sendo diagnosticado Trombose Venosa de Seio Sagital. Iniciada Plásmaferese (feito 5 sessões em dias alternados com troca por albumina). Na quinta sessão de plasmaférese estava com D dímero 880, plaquetas 71 mil e fibrinogênio 58. Após 4 dias do término da plasmaférese, paciente apresentou retorno da cefaleia. Dosado D dímero 2300. Reiniciado Plasmaférese (Plasma 1:Albumina 1). Foram realizadas mais 2 sessões com plaquetas acima de 150 mil. Após a quarta sessão, no D27 internação estava com D dímero 470, plaquetas 362 mil e PF4 2,2. Paciente 2: Paciente do sexo masculino, 85 anos, foi admitido no hospital 21 dias após a segunda dose da vacina da AstraZeneca com quadro de fraqueza, astenia, confusão mental e inapetência, associado a tromboembolismo pulmonar. Paciente previamente renal crônico não dialítico, hipertenso, diabético, 2 cirurgias cardíacas prévias (2014 e 2017) e púrpura trombocitopênica idiopática crônica sem necessidade de tratamento prévio. A admissão, exames demonstravam plaquetas de 47.000, TTPa 35,8, INR 1,5 e fibrinogênio de 234. O Anticorpo anti-PF4 foi de 4,8 U/mL, e as plaquetas chegaram a 19.000. Foram realizados dois ciclos de IGIV, sem resposta, e mesmo com associação de corticóide 1 mg/kg/dia, não houve resposta. Foi optado por realizar plasmaférese terapêutica com realização em dias seguidos com troca de 1 volemia plasmática e reposição realizada com plasma fresco congelado em todas as sessões. Após 4 sessões, paciente apresentou melhora clinica, a despeito de manter plaquetopenia. Nesse momento, devido a historia de PTI previa, foi optado por iniciar eltrombopag. Conclusão: Relatamos 2 casos clínicos, nos quais a plasmaférese terapêutica pode contribuir para evitar um desfecho desfavorável na VITT.