Imaging and Hematologic Findings in Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 (AstraZeneca) Vaccination Anmol Gangi, MBChB, BSc , FRCR* • Behnaz Mobashwera, MBBS, MRCP* • Mary Ganczakowski, MBBS, FRCP, FRCPath, PhD • Robert Ayto, MBBS, PhD, FRCPath, FRCP, BSc From the Departments of Radiology (A.G.) and Haematology (B.M., M.G., R.A.), Queen Alexandra Hospital, Southwick Hill Road, Portsmouth, PO6 3LY, England. Received June 18, 2021; revision requested July 12; revision received July 28; accepted August 2. Address correspondence to A.G. (e-mail: anmolgangi@nhs.net). * A.G. and B.M. contributed equally to this work. Conflicts of interest are listed at the end of this article. Radiology 2022; 302:319–325 • https://doi.org/10.1148/radiol.2021211546 • Content code: This case series reports six patients (four men and two women; median age, 38 years; interquartile range, 26–48 years) who pre- sented with vaccine-induced thrombocytopenia and thrombosis beginning 3–26 days after receiving the first dose of the ChAdOx1 nCoV-19 (AstraZeneca) vaccine for COVID-19. The patients were admitted to a general hospital between 9 and 31 days after the first dose. All patients had strongly detected antiplatelet factor 4 antibodies and severe thrombosis. Laboratory features in- cluded thrombocytopenia and elevated d-dimer levels. Thrombotic events were predominantly venous; two patients had arterial or mixed arterial and venous thrombosis. All patients recovered after receiving intravenous immunoglobulin and nonheparin-based anticoagulation. © RSNA, 2021 An earlier incorrect version appeared online. This article was corrected on August 18, 2021. This case series demonstrates rare thromboembolic events and thrombocytopenia after receiving the first dose of the ChAdOx1 nCoV-19 (AstraZeneca) vaccine. To our knowledge, no thromboembolic events have been found in randomized safety studies of the AstraZeneca vaccine (1,2). Vaccine-induced immune thrombotic thrombocytope- nia (VITT) is a rare syndrome of immune-driven throm- bosis and thrombocytopenia, which typically presents 5–28 days after 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 antiplatelet factor 4 (PF4) an- tibodies, and thrombotic events (3,4). Detected anti-PF4 antibodies on heparin-induced thrombocytopenia (HIT) enzyme-linked immunosor- bent assay of the immunoglobulin G subclass can recog- nize PF4-platelet neoantigens. They evoke a pronounced immune response, leading to thrombosis by platelet acti- vation, and are heparin independent in contrast to HIT. Reported sites of thromboembolism are atypical. They include venous, arterial, intracranial, 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 hemato- logic findings in VITT. GTI Diagnostics) was used to help detect anti-PF4 antibod- ies; an optical density greater than 0.4 was the cutoff for a positive HIT test result. Arterial and venous thromboses were depicted with CT, MRI, and abdominal US. Results Patient Characteristics Six patients (four men; median age, 38 years; interquartile range [IQR], 26–48 years]) were admitted following vacci- nation with thrombocytopenia. Four patients had cerebral venous thrombosis, two had pulmonary emboli, one had portomesenteric thrombosis, one also had pelvic arterial thrombosis, and another developed coronary artery throm- bosis. Two patients were transferred to a tertiary center, and one required intensive care. Clinical information, labora- tory results, and treatment are summarized in the Table. All patients were admitted between 9 and 31 days fol- lowing the first vaccine dose with symptoms developing 3–26 days after inoculation. One patient was taking the oral contraceptive pill, and another had a history of sec- ondary polycythemia. All patients continued to improve on 1-month follow-up. Treatment included nonheparin- based anticoagulation, steroids, intravenous immunoglob- ulin, and therapeutic plasma exchange. Materials and Methods 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 2021. Enzyme-linked immunosorbent assay (PF4 IgG, Immucor Laboratory Testing Nadir platelet count ranged from 8–117 3 109 