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What evidence is available regarding thrombosis and thrombocytopenia associated with adenoviral vector-based COVID-19 vaccines?

Two adenoviral vector-based COVID-19 vaccines (the Johnson & Johnson/Janssen [J&J/Janssen] vaccine and the AstraZeneca vaccine) have been made available in North American and European countries. The J&J/Janssen COVID-19 vaccine received an Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA) in February 2021.1 The vaccine utilizes a recombinant, replication-incompetent human adenovirus type 26 vector; it is authorized for use in patients aged 18 years or older and given as a single 0.5 mL intramuscular injection.2 Clinical trials have demonstrated that it is 66.9% efficacious against moderate to severe/critical symptomatic disease at 2 weeks post-vaccination.3 It is 76.7% efficacious against symptomatic severe/critical disease 2 weeks post-vaccination, and 85.4% efficacious against symptomatic severe/critical disease 28 days post-vaccination. Less evidence is available to establish its efficacy in preventing asymptomatic infection; however, preliminary analyses suggest that it is 59.7% efficacious in preventing asymptomatic infection at 28 days post-vaccination.

The adenoviral vector-based vaccine developed by AstraZeneca uses a modified chimpanzee adenovirus vector (ChAd).3 Although the AstraZeneca vaccine is not currently authorized for use in the United States, it is authorized for use in other countries (including the United Kingdom, Canada, and the European Union) under the brand names Vaxzevria and Covishield.3-6 It is authorized for use in patients aged 18 years or older and requires two 0.5 mL doses separated by 4 to 12 weeks.7 Clinical trials have estimated that the AstraZeneca vaccine has 63 to 76% efficacy against symptomatic COVID-19. No cases of severe or critical disease were reported among vaccinated patients in clinical trials.

In late February 2021, reports of atypical thrombosis and thrombocytopenia began to emerge among recipients of the AstraZeneca COVID-19 vaccine.5 In April, similar adverse events were reported in patients who received the J&J/Janssen vaccine. These reports led to temporary pauses in the use of these vaccinations in many countries worldwide. In the United States, 6 reported cases of cerebral venous sinus thrombosis (CVST) in patients who received the J&J/Janssen vaccine led to a pause in its use that lasted from April 13 through April 23.8,9 However, the FDA and the Centers for Disease Control and Prevention (CDC) concluded that the benefits of the vaccine outweigh the risks and allowed for vaccination with the J&J/Janssen vaccine to resume.9 This article will address the literature regarding risk of vaccine-induced thrombotic thrombocytopenia (VITT) with the AstraZeneca and J&J/Janssen COVID-19 vaccines, as well as recommendations pertaining to VITT diagnosis and management.

What is VITT?
Vaccine-induced thrombotic thrombocytopenia, also referred to as thrombosis with thrombocytopenia syndrome (TTS), is characterized by venous or arterial thrombosis in unusual locations, including the cerebral venous sinuses and the splanchnic veins; this thrombosis is accompanied by thrombocytopenia and anti-platelet factor 4 (PF4) antibodies on heparin-induced thrombocytopenia (HIT) enzyme-linked immunosorbent assay (ELISA).10 Symptoms of VITT most commonly present between 6 and 14 days post-vaccination, but they may present any time between post-vaccination day 4 and 42. Presenting symptoms may include severe headache, visual changes, abdominal pain, back pain, nausea/vomiting, shortness of breath, leg pain, leg swelling, and easily bruising or bleeding.

The pathophysiologic mechanism of VITT is not yet fully understood, but studies indicate that VITT is not likely to be a byproduct of COVID-19 infection.11 Thrombosis and thrombocytopenia associated with adenoviral vector-based COVID-19 vaccines have been linked to high levels of anti-PF4 antibodies, suggesting that VITT is a clinical variant of autoimmune HIT (aHIT). In aHIT, anti-PF4 antibodies cross-link FcgRIIA on platelets, monocytes, and neutrophils, setting off procoagulant cellular responses that lead to a profound hypercoagulable state. In VITT, it has been proposed that adenoviral DNA and/or other vaccine ingredients may bind to PF4, inducing autoantibody production and subsequent platelet activation.12

