Stroke Associated With COVID-19 Vaccines
Stroke Associated With COVID-19 Vaccines
Stroke Associated With COVID-19 Vaccines
From the aSchool of Medicine, Guilan University of Medical Sciences, Rasht, Iran; bSchool of Medicine, Shahroud University of Medical Sciences,
Shahroud, Iran ; cNeuroscience Research Center, Poursina Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran; dInsti-
tute of Medical Science and Technology, Shahid Beheshti University, Tehran, Iran; eDepartment of Neurology, Odense University Hospital, Univer-
sity of Southern Denmark, Odense, Denmark; fDepartment of Clinical Research, University of Southern Denmark, Odense, Denmark; gResearch
Unit of Clinical Physiology and Nuclear Medicine, Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark; hSteno Diabe-
tes Center Odense, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; iBRIDGE: Brain Research Interdisci-
plinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; and jNeuroscience Research
Center, Guilan University of Medical Sciences, Rasht, Iran.
Received September 23, 2021; revision received November 28, 2021; accepted December 11, 2021.
Address correspondence to Department of Clinical Research, University of Southern Denmark, Odense, Denmark. E-mail: [email protected].
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© 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license
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https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106440
Journal of Stroke and Cerebrovascular Diseases, Vol. 31, No. 6 (June), 2022: 106440 1
2 M. KAKOVAN ET AL.
PF4 antibody). Such association between thrombocytope- Ischemic stroke after COVID-19 vaccination
nia and thrombosis with a catastrophic clinical picture has
In ischemic stroke, a region of the brain is dispossessed
raised clinical attention. Association of thrombosis and
of blood flow which can be due to thrombosis of an artery
thrombocytopenia rarely occurs in thrombotic thrombo-
or, in rare instances, a vein. Thrombosis can occur in the
cytopenic purpura, heparin-induced thrombocytopenia
vessels following COVID-19 vaccination. They are usually
(HIT), autoimmune HIT, antiphospholipid syndrome
seen in the context of VITT. These cases were mostly diag-
(APS),50 and disseminated intravascular coagulation
nosed following ChAdOx1 nCoV-19 vaccine, especially
(DIC).51 Unusual thrombotic events with thrombocytope-
with the involvement of the middle cerebral artery
nia following COVID-19 vaccination and the presence of
(MCA). The emergence of persistent or unusual neurolog-
anti-PF4 antibody have led to the concept of VITT, which
ical symptoms after receiving the COVID-19 vaccines
is also called thrombosis with thrombocytopenia syn-
should urgently be evaluated for VITT with neuroimag-
drome (TTS).52 The clinical picture mirrors what is seen in
ing techniques and laboratory tests.
HIT.53 Anti-PF4 antibodies are typically detected in HIT54
De Michele et al.64 carried out clot analysis after throm-
probably due to molecular mimicry between proteins on
bectomy in patients with ischemic stroke following the
the virus and platelet antigens,55,56 On another reading,
ChAdOx1 nCoV-19 vaccine and suggested that the clot
the antibodies produced against the spike (S) proteins
collected during the first thrombectomy was mainly com-
might cross-react with specific antigens expressed on the
posed of platelets (85% of the total material examined)
platelet surface.28 However, in one preliminary report,
and was massively infiltrated by neutrophils with scarce
Greinacher et al.57 suggested that anti-PF4 antibody do
evidence of karyorrhexis. Histological features consistent
not cross-react with the S protein.
with the presence of neutrophil DNA extracellular traps
Another hypothesis is that the breakdown of fibrin
(NETs) were also observed. Furthermore, the clot col-
leads to the production of D-dimer.58 Elevated D-dimer
lected during the second endovascular procedure was a
associated with thrombocytopenia is suggestive of activa-
red-blood-cell-rich thrombus (90% of red blood cells and
tion of systemic anticoagulation. Therefore, increased D-
10% fibrin and platelets) with scarce neutrophils. Nor-
dimer level may be a helpful parameter to distinguish idi-
mally, platelet-rich thrombi are formed by Von Wille-
opathic primary thrombocytopenia from secondary
brand factor, neutrophil extracellular traps, and fibrin.65
thrombocytopenia due to systemic thrombosis.58 Further-
However, platelet/fibrin thrombi were also found in
more, CSVT incidence is significantly correlated with D-
veins and arteries of multiple organs,66 so-called “white
dimer level.59
clot syndrome”.67 Despite this, it would be difficult to
A prospective Chinese cohort study suggested that
account for their potential pathophysiological differences.
inactivated COVID-19 vaccine (BBIBP-CorV, Sinopharm)
In fact, the main difference between the clots is their age.64
did not influence the profile of antiphospholipid antibody
Table 1 shows that most of the patients with ischemic
and anti-PF4-heparin antibody nor increased the risk of
stroke after COVID-19 vaccination were women within
thrombosis.60 Additionally, Campello et al.61 suggested
the age range of 26-60 years and after vaccination with
that significant activation of fibrinogen-driven coagula-
ChAdOx1 nCoV-19 vaccines and within 1 to 21 days after
tion, plasma thrombin generation, or clinically meaning-
the vaccination.
