Research

JAMA | Original Investigation
US Case Reports of Cerebral Venous Sinus Thrombosis
With Thrombocytopenia After Ad26.COV2.S Vaccination,
March 2 to April 21, 2021

Isaac See, MD; John R. Su, MD, PhD, MPH; Allison Lale, MD, MPH; Emily Jane Woo, MD, MPH;
Alice Y. Guh, MD, MPH; Tom T. Shimabukuro, MD, MPH, MBA; Michael B. Streiff, MD; Agam K. Rao, MD;
Allison P. Wheeler, MD, MSCI; Suzanne F. Beavers, MD; Anna P. Durbin, MD; Kathryn Edwards, MD;
Elaine Miller, RN, MPH; Theresa A. Harrington, MD, MPH&TM; Adamma Mba-Jonas, MD, MPH; Narayan Nair, MD;
Duong T. Nguyen, DO; Kawsar R. Talaat, MD; Victor C. Urrutia, MD; Shannon C. Walker, MD; C. Buddy Creech, MD;
Thomas A. Clark, MD, MPH; Frank DeStefano, MD, MPH; Karen R. Broder, MD

Editorial page 2445

IMPORTANCE Cerebral venous sinus thrombosis (CVST) with thrombocytopenia, a rare and
serious condition, has been described in Europe following receipt of the ChAdOx1 nCoV-19
vaccine (Oxford/AstraZeneca), which uses a chimpanzee adenoviral vector. A mechanism
similar to autoimmune heparin-induced thrombocytopenia (HIT) has been proposed. In the
US, the Ad26.COV2.S COVID-19 vaccine (Janssen/Johnson & Johnson), which uses a human
adenoviral vector, received Emergency Use Authorization (EUA) on February 27, 2021. By
April 12, 2021, approximately 7 million Ad26.COV2.S vaccine doses had been given in the US,
and 6 cases of CVST with thrombocytopenia had been identified among the recipients,
resulting in a temporary national pause in vaccination with this product on April 13, 2021.

OBJECTIVE To describe reports of CVST with thrombocytopenia following Ad26.COV2.S
vaccine receipt.

DESIGN, SETTING, AND PARTICIPANTS Case series of 12 US patients with CVST and
thrombocytopenia following use of Ad26.COV2.S vaccine under EUA reported to the Vaccine
Adverse Event Reporting System (VAERS) from March 2 to April 21, 2021 (with follow-up
reported through April 21, 2021).

EXPOSURES Receipt of Ad26.COV2.S vaccine.

MAIN OUTCOMES AND MEASURES Clinical course, imaging, laboratory tests, and outcomes
after CVST diagnosis obtained from VAERS reports, medical record review, and discussion
with clinicians.

RESULTS Patients’ ages ranged from 18 to younger than 60 years; all were White women,
reported from 11 states. Seven patients had at least 1 CVST risk factor, including obesity (n = 6),
hypothyroidism (n = 1), and oral contraceptive use (n = 1); none had documented prior heparin
exposure. Time from Ad26.COV2.S vaccination to symptom onset ranged from 6 to 15 days.
Eleven patients initially presented with headache; 1 patient initially presented with back pain
and later developed headache. Of the 12 patients with CVST, 7 also had intracerebral
hemorrhage; 8 had non-CVST thromboses. After diagnosis of CVST, 6 patients initially received
heparin treatment. Platelet nadir ranged from 9 ×103/μL to 127 ×103/μL. All 11 patients tested
for the heparin-platelet factor 4 HIT antibody by enzyme-linked immunosorbent assay (ELISA)
screening had positive results. All patients were hospitalized (10 in an intensive care unit [ICU]).
As of April 21, 2021, outcomes were death (n = 3), continued ICU care (n = 3), continued
non-ICU hospitalization (n = 2), and discharged home (n = 4).

CONCLUSIONS AND RELEVANCE The initial 12 US cases of CVST with thrombocytopenia after
Ad26.COV2.S vaccination represent serious events. This case series may inform clinical
guidance as Ad26.COV2.S vaccination resumes in the US as well as investigations into the
potential relationship between Ad26.COV2.S vaccine and CVST with thrombocytopenia.

