Pi Is 0140673621016081
Pi Is 0140673621016081
Summary
Background A new syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT) has emerged as a Lancet 2021; 398: 1147–56
rare side-effect of vaccination against COVID-19. Cerebral venous thrombosis is the most common manifestation of Published Online
this syndrome but, to our knowledge, has not previously been described in detail. We aimed to document the features August 6, 2021
https://doi.org/10.1016/
of post-vaccination cerebral venous thrombosis with and without VITT and to assess whether VITT is associated with
S0140-6736(21)01608-1
poorer outcomes.
See Comment page 1107
*Contributed equally
Methods For this multicentre cohort study, clinicians were asked to submit all cases in which COVID-19 vaccination
†A complete list of the
preceded the onset of cerebral venous thrombosis, regardless of the type of vaccine, interval between vaccine and onset of collaborators is given in the
cerebral venous thrombosis symptoms, or blood test results. We collected clinical characteristics, laboratory results appendix (p 1)
(including the results of tests for anti-platelet factor 4 antibodies where available), and radiological features at hospital Comprehensive Stroke Service,
admission of patients with cerebral venous thrombosis after vaccination against COVID-19, with no exclusion criteria. We National Hospital for
defined cerebral venous thrombosis cases as VITT-associated if the lowest platelet count recorded during admission was Neurology and Neurosurgery
(R J Perry PhD,
below 150 × 10⁹ per L and, if the D-dimer was measured, the highest value recorded was greater than 2000 μg/L. We Prof D J Werring PhD) and
compared the VITT and non-VITT groups for the proportion of patients who had died or were dependent on others to Department of Haematology
help them with their activities of daily living (modified Rankin score 3–6) at the end of hospital admission (the primary (B Craven MBBCh,
outcome of the study). The VITT group were also compared with a large cohort of patients with cerebral venous thrombosis D Warcel MBBS,
Prof M Scully MD), UCL
described in the International Study on Cerebral Vein and Dural Sinus Thrombosis. Hospitals NHS Foundation
Trust, London, UK; Stroke
Findings Between April 1 and May 20, 2021, we received data on 99 patients from collaborators in 43 hospitals across Research Centre, UCL Queen
the UK. Four patients were excluded because they did not have definitive evidence of cerebral venous thrombosis on Square Institute of Neurology,
London, UK (R J Perry,
imaging. Of the remaining 95 patients, 70 had VITT and 25 did not. The median age of the VITT group (47 years, Prof D J Werring); National
IQR 32–55) was lower than in the non-VITT group (57 years; 41–62; p=0·0045). Patients with VITT-associated cerebral Institute for Health Research
venous thrombosis had more intracranial veins thrombosed (median three, IQR 2–4) than non-VITT patients Health Protection Research
(two, 2–3; p=0·041) and more frequently had extracranial thrombosis (31 [44%] of 70 patients) compared with non- Unit in Emerging and Zoonotic
Infections, Institute of
VITT patients (one [4%] of 25 patients; p=0·0003). The primary outcome of death or dependency occurred more Infection, Veterinary and
frequently in patients with VITT-associated cerebral venous thrombosis (33 [47%] of 70 patients) compared with the Ecological Sciences, University
non-VITT control group (four [16%] of 25 patients; p=0·0061). This adverse outcome was less frequent in patients of Liverpool, Liverpool, UK
with VITT who received non-heparin anticoagulants (18 [36%] of 50 patients) compared with those who did not (A Tamborska MBChB,
B Singh MRCP,
(15 [75%] of 20 patients; p=0·0031), and in those who received intravenous immunoglobulin (22 [40%] of 55 patients) Prof T Solomon FMedSci);
compared with those who did not (11 [73%] of 15 patients; p=0·022). Tropical and Infectious
Diseases Unit, Royal Liverpool
University Hospital, Liverpool,
Interpretation Cerebral venous thrombosis is more severe in the context of VITT. Non-heparin anticoagulants and
UK (B Singh); Department of
immunoglobulin treatment might improve outcomes of VITT-associated cerebral venous thrombosis. Since existing Stroke Medicine, University
criteria excluded some patients with otherwise typical VITT-associated cerebral venous thrombosis, we propose new Hospital Southampton NHS
diagnostic criteria that are more appropriate. Foundation Trust,
Southampton UK
(R Marigold FRCP);
Funding None. John van Geest Centre for Brain
Repair, Department of Clinical
Copyright © 2021 Elsevier Ltd. All rights reserved. Neurosciences, Cambridge, UK