ful platelet aggregation did not occur after ChAdOx1
nCoV-19 or BNT162b2 vaccination. Nevertheless, Simp-
Hemorrhagic stroke after COVID-19
son et al.62 evaluated associations between ChAdOx1
vaccination
nCoV-19 or BNT162b2 vaccination and hematological
and vascular adverse events. They demonstrated an asso- Hemorrhagic strokes occur when a blood vessel rup-
ciation between vaccination with ChAdOx1 (but not vac- tures. ICH and subarachnoid hemorrhage (SAH) can
cination with BNT162b2) and idiopathic occur after COVID-19 vaccination, which can be primary
thrombocytopenic purpura (ITP), arterial thromboembolic or secondary to venous thrombosis.23,71 76 While ICH
events and hemorrhagic events. after COVID-19 vaccination can occur in the context of
Using an animal model, Nicolai et al.63 showed that VITT, Silva et al.75 described primary hemorrhagic stroke
intravenous injection of ChAdOx1 nCov-19 triggers plate- following ChAdOx1 nCoV-19 vaccination in a patient
let-targeted autoimmunity in the spleen that may result in without thrombocytopenia, coagulation disorder, or coag-
thrombocytopenia syndrome. Hence, aspiration (to ulation risk factors. Argument for such a causal relation is
ensure the needle is not in a blood vessel) prior to injection that arterial hypertension77 and ICH23,78 are complica-
of the vaccine could be a potential preventive measure for tions of COVID-19 vaccination. More to the point, hyper-
this important side effect. tension is an important risk factor of ICH.
Most of the reports of stroke after COVID-19 are from Finsterer et al.79 suggested that the second dose of
Europe. In addition, most of the patients were women SARS-CoV-2 vaccination may be followed by ICH even
within an age range of 18-77 years and within 1-24 days when the first dose was uneventful Table 2. summarizes
after the ChAdOx1 nCov-19 vaccination. reports of ICH following COVID-19 vaccination. As can
4
Table 1. Summary of reports of ischemic stroke cases following the COVID-19 vaccination.
Vaccine Number Age Gender Interval (days) Clinical Imaging and lab findings Treatment Outcome Author, year, ref
of cases (F, M) between presentation
vaccination and
diagnosis
ChAdOx1 3 35-43 11-21 Case 1: headache, Case 1: MCA infarct Case 1: IVIg, plasma- Case1: death Al-Mayhani
nCoV-19 F = 2, M = 1 left hemiparesis, Case 2: ICA infart and CVST pheresis, Fondapari- Case 2: improved et al., 202127
(AstraZeneca) right gaze prefer-Case 3: MCA infarct nux, and clinically
ence, and drowsi- Thrombocytopenia, positive decompressive hemi- Case3: discharged
ness anti-PF4 antibody, and craniectomy with favorable
Case 2: diffuse increased D-dimer in all Case2: IVIg, plasma- clinical outcome
headache, left three patients pheresis, methyl-
visual field loss, prednisolone, and
confusion, and Fondaparinux
left arm weakness Case 3: platelet trans-
Case 3: dysphasia fusion, IVIg, and
Fondaparinux
1 60 8 headache and left- Ischemic stroke in the terri- Hydrocortisone, plate- Death Blauenfeldt
F=1 weakness and eye tory of ICA and MCA let concentrates, et al., 2021
deviation to the Thrombocytopenia, positive hemicraniectomy, (53)
right anti-PF4 antibody, and and dalteparin
increased D-dimer
1 26 1 Persistent nausea Ischemic stroke in the terri- Corticosteroids, plas- Only gripping difficul- Garnier et al.,
F=1 and headache and tory of MCA matic exchange, and ties and minor phasic 202168
right hemiplegia Thrombocytopenia, positive anticoagulants troubles were
and aphasia anti-PF4 antibody, remaining
decreased fibrinogen level
23 21-77 6-24 (mean:12) NM Thirteen cases of CVST NM Seven patients died Scully et al.,
(mean:46) Two cases of ischemic stroke 202169
F = 14 M = 9 antiPF4 antibody was posi-
tive in 22 patients
Thrombocytopenia in 22
patients, low fibrinogen
levels in 13 patients, and
increased D-dimer levels in
M. KAKOVAN ET AL.
21 patients
1 31 8 Acute headache, Occlusion of MCA with the IV thrombolysis, Aspi- Favorable clinical Walter et al.,
M=1 aphasia, and source of thrombus ipsilat- rin, Danaparoid, outcome 202170
hemiparesis eral in the carotid bulb, Phenprocoumon
elevated D-dimer level
slightly, and positive anti-
PF-4 antibody
STROKE ASSOCIATED WITH COVID-19 VACCINES 5
et al., 202164
administration of ChAdOx1 nCoV-19 vaccine and in peo-
De Michele
Note: MCA: Middle Cerebral Artery; CVST: Cerebral Venous Sinus Thrombosis; Anti-PF4-antibody: anti-platelet factor 4 antibody; IVIg: Intravenous Immunoglobulin; IV: Intravenous.
ple 30 57 years of age, 5 12 days after the vaccination
Table 2. shows the summary of reports of ICH following
the COVID-19 vaccination.
