key: cord-0955459-5tkyir3r authors: Watts, Isabella; Smith, David; Mounter, Sarah; Baker, Emma H.; Hitchings, Andrew W.; Gill, Dipender title: A case series of vaccine‐induced thrombotic thrombocytopenia in a London teaching hospital date: 2021-11-09 journal: Br J Clin Pharmacol DOI: 10.1111/bcp.15116 sha: 659803708828ff9951e6ac29e1c8cbad779cb829 doc_id: 955459 cord_uid: 5tkyir3r The ChAdOx1 nCoV‐19 vaccine has been associated with increased risk of thrombosis. Understanding of the management of these rare events is evolving, and currently recommended treatments include human normal immunoglobulin and nonheparin anticoagulation such as direct oral anticoagulants. Our report describes three consecutive patients presenting to a London teaching hospital with vaccine‐induced thrombotic thrombocytopenia (VITT), also referred to as vaccine‐induced prothrombotic immune thrombocytopenia. The patients ranged in age from 40 to 54 years and two had no known previous medical comorbidities. Two patients had cerebral venous sinus thrombosis and one had a deep vein thrombosis. Two were treated with anticoagulation, one with oral rivaroxaban and the other with an intravenous argotraban infusion that was later converted to oral apixaban. One patient received three doses of human normal immunoglobulin and 5 days of therapeutic plasma exchange. This case series may be used to improve understanding of the clinical course and management of VITT. The ChAdOx1 nCoV-19 vaccine has been associated with increased risk of thrombosis. Understanding of the management of these rare events is evolving, and currently recommended treatments include human normal immunoglobulin and nonheparin anticoagulation such as direct oral anticoagulants. Our report describes three consecutive patients presenting to a London teaching hospital with vaccine-induced thrombotic thrombocytopenia (VITT), also referred to as vaccine-induced prothrombotic immune thrombocytopenia. The patients ranged in age from 40 to 54 years and two had no known previous medical comorbidities. Two patients had cerebral venous sinus thrombosis and one had a deep vein thrombosis. Two were treated with anticoagulation, one with oral rivaroxaban and the other with an intravenous argotraban infusion that was later converted to oral apixaban. One patient received three doses of human normal immunoglobulin and 5 days of therapeutic plasma exchange. This case series may be used to improve understanding of the clinical course and management of VITT. vaccine, the incidence of VITT has since been estimated at 14.8 per million first or unknown doses. 5 During the initial phase 3 trial of the vaccine, one case of cerebral venous sinus thrombosis was noted in a 25-year-old man with no past medical history or regular medications. 6 The pathogenesis of these thrombotic events is still under investigation but involves IgG antibodies that adhere to platelet factor 4 (PF4), resulting in activation of the coagulation cascade. 7 Reports of these clots have led to vaccine administration being paused in some countries, and a withdrawal or caution against use in younger age groups in other countries. 8, 9 Understanding of the pathogenesis and management of these blood clots is crucial in the ongoing roll out of the Medicines and Healthcare Products Regulatory Agency (MHRA) via the Yellow Card system. 11 Recommended initial investigations include a full blood count and blood film to confirm true thrombocytopenia and a coagulation screen to include both fibrinogen and D-dimer measurements. If these tests are suggestive of VITT, testing to identify antibodies to PF4 to confirm the diagnosis and imaging to confirm thrombosis should be performed. Treatment strategies include anticoagulation with a nonheparin agent, correction of low fibrinogen with cryoprecipitate, consideration of intravenous normal human immunoglobulin (IVIG), steroids, and plasma exchange. The proposed mechanism for the effect of IVIG in VITT is thought to be similar to its effects in heparin-induced thrombocytopenia, where IVIG competitively inhibits the IgG antibodies that adhere to PF4, reducing platelet consumption and activation of the coagulation cascade. 