(P Arthur-Farraj PhD); Queen’s
Medical Centre, Nottingham
Introduction were reported in Norway, each starting 7–10 days after University Hospitals NHS Trust,
Globally, more than 4·1 million people have died administration of the first vaccine dose. Four of these Nottingham, UK
from COVID-19.1 In response to this public health cases had cerebral venous sinus thrombosis.3 This (J M Yeo MRCP); Department of
Neurology, St George’s
emergency, several vaccines against COVID-19 have been syndrome has since been termed vaccine-induced
University Hospital NHS
developed, with more than 3·7 billion doses administered immune thrombotic thrombocytopenia (VITT).3–5 A Foundation Trust, London, UK
worldwide.2 After the introduction of the adenovirus similar condition has been described with another (L Zhang PhD); Department of
vector vaccine ChAdOx1 (Oxford–AstraZeneca), five cases adenovirus vector vaccine, Ad26.COV2.S (Johnson & Neurology, Queen Elizabeth
Hospital Birmingham,
of severe venous thrombosis with thrombocytopenia Johnson).6,7 There are also case reports in which two
University Hospitals
Birmingham NHS Foundation Research in context
Trust, Birmingham, UK
(G Hassan-Smith PhD, Evidence before this study Added value of this study
D White MRCP); Manchester We searched PubMed on May 26, 2021, for articles published To our knowledge, our report describes the largest study of
Centre for Clinical in any language in 2021, with titles containing any of the cerebral venous thrombosis after vaccination against
Neurosciences, Salford Royal
NHS Foundation Trust, Salford,
following three search terms or their synonyms: “thrombosis”, COVID-19. We can make the first direct comparison between
UK (M Jones MD, “platelet”, or “PF4”, together with any of the following: 70 patients with VITT-associated cerebral venous thrombosis
C Hutchcroft MRCP); Royal “ChAdOx”, “AstraZeneca”, “Vaxzevria”, “Ad26.COV2.S”, and 25 patients who developed cerebral venous thrombosis
Hallamshire Hospital, Sheffield “Janssen”, “Johnson”, “mRNA-1273”, “Moderna”, “BNT162b2”, after vaccination but did not have VITT, in addition to
Teaching Hospitals NHS
Foundation Trust, Sheffield, UK
“Pfizer”, “Comirnaty”, “COVID” and “vaccine”, or “SARS” and secondary comparisons with a large historical cohort with
(E Hobson PhD); Stroke Service, “vaccine”. 63 articles were identified, of which 29 were case cerebral venous thrombosis. Our results show, for the first
University Hospitals of reports or small case series (nine focused specifically on cerebral time to our knowledge, that when they are compared with
North Midlands NHS Trust, venous sinus thrombosis), six were summaries of drug side- those without VITT, patients with VITT-associated cerebral
Stoke-on-Trent, UK
(P Ferdinand MRCP,
effect reports submitted to surveillance agencies, six were venous thrombosis were younger, had fewer venous
Prof C Roffe MD); Nuffield consensus statements regarding guidelines for diagnosis or thrombosis risk factors, and were more likely to have been
Department of Clinical management, 19 were reviews, commentaries, or editorials, given the ChAdOx1 vaccine. They developed more extensive
Neurosciences, John Radcliffe
and three were relevant immunological studies in individuals cerebral venous thrombosis with more veins or sinuses
Hospital, Oxford, UK
(A Webb DPhil); Department of who were vaccinated and remained healthy. Most case reports thrombosed, and multiple intracerebral haemorrhage was
Neurology, Walton Centre NHS and small series were of vaccine-induced immune thrombotic more common. They were more likely to have concurrent
Foundation Trust, Liverpool, thrombocytopenia (VITT) after vaccination with the adenovirus extracranial venous or arterial thromboses. Their outcomes at
UK (Prof T Solomon);
vector vaccine ChAdOx1 (Oxford–AstraZeneca), with the typical the end of hospital admission were worse, with higher rates
Haemostasis Research Unit,
University College London, features of very low platelets, very high D-dimers, and, of death and disability. Although the response of patients
London, UK (Prof M Scully); most commonly, cerebral venous sinus thrombosis or hepatic with VITT-associated cerebral venous thrombosis to
Faculty of Medicine and Health portal vein thrombosis. A similar syndrome has been reported treatment is difficult to assess in a purely observational study,
Sciences, Keele University,
following another adenovirus vector vaccine Ad26.COV2.S non-heparin anticoagulants and intravenous
Stoke-on-Trent, UK
(Prof C Roffe) (Janssen/Johnson & Johnson). In both cases, anti-platelet immunoglobulin were both associated with better outcomes.
