key: cord-0871434-0aptbc6b authors: Gangi, Anmol; Mobashwera, Behnaz; Ganczakowski, Mary; Ayto, Robert title: Imaging and Hematologic Findings in Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 (AstraZeneca) Vaccination date: 2021-08-17 journal: Radiology DOI: 10.1148/radiol.2021211546 sha: 0bf39b73759724ec4342b49e672299e6d148afd1 doc_id: 871434 cord_uid: 0aptbc6b An earlier incorrect version appeared online. This article was corrected on August 18, 2021. This case series reports six patients (4 men; median age 38 years; interquartile range 26-48) presenting with vaccine-induced thrombocytopenia and thrombosis beginning 3 to 26 days after receiving the first dose of the ChAdOx1 nCoV-19 (AstraZeneca) vaccine. The patients were admitted to a general hospital between 9 to 31 days after the first dose. All patients had strongly detected anti-platelet factor 4 antibodies and severe thrombosis. Laboratory features included thrombocytopenia and elevated D-Dimer levels. Thrombotic events were predominantly venous; two patients had arterial or mixed arterial/venous thrombosis. All patients recovered after receiving intravenous immunoglobulin and non-heparin based anticoagulation. This case series demonstrates rare thromboembolic events and thrombocytopenia after receiving the first dose of the ChAdOx1 nCoV-19 (AstraZeneca) vaccine. No thromboembolic events have been found in randomized safety studies of the AstraZeneca vaccine (1) (2) . Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare syndrome of immune-driven thrombosis and thrombocytopenia, which typically presents 5 to 28 days post-vaccination. At present, there is no clear indication of risk factors, although younger age has been suggested. Clinical features include thrombocytopenia, high D-Dimer levels, positive anti-platelet factor 4 (PF4) antibodies and thrombotic events (3) (4) . Detected anti-PF4 antibodies on HIT (Heparin-Inducted Thrombocytopenia) Enzyme-Linked Immunosorbent Assay) of the IgG subclass can recognize PF4-platelet neoantigens. They evoke a pronounced immune response, leading to thrombosis by platelet activation, and are heparin independent in contrast to HIT. Reported sites of thromboembolism are atypical. They include venous, arterial, intra-cranial, and abdominal sites (5) , which is more akin to patients with myeloproliferative disorders or Paroxysmal Nocturnal Hemoglobinuria. This hospital-based case series highlights imaging and hematology findings in VITT. Waiving ethical approval, this is a retrospective single center study of consecutive patients admitted to a large district general hospital, Queen Alexandra Hospital, Portsmouth, England, with VITT between March 2021 and May 2020. Enzyme-Linked Immunosorbent Assay (PF4 IgG, Immucor GTI Diagnostics) was used to detect anti-PF4 antibodies; an optical density greater than 0.4 was the cut-off for a positive HIT test. Arterial and venous thrombosis were detected by CT, MRI and abdominal ultrasound. Six patients [4 men; median age 38 years; interquartile range (IQR) 26-48 years] were admitted following vaccination with thrombocytopenia. Four patients had cerebral venous thrombosis, two had pulmonary emboli, one had portomesenteric thrombosis, one also had pelvic arterial thrombosis, and another additionally developed coronary artery thrombosis. Two patients were transferred to a tertiary center, and one required intensive care. Clinical information, laboratory results, and treatment are summarized in the Table. All patients were admitted between 9 and 31 days following the first vaccine dose with symptoms developing 3 to 26 days after inoculation. One patient was on the oral contraceptive pill, and another had a history of secondary polycythemia. All patients continue to improve on 1-month follow-up. Treatment included non-heparin anti-coagulation, steroids, intravenous immunoglobulin (IVIG), and therapeutic plasma exchange (TPE). Nadir platelet count ranged from 8-117 10 9 /liter, median value of 50 x 10 9 /liter (n=6; IQR 18-111). D-Dimer was elevated in all patients (median 5690 mcg/liter, IQR 5395-42750 mcg/liter, n=5). Activated partial thromboplastin time and the International normalized ratio (INR) were normal in all patients. Fibrinogen was very low (0.1g/liter) in patient 4 leading to cryoprecipitate support (median 2.1, IQR 0.8-2.85, n=5). High troponin was found in patients 1 and 3 who presented with coronary artery thrombosis and pulmonary embolism, I n p r e s s respectively. No patient had prior history of thrombosis, signs