Ischemic stroke
Case 2 = 10
contrast, mRNA vaccines, compared to hormonal con- patients were female at 18-77 years of age. Most of these
traceptive use, do not show a disproportional rate of CVST cases were reported following ChAdOx1 nCoV-19
thromboembolic events in younger women.91 vaccine administration. Moreover, these patients received
A multicenter cohort study92 collected data from 43 the vaccine 2-24 days before the diagnosis of stroke.
hospitals across the UK and between April 1st and May
20th, 2021, reporting 95 patients with stroke, of which 70
Comparison of different vaccines associated
had VITT. The median age of the VITT group was
with stroke
47 years, compared to that in the non-VITT group, which
was 57 years (p=0¢005). The primary outcome of death or Since the basic characteristics of vaccine recipients are
dependency occurred more frequently in the patients different, it is not easy to compare various COVID-19 vac-
with VITT-associated CVT (33/70), compared with the cines triggering stroke. The manufacturing technology for
non-VITT control group (4/25) (p=0¢0061). This adverse mRNA-based vaccines is different from that for adenovi-
outcome was less frequent in the patients with VITT who rus-based vaccines, and hence the mechanism of thrombo-
received non-heparin anticoagulants (18/50), compared sis formation differs in these vaccines.112 CVST after
with those who did not receive non-heparin anticoagu- ChAdOx1 nCov-19 vaccination is more frequent and is
lants (15/20) (p=0¢0031), and in those who received IVIg associated with venous thrombotic events and a higher
(22/55), compared with those who did not receive IVIg mortality rate than that after the BNT162b2 and mRNA-
(11/15) (p=0¢022). In this study, it was also suggested 1273 vaccines.94 In addition, thrombocytopenia and posi-
that non-heparin anticoagulants and immunoglobulin tive anti-PF4 antibodies have been reported more fre-
treatment might improve outcomes of VITT-associated quently after the ChAdOx1 nCov-19 vaccine than after
CVT. the mRNA-based vaccine.94 Furthermore, the clinical
CVST after vaccination mostly occurs with adenoviral manifestations of CVST after ChAdOx1 nCov-19 vaccine
COVID-19 vector vaccines, especially ChAdOx1 nCoV-19 and mRNA-based vaccine are different. CVST after ChA-
vaccine; nonetheless, CVST may also occur following dOx1 nCov-19 vaccination has a clinical picture different
mRNA-based COVID-19 vaccines. rAd26-S and rAd5-S is from CVST patients unrelated to vaccination; however,
another recombinant adenovirus vaccine but no CVT CVST which occurs after receiving mRNA vaccines is sim-
cases have been reported following its use. Nonetheless, ilar to pre-COVID-19 CVST cases unrelated to vaccina-
that is not to say that CVT does not occur following this tion.94 These differences can even extend to differences
vaccine. between vaccines that are made with similar technology.
CVST usually has a good prognosis. However, CVST Indeed, patients who received the Ad26.COV.2.S vaccine
after COVID-19 vaccination may follow a catastrophic tend to develop clinical manifestations later than those
course. The outcome for these patients may be poor due receiving ChAdOx1 nCoV-19.114 Additionally, D-dimer
to refractory increased ICP; indeed, almost half of patients and activated Partial Thromboplastin Time (aPTT) levels
with CVT in the context of VITT die within a few days might be lower in patients after Ad26.COV.2.S than sub-
and death often occurs following brain infarction often jects receiving ChAdOx1 nCoV-19.114 Also, the probabil-
associated with ICH.69,78,93 ity of a positive platelet function test in ChAdOx1 nCoV-
Table 3 summarizes reports of CVST following the 19 recipients is much higher than in the Ad26.COV.2.S
COVID-19 vaccination. The table shows that most of the recipients; nonetheless, in both groups, most patients are
patients were female at 24-56 years of age. Most of these positive for HIT antibody test using ELISA.114 Notably,
CVST cases were reported following ChAdOx1 nCoV-19 patients with CVT after Ad26.COV.2.S administration is
vaccine administration. Furthermore, all of the patients more likely to suffer ICH and internal jugular vein throm-
received the vaccine 7-20 days before the diagnosis of bosis than those with CVT after ChAdOx1 nCoV-19.114
stroke. There are no significant differences between the two vac-
cines in mortality and presenting symptoms, viz head-
ache, visual disturbance, hemiparesis, and fever.114
Ischemic and hemorrhagic stroke subsequet
Beyond the comparison between different COVID-19 vac-
to CVST after COVID-19 vaccination
cines, Pawlowski et al.115 assessed the association of
Ischemic or hemorrhagic stroke may occur with CVST COVID-19 vaccines and non-COVID-19 vaccines with
subsequent to COVID-19 vaccination. Obstruction of the CVST in a cohort of 771,805 vaccination events across
brain’s venous system increases ICP and may rupture 266,094 patients in the Mayo Clinic Health System
blood vessels leading to hemorrhagic stroke. Further- between 01/01/2017 and 03/15/2021 and found that the
more, hypercoagulable state may cause further clot for- risk of CVST is similar in the 30 days prior to COVID-19
mation causing ischemic stroke. These complications have vaccination compared to that in the 30 days after vaccina-
a direct impact on the treatment strategy. tion. In addition, the risk of CVST within 30 days follow-
Table 4 summarizes reports of CVST with ischemic or ing COVID-19 vaccination is similar to the risk of CVST
hemorrhagic stroke. The table shows that most of the within 30 days after all analyzed non-COVID
STROKE ASSOCIATED WITH COVID-19 VACCINES
Table 2. Summary of reports of ICH following the COVID-19 vaccination.