per liter, with a median value of 50 3 109 per liter (n = 6 [IQR, 18–111 3 109]). The d-dimer level was elevated in all pa- tients (median, 5690 mcg/liter; n = 5 [IQR, 5395–42750 mcg/liter]). Activated partial thromboplastin time and the This copy is for personal use only. To order printed copies, contact reprints@rsna.org ORIGINAL RESEARCH •CASE SERIES Abbreviations HIT = heparin-induced thrombocytopenia, IQR = interquartile range, PF4 = platelet factor 4, VITT = vaccine-induced immune thrombotic thrombocytopenia Summary Vaccine-induced thrombotic thrombocytopenia rarely complicates ChAdOx1 nCoV-19 (AstraZeneca) vaccination and presents with extensive thrombosis, blood clots at atypical sites, asymptomatic thrombus, thrombocytopenia, and raised d-dimer levels. international normalized ratio were normal in all patients. Fi- brinogen level was very low (0.1 g/L) in patient 4 leading to cryoprecipitate support (median value, 2.1; n = 5 [IQR, 0.8– 2.85]). High troponin level was found in patients 1 and 3 who presented with coronary artery thrombosis and pulmonary em- bolism, 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 median value, 2.5 [IQR, 0.8–2.85]). CT, MRI, and US Findings Patient 1 was admitted with a posterior-inferior ST-elevation myocardial infarction. Diagnostic angiogram demonstrated thrombosis within the proximal circumflex and the posterior descending arteries, and the patient underwent percutaneous coronary intervention. No significant atheroma was identified. The CT pulmonary angiogram obtained on day 4 due to in- creased oxygen requirement showed multiple pulmonary emboli and a large left atrial appendage thrombus (Fig 1A) in addition to bilateral ground-glass opacification within the lungs (Fig 1B). He developed acute kidney injury on day 6 and imaging did not confirm intra-abdominal thrombosis. Laboratory features included thrombocytopenia, high d-dimer level, and strongly positive anti-PF4 antibodies (Table). Patient 2 was admitted with a headache and blurred vision. Noncontrast head CT demonstrated hyperdensity involving the superior sagittal sinus and bilateral transverse sinuses. CT ve- nography confirmed thrombotic disease within this distribution (Fig 2A, 2B). His condition deteriorated further as he developed seizures and his Glasgow Coma Scale score decreased. He was transferred to a tertiary intensive therapy unit for consideration of decompressive craniotomy. A week following initial admis- sion, the patient developed new left-sided weakness, variable sensory signs, and brisk reflexes. Brain MRI images demon- strated high T2 signal within the frontal lobes bilaterally thought to represent venous infarcts (Fig 2C, 2D). Patient 3 presented with shortness of breath, hemoptysis, and pleuritic chest pain; an admission CT pulmonary angiogram Summary of Clinical Information, Laboratory Results, and Management of Each Patient with Vaccine-induced Immune Thrombotic Thrombocytopenia Parameter Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Age Sex Vaccination dose Vaccination to 47 Male 1st 9 admission time (d) Time from 7 vaccine to symptoms (d) Presenting complaint Chest pain Past medical history Hypertension, diverticulitis Previous exposure No to heparin Platelet nadir (109/L) d-dimer level on admission (mcg/L) 8 5370 28 Male 1st 12 3–4 21 Female 1st 31 48 Male 1st 15 26 3 54 Male 1st 19 11 Yes 117 5420 26 Female 1st 11 11 No 64 NA Severe headache, blurred vision, vomiting Cardiomyopathy, secondary polycythemia Pleuritic chest pain, hemoptysis, shortness of breath Left hip arthroscopy Headache, retro- orbital pain, abdominal pain Depression Headache Headache Guillain Barre (in April 2019) COVID-19 infection (in 2020) Asthma, depression PCOS, current smoker No 37 No 111 No 18 5690 19500 66000 Table (Continues) 320 radiology.rsna.org  n  Radiology: Volume 302: Number 2—February 2022 Findings in Thrombosis and Thrombocytopenia after AstraZeneca Vaccination (g/L) SARS-CoV-2 antibody test HIT ELISA to detect PF4 antibody Cerebral venous thrombosis Porto-mesenteric thrombosis Pulmonary embolus Other No Yes (Continued): Summary of Clinical