JAMA. 2021;325(24):2448-2456. doi:10.1001/jama.2021.7517
Published online April 30, 2021.

2448

© 2021 American Medical Association. All rights reserved.

Author Affiliations: Centers for
Disease Control and Prevention
COVID-19 Response Team, Atlanta,
Georgia (See, Su, Lale, Guh,
Shimabukuro, Rao, Beavers, Miller,
Harrington, Nguyen, Clark,
DeStefano, Broder); Food and Drug
Administration, Center for Biologics
Evaluation and Research, Silver
Spring, Maryland (Woo, Mba-Jonas,
Nair); Johns Hopkins University,
Baltimore, Maryland (Streiff, Durbin,
Talaat, Urrutia); Vanderbilt University
Medical Center, Nashville, Tennessee
(Wheeler, Edwards, Walker, Creech).

Corresponding Author: Isaac See,
MD, Centers for Disease Control and
Prevention COVID-19 Response
Team, 1600 Clifton Rd, HT 16-3,
Atlanta, GA 30329 (isee@cdc.gov).

(Reprinted)

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Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination

Original Investigation Research

O n February 27, 2021, the US Food and Drug Adminis-

tration (FDA) issued an Emergency Use Authoriza-
tion (EUA) for the single-dose Janssen/Johnson &
Johnson COVID-19 (Ad26.COV2.S) vaccine, a replication-
incompetent human adenovirus 26 vector vaccine.1 As of April
12, 2021, approximately 7 million doses of this vaccine had been
administered nationwide.2,3

On March 18, 2021, the European Medicines Agency an-
nounced findings of a rare thrombosis with thrombocytope-
nia syndrome (TTS) after receipt of the ChAdOx1 nCoV-19
vaccine (Vaxzevria, Oxford/AstraZeneca), which uses a recom-
binant replication-deficient chimpanzee adenovirus vector.4-6
Cerebral venous sinus thrombosis (CVST), a rare and serious
condition,7 was noted in 72% of these initial TTS reports.
A mechanism similar to autoimmune heparin-induced throm-
bocytopenia (HIT),8 in which platelet-activating antibodies de-
velop in the absence of heparin exposure, has been proposed
to explain the occurrence of CVST with thrombocytopenia af-
ter ChAdOx1 nCoV-19 vaccination.9-11

One case of CVST with thrombocytopenia in a male pa-
tient was reported during the phase 3 clinical trial of the
Ad26.COV2.S vaccine.12 Six cases of CVST with thrombocyto-
penia after Ad26.COV2.S vaccination were reported through the
Vaccine Adverse Event Reporting System (VAERS) to the Cen-
ters for Disease Control and Prevention (CDC) and FDA as of April
12, 2021; information about 1 case was published.13 On April 13,
the CDC and FDA recommended a pause in the use of the
Ad26.COV2.S vaccine.2,14 By April 21, 6 additional cases of CVST
with thrombocytopenia and 3 cases of non-CVST TTS follow-
ing administration of Ad26.COV2.S vaccine were reported to
VAERS.15 On April 23, after reviewing data on TTS cases follow-
ing postauthorization Ad26.COV2.S vaccination, CDC’s Advi-
sory Committee on Immunization Practices (ACIP) reaffirmed
its interim recommendation for use of the Ad26.COV2.S vac-
cine in all persons aged 18 years or older in the US.16

The aim of this case series was to describe the clinical
and laboratory details of the first 12 US post-EUA cases of
CVST with thrombocytopenia after Ad26.COV2.S vaccination
reported to VAERS.

