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The cerebral venous thrombosis (CVT) that occurs as part of the rare adverse reaction to the adenovirus vector COVID-19 vaccines from Astra Zeneca and Johnson & Johnson is much more severe and associated with greater mortality and disability than sporadic CVT, new data show.
The UK study also provides more details of how the vaccine-associated CVT differs from the sporadic form in terms of presenting characteristics and responses to therapies, providing updated guidance for doctors on how to identify and treat the condition.
The two adenoviral vector COVID-19 vaccines have been associated with a condition characterized by severe venous thrombosis with thrombocytopenia, which has been named vaccine-induced thrombotic thrombocytopenia (VITT) and has been found to be linked to the generation of antiplatelet factor 4 (PF4) antibodies in response to the vaccine. CVT is a frequent and severe manifestation of VITT.
The new UK study was presented at the virtual European Stroke Organisation Conference on September 2 by lead investigator, Richard Perry, PhD, University College London, England. It was also recently published online in The Lancet.
“This is the first large study focusing on CVT associated with the COVID-19 vaccination and how it differs from sporadic CVT,” Perry noted.
“Our data show that CVT associated with VITT is very different from sporadic CVT that we are used to seeing,” he said, and was much more likely to result in death or severe disability than sporadic CVT. “It also has several particular characteristics that differ from sporadic CVT such as the frequent presence of venous thromboses in other parts of the body, a low platelet count, and much higher D-dimer levels,” he noted.
“To our knowledge, our study provides the most detailed information reported to date on the clinical and radiological characteristics of VITT-associated CVT in a large number of patients. This can be used to update guidance on how to recognize and treat this condition.”
Benefit of Vaccine Still Outweighs Risk
The researchers did not try to estimate the incidence of VITT in this study, but Perry emphasized that although this adverse effect is very serious with a high mortality rate, it is very rare.
“It is much more likely for an individual to get seriously ill or die from COVID-19 than it is to get VITT. We need to get our data out to doctors so they know how to identify and treat this condition, but we don’t want to scare people away from having the vaccine,” he said. “Our society has opened up because of these vaccines. The benefit to society is vastly greater than the risk.”
Perry also pointed out that this VITT reaction occurs almost exclusively after the first dose of the Astra Zeneca vaccine. “In this study, all of the VITT cases occurred after a first dose of the vaccine. There have been a few cases of CVT reported after the second dose, but we do not know whether any of these were caused by VITT. Given this observation, it seems unlikely that it will occur after subsequent booster doses,” he said.
Most Detailed Dataset Available
For the study, clinicians involved in the care of patients with CVT after COVID-19 vaccination were asked to submit all cases, regardless of the type of vaccine, interval between vaccine and onset of CVT or blood test results. Data on demographics, venous thrombosis risk factors, clinical features, laboratory results, radiological findings, and treatments given were recorded, as well as outcomes (death or dependency) at the end of hospital admission.
Patients were divided into two groups based on whether the CVT was believed to be caused by VITT or not as determined by data on platelet counts and D-dimer levels.
Results showed that of 95 confirmed cases of CVT after COVID vaccination reported in the study, 70 appeared to be related to VITT and 25 were not.
While the clinical features of CVT were similar in the VITT and non-VITT groups, there were many other differences. Patients with VITT-associated CVT had more intracranial veins thrombosed and more frequently had thrombosis in other parts of the body (44% vs 4%).
The primary outcome of death or dependency occurred more frequently in patients with VITT-associated CVT (47%) compared with the non-VITT control group (16%).
Death occurred in 29% of the VITT group vs 4% of the non-VITT group.
A good functional outcome (defined as a modified Rankin Scale score of 0-2) occurred in 53% of the VITT patients vs 84% of the non-VITT patients.
In terms of treatments given to the VITT group, the number of patients achieving a good functional outcome was similar (around 50%) whether they were given heparin or not, but better with non-heparin anticoagulants (64%) than those not receiving such treatment (25%).
Similarly, IV immunoglobulin (IVIG) was linked to a 60% chance of a good outcome vs 27% in those not receiving IVIG.
Platelet transfusions were linked to a worse outcome, with only 16% of patients given platelets achieving a good functional outcome vs 73% of those not given platelet transfusions.
Perry told Medscape Medical News that observations from this dataset could improve the diagnosis and treatment of VITT-related CVT.
“Firstly, current guidelines tend to recommend D-dimer levels of more than 4000 μg/L for a VITT diagnosis, but we found a level of more than 2000 μg/L was more useful,” he said.
“Current guidance also stipulates that platelet count has to be below 150 × 109 per L but we described one patient whose platelet count never quite fell below this threshold, but who nonetheless had other strong evidence for a diagnosis of VITT and who was treated for this condition,” he added.
“Current guidance tends to use hard cutoffs, but our data show that by using such simple criteria, some patients will be missed. I would say that of the three diagnostic criteria for VITT — raised D-dimer, low platelet count, and presence of anti-PF4 antibodies — if the patient has two of these then that would be strongly suggestive of VITT. They may not fulfill every criterion to the letter.”
The finding of thrombus elsewhere in the body is very unusual for sporadic CVT, but is a particular feature of VITT, Perry noted.
“There is also a tight temporal relation. The vast majority of cases happen more than 3 days but less than 3 weeks after vaccination,” he added.
“These patients can get seriously unwell very quickly, so prompt treatment is essential. Generalist and emergency doctors need to be aware of this condition and to do the right tests and give the right treatment straight away,” he said.
Perry and colleagues are proposing that there should be two categories: (1) “definite VITT” when a patient has a platelet count below 150, a venous thrombosis, and has the presence of anti-PF4 antibodies; and (2) “probable VITT” which would include patients who don’t quite satisfy all the criteria but should still be treated as though they have VITT.
“We don’t want a situation where a patient does not get the correct treatment for VITT because they are presenting with a slightly different manifestation,” he commented.
“Patients coming to the emergency department with a bad headache a few days/weeks after the AZ or J&J jab should be immediately given a platelet and D-dimer test and receive neuroimaging for venous thrombosis. PF4 antibodies are also desirable, but this test can take days to come back and we shouldn’t wait for that to start treatment,” Perry said.
“Our data suggest that patients in this situation who have cerebral venous thrombosis and evidence of raised D-dimer, low platelet count, or other blood clots elsewhere in the body should immediately be given IVIG and a non-heparin anticoagulant such as argatroban or fondaparinux.”
He stressed that platelet transfusions are not recommended. “This would not be an unreasonable thing to do for a patient with a low platelet count but in this study patients who got platelets did much worse. Platelets are the cause of the clot in VITT — giving platelets is adding fuel to the fire.”
This work was undertaken at UCL Hospitals/UCL, which receives a proportion of funding from the UK Department of Health NIHR Biomedical Research Centre funding scheme. Perry has disclosed no relevant financial relationships.
European Stroke Organisation Conference 2021. Presented September 1, 2021.
Lancet. Published online August 6, 2021. Full text