Data on VITT Events Associated with the AstraZeneca COVID-19 Vaccine
EudraVigilance is the European Medicines Agency (EMA) database for electronic adverse event reporting.13 As of April 4, 2021, 169 cases of CVST and 53 cases of splanchnic vein thrombosis (SVT) were reported to EudraVigilance from the 34 million people that received the AstraZeneca vaccine in Europe and the United Kingdom.14 Most of these cases occurred within the first 2 weeks of vaccination in women younger than 60 years of age. The EMA currently estimates that VITT may occur in up to 1 in 10,000 people receiving the AstraZeneca vaccine.4

Estimating Risk and Reported Cases of VITT-Related Events
Several large studies from various countries have reported on the estimated risk of VITT-related adverse events with the AstraZeneca COVID-19 vaccine (Table). Gras-Champel and colleagues reported data from the French Network of Regional Pharmacovigilance Centres.15 As of April 15,2021, a total of 11,206 adverse drug reactions had been reported after a total of 3,263,188 AstraZeneca vaccine doses. Of these, 360 adverse drug reaction reports mentioned venous and/or arterial thrombosis; 27 cases were considered atypical thrombosis. The median time to onset of atypical thrombosis was 11 days (range, 2 to 35 days), and there were 8 fatalities among patients with atypical thrombosis.

Pottegard and colleagues assessed the rates of cardiovascular and hemostatic events in the first 28 days following receipt of the AstraZeneca vaccine.16 Data from the national health registries of Denmark and Norway were used to assess event rates among vaccinated patients and compare them to event rates observed in the general population. The vaccinated cohort consisted of individuals aged 18 to 65 years in Denmark and Norway who received a first dose of the AstraZeneca vaccine between February 9, 2021 and March 11, 2021. The final vaccinated cohort included 148,792 individuals from Denmark (median age, 45 years; 80.1% women) and 132,472 individuals from Norway (median age, 44 years; 77.6% women). The number of arterial events reported in the vaccinated cohort was not significantly different from the number of arterial events expected in the general population. However, rates of venous thromboembolism, including CVST and pulmonary embolism, were significantly increased among vaccinated patients. Thrombocytopenia/coagulation disorders and bleeding events were also slightly increased in the vaccinated cohort, but this increase was not statistically significant. Fifteen deaths were observed in the vaccinated cohort, which was less than the 44 expected deaths based on general population mortality rates.

Sørvoll and colleagues investigated the prevalence of thrombocytopenia and anti-PF4 antibodies in Norwegian patients from 2 hospitals who had received a first dose of the AstraZeneca vaccine within 10 to 35 days prior to study enrollment.17 A total of 492 vaccinated participants were recruited, with blood draws occurring a median of 20 days post-vaccination; patients in this cohort were 76% female with a median age of 44 years (range, 21 to 69 years). A control cohort of 110 nonvaccinated blood donors was used for comparison – these donors were 51% female and had a median age of 43 years (range, 21 to 66 years). The vaccinated cohort had 8 subjects with thrombocytopenia, but all platelet levels were greater than 100,000/mcL and no instances of severe thrombocytopenia (platelet count <50,000/mcL) were reported. Six subjects were positive (optical density ≥0.4 on ELISA) for anti-PF4 antibodies, but these patients all had normal platelet levels. No subjects in the control group tested positive for anti-PF4 antibodies. Overall, authors concluded that the prevalence of thrombocytopenia is low after receipt of the AstraZeneca COVID-19 vaccine, as is the prevalence of anti-PF4 antibodies.

