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

Abstract

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.

Funding: None.

Figure 1

Imaging from patient A, who had typical vaccine-induced immune thrombotic thrombocytopenia-associated cerebral venous thrombosis This man in his 50s was well before vaccination with the ChAdOx1 (AstraZeneca) vaccine, but 17 days later developed a headache, abdominal pain, vomiting, dysphasia and confusion. (A) Axial CT without contrast showing a large haemorrhagic venous infarct in the left temporal lobe. (B–E). Axial CT venogram. Arrows indicate voids left by thrombus in the left transverse sinus (B, C) and the left sigmoid sinus (D) and lack of opacification of the left internal jugular vein (E). Each structure can be compared with its well-opacified counterpart on the right side. (F) CT pulmonary angiogram showing thrombus in the left pulmonary artery.

Figure 2

Distributions of lowest platelet counts (A) and highest D-dimers (B) recorded during admission, in patients with anti-PF4 antibodies, without PF4 antibodies, or not tested The x-axis labels represent the lowest limit of the bin, so that the label 100 refers to the range 100–125, the label 126 refers to the range 126–157 and so on. Patients with atypical anti-PF4 results are described in the appendix (p 3) as follows: the patient with a normal platelet count and positive anti-PF4 antibodies is patient B; the patient with normal D-dimers and positive anti-PF4 antibodies is patient C; the two patients with high D-dimers and negative anti-PF4 antibodies are patients E and F. PF4=platelet factor 4.

Figure 3

Comparison of disability on discharge (A) Comparison of the outcomes from cerebral venous thrombosis in patients with VITT versus patients without VITT. (B) Comparison between VITT-associated cerebral venous thrombosis and historical data from the International Study on Cerebral Vein and Dural Sinus Thrombosis cohort. Each horizontal bar represents the percentage of patients in each modified Rankin scale category, which varies from 0 (no symptoms) through to 5 (severe disability). 6 represents death during this hospital admission. Diagonal lines and p values show comparisons of death and dependency (modified Rankin score 3–6) or death (modified Rankin score 6). VITT=vaccine-induced immune thrombotic thrombocytopenia.