Methods

VAERS is the US passive surveillance (spontaneous reporting)
system for adverse events after immunization and is jointly
administered by CDC and FDA. This investigation was con-
ducted as part of the routine activities of VAERS and the
Clinical Immunization Safety Assessment (CISA) Project.17
VAERS and CISA clinical consult activities are long-running
surveillance programs conducted for public health purposes.
CDC does not consider these to be research activities. The
activities herein were confirmed to be nonresearch under the
Common Rule in accordance with institutional procedures
and therefore were not subject to institutional review board
requirements. Informed consent was not obtained for this
secondary use of existing information (see, eg, 45 CFR
§46.102(I)(2), 21 CFR §56; 42 USC §241(d); 5 USC §552a; 44
USC §3501 et seq).

Key Points

Question What were the clinical characteristics of the first US
patients reported to have cerebral venous sinus thrombosis
(CVST) with thrombocytopenia following receipt of the
Ad26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccine?

Findings In this case series of 12 patients, all were women,
younger than 60 years, and had symptom onset ranging from 6 to
15 days after vaccination requiring hospitalization. Of 11 patients
with heparin-platelet factor 4 enzyme-linked immunosorbent
assay (ELISA) heparin-induced thrombocytopenia (HIT) antibody
test results, all were positive. At last follow-up, outcomes were
death (n = 3), intensive care unit (ICU) care (n = 3), non-ICU
hospitalization (n = 2), and discharge to home (n = 4).

Meaning This case series may inform clinical guidance and
investigations into the potential relationship between the
Ad26.COV2.S vaccine and CVST with thrombocytopenia.

VAERS accepts reports from clinicians, vaccine manufac-
turers, and the public regardless of clinical severity of the event
or determination of causality. Physicians at FDA identified re-
ports received by VAERS describing cases of CVST with throm-
bocytopenia by manually reviewing all serious reports. CDC
and FDA also received notification through direct outreach
from clinicians and public health officials; these reports were
ultimately also captured in VAERS. In addition, CDC and FDA
investigators searched symptom text and performed auto-
mated coding searches. US reports of CVST with thrombocy-
topenia in the VAERS database from March 2 through April 21,
2021, following post-EUA Ad26.COV2.S vaccine receipt were
included. Confirmation of a diagnosis of CVST with thrombo-
cytopenia, as well as signs, symptoms, diagnostic test re-
sults, and outcomes of reported cases, were obtained through
medical record review or discussions with treating clinicians.
CVST risk factors were defined as described in a review.7 Case
information was also reviewed with physician investigators
from CDC’s CISA Project, including specialists in infectious dis-
eases, neurology, and hematology. Cases were also reviewed
to determine if they satisfied Brighton Collaboration interim
case definition 9.2 for TTS, which includes new-onset throm-
bocytopenia (platelet count <150 ×103/μL) without evidence
of platelet clumping, venous or arterial thrombosis, and ab-
sence of prior exposure to heparin.18

To protect patient privacy, age is reported in 2 categories: 18
to 39 years or 40 to 59 years. Race was noted because COVID-19
has been documented to disproportionately affect racial/ethnic
minority groups.19 Race was categorized as White, Black, Asian,
or all other races and determined based on medical record review
by CDC abstractor or from the reported race on the VAERS report.
Data were also collected on Hispanic ethnicity.

Results

Twelve cases of CVST with thrombocytopenia were reported
during March 2 to April 21, 2021, after receipt of the
Ad26.COV2.S vaccine (Table 1), which is administered as a
single dose. The last follow-up date for patient outcomes and

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Research Original Investigation

Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination

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Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination

Original Investigation Research

Box. Clinical Presentations Leading Up to Diagnosis for the Initial
6 Patients With Cerebral Venous Sinus Thrombosis and
Thrombocytopenia Following Emergency Authorization Receipt
of Ad26.COV2.S Vaccine—US, 2021

Case 1 (Age ≥40 y)
• Six days after vaccination, the patient developed lethargy.
• Eight days after vaccination, she started to have a mild headache,

which became persistent.

• Eleven days after vaccination, her headache acutely worsened

and she developed dry heaving with left-sided weakness.