Risk of VITT-Related Events Relative to Other COVID-19 Vaccines
An analysis of EudraVigilance and European Centre for Disease Prevention and Control data compared the number of thrombocytopenia, bleeding, and thrombosis events reported in association with the AstraZeneca and Pfizer-BioNTech COVID-19 vaccines.18 In this study, thrombocytopenia and thrombosis events were more commonly reported in patients receiving the AstraZeneca vaccine (Table). However, it is possible that this finding was influenced by reporting bias, given the significant warnings and media coverage pertaining to thrombotic adverse events associated with the AstraZeneca vaccine. A matched case-control study using prospectively collected data from a national public health surveillance program in Scotland also examined the risk of certain adverse events after the first dose of the AstraZeneca or Pfizer-BioNTech COVID-19 vaccine.19 In this study, the AstraZeneca vaccine was associated with an increased risk of idiopathic thrombocytopenic purpura compared to no vaccination; this finding was consistent in both the primary nested case-control analysis and the confirmatory post hoc self-controlled case series analysis. Increased risks of arterial thrombotic events and hemorrhagic events were also observed with the AstraZeneca vaccine versus no vaccine in the primary analysis, but these findings were not confirmed in a post hoc self-controlled case series analysis, suggesting that residual confounding may have influenced the observed results in the case-control analysis. The Pfizer-BioNTech vaccine was not associated with an increased risk of any of the adverse events examined compared with no vaccine.

Case Series – Presentation and Treatment of VITT
Several case reports and case series of thrombosis and/or thrombocytopenia after receipt of the AstraZeneca vaccine have been published in the literature. Earlier case series focused on describing the features of these novel vaccine-associated adverse events in more detail. The largest case series, reported by Scully and colleagues, included 23 patients who had received the AstraZeneca vaccine 6 to 24 days before presentation.20 Patients were 61% female, with a median age of 46 years (range, 21 to 77 years). One patient had a history of deep vein thrombosis, and 1 patient was taking combined oral contraceptives; the other patients in the series had no additional risk factors for thrombosis. Of the 23 patients, 13 presented with clinical features consistent with CVST, 4 had pulmonary embolism, 1 had deep vein thrombosis and bilateral adrenal hemorrhage, 2 had ischemic stroke, and 2 had portal vein thrombosis. One patient presented with significant bruising but no evidence of thrombosis. Enzyme-linked immunosorbent assay testing for antibodies to PF4 revealed that 22 of the 23 patients had developed these antibodies. D-dimer levels were also significantly elevated (median, 31,301 fibrinogen-equivalent units; range, 5000 to 80,000). Seven patients in the series died, resulting in a mortality rate of 30%.

A separate case series of 11 patients presenting with thrombosis or thrombocytopenia 5 to 16 days after receiving the AstraZeneca vaccine similarly found that a majority of patients (9/11) tested positive for antibodies against PF4 using ELISA; the other 2 patients in the series were not tested for anti-PF4 antibodies.21 The median age in this series was 36 years (range, 22 to 49 years) and 9 of the 11 patients were female. Of the patients presenting with at least 1 thrombotic event (10/11), 9 presented with cerebral vein thrombosis, 3 had splanchnic vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses. The remaining patient presented with fatal intracranial hemorrhage. Six of the 11 (54%) patients in the series died due to thrombotic complications.

Ciconne and colleagues reported 10 additional cases of CVST occurring within 11 days of receiving the AstraZeneca vaccine.22 Patients were between the ages of 32 and 64 years, and 8 of 10 patients were female. Each of the patients presented with cerebral vein thrombotic involvement, indicated by symptoms that included headache, nausea, vomiting, drowsiness, and fever. Four of the 10 patients died, while 5 out of the 6 surviving patients had ongoing neurologic complications that included coma, aphasia, and hemiparesis.

Several smaller case series have described treatments and outcomes for patients with thrombosis or thrombocytopenia following vaccination with the AstraZeneca vaccine. Series including 5 or more patients are described in detail.