Vaccine Number of Age Gender Interval (days) Clinical presentation Imaging and lab findings Treatment Outcome Author, year, ref
cases (F, M) between vaccina-
tion and diagnosis
ChAdOx1 1 In her thir- 10 Headache, lethargy, ICH (MCA) IV tranexamic acid Death Bjørnstad et al.,
nCoV-19 ties uncoordinated move- Thrombocytopenia and 202123
(AstraZeneca) F=1 ments, reduced con- positive anti-PF4 anti-
sciousness, aphasia, body
central left facial Thrombi in the transverse
paresis with right gaze sinus in autopsy
deviation, and left
hemiparalysis
1 57 5 Fever, headache, left ICH Decompressive On Day 15 left hemi- Silva et al.,
F=1 hemiparesis, vomiting, craniectomy paretic, obeying sim- 202175
and somnolence ple tasks, kept on
tracheostomy
mRNA-based 1 52 7 aphasia ICH in temporal lobe Sacubitril/valsartan, Aphasia resolved Finsterer et al.,
SARS-CoV-2 M=1 atorvastatin, and 202179
vaccine bisoprolol in the
rehabilitation
1 52 12 Intense headache, GCS;6 ICH Tranexamic acid, Death Wolthers
ChAdOx1 M=1 Thrombocytopenia, ele- platelet concentrate et al.,202180
nCoV-19 vated fibrin D-dimer
(Vaxzervia) level, low fibrinogen
level, slightly increased
INR
Note: MCA: Middle Cerebral Artery; Anti-PF4-antibody: anti-platelet factor 4 antibody; ICH: Intracerebral Hemorrhage; INR: International Normalized Ratio; IV: Intravenous; GCS: Glasgow
Coma Scale.
7
8 M. KAKOVAN ET AL.
vaccinations. Finally, the authors suggested that CVST is present 5 28 days after vaccination and are characterized
rare and not significantly associated with COVID-19 vac- by thrombocytopenia, elevated D-dimer level and throm-
cination in their study. bosis, which often rapidly deteriorate (definite case). In
addition to diagnostic criteria and laboratory findings,
radiological imaging should be used to confirm the diag-
Recommendations for diagnosis and
nosis. In the event of acute onset of CVST, a non-contrast
management of CVST after COVID-19
brain computed tomography (CT) should be the first eval-
vaccination
uation. Nevertheless, a non-contrast CT has poor sensitiv-
Many cases of stroke after COVID-19 vaccination is ity since it only displays indirect and suggestive
associated with VITT. Following the first post-COVID-19 alterations of CVST in 30% of patients.118 Consequently, if
vaccination VITT reports several international scientific CVST is suspected, non-contrast CT should be carried out
societies and panels of experts made recommendations on along with a contrast CT scan to create a three-dimen-
the management of patients with suspected VITT syn- sional venous reconstruction (CT venography).119 124 In
drome from diagnosis to treatment. Management of patients with subacute onset, magnetic resonance imaging
stroke associated with VITT is challenging and complex. (MRI) is, however, the study of choice.118 In a meta-analy-
In addition, clinicians should be aware that management sis study, CT and MRI showed similar diagnostic perfor-
recommendations of CVST after COVID-19 vaccination mance for CVST diagnosis.123 Although Kennedy et al.125
markedly differ from the routine treatment of CVST. reported a case of VITT following Ad26.COV2.S COVID-
The diagnosis of VITT is rather challenging owing to its 19 vaccination without radiographically thrombosis
diverse clinical manifestations. Clinicians should maintain demonstrable by radiography (Brain MRI) at presenta-
a high degree of suspicion in patients with symptoms sug- tion. Withal, Ikenberg et al.76 reported a patient whose ini-
gestive of thrombotic events after COVID-19 vaccination, tial brain MRI was seemingly normal, but follow-up brain
and along with this, wise comprehensive diagnostic crite- MRI findings indicated an extensive CVST, and labora-
ria can be advantageous. The Expert Hematology Panel tory report confirmed VITT. Therefore, if clinical suspi-
(EHP) of UK116 and the American Society of Hematology cion of CVST after COVID-19 persists, a repeat MRI is
(ASH)117 produced recommendations for the diagnosis of useful.