Information, Laboratory Results, and Management of Each Patient with Vaccine-induced Immune Thrombotic Thrombocytopenia Parameter Patient 1 Patient 2 Patient 3 Patient 4 Fibrinogen nadir 1.5 2.1 3.6 0.1 Patient 5 2.1 Patient 6 NA Negative Negative Negative Negative Negative Negative Positive, OD of 3.5 Positive, Positive, Positive, Positive, OD of 2.2 OD of 3.0 OD of 2.04 OD of 2.5 Unknown Unknown Yes Unknown NA No No Yes NA Yes Yes Unknown Yes No No Right internal iliac artery thrombus NA Coronary artery and left atrial appendage thromboses Fondaparinux, argatroban (during TPE), DOAC IVIG (two doses), steroids, TPE, clopidogrel Full recovery Anticoagulation Fondaparinux Fondaparinux, DOAC Fondaparinux, argatroban (during TPE), warfarin IVIG, steroids, TPE Fondaparinux, warfarin Treatment dose LMWH, fondaparinux, warfarin steroids, TPE steroids Other treatments IVIG (1 dose) IVIG, steroids IVIG (two doses), IVIG (five doses), Outcome Transferred to Full recovery Full recovery Full recovery tertiary center (full recovery) Note.—DOAC = direct oral anticoagulant, ELISA = enzyme-linked immunosorbent assay, HIT = heparin-induced thrombocytopenia, IVIG = intravenous immunoglobulin, LMWH = low-molecular-weight heparin, NA = not available, OD = optical density, PCOS = polycystic ovary syndrome, PF4 = platelet factor 4, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, TPE = therapeutic plasma exchange. Positive (OD carried out at tertiary hospital) Yes Yes No NA Transferred to tertiary center (full recovery) Figure 1: Axial CT pulmonary angiogram images in a 47-year-old man demonstrate (A) a left atrial appendage thrombus (blue arrow), right lobar pulmonary embolus (white arrow), and (B) bilateral ground-glass opacification. Radiology: Volume 302: Number 2—February 2022  n  radiology.rsna.org 321 Gangi and Mobashwera et al showed extensive pulmonary emboli (Fig 3A), features of right heart strain (Fig 3B), and pulmo- nary infarcts (Fig 3C). Abdomi- nal US and CT venography did not demonstrate portal vein, hepatic vein, or cerebral venous thrombosis. An echocardiogram showed right ventricular impair- ment and tricuspid regurgitation. Patient 4 presented with headache, retro-orbital pain, pleuritic chest pain, and abdom- inal pain. He had a low platelet count and high d-dimer level. CT venography showed throm- bosis within the right transverse sinus (Fig 4A) and right jugular vein. CT of the abdomen and pelvis demonstrated extensive occlusive thrombi within the main portal vein, right and left portal vein branches (Fig 4B), superior mesenteric vein, and splenic vein. In addition, CT showed acute thrombus within the right renal infarct (Fig 4C) and within the right internal iliac artery (Fig 4D). (A) Axial head CT image in a 28-year-old man shows hyperdense bilateral transverse cerebral sinuses Figure 2: (arrows) and (B) axial CT venogram image demonstrates filling defects within the transverse cerebral sinuses bilaterally (arrows). (C, D) T2 coronal fluid-attenuated inversion recovery brain MRI images demonstrate small foci of high T2 sig- nal within the frontal lobes bilaterally thought to represent venous infarcts (arrows). Patient 5 presented with a headache, and CT demon- strated asymmetric hyperden- sity within the left transverse, sigmoid, and straight sinuses. Extensive filling defects within the left transverse, sigmoid, and straight sinuses (Fig 5A, 5B) in addition to the left jugular vein was confirmed with subsequent CT venography. No further thrombosis was identified at CT of the chest, abdomen, and pel- vis. One day following admission, the patient developed new seizures. A repeat head CT showed a 2-cm left temporal cortical venous hemorrhage (Fig 5C). Patient 6 was admitted with headaches, photophobia, and nau- sea. Head CT demonstrated hyperdensity of the inferior sagittal and transverse sinuses (Fig 6A). The patient was transferred to the tertiary neurologic center. Thrombus within the straight sinus, bi- lateral transverse sinuses (Fig 6B), and right internal jugular vein was confirmed with subsequent CT venography. Abdominal US was performed on