of hemolysis or evidence of red cell fragments on blood film. All patients had high optical densities on HIT Enzyme-Linked Immunosorbent Assay [Optical density (OD) median 2.5, IQR 0.8-2.85]. This case series describes the imaging and hematology findings in six patients with VITT following AstraZeneca vaccination. Similar to published data, we found that cerebral venous sinus thrombosis was the most common thrombosis site, followed by intra-abdominal thrombosis (5) (6) . Patients, as in our series, typically present with symptoms 5-28 days following vaccination with moderate to severe thrombocytopenia and thrombosis in unusual sites (7) (8) (9) (10) . Patients had a high D-dimer, low platelet count, atypical arterial or venous thrombosis and developed symptoms four weeks or less following the first vaccine dose; fibrinogen levels were mostly normal. There are limited United Kingdom guidelines, which include those published by Royal Colleges and the British Society of Haematology (3, (11) (12) . These will be revised and evolve with better clinical understanding. We identified asymptomatic intra-cardiac thrombus in one patient. An argument could be made for scanning additional asymptomatic regions in patients with VITT, especially for co-existing asymptomatic cerebral venous thrombosis, potentially altering oral anti-coagulation choice. Reporting radiologists should remain alert to the possibility of additional thrombotic load, both in atypical sites and as incidental findings. Current understanding is insufficient to know whether there is any genetic, preexisting comorbidity or immune underlay predicting VITT. Thrombotic thrombocytopenic purpura, another differential diagnosis, was not suspected because of patient history, absence of hemolysis, and no excess of red blood cell fragments on smear analysis. Vaccination stimulates the immune system and can promote non-tolerance of self-antigens, resulting in immune thrombocytopenic purpura and hemolytic anemia. A common denominator in all six patients was a high level of anti-PF4 antibodies, higher than typically seen in HIT (13) . Proposed mechanisms of VITT include neoantigen formation between PF4 and vaccine proteins, leading to immunogenicity and high anti-PF4 titers. These antibodies, as in HIT, drive thrombosis by platelet, leucocyte, and endothelial activation. VITT antibodies can mimic the effect of heparin by binding to a similar site on PF4, leading to thrombosis with platelet activation (14) . These patients were managed according to interim guidelines and discussion with the UK Expert Haematology Panel. All six patients received IVIG, five of them were given steroids, and Fondaparinux was the most common non-heparin anti-coagulant. TPE was used in three patients, either due to being refractory to initial management including IVIG or extensive clot load. Those with cerebral venous sinus thrombosis or arterial ischemia were offered warfarin rather than novel oral anticoagulants. No patient had a fatal outcome. Primary care was advised against a second vaccine dose. Additional multicenter studies are required to assess the incidence, pathophysiology, and location of thromboses to develop best practice guidelines. I n p r e s s Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial Expert Haematology Panel. Guidance from the Expert Haematology Panel (EHP) on Covid-19 Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT) version 2.0. 2021 Expert Haematology Panel. Guidance from the Expert Haematology Panel (EHP) on Covid-19 Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT) version 1.7. 2021. Available from Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination SARS-CoV-2 Vaccine-Induced Immune Thrombotic Thrombocytopenia Expert Haematology Panel. Guidance from the Expert Haematology Panel (EHP) on Covid-19 Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT) version 1.7. 2021. Available from Diagnosis and management of gastrointestinal manifestation of vaccine induced thrombosis & thrombocytopaenia College's Quality in Emergency Care (QEC) committee. Management of patients presenting to the Emergency Department / Acute Medicine with symptoms of Covid-19 Vaccine induced Thrombosis and Thrombocytopenia (VITT) Autoimmune heparin-induced thrombocytopenia Antibody epitopes in vaccineinduced immune thrombotic thrombocytopenia Naji Al-Khudairi, Chris Ball, Richard Beable, Michelle Dinsey and Rachael Harrison and contributed to the radiology reports for the images included in this case series. I n p r e s s