Correspondence to: factor 4 antibodies were found in most patients. The mRNA- The starting criteria for VITT, based on low platelets and high
Dr Richard J Perry, based vaccines produced by Moderna (mRNA-1273) and Pfizer– D-dimers, appeared to miss two patients who had typical
Comprehensive Stroke Service, BioNTech (BNT162b2) have also been associated with a features for this condition.
National Hospital for Neurology
syndrome of profound thrombocytopenia, but in this case the
and Neurosurgery, Implications of all the available evidence
London WC1N 3BG, UK phenotype is typically idiopathic thrombocytopenic purpura,
VITT is specifically associated with adenovirus vector vaccines
[email protected] with a purpuric rash and mucosal bleeding as the most typical
against COVID-19 and urgent work is needed to elucidate the
See Online for appendix features. Although there have been occasional reports of
trigger for this reaction, in the hope that future vaccines can be
thrombosis after mRNA vaccines, these did not have the
designed to avoid this. Clinicians need to be aware of the
characteristics of VITT and could have been incidental.
clinical, laboratory, and radiological markers of this condition,
Although cerebral venous thrombosis is the most severe
as without prompt treatment the outcome is very poor.
manifestation of VITT, to date, to our knowledge, there have
Adoption of our proposed definition of VITT-associated cerebral
been no large studies focusing on this condition, and none of
venous thrombosis should make it less likely that atypical cases
the reports so far have included a control group, making it
will be missed, but these diagnostic criteria will need to be
difficult to draw inferences about how this condition differs
tested as more data accumulate.
from cerebral venous thrombosis without VITT.
mRNA vaccines, mRNA-1273 (Moderna)8,9 and BNT162b2 of patients with VITT-associated cerebral venous
(Pfizer–BioNTech),10 are associated with thrombocy thrombosis, and to compare these with patients with
topenia, although typically with purpura and mucosal cerebral venous thrombosis without VITT, and with
bleeding8–11 rather than thrombosis.11 historical data from the 624 patients in the International
Scully and colleagues4 proposed the following definition Study on Cerebral Vein and Dural Sinus Thrombosis
for VITT: patients presenting with acute thrombosis (ISCVT) cohort.12
and thrombocytopenia with elevated D-dimers, using a
D-dimer threshold of <2000 μg/L for VITT unlikely Methods
and >4000 μg/L for VITT suspected. They showed that Study design and participants
22 (96%) of 23 patients with VITT had antibodies against For this multicentre cohort study, clinicians involved in
platelet factor 4 (PF4). Similar observations were made the care of patients with cerebral venous thrombosis after
in other smaller case series.3,5 vaccination against COVID-19 were identified through
We aimed to document the clinical features, laboratory existing networks of communication among UK doctors,
and imaging results, and outcomes in a large cohort advertisement through the Association of British
A
14 Anti-PF4 positive
Anti-PF4 negative
12 Not tested
10
8
Frequency
020 199
21 209
22 219
23 229
10 9
20 9
30 9
40 9
50 9
60 9
70 9
80 9
90 9
10 –99
11 09
12 119
13 129
14 139
15 149
16 159
17 69
18 179
19 189
24 239
25 249
26 259
27 269
28 279
29 289
30 299
31 309
32 319
33 329
34 339
9
50
0–
–1
–2
–3
–4
–5
–6
–7
–8
34
≥3
1
1
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
0–
Lowest platelet count during admission (×109 per L)
B
14
12
10
8
Frequency
0
0
6
8
0
1
6
8
1
1
4
00
59
85
95
12
62
81
12
10
43
12 0
9
9
3
31 9
3
50 1
9
79 6
≥1 33
0
25
50
63
81
95
62
10
20
00
00
79
58
84
11
11
12
15
31
39
09
25
50
4
63
39
79
12
15
19
31
10
39
19
25
10
00
63
15
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.
manifestation of VITT, 21 days after vaccination. The deep We compared the 70 patients with VITT-associated
vein thrombosis was initially treated with tinzaparin, but cerebral venous thrombosis with the 25 patients who
the patient was found to be thrombocytopenic before this developed cerebral venous thrombosis without evidence
treatment was started. This patient was the only individual of VITT after vaccination, as well as with historical data
in the whole study to receive any form of heparin within from the 624 patients with cerebral venous thrombosis
the 2 weeks preceding the cerebral venous thrombosis. in the ISCVT cohort (table 1).12 Patients with VITT were
The age distribution of patients with VITT-associated significantly younger than patients who did not have
cerebral venous thrombosis showed an abrupt increase VITT (table 1). All 70 cases of VITT-associated cerebral
in the frequency of cases in patients older than 45 years, venous thrombosis occurred after a first dose of the
in keeping with the UK COVID-19 vaccination strategy ChAdOx1 (Oxford–AstraZeneca) vaccine, compared
(appendix p 10). The patients in this study were all with 21 (85%) of 25 patients with non-VITT cerebral
vaccinated on or before April 30, 2021, and before this venous thrombosis, in whom the remaining four
date most individuals vaccinated in the UK were aged patients had been given their first dose (three patients)
45 years or older (appendix p 1). When adjusted for the or second dose (one patient) of BNT162b2 (Pfizer–
UK rate of vaccination per age group, using data from BioNTech) vaccine. The clinical features of cerebral
OpenSAFELY,14 the step-change in frequency above age venous thrombosis were similar in the VITT and
45 years was no longer apparent (appendix p 10). non-VITT groups (appendix p 4).