VITT that included receipt of a COVID-19 vaccine (Jans- Treatment of stroke in the setting of VITT is challeng-
sen/Vaxzevria) 4 to 30 days previously, thrombosis (often ing. What is important is to act according to the existing
cerebral or abdominal), thrombocytopenia, and positive guidelines considering the specific condition of each
PF4-HIT test using ELISA. They also recommended patient. The key element of management of VITT-associ-
urgent medical evaluation for VITT if any of the symp- ated CVT is high-dose IVIg and anticoagulation using
toms including severe headache, visual changes, abdomi- direct oral anticoagulants.86,126,127 The use of non-heparin
nal pain, nausea and/or vomiting, backache, shortness of anticoagulants and IVIg can be related to a low probabil-
breath, leg pain or swelling, petechiae, or easy bruising ity of VITT-associated CVT death or dependency at the
develop 4 to 30 days after vaccination. Urgent diagnostic end of hospital admission.92 IVIg prevents platelet activa-
workup in suspected VITT also includes complete blood tion by PF4 antibodies and rapidly restores the platelet
count (CBC) and peripheral blood smear, PF4-ELISA (HIT count.105 Immune globulin prevents antibody-mediated
assay) using blood drawn prior to any therapies, fibrino- platelet clearance and may down-regulate platelet activa-
gen level, and imaging for thrombosis based on signs/ tion by immune complexes by blocking platelet FcRgIIA
symptoms.116,117 In addition to the above-mentioned rec- receptors.127 Therefore, prompt initiation of IVIg (1g/kg
ommendations for lab tests, a D-dimer check seems useful over two days if needed) that is likely to influence the dis-
for the diagnosis of VITT associated with COVID-19 vac- ease process, regardless of the severity of thrombocytope-
cination. Scully et al.69 demonstrated that D-dimer levels nia, and continuing to review the clinical course, is
in patients with thrombosis and thrombocytopenia after recommended for VITT.128 Contrastingly, clinicians
receiving the ChAdOx1 nCoV-19 vaccine were much should avoid all forms of heparin (i.e. unfractionated hep-
higher than what was expected in patients with acute arin, even for line flushes, or LMWH e.g. enoxaparin) in
venous thromboembolism. In addition, the EHP116 classi- VITT-associated CVT.74 However, non-heparin-based
fies clinical presentation of VITT as follows: patients pre- anticoagulants such as direct thrombin inhibitors (includ-
senting with acute thrombosis and new-onset ing bivalirudin, argatroban, and dabigatran), direct factor
thrombocytopenia within 28 days of receiving COVID-19 Xa inhibitors (e.g., rivaroxaban, apixaban, and edoxaban),
vaccination (possible case), patients with either a low and indirect antithrombin dependent Xa inhibitors (e.g.,
platelet count without thrombosis or with a D-dimer fondaparinux) are not contraindicated in VITT.129 Admin-
count at or about normal levels (< 2000 mg/L) but with istration of anticoagulation should not be avoided in
and normal fibrinogen (2 4 g/L) levels (unlikely case), VITT patients with low fibrinogen levels or bleeding asso-
increased D-dimers (>4000 mg/ L > 2000 with a strong ciated with VITT, particularly if the platelet count is
clinical suspicion) (probable case), and cases usually >20,000/mL or increases following IVIg initiation.116,117
STROKE ASSOCIATED WITH COVID-19 VACCINES
Table 3. Summary reports of CVST following the COVID-19 vaccination.
Vaccine Number of Age, Gender Interval (days) Clinical presentation Imaging and lab Treatment Outcome Author,
cases (F, M) between findings year, ref
vaccination and
diagnosis
ChAdOx1 nCoV- A total of 213 Median of Nine days in the NM CVST in all of the NM Of the 117 patients with a Krzywicka
19, BNT162b2 ChAdOx1 age: 46 ChAdOx1 patients reported outcome in the et al.,
mRNA, and nCoV-19 (187 75% women nCov-19 Thrombocytopenia in ChAdOx1 nCov- 19 group, 202194
mRNA-1273 patients), in ChA- group and 107 patients amongst 44 died, compared to 2
BNT162b2 dOx1 7 days in the 187 patients receiv- deaths out of 10 deaths with
mRNA (25 nCoV-19 mRNA vac- ing the ChAdOx1 reported outcome in the
patients), and recipients cine group nCoV-19 vaccine mRNA vaccine group and 3
mRNA-1273 and 77% in deaths out of 100 patients
(1 patient) mRNA with reported outcome in
vaccine the pre- COVID- 19 group.