day 6 due to raised alanine transaminase level, which confirmed intrahepatic main and right portal vein throm- bosis (Fig 6C) with suspected cavernous transformation. Discussion This case series describes the imaging and hematologic findings in six patients with vaccine-induced immune thrombotic throm- bocytopenia following AstraZeneca vaccination. Similar to pub- lished 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 se- vere thrombocytopenia and thrombosis in unusual sites (4,6–8). Patients had a high d-dimer level, low platelet count, and atypi- cal arterial or venous thrombosis; they developed symptoms 4 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 (3,9,10). These will be revised and evolve with bet- ter clinical understanding. We identified asymptomatic intracar- diac thrombus in one patient. An argument could be made for imaging additional asymptomatic regions in patients with VITT, especially for coexisting asymptomatic cerebral venous throm- bosis, potentially altering oral anticoagulation choice. Reporting radiologists should remain alert to the possibility of additional thrombotic load, both in atypical sites and as i ncidental findings. Current understanding is insufficient to know whether there is any genetic preexisting comorbidity or immune under- lay predicting VITT. 322 radiology.rsna.org  n  Radiology: Volume 302: Number 2—February 2022 Findings in Thrombosis and Thrombocytopenia after AstraZeneca Vaccination (A) Axial CT pulmonary angiogram image in a Figure 3: 21-year-old woman shows bilateral central pulmonary emboli (arrows) with (B) enlargement of the right heart and flattening of the intraventricular septum in keeping with right heart strain (ar- rows). (C) Lung window axial CT pulmonary angiogram demon- strates bilateral peripheral areas of opacification in keeping with pulmonary infarcts (arrows). Figure 4: (A) Axial CT venogram image in a 48-year-old man shows a right transverse sinus filling defect in keeping with thrombosis (arrow). (B) Axial portal venous CT of the abdomen and pelvis demonstrates portal vein and splenic vein thromboses (arrows) in ad- dition to (C) right upper pole renal infarct (ar- row) and (d) acute right internal iliac artery thrombus (arrow). Radiology: Volume 302: Number 2—February 2022  n  radiology.rsna.org 323 Gangi and Mobashwera et al (A) Sagittal head CT in a 54-year-old man shows a hyperdense Figure 5: straight sinus (arrow) confirmed with (B) CT venogram (arrow). (C) Axial head CT shows a 2-cm left temporal lobe cortical venous hemorrhage (arrow). Figure 6: defect (arrow). (C) Doppler US image shows no flow within the intrahepatic main portal vein in keeping with thrombosis (arrow). (A) Axial noncontrast head CT in a 27-year-old woman shows a hyperdense right transverse sinus (arrow) confirmed with (B) CT venogram with a filling 324 radiology.rsna.org  n  Radiology: Volume 302: Number 2—February 2022 Findings in Thrombosis and Thrombocytopenia after AstraZeneca Vaccination 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 nontolerance 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 (11). Proposed mechanisms of VITT include neoantigen formation be- tween PF4 and vaccine proteins, leading to immunogenicity and high anti-PF4 titers. These antibodies, as in HIT, drive thrombosis by platelet, leukocyte, and endothelial activation. The VITT anti- bodies can mimic the effect of heparin by binding to a similar site on PF4, leading to thrombosis with platelet activation (12). These patients were managed according to interim guidelines and discussion with the UK Expert Haematology Panel. All six patients received intravenous immunoglobulin, five of them were given steroids, and fondaparinux was the most common nonheparin anticoagulant. Therapeutic plasma exchange was used in three patients, either due to being refractory to initial management including intravenous immunoglobulin or exten- sive clot load. Those with cerebral venous sinus thrombosis or arterial ischemia were offered warfarin rather than novel oral an- ticoagulants. No patient had a fatal outcome. Primary care was advised against a second vaccine dose. Additional multicenter studies are required to assess the inci- dence, pathophysiology, and location of thromboses to develop best practice guidelines. Author contributions: Guarantors of integrity of entire study, A.G., R.A.