VITT (n=70) Non-VITT (n=25) p value (VITT vs ISCVT cohort p value (VITT vs
non-VITT) (n=624) ISCVT)
Age, years 47 (32–55) 57 (41–62) 0·0045 37 0·0001
Sex 0·31 0·0007
Female 39 (56%) 11 (44%) 465 (75%)
Male 31 (44%) 14 (56%) ·· 159 (25%)
Ethnicity
White 61 (87%) 21 (84%) 0·74 550/621 (89%) 0·72
Asian 7 (10%) 2 (8%) 1·00 21/621 (3%) 0·017
Black 0 1 (4%) 0·26 31/621 (5%) 0·063
Other or mixed 2 (3%) 1 (4%) 1·00 19/621 (3%) 1·00
Vaccine details
Proportion given AstraZeneca vaccine 70 (100%) 21 (84%) 0·0040 ·· ··
Time from vaccine to cerebral venous 9 (7–12) 11 (6–21) 0·10 ·· ··
thrombosis, days
Venous risk factors
Patients with no venous risk factors 46 (66%) 11 (44%) 0·057 ·· ··
Patients with no ISCVT risk factors 61 (87%) 20 (80%) 0·51 78 (13%) <0·0001
Fibrinogen, g/L 2·0 (1·3–2·8)* 3·3 (2·9–4·1)† 0·0001 ·· ··
Prothrombin time, s 13·0 (11·9–14·8)‡ 11·5 (10·8–12·6)§ 0·0005 ·· ··
Activated partial thrombloplastin time, s 28·8 (25·1–34·8)¶ 26·9 (24·4–32·7)|| 0·030 ·· ··
Anti-platelet factor 4 antibodies
Positive on ELISA 56/58 (97%) 2/16 (13%) <0·0001 ·· ··
Positive on Acustar HIT-IgG assay 3/13 (23%) 0 0·52 ·· ··
Data are median (IQR), n (%), or n/N (%). Blood results were the closest available to the admission date. Normal ranges are typically fibrinogen 1·9–4·3 g/L, prothrombin time
10–13 s, and activated partial thromboplastin time 23–30 s. VITT=vaccine-induced immune thrombotic thrombocytopenia. ISCVT=International Study on Cerebral Venous
Vein and Dural Sinus Thrombosis. *n=59. †n=15. ‡n=69. §n=24. ¶n=67. ||n=24.
Table 1: Demographics, vaccine details, and blood results on admission in patients with VITT-associated cerebral venous thrombosis and those with
non-VITT cerebral venous thrombosis
Patients with VITT-associated cerebral venous thrombosis, arterial thrombosis, or both, with pulmonary
thrombosis had lower levels of fibrinogen at hospital embolism and hepatic portal vein thrombosis being
admission than the non-VITT group (table 1; appendix particularly common (appendix p 5). By contrast,
p 11), although both medians were within the normal extracranial thrombosis was only seen in one (4%) of
range (1·9–4·3 g/L). 56 (97%) of 58 patients with VITT 25 patients classified as non-VITT. This patient
who were investigated for anti-PF4 antibodies using an (patient D; appendix p 3) had pulmonary embolism and
ELISA assay tested positive; the characteristics of the other hepatic vein thrombosis in addition to cerebral venous
two patients are given in the appendix (p 3; patients E thrombosis and presented with a platelet count of
and F). Two patients with anti-PF4 antibodies on ELISA 57 × 10⁹ per L. Even though the patient was not classified
were classified as non-VITT using the current criteria, one as having VITT in this study, because her highest
because her platelet count never fell below 150 × 10⁹ per L D-dimer was only 822 μg/L, the clinical team treated her
(patient B) and the other because her D-dimers never rose for VITT.