recipients
9
10
Table 3 (Continued)
Vaccine Number of Age, Gender Interval (days) Clinical presentation Imaging and lab Treatment Outcome Author,
cases (F, M) between findings year, ref
vaccination and
diagnosis
1 36 14 Fever with vomiting CVST Enoxaparin, Death Aladdin et
F=1 and severe headache, Thrombocytopenia, antibiotics, al., 202199
and hypofibrinogenemia, and antivirals
sudden onset of focal leukocytosis, ane-
left-sided convul- mia, increased D-
sions for 5 min fol- dimer level, and liver
lowed by weakness enzymes, high creati-
in the left arm. nine severe acidosis
(acute kidney injury),
and prolonged PT,
PTT, and INR
2 24,39 8, 12 Case 1: severe holoce- Case 1: CVST Case 1: danapa- Cases 1 and 2: discharged Gattringer
F=2 phalic headache Case 2: CVT with roid, dexa- without any symptoms et al.,
(before admission), related small frontal methasone, 2021100
new left dull occipi- right juxtacortical IVIg, argatro-
tal headache(during hemorrhage ban, and dabi-
admission) Thrombocytopenia, gatran
Case 2: severe persist- positive anti-PF4 Case 2: IVIg,
ing headache antibody, increased dexametha-
D-dimer and sone, and
decreased fibrinogen argatroban
level
Ad26.COV2.S 1 40 12 Headache, sinus pres- CVST Bivalirudin, Resolution of headache and a Clark et al.,
(Johnson & John- F=1 sure, myalgias, and Thrombocytopenia IVIg, steady improvement in lab- 2021101
son/ Jansen) sore throat with ton- increased D-dimer prednisone oratory markers of
sillar exudate, photo- levels, and mild ele- thrombocytopenia
phobia, and vation of serum
intermittent dizziness transaminases
M. KAKOVAN ET AL.
STROKE ASSOCIATED WITH COVID-19 VACCINES
Table 3 (Continued)
Vaccine Number of Age, Gender Interval (days) Clinical presentation Imaging and lab Treatment Outcome Author,
cases (F, M) between findings year, ref
vaccination and
diagnosis
1 48 14 New-onset headache CVST UFH, Argatro- Remained critically ill Muir et al.,
F=1 Severe thrombocyto- ban and IVIg 2021102
penia, low fibrinogen
level, prolonged acti-
vated partial throm-
boplastin time, and
marked elevation of
the D-dimer level
1 43 10 Generalized CVST IVIg and TIA one day after discharge Malik et al.,
F=1 headache, fever, Thrombocytopenia, fondaparinux 2021103
body aches, chills, positive anti-PF4
and mild dyspnea, antibody, and ele-
and lightheadedness vated D-dimer
level
Note: CVST: Cerebral Venous Sinus Thrombosis; Anti-PF4-antibody: anti-platelet factor 4 antibody; TIA: Transient Ischemic Attack; LMWH:Low Molecular Weight Heparin; IVIg: Intravenous
Immunoglobulin; UFH: Unfractionated Heparin; NM: Not Mentioned; CRP: C-Reactive Protein); mRNA: messenger Ribonucleic Acid; COVID-19: coronavirus disease 2019; PT: Prothrombin
Time; PTT: Partial Thromboplastin Time; INR: International Normalized Ratio; aPTT: activated Partial Thromboplastin Time.
11
12
Table 4. Summary of reports of CVST with ischemic or hemorrhagic stroke.
Vaccine Number of Age Gender Interval (days) Clinical presentation Imaging and lab findings Treatment Outcome Author,
cases (F, M) between year, ref
vaccination and
diagnosis
ChAdOx1 23 21-77 6-24 (mean:12) NM Thirteen cases of CVST NM Seven patients Scully et al.,
nCoV-19 (mean:46) Two cases of ischemic died 202169
(AstraZeneca) F = 14 M = 9 stroke
Positive antiPF4 antibody
in 22 patients
Thrombocytopenia in 22
patients, low fibrinogen
levels in 13 patients, and
increased D-dimer lev-
els in 21 patients
ChAdOx1 1 50 11 Headache, slight deviation of ICH Bilateral decompres- Brain death Castelli et al.,
nCoV-19 M=1 the right buccal rim, loss of CVST sive craniectomy 202171
(AstraZeneca) strength in the right lower Thrombocytopenia, low
limb, unstable walking, and fibrinogen level,
slight visual impairment increased amounts of D-
dimer, CRP, and
homocysteine
ChAdOx1 1 54 12 Left side signs ICH NM Death D’Agostino
nCoV-19 F=1 CVST et al.,
(AstraZeneca) Thrombocytopenia, and 202172
elevated D-dimer level
ChAdOx1 1 50 11 Headache, unconsciousness ICH Red blood cell and Death Franchini et
