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Cerebral venous thrombosis and the AstraZeneca vaccine — UK cohort study

The largest study yet of cerebral venous thrombosis after vaccination against COVID-19 (VITT), shows that those affected were younger, had fewer venous thrombosis risk factors, and were more likely to have been given the Oxford–AstraZeneca vaccine, according to a study in The Lancet. Non-heparin anticoagulants and intravenous immunoglobulin were both associated with better outcomes.

Globally, more than 4·1 million people have died from COVID-19. In response to this public health emergency, several vaccines against COVID-19 have been developed, with more than 3·7 billion doses administered worldwide.

According to a study in The Lancet, after the introduction of the adenovirus vector vaccine ChAdOx1 (Oxford–AstraZeneca), five cases of severe venous thrombosis with thrombocytopenia were reported in Norway, each starting seven to 10 days after administration of the first vaccine dose. Four of these cases had cerebral venous sinus thrombosis.

This syndrome has since been termed vaccine-induced immune thrombotic thrombocytopenia (VITT).

A similar condition has been described with another adenovirus vector vaccine, Ad26.COV2.S (Johnson & Johnson). There are also case reports in which two mRNA vaccines, mRNA-1273 (Moderna), and BNT162b2 (Pfizer–BioNTech), are associated with thrombocytopenia, although typically with purpura and mucosal bleeding, rather than thrombosis.

Added value of this study

To our knowledge, our report describes the largest study of cerebral venous thrombosis after vaccination against COVID-19. We can make the first direct comparison between 70 patients with VITT-associated cerebral venous thrombosis and 25 patients who developed cerebral venous thrombosis after vaccination but did not have VITT, in addition to secondary comparisons with a large historical cohort with cerebral venous thrombosis.

Our results show, for the first time to our knowledge, that when they are compared with those without VITT, patients with VITT-associated cerebral venous thrombosis were younger, had fewer venous thrombosis risk factors, and were more likely to have been given the ChAdOx1 vaccine.

They developed more extensive cerebral venous thrombosis with more veins or sinuses thrombosed, and multiple intracerebral haemorrhage was more common. They were more likely to have concurrent extracranial venous or arterial thromboses. Their outcomes at the end of hospital admission were worse, with higher rates of death and disability.

Although the response of patients with VITT-associated cerebral venous thrombosis to treatment is difficult to assess in a purely observational study, non-heparin anticoagulants and intravenous immunoglobulin were both associated with better outcomes. The starting criteria for VITT, based on low platelets and high D-dimers, appeared to miss two patients who had typical features for this condition.

Implications of all the available evidence

VITT is specifically associated with adenovirus vector vaccines against COVID-19 and urgent work is needed to elucidate the trigger for this reaction, in the hope that future vaccines can be designed to avoid this. Clinicians need to be aware of the clinical, laboratory, and radiological markers of this condition, as without prompt treatment the outcome is very poor. Adoption of our proposed definition of VITT-associated cerebral venous thrombosis should make it less likely that atypical cases will be missed, but these diagnostic criteria will need to be tested as more data accumulate.

Study details

Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study

Richard J Perry, Arina Tamborska, Bhagteshwar Singh, Brian Craven, Richard Marigold, Peter Arthur-Farraj, Jing Ming Yeo, Liqun Zhang, Ghaniah Hassan-Smith, Matthew Jones, Christopher Hutchcroft, Esther Hobson, Dana Warcel, Daniel White, Phillip Ferdinand, Alastair Webb, Prof Tom Solomon, Prof Marie Scully, Prof David J Werring, Prof Christine Roffe, on behalf of the CVT After Immunisation Against COVID-19 (CAIAC) collaborators

Published in The Lancet 6 August 2021

Summary

Background
A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with poorer outcomes.

Methods
For this multicentre cohort study, clinicians were asked to submit all cases in which COVID-19 vaccination preceded the onset of cerebral venous thrombosis, regardless of the type of vaccine, interval between vaccine and onset of cerebral venous thrombosis symptoms, or blood test results. We collected clinical characteristics, laboratory results (including the results of tests for anti-platelet factor 4 antibodies where available), and radiological features at hospital admission of patients with cerebral venous thrombosis after vaccination against COVID-19, with no exclusion criteria. We defined cerebral venous thrombosis cases as VITT-associated if the lowest platelet count recorded during admission was below 150 × 109 per L and, if the D-dimer was measured, the highest value recorded was greater than 2000 μg/L.

We compared the VITT and non-VITT groups for the proportion of patients who had died or were dependent on others to help them with their activities of daily living (modified Rankin score 3–6) at the end of hospital admission (the primary outcome of the study). The VITT group were also compared with a large cohort of patients with cerebral venous thrombosis described in the International Study on Cerebral Vein and Dural Sinus Thrombosis.

Findings
Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on imaging. Of the remaining 95 patients, 70 had VITT and 25 did not. The median age of the VITT group (47 years, IQR 32–55) was lower than in the non-VITT group (57 years; 41–62; p=0·0045).

Patients with VITT-associated cerebral venous thrombosis had more intracranial veins thrombosed (median three, IQR 2–4) than non-VITT patients (two, 2–3; p=0·041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non-VITT patients (one [4%] of 25 patients; p=0·0003). The primary outcome of death or dependency occurred more frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the non-VITT control group (four [16%] of 25 patients; p=0·0061).

This adverse outcome was less frequent in patients with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (15 [75%] of 20 patients; p=0·0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) compared with those who did not (11 [73%] of 15 patients; p=0·022).

Interpretation
Cerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new diagnostic criteria that are more appropriate.

 

 

Full Lancet article – Cerebral venous thrombosis after vaccination against COVID-19 in the UK: a multicentre cohort study (Open access)

 

See more from MedicalBrief archives:

 

Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination

 

Risk of deep vein thrombosis and pulmonary embolism in patients with COVID-19

 

Successful treatment of VITT — University of Vienna case study

 

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