above 2000 μg/L (patient C, appendix p 3). We compared the modified Rankin scale13 at discharge
The number of veins thrombosed on the first venogram for patients with VITT compared with the non-VITT
was higher in the VITT group (median 3, IQR 2–4) than group (figure 3A) and the ISCVT cohort (figure 3B). The
in the non-VITT group (2, 2–3; p=0·041; appendix pp 5, 11). primary outcome, death or dependency on others for care
On neuroimaging at the time of admission, patients with (modified Rankin score 3–6), was significantly more
VITT were more likely to have evidence of multiple common in patients with VITT-associated cerebral venous
venous infarction (10 [14%] of 70 patients) than those thrombosis (33 [47%] of 70 patients) than in patients
without VITT (0 of 25 patients; p=0·046), and more likely without VITT (four [16%] of 25 patients; p=0·0061). More
to have multiple intracerebral haemorrhages (23 [33%] of patients died during admission in the VITT-associated
70 patients) than non-VITT patients (three [12%] of cerebral venous thrombosis group (20 [29%] of 70 patients)
25 patients; p=0·045; appendix p 5). than in the non-VITT group (one [4%] of 25 patients;
31 (44%) of 70 patients with VITT-associated cerebral p=0·011). Low Glasgow Coma Scale15 on admission and
venous thrombosis had evidence of extracranial venous cerebral haemorrhage were the strongest predictors of
before being switched to argatroban later on the same 150 × 10⁹ per L for defining thrombocytopenia risks
day). Six (67%) of nine patients with VITT-associated excluding patients who have good evidence of VITT.
cerebral venous thrombosis who received some form of Additionally, making D-dimer greater than 2000 μg/L
heparin as their only parenteral anticoagulant had died or an absolute requirement for diagnosis of VITT-associated
were dependent on others for their care at the end of cerebral venous thrombosis might have been suboptimal.
their hospital admission, whereas 16 (37%) of 43 patients Patient C (appendix p 3) had cerebral venous sinus
given a non-heparin alternative as their only parenteral thrombosis, a platelet count of 110 × 10⁹ per L, and
anticoagulant had this poor outcome, although this positive anti-PF4 antibodies, which is strong evidence for
difference was not significant (p=0·14). VITT, but even after repeated testing her D-dimer was
never higher than 410 μg/L. Patient D (appendix p 3) had
Discussion a lowest platelet count of 37 × 10⁹ per L and in addition to
To our knowledge, our study provides the most detailed her cerebral venous sinus thrombosis had evidence of
information reported to date on the clinical and radio hepatic vein thrombosis, suspicious for VITT even
logical characteristics of VITT-associated cerebral though her anti-PF4 antibody was negative, yet the
venous thrombosis. The age distribution of our patient highest D-dimer was only 822 μg/L. Neither patient
population was skewed towards older ages because of met the criteria for VITT-associated cerebral venous
the UK policy of vaccinating older patients first, thrombosis used in this study, yet both were judged to
but patients with VITT-associated cerebral venous have VITT by their treating clinicians.
thrombosis were younger than those without VITT. Aside from the lowest platelet count and highest
Other key findings were that, compared with non-VITT D-dimer that were used to make the diagnosis of VITT-
patients, those with VITT-associated cerebral venous associated cerebral venous thrombosis, three other
thrombosis had more extensive venous thrombosis and features showed a significant association with the diag
higher rates of multiple infarcts, multiple intracerebral nosis: anti-PF4 antibodies, fibrinogen, and extracranial
haemorrhages, and extracranial thrombosis. VITT was venous thromboses. The specificity of anti-PF4 antibodies
associated with significantly more death or dependency was probably underestimated in our study, as the only
at the end of hospital admission, but both the use two patients who were positive for the antibody but
of non-heparin anticoagulants and of intravenous were classified as non-VITT using current criteria
immunoglobulin were associated with an improved were patients B and C (appendix p 3)—ie, patients with
outcome. As these treatments become better established, probable VITT who were most likely misclassified.