Schultz and colleagues reported on a series of 5 patients who experienced thrombosis and were admitted to the hospital within 10 days of receiving the AstraZeneca vaccine.23 All patients were under the age of 65 years (range, 32 to 54 years), and 4 out of 5 were female. Patient 1 presented 1 week after vaccination with severe thrombocytopenia and thrombosis in the left transverse and sigmoid sinuses. She was treated with dalteparin 2500 IU daily, but developed a massive cerebellar hemorrhage and died on day 2 after decompressive craniectomy. Patient 2 presented 1 week after vaccination with severe thrombocytopenia, venous thrombosis occluding the transverse and sigmoid sinuses, and hemorrhagic infarction in the left hemisphere. Hemicraniectomy was performed, and the patient was treated with dalteparin 2500 IU daily; on day 8, intravenous immune globulin (IVIG) 1 g/kg/day and methylprednisolone 1 mg/kg/day were additionally given. Although the patient’s platelet counts improved, the patient ultimately died due to increased intracranial pressure and severe cerebral hemorrhagic infarction. Patient 3 presented 1 week after vaccination with severe thrombocytopenia and thrombosis of several branches of the portal vein, including occlusion of the left intrahepatic portal vein and left hepatic vein. The patient was treated with 1 g/kg IVIG for 2 days, 1 mg/kg/day prednisolone, and dalteparin (5000 IU for 3 doses until platelet recovery, then 200 IU/kg/day). Platelet count returned to normal, and the patient was discharged on day 12 with warfarin and tapering doses of prednisolone.  Patient 4 presented 10 days after vaccination with thrombocytopenia, massive thrombosis in the deep and superficial cerebral veins, and right cerebellar hemorrhagic infarction. She was treated with IVIG 1 g/kg/day for 2 days, dalteparin 200 IU/kg/day, and prednisolone 1 mg/kg/day.  Platelet count normalized within 2 days and the patient was discharged after 10 days on warfarin and tapering doses of prednisolone. Patient 5 presented 1 week after vaccination with severe thrombocytopenia, right frontal hemorrhage, and massive cerebral vein thrombosis. She was treated with methylprednisolone 1 mg/kg/day and IVIG 1 g/kg/day for 2 days. Treatment was withdrawn after 2 days due to uncontrollable increased intracranial pressure, and the patient died. Overall, 3 of the 5 patients died, resulting in a mortality rate of 60%. High levels of antibodies to PF4 were detected in all 5 patients.

Another case series reported 5 patients who presented with prothrombotic immune thrombocytopenia 5 to 11 days after receiving the AstraZeneca vaccine.24 The patients were women between the ages of 41 and 67 years. All 5 patients exhibited elevated D-dimer levels and tested positive for antibodies to PF4 on ELISA analysis; 3 patients initially presented with thrombosis, while 1 developed thrombosis during hospitalization and 1 presented with symptoms of headache and visual disturbance without imaging abnormalities. All patients received anticoagulation with unfractionated heparin (1 patient) or argatroban (4 patients). One patient recovered with argatroban therapy alone and required no further treatment, while a 4-day course of pulse-dose dexamethasone was added on for 3 of the 4 remaining patients. Intravenous immune globulin 1 g/kg for 2 days was given to 3 of the 4 remaining patients, resulting in a favorable outcome with no further events for 1 patient. One patient who received IVIG developed extensive splanchnic vein thrombosis after platelet recovery, and another had popliteal artery occlusion. Eculizumab 900 mg weekly was given to 2 patients as salvage therapy after progression on IVIG or, in 1 case, due to the presence of renal failure and thrombotic microangiopathy. All patients were recovered or recovering at the time of publication.

Several smaller case series and case reports have also been published on the treatment of VITT; successful treatment regimens in these reports commonly included non-heparin anticoagulation (eg, argatroban, fondaparinux 7.5 to 10 mg/day, apixaban 5 to 10 mg twice daily, dabigatran 150 mg twice daily) and high-dose IVIG (eg, 1 g/kg/day for 2 days).25-33 Short courses of prednisolone and dexamethasone have also been used alongside IVIG and systemic anticoagulation in some cases.25,29,30,32

Table. Estimated Risk and Reported Cases of VITT with AstraZeneca and J&J/Janssen COVID-19 vaccines.4,14-19,34,35
Citation/Data SourceTotal vaccinations administeredNumber of VITT events reportedRisk/Rate of VITT events
(As of April 4, 2021)4,14
34,000,000 people who received the AstraZeneca vaccine
169 cases of CVST
53 cases of SVT
Up to 1 in 10,000 people
Gras-Champel et al (French Network of Regional Pharmacovigilance Centres, as of April 15, 2021)153,263,188 AstraZeneca vaccine doses27 cases of atypical thrombosis0.8 events per 100,000 doses
Pottegard et al (Cohort study using data from national healthcare registers in Denmark and Norway)16281,264 people who received a first AstraZeneca vaccine dose between February 9, 2021 and March 11, 2021