12, 13 In this short report, we describe a series of consecutive patients who presented to a London teaching hospital with thrombosis after receiving a ChAdOx1 nCoV-19 vaccine, all with confirmed anti-PF4 antibodies. We describe their clinical presentation, investigations, and management to contribute to the collective understanding of this condition and its treatment. What is already known about this subject • Vaccination with the ChAdOx1 nCoV-19 vaccine has been associated with pathological thrombosis, including cerebral venous sinus thrombosis. • Strategies to treat these rare events are being investigated and include the use of nonheparin anticoagulation and human normal immunoglobulin. • Treatment guidelines are still evolving. What this study adds • On presentation all patients had low platelet count, raised D-dimer measurement and were anti-PF4-antibody positive. • These observations may be used to gain insight into the pathophysiology and optimal management of VITT. (Table 1) . F I G U R E 4 Platelet count, fibrinogen levels and treatments in patient 3 over the hospital admission All patients had thrombocytopenia at baseline, confirmed on blood film microscopy (Table 1 ). In patient 1, who died shortly after admission, the baseline platelet count was 8 Â 10 9 /L. In patient 2, the platelet count was initially 90 Â 10 9 /L. The platelet counts of patient 3, in relation to relevant therapeutic interventions, are presented in Figure 4 . T A B L E 1 Anti-PF4 Our case series adds to the growing body of literature discussing VITT. [12] [13] [14] [15] Early studies observed cases occurring primarily in women under 40 years of age. 7, 14, 16 Our series describes VITT affecting two women and one man, somewhat older than the initial cases reported elsewhere. Whilst it was supposed that there may be a link between age and risk of VITT, this was not supported by a recent analysis per- Our patient had no relapse of these features but was given a repeat dose of IVIG due to the severity of her initial presentation and the persistence of anti-PF4 antibodies. The guidance also suggests that in cases refractory to IVIG, rituximab (a monoclonal antibody that targets CD20 protein on B cells) can be considered. 10 Our patient also had five sessions of plasma exchange, and a recent study indicated that in patients not responsive to IVIG, plasma exchange was effective in treating vaccine-induced thromboses. 19 COVID-19 is itself a prothrombotic disease and thrombocytopenia is also frequently observed, with several putative explanations. 30 Therefore, another potential mechanism is cross-reactivity of the anti-SARS-Cov2 spike protein antibodies with PF4. 31 However, this does not explain the apparent difference in rate of VITT between different vaccine platforms, which all employ the SARS-CoV-2 spike protein as the antigenic target. Our case series has several limitations. There are only three patients, so broad inferences about ongoing management strategies cannot be made. Patient 1 was transferred from a district hospital, and investigation results prior to the transfer were not available to us. Additionally, some laboratory investigations were not performed in all patients. We collected data retrospectively, and some relevant information was not available. Despite these limitations, this series adds to the collective body of evidence on the presentation, clinical course and management of this rare condition. In our three VITT cases, one patient died, one was managed in ambulatory care and the third is recovering in hospital, with life-changing neurological impairment. Where immunomodulatory treatments (immunoglobulin and therapeutic plasma exchange) were employed in one case, this was followed by an improvement in platelet count. Likewise, use of nonheparin anticoagulants in two cases was followed by amelioration of the prothrombotic process. This aligns with reports from other centres. Through sharing of experiences of this rare complication, understanding and management can be optimised. St George's Hospital audit registration number AUDI001000. Signed consent from the patient or their next-of-kin was obtained for anonymised data to be published in this report. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. The Lancet COVID-19) Vaccinations -Statistics and Research -Our World in Data Global Advisory Committee on Vaccine Safety (GACVS) review of latest evidence of rare adverse blood coagulation events with AstraZeneca COVID-19 Vaccine (Vaxzevria and Covishield) COVID-19 Vaccine AstraZeneca: benefits still outweigh the risks despite possible link to rare blood clots with low blood platelets Coronavirus vaccine -weekly summary of Yellow Card reporting -GOV.UK. 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All authors interpreted the data, critically revised the manuscript and provided final approval of the version to be submitted. Anonymised data is available on reasonable request to the corresponding author. https://orcid.org/0000-0003-1974-2365Emma H. Baker https://orcid.org/0000-0002-0871-3721