the outcomes after VITT-associated cerebral venous However, patients E and F (appendix p 3) had evidence
thrombosis might improve. for VITT but both were negative for anti-PF4 antibodies
The ratio of patients with VITT to patients without on two different ELISA assays, suggesting that a negative
VITT was 2·8:1, as expected from the estimated ELISA result should not be used to define VITT as
incidence of VITT-associated cerebral venous thrombosis unlikely19 or to cease further investigation,18 as is recom
in individuals receiving a first dose of the ChAdOx2 mended in existing guidelines.18,19
vaccine (12·3 per million16) and the expected background These observations lead us to propose a new set of
incidence of cerebral venous thrombosis in the same diagnostic criteria for VITT-associated cerebral venous
subpopulation during the 4-month study period (4·4 per thrombosis (panel). A diagnosis of possible VITT-
million17), suggesting that cerebral venous thrombosis associated cerebral venous thrombosis will alert
was probably unrelated to vaccination in most or all of clinicians to an urgent need for further investigation for
our non-VITT cases and that there was no significant this condition and they are likely to avoid the use of
bias towards reporting of VITT cases. heparins or platelet transfusions if possible. A diagnosis
A normal platelet count (conventionally ≥150 × 10⁹ per L) of probable VITT constitutes sufficient evidence to offer
is regarded as ruling out VITT in existing peer-reviewed a patient full treatment for this condition, including
published guidelines,18,19 but adopting a platelet count intravenous immunoglobulin or plasma exchange. A
threshold of less than 150 × 10⁹ per L as a criterion for definite diagnosis will be useful for defining a population
VITT-associated cerebral venous thrombosis in the for future research studies on this condition. According
present study could have been a weakness. First, defining to these criteria it is possible to make a diagnosis of
thrombocytopenia as a fall to less than 50% of a known probable VITT in patients with a normal platelet count
baseline platelet count is recommended in the analogous (≥150 × 10⁹ per L), a normal D-dimer, or a negative
condition of heparin-induced thrombocytopenia.20 Second, anti-PF4 antibody test, provided other evidence strongly
patient B (appendix p 3), who was excluded from our supports the diagnosis.
VITT group because her platelet count did not fall In patients with cerebral venous thrombosis following
below 150 × 10⁹ per L, was treated as having VITT because COVID-19 vaccination, anti-PF4 testing should not be
of positive anti-PF4 antibodies and very high D-dimer of reserved for patients with admission platelet counts
4985 μg/L. Although we regard thrombocytopenia as below 150 × 10⁹ per L. This strategy would risk missing
the hallmark for VITT, adopting a hard threshold of patients with VITT. A patient with a low-normal platelet
count may still have anti-PF4 antibodies, as was the case radiology reports for interpretation of scans, and on
for patient B (appendix pp 3–4), and a diagnosis of VITT routine clinical obser vations, laboratory tests, and
should still be considered while further diagnostic tests radiology, which might have led to indication bias. For
are undertaken, including further full blood counts. example, we found only one patient with anti-PF4
Clinicians should be aware that patients with VITT- antibodies but normal platelets (patient B; appendix p 3),
associated cerebral venous thrombosis are more likely but nine (45%) of 20 patients with normal platelets were
to have extracranial thrombosis than other patients with not checked for anti-PF4 antibodies, so other cases with
cerebral venous thrombosis. Some patients, such as this combination might have been missed. We were
patient A (figure 1; appendix p 3), might be dysphasic unable to draw firm conclusions about treatments for
and have difficulty reporting their symptoms. VITT-associated cerebral venous thrombosis because we
Anticoagulation and treatment with intravenous could not control for differences in the baseline
immunoglobulin were associated with a lower probability characteristics between patients offered or not offered
of death or dependency at the end of hospital admission, those treatments.
but this finding is difficult to interpret, as the most unwell In conclusion, we have described the clinical features
patients might have died before these treatments could of VITT-associated cerebral venous thrombosis in detail,
be offered, biasing the results. Similarly, the association allowing us to propose diagnostic criteria for this
between decompressive hemicraniectomy and poor condition. We recommend that all patients presenting
outcome probably reflects selection of patients with the with cerebral venous thrombosis within 28 days of
most severe cerebral venous thrombosis for this invasive COVID-19 vaccination should be checked for anti-PF4
procedure. However, the mortality rate of 54% after antibodies, whatever their platelet count, until there are
decompressive hemicraniectomy for VITT-associated sufficient data to set an upper limit on the platelet count
cerebral venous thrombosis is high compared with a with which VITT-associated cerebral venous thrombosis
historical mortality of 16% after this procedure in cerebral might occur. We have shown that VITT-associated
venous thrombosis.21 cerebral venous thrombosis has poorer outcomes than
The relationship between platelet transfusion and other forms of cerebral venous thrombosis and our
poor outcome in VITT-associated cerebral venous data suggest that non-heparin anticoagulants and
thrombosis appears to support concerns about the safety immunoglobulin might improve outcomes. However,
of this treatment,4 but the findings are difficult to interpret; VITT appears to be a very rare side-effect of vaccination
in 12 (48%) of 25 patients offered this treatment, the with the ChAdOx1 (Oxford–AstraZeneca) vaccine, the
indication was to support decompressive hemicraniectomy, risk of which is likely to be greatly outweighed by the
which was only offered to patients with severe cerebral benefit of vaccination against COVID-19 for most
venous thrombosis. people.22
We present the largest and most detailed study of Contributors
VITT-associated cerebral venous thrombosis to date, with CR and RJP conceived the study. The Steering Committee comprised
a well-matched control group consisting of patients RJP, AW, TS, MS, DJW, and CR. RJP wrote the protocol and clarified
the regulatory framework of the study. TS, AT, and BS independently
presenting to UK hospitals with cerebral venous initiated a similar study that was amalgamated into this one.