AE rates within 28 days after vaccination were compared to AE rates among the general population aged 18 to 65 years between 2016 and 2018 (Denmark) or 2018 and 2019 (Norway)
AstraZeneca (number of events within 28 days post-vaccination):
83 arterial events
59 venous thromboembolic events (including 7 CVST events)
24 thrombocytopenia/
coagulation disorder events
74 bleeding events
Expected number of events based on general population rates:
86 arterial events
30 venous thromboembolic events (including 0.3 CVST events)
16 thrombocytopenia/ coagulation disorder events
60 bleeding events
Arterial events: no increased risk versus general population (standardized morbidity ratio, 0.97; 95% CI, 0.77 to 1.20)
Venous thromboembolic events: 11 excess events per 100,000 vaccinations (standardized morbidity ratio, 1.97; 95% CI, 1.50 to 2.54)
CVST events: 2.5 excess events per 100,000 vaccinations (standardized morbidity ratio, 20.25; 95% CI, 8.14 to 41.73)
Thrombocytopenia/coagulation disorder: 3 excess events per 100,000 vaccinations (standardized morbidity ratio, 1.52; 95% CI, 0.97 to 2.25)
Bleeding events: 5.1 excess events per 100,000 vaccinations (standardized morbidity ratio, 1.23; 95% CI, 0.97 to 1.55)
Sørvoll et al (Prospective study of healthcare workers at 2 hospitals in Norway)17492 patients who received a first AstraZeneca vaccine dose within 10 to 35 days prior to recruitment
A control group of 110 blood donors was also examined
8 patients with thrombocytopenia (none with platelets <50,000/mcL)
6 patients positive for anti-PF4 antibodies; none of these patients had concomitant thrombocytopenia
Control group:
No samples positive for anti-PF4 antibodies
Cari et al (EudraVigilance and European Centre for Disease Prevention and Control, as of April 16, 2021)18AstraZeneca: 20,869,192 doses
Pfizer/BioNTech: 71,210,981 doses
3159 severe AEs and 273 deaths related to thrombocytopenia, thrombosis, and bleeding
627 severe AEs and 100 deaths related to CVST, SVT, and/or thrombocytopenia
2528 severe AEs and 313 deaths related to thrombocytopenia, thrombosis, and bleeding
285 severe AEs and 27 deaths related to CVST, SVT, and/or thrombocytopenia
Thrombocytopenia, thrombosis, and bleeding
AstraZeneca: 151.4 severe AEs and 13.1 deaths per million doses
Pfizer/BioNTech: 35.5 severe AEs and 4.4 deaths per million doses
Risk of severe AEs and death with the AstraZeneca vaccine increased by 4.3-fold and 3.0-fold respectively compared to the Pfizer-BioNTech vaccine
CVST, SVT, and/or thrombocytopenia
AstraZeneca: 30 severe AEs and 4.8 deaths per million doses
Pfizer/BioNTech: 4 severe AEs and 0.4 deaths per million doses
Simpson et al (Nested case-control study using EAVE II prospective cohort data for vaccinations given between December 8, 2020 and April 14, 2021)19AstraZeneca (first dose): 1.71 million people
Pfizer/BioNTech (first dose): 0.82 million people
AstraZeneca (events within 27 days post-vaccination):
Thrombocytopenia: 46 events
ITP: 23 events
Venous thromboembolism (including CVST): 423 events
Arterial thromboembolism: 1348 events
Hemorrhagic events: 149 events
Pfizer/BioNTech (events within 27 days post-vaccination):
Thrombocytopenia: 13 events
ITP: ≤5 events
Venous thromboembolism (including CVST): 137 events
Arterial thromboembolism: NR
Hemorrhagic events: 61 events
AstraZeneca (adjusted RR for event within 27 days post-vaccination versus unvaccinated individuals):
Thrombocytopenia: 1.42 (95% CI, 0.86 to 2.37)
ITP: 5.77 (95% CI, 2.41 to 13.83)
Venous thromboembolism (including CVST): 1.03 (95% CI, 0.89 to 1.21)
Arterial thromboembolism: 1.22 (95% CI, 1.12 to 1.34)
Hemorrhagic events: 1.48 (95% CI, 1.12 to 1.96)
Pfizer/BioNTech (adjusted RR for event within 27 days post-vaccination versus unvaccinated individuals):
Thrombocytopenia: 0.67 (95% CI, 0.32 to 1.43)
ITP: 0.54 (95% CI, 0.10 to 3.02)
Venous thromboembolism (including CVST): 0.48 (95% CI, 0.39 to 0.61)
Arterial thromboembolism: 0.92 (95% CI, 0.81 to 1.04)
Hemorrhagic events: 0.92 (95% CI, 0.64 to 1.30)
CDC 34,35As of July 12, 2021:
Over 12.8 million doses
As of July 12, 2021:
38 cases
Expected cases of VITT (estimated using data as of April 24, 2021):
7 per million vaccine doses in women aged 18 through 49 years
1 per million vaccine doses in women aged 50 years or older and men aged 18 to 49 years
0 per million vaccine doses in men aged 50 years or older
Abbreviations: AE=adverse event; CDC=Centers for Disease Control and Prevention; CI=confidence interval; CVST=cerebral venous sinus thrombosis; EAVE II= Early Pandemic Evaluation and Enhanced Surveillance of COVID-19; EMA=European Medicines Agency; ITP=idiopathic thrombocytopenic purpura; J&J/Janssen=Johnson & Johnson/Janssen; NR=not reported; PF4=platelet factor 4; RR=rate ratio; SVT=splanchnic vein thrombosis; VITT=vaccine-induced thrombotic thrombocytopenia.