nCoV-19 M=1 CVST platelet apheresis al., 202173
(AstraZeneca) Thrombocytopenia, posi- transfusion, infusion
tive anti-PF4 antibody, of fibrinogen concen-
increased prothrombin trate, neurosurgical
time and D-dimer, low intervention
fibrinogen level, hypo-
homocysteinemia, and
low folic acid level
M. KAKOVAN ET AL.
STROKE ASSOCIATED WITH COVID-19 VACCINES
Table 4 (Continued)
Vaccine Number of Age Gender Interval (days) Clinical presentation Imaging and lab findings Treatment Outcome Author,
cases (F, M) between year, ref
vaccination and
diagnosis
ChAdOx1 2 Case 1 = 25, Case 1 = 6, Case Case 1: thunderclap head- ICH, SAH Case 1: no specific Brain stem Mehta et al.,
nCoV-19 Case 2=9 ache, left- incoordination, CVST hematological or death 202174
(AstraZeneca) 2 = 32 and hemiparesis Thrombocytopenia and immunological treat-
M=2 Case 2: headache with photo- low fibrinogen level ments were adminis-
phobia, neck stiffness, tered
visual disturbances, associ- Case 2: UFH, platelet
ated with a non-blanching transfusions, dexa-
petechial rash over lower methasone, IVIg
limbs, bleeding of gums,
left hemiparesis and hemi-
sensory loss, and focal
motor seizures
ChAdOx1 1 In early 30s 10 Mild myalgia, holocephalic CVST Argatroban, IVIg, and Persistent mini- Ikenberg et
nCoV-19 F=1 headache, chills, and per- ICH argatroban mal gait ataxia al., 202176
(AstraZeneca) sisting headaches Thrombocytopenia, posi- and amnestic
tive anti-PF4 antibody, deficits
elevated D-dimer level
ChAdOx1 1 69 13 Headache associated with CVST NM Brain death Jamme et al.,
nCoV-19 F=1 behavioral symptoms and ICH 2021104
(AstraZeneca) decreased level of Thrombocytopenia, posi-
consciousness tive anti-PF4 antibody
ChAdOx1 1 33 12 Headache, vomiting, sudden ICH, SAH, and CVT FFP, platelet concen- Death Choi et al.,
nCoV-19 M=1 onset of a tingling in the Thrombocytopenia, ele- trate, IVIg, methyl- 2021105
(AstraZeneca) right arm, mental change, vated D-dimer level, prednisolone, and
drowsiness, dysarthria, and low fibrinogen level, and thrombectomy
right hemiparesis positive anti-PF4
antibody
(Continued)
13
14
Table 4 (Continued)
Vaccine Number of Age Gender Interval (days) Clinical presentation Imaging and lab findings Treatment Outcome Author,
cases (F, M) between year, ref
vaccination and
diagnosis
ChAdOx1 3 22-46 7-17 Case 1: new frontally accen- Case 1:CVST, SAH Case 1: endovascular Case 1: mRS 0 Wolf et al.,
nCoV-19 F=3 tuated headache, a self-lim- Case 2: CVST. ICH rheolysis, levetirace- Case 2: mRS 1 2021106
ited generalized epileptic Case 3: CVST tam, enoxaparin, and Case 3: mRS 0
seizure Thrombocytopenia and dabigatran
Case 2: severe headache, positive anti-PF4 anti- Case 2: enoxaparin,
mild aphasia, hemianopia to body in all the three danaparoid, and
the right, somnolence patients dabigatran
Case 3: severe headache, Case 3: danaparoid,
acute somnolence and right- endovascular rheoly-
hand hemiparesis sis, enoxaparin, and
dabigatran
ChAdOx1 11 22-49 5-16 NM CVST in 9 patients NM Death in 6 Greinacher
nCoV-19 F = 9: M = 2 ICH in one patient patients, et al.,
(AstraZeneca) Thrombocytopenia in all recovery in 4 202178
of the patients, and posi- patients,
tive anti-PF4 antibody in No information
one patient about one
patient
M. KAKOVAN ET AL.
STROKE ASSOCIATED WITH COVID-19 VACCINES
Table 4 (Continued)
Vaccine Number of Age Gender Interval (days) Clinical presentation Imaging and lab findings Treatment Outcome Author,
cases (F, M) between year, ref
vaccination and
diagnosis
ChAdOx1 4 41-67 5-11 Case 1: headache, somno- Case 1: CVST and ICH Case 1: heparin and Case 1: Recov- Tiede et al.,
nCoV-19 F=4 lence, dysphasia, right hem- Case 2: cortical infarc- eculizumab ering 2021107
(AstraZeneca) iparesis, and arterial tions and aortic arch Case 2: argatroban and Case 2, 3, and 4:
hypertension thrombi IVIg Recovered
Case 2: headache Case 3: no pathology in Case 3: argatroban
Case 3: headache and diplo- imaging findings Case 4: argatroban and
pia Case 4: ischemic stroke in IVIg
Case 4: headache, dysarthria, ICA and MCA territory
left- hemiplegia, and conju- with hemorrhagic trans-
gated gaze palsy formation
Thrombocytopenia,
increased D-dimer level,
positive anti-PF4 anti-
body in all of the
patients
ChAdOx1 4 37-54 7-10 Case 1: fever and persistent Case 1: CVST and ICH Case 1: platelet trans- Case 1: death Schultz et
nCoV-19 F= 4 headaches Case 2: CVST and hemor- fusions and decom- Case 2: death al., 202193
(AstraZeneca) Case 2: headaches, reduced rhagic infarction pressive craniectomy Case 3: full
consciousness Case 3: CVT and hemor- Case 2: hemicraniec- recovery