thrombosis after vaccination against COVID-19 but RJP designed the case report form and AT, BS, PF, AW, MS, DJW, and
without evidence of VITT. However, our study has some CR provided critical review of the content. RJP designed, implemented,
limitations. The number of patients in each group in our and maintained the database and uploaded the data. RJP, AT, and
BS continuously reviewed the data to ensure its validity and submitted
study was small, because of the rarity of these conditions. data queries where there were errors or omissions. BC provided data
The study was underpowered for some of the comparisons on where some of the cases had been seen. RJP, AT, RM, PA-F, JMY,
made between the VITT and non-VITT groups. Although LZ, MJ, EH, DWh, PF, and AW coordinated data collection in their
our study will generate important hypotheses for sites and submitted case report forms. GH-S, CH, and DWa submitted
case report forms. RJP performed the statistical analysis and wrote the
future research, we cannot draw inferences about other manuscript. All authors critically reviewed the manuscript, had full
populations of patients with cerebral venous thrombosis access to the data in the study, and shared responsibility for the
after COVID-19 vaccination. Comparison of our patients decision to submit for publication.
with the much larger historical ISCVT cohort12 might Declaration of interests
have been confounded by the higher age of our patients, RJP receives grants from Randox Laboratories on an unrelated subject
attributable to COVID-19 vaccination policy in the UK, and from The Stroke Association for work on COVID-19 and stroke,
not related to vaccination. PA-F receives grants from the Wellcome Trust
rather than to VITT. The median interval between for work on an unrelated subject. EH receives grants from MND
vaccination and symptom onset could be an under Scotland and the National Institute for Health Research (NIHR) for work
estimate; in some cases in which the first symptom of on an unrelated subject. TS sits on the Medicines and Healthcare
products Regulatory Agency Vaccine Benefit Versus Risk Expert Working
cerebral venous thrombosis was reported as headache,
Group and was on the Data Safety Monitoring Committee of the GSK
this symptom might initially have been caused by study to evaluate the safety and immunogenicity of a candidate Ebola
mechanisms other than cerebral venous thrombosis, and vaccine in children GSK3390107A (ChAd3 EBO-Z) vaccine. MS receives
also patients with a shorter interval might have been grants from Shire and Novartis, and has received personal fees from
Takeda, Novartis, Octapharma, and Sanofi for work on unrelated
preferentially reported. We were dependent on local
subjects. BS received a grant from the Medical Research Council, via the 8 Helms JM, Ansteatt KT, Roberts JC, et al. Severe, refractory
UK Research Institutes/NIHR Global Effort on COVID-19 Research to immune thrombocytopenia occurring after SARS-CoV-2 vaccine.
study neurological disease in relation to COVID-19, and has been a case J Blood Med 2021; 12: 221–24.
management consultant to WHO-South-East Asia via the Global 9 Malayala SV, Mohan G, Vasireddy D, Atluri P. Purpuric rash and
Outbreak Alert and Response Network since April, 2020, but vaccination thrombocytopenia after the mRNA-1273 (Moderna) COVID-19
against the infection is not the focus in either case. CR receives grants vaccine. Cureus 2021; 13: e14099.
from the NIHR for work on an unrelated subject and is also 10 Lee E-J, Cines DB, Gernsheimer T, et al. Thrombocytopenia
collaborating with FirstKind Medical on a grant on an unrelated subject. following Pfizer and Moderna SARS-CoV-2 vaccination.
CR is chair of the NIHR Hyperacute Stroke Research Oversight Group Am J Hematol 2021; 96: 534–37.
and is a member of the European Stroke Organization board of 11 Smadja DM, Yue Q-Y, Chocron R, Sanchez O, Lillo-Le Louet A.
directors. DJW has received personal fees from Bayer, Alnylam, and Vaccination against COVID-19: insight from arterial and venous
thrombosis occurrence using data from VigiBase. Eur Respir J 2021;
Portola, unrelated to the work presented here. All other authors declare
58: 2100956.
no competing interests.