Data on VITT Events Associated with the J&J/Janssen COVID-19 Vaccine
An EUA for the J&J/Janssen vaccine was issued on February 27, 2021; by April 12, 2021, approximately 7 million people in the United States had received the J&J/Janssen vaccine, and 6 cases of CVST and thrombocytopenia associated with vaccine administration had been reported to the FDA and CDC through the Vaccine Adverse Event Reporting System (VAERS).1,36 The FDA and CDC promptly began investigating these cases. Additional cases of CVST and non-CVST VITT have been reported through VAERS since that time (Table).

See and colleagues published a case series on the first 12 patients reporting CVST and thrombocytopenia after receipt of the J&J/Janssen vaccine (including the 6 original cases reported to VAERS).36 All patients were Caucasian women aged 18 to 60 years. Eight of the women were aged 18 to 39 years, and 4 were aged 40 years or older. Seven of the 12 women had at least 1 CVST risk factor, including obesity (6 women), hypothyroidism (1 woman), and/or combined oral conceptive use (1 woman). Symptom onset occurred 6 to 15 days post-vaccination. All 12 patients required hospitalization, with hospital admission occurring 10 to 25 days post-vaccination. Initial symptoms included headache, lethargy, nausea, vomiting, fever, chills, bruising, abdominal/back pain, body ache, and photophobia. Seven patients also presented with intracerebral hemorrhage, and 8 were diagnosed with other concomitant thromboses, including portal vein thrombosis, pulmonary embolus, and/or internal jugular vein thrombosis. Eleven of the 12 patients were positive for anti-PF4 antibodies on ELISA (the remaining patient was not tested). Ten out of the 12 women were managed with anticoagulation; 6 of the patients were initially treated with heparin after their CVST diagnosis, but heparin was eventually discontinued in all of them and a non-heparin anticoagulant was initiated. Seven patients also received IVIG, 3 received systemic corticosteroids, and 4 received platelet transfusions. At the time of last follow-up, 3 patients had died, 3 remained in the intensive care unit (ICU) for care, 2 were receiving non-ICU care, and 4 had been discharged.