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all au- thors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, A.G., B.M., M.G.; clinical studies, B.M., M.G., R.A.; statistical analysis, A.G., B.M.; and manuscript editing, all authors Acknowledgments: Dr Naji Al-Khudairi, Dr Chris Ball, Dr Richard Beable, Dr Michelle Dinsey, Dr Janine Domjan, Dr Rachael Harrison, and Dr Jenny Latham contributed to the radiology reports for the images included in this case series. Disclosures of conflicts of interest: A.G. No relevant relationships. B.M. No rel- evant relationships. M.G. No relevant relationships. R.A. Grant from Celgene; pay- ment or honoraria from Abbvie for podcast; payment or honoraria from Abbvie, Cel- gene, Gilead, Janssen, and Takeda for educational event attendance. References 1. Voysey M, Clemens SAC, Madhi SA, et  al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an in- terim analysis of four randomised controlled trials in Brazil, South Af- rica, and the UK. Lancet 2021;397(10269):99–111. 2. Ramasamy MN, Minassian AM, Ewer KJ, et  al. Safety and immuno- genicity 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. Lancet 2021;396(10267):1979–1993. 3. Expert Haematology Panel. Guidance from the Expert Haematology Panel (EHP) on Covid-19 Vaccine-induced Immune Thrombocytope- nia and Thrombosis (VITT) version 2.0. https://b-s-h.org.uk/about- us/news/guidance-produced-by-the-expert-haematology-panel-ehp- focussed-on-vaccine-induced-thrombosis-and-thrombocytopenia-vitt/. Published 2021. Accessed June 2021. 4. Expert Haematology Panel. Guidance from the Expert Haematology Panel (EHP) on Covid-19 Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT) version 1.7. https://b-s-h.org.uk/media/19590/ guidance-version-17-on-mngmt-of-vitt-20210420.pdf. Published 2021. Accessed June 2021. 5. Scully M, Singh D, Lown R, et  al. Pathologic Antibodies to Plate- let Factor 4 after ChAdOx1 nCoV-19 Vaccination. N Engl J Med 2021;384(23):2202–2211. 6. Cines DB, Bussel JB. SARS-CoV-2 Vaccine-Induced Immune Throm- botic Thrombocytopenia. N Engl J Med 2021;384(23):2254–2256. 7. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and Throm- bocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med 2021;384(22):2124–2130. 8. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, Eichinger S. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccina- tion. N Engl J Med 2021;384(22):2092–2101. 9. Intercollegiate Multidisciplinary Guidance for Clinicians. Diagnosis and management of gastrointestinal manifestation of vaccine induced thrombosis & thrombocytopaenia. https://www.acpgbi.org.uk/content/ uploads/2021/05/VITT-guidance-GI-manifestations-6-May-2021.pdf. Published 2021. Accessed June 2021. 10. 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 Throm- bocytopenia (VITT). https://www.rcem.ac.uk/RCEM/Quality-Policy/ Clinical_Standards_Guidance/RCEM_Guidance_Folder/College_ Guidelines. Published 2021. Accessed June 2021. 11. Greinacher A, Selleng K, Warkentin TE. Autoimmune heparin-induced thrombocytopenia. J Thromb Haemost 2017;15(11):2099–2114. 12. Huynh A, Kelton JG, Arnold DM, Daka M, Nazy I. Antibody epitopes in vaccine-induced immune thrombotic thrombocytopaenia. Nature 2021. 10.1038/s41586-021-03744-4. Published online July 7, 2021. Radiology: Volume 302: Number 2—February 2022  n  radiology.rsna.org 325 Gangi and Mobashwera et al Erratum Originally published in: Erratum in: https://doi.org/10.1148/radiol.2021211546 https://doi.org/10.1148/radiol.2021219018 Anmol Gangi and Behnaz Mobashwera share equal contribution. Imaging and Hematologic Findings in Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 (AstraZen- eca) Vaccination Anmol Gangi, Behnaz Mobashwera, Mary Gancza- kowski, Robert Ayto This copy is for personal use only. To order printed copies, contact reprints@rsna.org COMMUNICATIONS • ERRATUM