12 Ferro JM, Canhão P, Stam J, et al. Prognosis of cerebral vein and
Data sharing dural sinus thrombosis: results of the International Study on
After publication, anonymised individual patient data will be made Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004;
available on any reasonable request made to the corresponding author, 35: 664–70.
subject to a data sharing agreement and the constraints imposed by 13 van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJA,
UK data control and research governance regulations. van Gijn J. Interobserver agreement for the assessment of handicap
in stroke patients. Stroke 1988; 19: 604–07.
Acknowledgments 14 The OpenSAFELY Collaborative. OpenSAFELY NHS COVID-19
We thank the wider group of Cerebral venous thrombosis After Vaccine Coverage. https://www.opensafely.org/research/2021/covid-
Vaccination Against COVID-19 (CAIAC) collaborators who submitted vaccine-coverage (accessed May 12, 2021).
cases. We also thank the British Association of Stroke Physicians and 15 Teasdale G, Jennett B. Assessment of coma and impaired
the Association of British Neurologists for promoting the study. consciousness. A practical scale. Lancet 1974; 2: 81–84.
This work was undertaken at UCL Hospitals/UCL, which receives a 16 GOV.UK. Medicines and Healthcare products Regulatory Agency.
proportion of funding from the UK Department of Health NIHR Coronavirus vaccine—weekly summary of yellow card reporting.
Biomedical Research Centre funding scheme. RJP is supported by https://www.gov.uk/government/publications/coronavirus-covid-19-
The Stroke Association for his work on COVID-19 and stroke. TS is vaccine-adverse-reactions/coronavirus-vaccine-summary-of-yellow-
supported by the NIHR Health Protection Research Unit in Emerging card-reporting (accessed May 12, 2021).
and Zoonotic Infections (grant number NIHR200907), NIHR Global 17 Coutinho JM, Zuurbier SM, Aramideh M, Stam J. The incidence of
Health Research Group on Brain Infections (17/63/110), and the cerebral venous thrombosis: a cross-sectional study. Stroke 2012;
UK Medical Research Council Global Effort on COVID-19 Programme 43: 3375–77.
(MR/V033441/1) for his work on COVID-19 and neurological disease, 18 Oldenburg J, Klamroth R, Langer F, et al. Diagnosis and
including stroke. TS and BS are supported by the NIHR Global Health management of vaccine-related thrombosis following AstraZeneca
Research Group on Brain Infections (17/63/110). COVID-19 vaccination: guidance statement from the GTH.
Hamostaseologie 2021; 41: 184–89.
References 19 Nazy I, Sachs UJ, Arnold DM, et al. Recommendations for the
1 Our World in Data. Coronavirus (COVID-19) deaths. https:// clinical and laboratory diagnosis of VITT against COVID-19:
ourworldindata.org/covid-deaths (accessed July 22, 2021). communication from the ISTH SSC Subcommittee on Platelet
2 Our World in Data. Coronarivus (COVID-19) vaccinations. https:// Immunology. J Thromb Haemost 2021; 19: 1585–88.
ourworldindata.org/covid-vaccinations (accessed July 22, 2021). 20 Warkentin TE, Roberts RS, Hirsh J, Kelton JG. An improved
3 Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and definition of immune heparin-induced thrombocytopenia in
thrombocytopenia after ChAdOx1 nCoV-19 vaccination. postoperative orthopedic patients. Arch Intern Med 2003;
N Engl J Med 2021; 384: 2124–30. 163: 2518–24.
4 Scully M, Singh D, Lown R, et al. Pathologic antibodies to platelet 21 Avanali R, Gopalakrishnan MS, Devi BI, Bhat DI, Shukla DP,
factor 4 after ChAdOx1 nCoV-19 vaccination. N Engl J Med 2021; Shanbhag NC. Role of decompressive craniectomy in the
384: 2202–11. management of cerebral venous sinus thrombosis. Front Neurol
5 Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA, 2019; 10: 511.
Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-19 22 Taquet M, Husain M, Geddes JR, Luciano S, Harrison PJ. Cerebral
vaccination. N Engl J Med 2021; 384: 2092–101. venous thrombosis and portal vein thrombosis: a retrospective
6 Muir KL, Kallam A, Koepsell SA, Gundabolu K. Thrombotic cohort study of 537 913 COVID-19 cases. EClinicalMedicine 2021;
thrombocytopenia after Ad26.COV2.S vaccination. N Engl J Med 39: 101061.
2021; 384: 1964–65.
7 See I, Su JR, Lale A, et al. US case reports of cerebral venous sinus
thrombosis with thrombocytopenia after Ad26.COV2.S vaccination,
March 2 to April 21, 2021. JAMA 2021; 325: 2448–56.