Further details on a patient included in the case series above describes a 48-year-old woman who presented to the emergency department with a 3-day history of malaise and abdominal pain.37 She was found to have mild anemia, severe thrombocytopenia (platelet count of 13,000/mcL), and low fibrinogen; computed tomographic (CT) imaging of her abdomen and pelvis found extensive splanchnic vein thrombosis. During hospitalization, the patient additionally reported a new-onset headache. A head CT was performed, and she was found to have CVST. Unfractionated heparin was initiated for treatment, but the patient’s disease continued to progress, leading to additional thrombi in the right hepatic and splenic veins as well as hemorrhagic stroke. After noting that the patient had received a J&J/Janssen COVID-19 vaccine 14 days prior to symptom onset, the patient was tested for antibodies against PF4 via ELISA and found to be positive (although an initial latex-enhanced immunoassay screening test for anti-PF4 antibodies was negative). Due to this finding, argatroban and IVIG (1 g/kg of ideal body weight for 2 days) were initiated and heparin discontinued. Although this treatment increased her platelet count to 145,000/mcL, she remained in a critical state at the time of the report.

Clark and colleagues published an additional case report describing a 40-year-old woman with thrombocytopenia, CVST, and pulmonary embolism after receiving the J&J/Janssen vaccine.38 She presented to the emergency department with headache, photophobia, and dizziness 12 days after vaccination. Initial screening for HIT or anti-PF4/heparin antibodies was negative, but confirmatory ELISA testing was positive for anti-PF4 antibodies. She was treated with bivalirudin, IVIG (1 mg/kg/day for 2 days), and prednisone 1 mg/kg daily. Thrombocytopenia improved (from 20,000/mcL to 115,000/mcL by day 5), and she was discharged from the hospital after 6 days.

Current Statements from Healthcare Authorities
The CDC, the FDA, and World Health Organization (WHO) have agreed that the benefits of the J&J/Janssen vaccine outweigh the risks.39-41 A statement from the WHO notes that, as the only authorized single-dose vaccine, it may play a key role in the vaccination of populations that are difficult to reach.39 However, the CDC notes that women aged less than 50 years should be aware of the rare but increased risk of thrombotic complications associated with the J&J/Janssen vaccine.40,41 The CDC also suggests that patients with a history of HIT or other immune-mediated syndromes characterized by thrombosis and thrombocytopenia should be offered a different vaccine if it has been 90 days or fewer since their illness resolved.40 Individuals with other risk factors for venous thromboembolism (eg, history of venous thromboembolism, pregnancy, receipt of hormonal contraceptives) do not have increased susceptibility to VITT after J&J/Janssen vaccination and may receive any authorized vaccine.

Organizations outside the United States have provided recommendations regarding use of the AstraZeneca vaccine. The EMA has stated that although rare cases of thrombosis and thrombocytopenia have occurred following receipt of the AstraZeneca vaccine, the benefits of the vaccine outweigh its risks in adults of all age groups.42 If VITT occurs after the first dose of the AstraZeneca vaccine, a second dose of the AstraZeneca vaccine should not be administered.43 The United Kingdom’s Joint Committee on Vaccination and Immunisation (JCVI) states that individuals aged 40 years or older or with underlying medical conditions may receive any of the available COVID-19 vaccines (including the AstraZeneca vaccine), as the benefits of COVID-19 protection outweigh the risk of VITT.44 Healthy individuals aged 18 to 39 years should preferably receive a COVID-19 vaccine other than the AstraZeneca vaccine, unless they have already received a first dose of the AstraZeneca vaccine. Finally, the Canadian National Advisory Committee on Immunization (NACI) preferentially recommends mRNA vaccines (eg, Pfizer/BioNTech, Moderna) over viral vector vaccines (eg, AstraZeneca, J&J/Janssen).3 The viral vector vaccines may be offered if mRNA vaccines are contraindicated or inaccessible.

Recognition and Management of VITT
The American Society of Hematology (ASH), the American Heart Association (AHA), and the International Society on Thrombosis and Haemostasis (ISTH) have published guidelines on the recognition and management of VITT.10,45,46 Patients are at risk for VITT if they present with symptoms indicative of thrombosis and/or thrombocytopenia within 4 to 42 days of receiving a COVID-19 vaccine (particularly a J&J/Janssen or AstraZeneca COVID-19 vaccine).10 Presenting symptoms may include severe/persistent abdominal pain, back pain, shortness of breath, chest pain, leg pain or swelling, mental status changes, vision changes, severe/persistent headache, nausea/vomiting, easy bruising, bleeding, or petechiae.10,45 Headache is the most common symptom of CVST, with about 90% of patients presenting with this complaint.46 Developing any of the above symptoms after vaccination warrants an urgent medical evaluation for VITT.10