Case 3: headache rhagic infarction tomy, dalteparin, Case 4: death
Case 4: hemiparesis Case 4: ICH and CVT methylprednisolone,
Thrombocytopenia and IVIg
positive anti-PF4 anti- Case 3: dalteparin,
body in all of the prednisolone and
patients IVIg
Case 4: platelet trans-
fusion, methylpred-
nisolone, IVIg,
thrombectomy, UFH,
and decompressive
hemicraniectomy
(Continued)
15
16
Table 4 (Continued)
Vaccine Number of Age Gender Interval (days) Clinical presentation Imaging and lab findings Treatment Outcome Author,
cases (F, M) between year, ref
vaccination and
diagnosis
ChAdOx1 1 27 12 Intermittent headache associ- CVST IVIg, dabigatan, idaru- Death Suresh et al.,
nCoV-19 M=1 ated with eye floaters and ICH cizumab, and 202126
(AstraZeneca) vomiting. Thrombocytopenia, posi- prednisolone
tive anti-PF4 antibody,
raised D- dimer, low
platelets, and fibrinogen
levels
ChAdOx1 1 62 13 Fever, weakness in the right CVST, Antibiotics, platelet Death Berezne et
nCoV-19 M=1 arm, and mental confusion SAH, concentrate, UFH, al., 2021108
(AstraZeneca) Large parietal hematoma intravenous
(after receiving hepa- methylprednisolone
rin),
Acute myocardial infarc-
tion
Increased CRP, leukocy-
tosis, thrombocytopenia,
increased D-dimer level,
increased high-sensitiv-
ity cardiac troponin I
level, positive anti-PF4
antibody
ChAdOx1 1 32 11 Headache associated with CVST and Enoxaparin, parietal Discharged with Kotal et al.,
nCoV-19 F=1 blurredvision and giddiness, ICH decompressive hemi- home neurore- 2021109
(Covishield) weakness on the left upper Thrombocytopenia, craniectomy, fonda- habilitation
and lower limb increased D-dimer, posi- parinux, IVIg, service
tive anti-PF4 antibody tracheostomy
M. KAKOVAN ET AL.
STROKE ASSOCIATED WITH COVID-19 VACCINES
Table 4 (Continued)
Vaccine Number of Age Gender Interval (days) Clinical presentation Imaging and lab findings Treatment Outcome Author,
cases (F, M) between year, ref
vaccination and
diagnosis
Ad26.COV2.S 12 18-60 6-15 Eleven patients initially pre- CVST Heparin treatment Death (n = 3), See et al.,
(Johnson & F = 12 sented with headache and (of the 12 patients with (later changed to ICU care 2021110
Johnson/ one patient initially showed CVST, seven also had non-heparin antico- (n = 3), non-
Jansen) back pain and later devel- ICH) agulant) in 6 ICU hospitali-
oped a headache Thrombocytopenia and patients; zation (n = 2),
elevated D-dimer level No and dis-
and decreased fibrino- anticoagulant therapy charged
gen level in 2 patients (n = 4)
Non-heparin anticoag-
ulant initially for
CVST treatment in 4
patients. In addition
to anticoagulation,
seven patients
received IVIg of
which three also
received systemic
corticosteroids and
four had platelet
transfusions.
mRNA-1273 1 45 8 Headache, neck pain, altered ICH,SAH, and Heparin and coumadin Discharged with Syed et al.,
M=1 mental, state after a wit- CVST no neurologi- 2021111
nessed seizure (GCS: 3) cal sequel
BNT162b2 2 47, 67 3, 6 Case 1: persistent headache, Case 1: CVST and SAH Case 1: enoxaparin and Case 1: slight Dias et al.,
mRNA(Pfizer) F=2 nausea, photophobia, and Case 2: CVST warfarin gait instability 2021112
sudden left motor deficit Case 2: enoxaparin, at two-month
Case 2: sudden right lower and dabigatran follow-up
limb clonic movements fol- Case 2:
lowed by motor deficit, loss discharged
of consciousness, and without neuro-
headache logical deficits
(Continued)
17
18 M. KAKOVAN ET AL.
Note: MCA: Middle Cerebral Artery; ICA: Internal Carotid Artery; CVST: Cerebral Venous Sinus Thrombosis; CVT: Cerebral Venous Thrombosis; Anti-PF4-antibody: anti-platelet factor 4 anti-
body; ICH: Intracerebral Hemorrhage; SAH: Subarachnoid Hemorrhage; LMWH: Low Molecular Weight Heparin; IVIg: Intravenous Immunoglobulin; UFH: Unfractionated Heparin; ICU: Inten-
Furthermore, continuing systemic anticoagulation for at
2021113
year, ref
Author, sis in the context of VITT is recommended.130 However,
warfarin is not recommended in this setting due to a para-
doxical increase in thrombotic tendency.129 In order to
recovery
Outcome
Case 3: LMWH,
IVIg, non-heparin anti-coagulation, and fibrinogen
replacement if its level is less than 1.5 g/L.116,117 Platelet
sive Care Unit; mRS: modified Rankin Scale; NM: Not Mentioned; CRP: C-Reactive Protein; FFP: Fresh Frozen Plasma; GCS: Glasgow Coma Scale.
Treatment
LMWH
CVST
to ensure that its level does not drop below 1.5 g/L.128
Moreover, steroids may be useful, although whether their
benefits outweigh the potential harm is uncertain.128
and left hemiparesis
Age Gender Interval (days) Clinical presentation
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