Cerebral vein thrombosis (CVT) has been reported as a complication of Ad26.COV2.S (Johnson & Johnson) and ChAdOx1 (Oxford-AstraZeneca) Covid-19 vaccines, though its incidence is rare.

A new Lancet study from the United Kingdom has said that even though occurrence of post-vaccine cerebral vein thrombosis is rare, it is much more severe and associated with greater mortality and disability than CVT not associated with the vaccine. The study also characterised vaccine-induced thrombotic thrombocytopenia(VITT)-associated CVT in terms of clinical features and response to various treatment and compared them with patients who developed cerebral venous thrombosis after vaccination but did not have VITT. The findings of the study were also presented at the virtual European Stroke Organisation Conference earlier this week.

Data from all cases of post-vaccine CVT were examined regardless of the vaccine used, interval between vaccine and onset of thrombosis or blood test results. Patients were grouped into two based on the association with VITT. There were 95 confirmed cases of CVT; of these, 70 had a likely association with VITT, while 25 cases seemed to have no such association. All of the VITT cases were found to have occurred after the first dose of the Astra-Zeneca vaccine. Clinically, the VITT and non-VITT groups were comparable, though differences between the two groups were noted in the study.

Compared to patients without VITT, intracranial thrombosis and coexisting extracranial thrombosis were more common in patients with VITT-associated CVT, who were also younger and more likely to be female. Patients with VITT associated CVT had more extensive venous thrombosis; they also had numerous intracerebral hemorrhages and multiple infarcts.

Mortality was higher in VITT-associated CVT than in the non-VITT group; 29% vs 4%, respectively. Similarly, dependency on others at the end of hospital admission was more frequent in VITT-associated CVT vs non-VITT group.

An association between treatment given and functional outcome was also noted. The functional outcome was better in VITT patients treated with non-heparin anticoagulants (64%) compared to those who were not given this treatment (25%). On a similar note, the outcome was better with intravenous immunoglobulin (IVIG) compared with those who did not receive them; 60% vs 27%, respectively. Mortality and dependency were lower in the IVIG treated patients.

However, just 16% of patients who were administered platelet transfusions had a good functional outcome in comparison to 73% of those not given platelet transfusions with the authors suggesting that platelet transfusion is like “adding fuel to the fire” as vaccine-related clots occur despite low platelets. Increased platelet clearance and consumption when they become activated due to an autoimmune process causing thrombocytopenia have been proposed as the pathogenic mechanisms. The activated platelets activate the clotting system, the platelet aggregate together and form clots and platelets further fall. Both high clearance and consumption have been linked to vaccine-associated low platelets.

Researchers have also proposed a new set of diagnostic criteria for VITT-associated CVT in this study.

“Definite VITT-associated CVT: Post-vaccine cerebral venous thrombosis (proven on neuroimaging and with first symptom of venous thrombosis within 28 days of vaccination against COVID-19) and Thrombocytopenia (lowest recorded platelet count <150 × 10⁹ per L or documented platelet count decrease to less than 50% of baseline) and Anti-PF4 antibodies (detected on ELISA or functional assay)

Probable VITT-associated CVT: Post-vaccine cerebral venous thrombosis and Either thrombocytopenia or anti-PF4 antibodies and Coagulopathy (D-dimer >2000 μg/L or fibrinogen <2·0 g/L with no other explanation such as severe sepsis, malignancy, or recent trauma or surgery) or extracranial venous thrombosis (clinical or imaging evidence with onset since vaccination against COVID-19).

Possible VITT-associated CVT: Post-vaccine cerebral venous thrombosis and either thrombocytopenia or anti-PF4 antibodies“

This study has shown an association of VITT with adenovirus vector COVID-19 vaccines, particularly the AstraZeneca vaccine.

According to the authors, mRNA vaccines (Moderna and Pfizer-BioNTech) are also “associated with a syndrome of profound thrombocytopenia, but in this case the phenotype is typically idiopathic thrombocytopenic purpura, with a purpuric rash and mucosal bleeding as the most typical features”.

VITT-associated CVT was found to be more common in the younger study subjects. They also suggest that interval between the vaccine and clot formation should be counted from the day of the first symptom regardless of cranial or extracranial thrombosis. Patients with probable VIIT should still be managed as patients with definite VITT.

It is important that clinicians managing such patients be aware of the clinical and laboratory presentations so that they can be managed without any delay for a better patient outcome. Patients who complain of a severe headache after taking the vaccine should be promptly subjected to platelet counts, d-dimer test and neuroimaging. PF4 antibodies can be done but results take long. Presence of any two of the following three: raised d-dimer (more than 2000), thrombocytopenia (below 150) and anti-PF4 antibodies are strongly indicative of VITT.

However, the authors emphasize that the benefits of the vaccines still outweigh the risks as VITT is a rare adverse effect of the vaccine. They write, “It is much more likely for an individual to get seriously ill or die from COVID-19 than it is to get VITT.”

Source

1. Sue Hughes. Cerebral thrombosis after COVID vax deadlier than sporadic form - Medscape - Sep 03, 2021.
2. Perry RJ, et al. Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study. Lancet. 2021 Aug 6;S0140-6736(21)01608-1.

Dr Rahul Pandit,

Director, Critical Care, Fortis hospital, Mumbai