The initial work up for suspected VITT should include a complete blood count (CBC) with platelet count and peripheral smear, as well as CT or magnetic resonance imaging for thrombosis based on the location of the patient’s symptoms.10 A PF4/heparin ELISA test should be performed, and fibrinogen and D-dimer levels should be obtained.10,45 Blood for the PF4/heparin ELISA test should be drawn prior to the initiation of therapy.10 Of note, non-ELISA rapid immunoassays for HIT are not sensitive or specific for VITT and should not be used. A VITT diagnosis is confirmed if the patient has venous or arterial thrombosis, thrombocytopenia, and a positive PF4 ELISA assay within 42 days of COVID-19 vaccination; however, platelet counts may be normal if the patient is in the early stages of VITT. If the turnaround time for a PF4/heparin ELISA assay is slow, D-dimer levels can be used to help estimate the likelihood of VITT.45 A high D-dimer level (eg, >4 times the threshold for exclusion of venous thromboembolism) supports a possible VITT diagnosis.

The ISTH guideline recommends initiating VITT treatment if a VITT diagnosis is likely, even if PF4/heparin ELISA results are not yet available.45 The ASH guideline similarly states that treatment should be initiated pending PF4/heparin ELISA results if there are signs or symptoms of serious thrombosis and either positive imaging, low platelets, or both.10 The ASH guideline also states that patients without thrombosis who present with low platelets and very high/rising D-dimer levels or positive PF4/heparin ELISA should receive treatment for VITT.

Anticoagulation with non-heparin parenteral anticoagulants (eg, fondaparinux, argatroban, bivalirudin) or direct oral anticoagulants should generally be initiated in patients with suspected VITT.10,45,46 The ISTH guideline recommends initiating anticoagulation in patients with platelet counts over 50,000/mcL and no serious bleeding; however, the ASH guideline states that low fibrinogen or bleeding should not absolutely preclude patients from receiving anticoagulation, particularly if platelets are greater than 20,000/mcL or increasing after IVIG administration.10,45 In patients with CVST, the AHA guideline recommends initiating anticoagulation even if secondary intracranial hemorrhage is present.46 Treatment of VITT should also include IVIG 1 g/kg daily for 2 days.10,45,46 The ISTH guideline states that steroids (eg, prednisone 1 to 2 mg/kg) can be considered in addition to IVIG if platelets are less than 50,000/mcL; however, the ASH guideline notes that it is unclear whether the addition of steroid therapy offers significant benefit.10,45 The ISTH guideline states that if platelets remain less than 30,000/mcL despite IVIG and steroid treatment or if fibrinogen levels are less than 1 g/L, plasma exchange or fibrinogen supplementation to levels greater than 1 g/L may be beneficial.45 The ASH guideline states that fibrinogen supplementation can be considered in patients with bleeding or significant fibrinogen deficiency, but plasma exchange is not recommended unless thrombosis continues despite use of non-heparin anticoagulants and IVIG.10 Heparin, low-molecular-weight heparin, aspirin, and vitamin K antagonists should be avoided in patients with VITT, and platelet transfusions should only be administered if necessary for urgent surgery or life-threatening bleeding.10,45

The adenoviral vector-based COVID-19 vaccines have been associated with VITT, a rare but serious adverse event. This syndrome is similar to aHIT and characterized by venous or arterial thrombosis at atypical sites, thrombocytopenia, and anti-PF4 antibodies occurring within 42 days of vaccination. Complications of VITT frequently lead to hospitalizations and/or death, so recognition and appropriate management are vital. Treatment of confirmed or suspected VITT should generally include high-dose IVIG and non-heparin anticoagulation; fibrinogen replacement, steroids, and plasma exchange may also be considered in certain cases.


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  2. Janssen COVID-19 Vaccine. Package insert. Janssen Biotech, Inc; 2021.
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Prepared by:
Rana Hamad, PharmD Candidate Class of 2022
Syed Haque, PharmD Candidate Class of 2022
University of Illinois at Chicago College of Pharmacy

Reviewed by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

August 2021

The information presented is current as of July 15, 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.