• She was transported by emergency medical services to the local
hospital where her platelet count was 43 ×103/μL and CT of the
head revealed a large right temporoparietal hemorrhage. During
transfer to a higher level of care on the same day, the paramedics
noted her right pupil had become dilated and fixed. Upon arrival,
CT angiography of the head and neck identified right transverse
and sigmoid sinus thromboses.

Case 2 (Age 18-39 y)
• Nine days after vaccination, the patient developed a persistent

headache.

speaking.

• Fifteen days after vaccination, she began to have difficulty

• Sixteen days after vaccination, she had a severe headache

associated with nausea and increased difficulty with speech.
In the ED a head CT showed a left temporal lobe hemorrhage
and suspected underlying sinus thrombosis. Upon transfer to
a tertiary hospital the same day, platelet count was 78 ×103/μL
and CT venogram identified thromboses in the straight sinus,
confluence of sinuses, left transverse sinus, left sigmoid sinus,
and left intracranial internal jugular vein.

Case 3 (Age 18-39 y)
• One day after vaccination, the patient developed a transient fever.
• Approximately 8 days after vaccination, she developed a

headache and nausea, which also resolved.

• Approximately 11 days after vaccination, headache, nausea, and
fever recurred, accompanied by vomiting. For the next 4 days,
symptoms continued intermittently.

• Seventeen days after vaccination, she developed a change in

affect, vomiting, and change in speech. She was taken to an ED,
where left gaze deviation and left-sided weakness were noted
and her platelet count was 18 ×103/μL. She had a seizure in the
ED. CT angiogram of the head and neck and magnetic resonance
imaging and venogram of the brain revealed a right frontal lobe
hemorrhage, possible right subarachnoid hemorrhage, and right
superior sagittal sinus vein thrombosis.

Case 4 (Age 18-39 y)
• Eight days after vaccination, the patient developed chills

and myalgia.

• Nine days after vaccination, she developed fever (temperature
up to 38.0 °C) and a severe posterior headache that progressed
to the right side of her head. The headache increased in severity
over the next 3 days and was associated with nausea
and vomiting.

• Twelve days after vaccination, she was evaluated in the ED and

discharged with an over-the-counter product containing aspirin,
acetaminophen, and caffeine given for treatment of a possible
migraine. There was some improvement in her symptoms.

• Fourteen days after vaccination, she developed abdominal pain

with severe bloating and maximum temperature of 38.1 °C.

Box. (continued)

• Sixteen days after vaccination, she returned to the ED for
evaluation of her abdominal pain and recurrence of her
headache. An ultrasound of the abdomen revealed a portal vein
thrombosis. CT angiography of the chest showed a right
pulmonary embolism. A magnetic resonance venogram revealed
a right transverse and sigmoid sinus thrombosis. She also had
a platelet count of 127 ×103/μL.

Case 5 (Age 18-39 y)
• Shortly after vaccination, the patient developed a single

self-limited febrile episode.

• Approximately 6 days after vaccination, she developed fever,
rigors, shortness of breath, jaw pain, and headache. Testing at
an ED did not identify a specific etiology; she was prescribed
azithromycin. Fevers, rigors, and shortness of breath resolved,
but headaches associated with visual changes continued.

• Approximately 16 days after vaccination, she developed

ecchymoses, periorbital and lower extremity petechiae, bilateral
lower extremity pain and right lower extremity swelling, and
intermittent shortness of breath. She presented to an outpatient
facility for care. An ultrasound revealed a right lower extremity
deep vein thrombosis and she was prescribed dabigatran
(a direct thrombin inhibitor). No platelet count was recorded.

• Seventeen days after vaccination, she lost consciousness

and was transported to the ED; she had a platelet count of
10 ×103/μL. Magnetic resonance imaging of the brain revealed
right transverse sinus venous thrombosis and right internal
jugular vein thrombosis.

Case 6 (Age ≥40 y)
• Approximately 13 days after vaccination, the patient developed
back pain and malaise. Over the next 2 days, she noticed unex-
plained right forearm bruising and abdominal pain.

• Fifteen days after vaccination, her platelet count was 13 ×103/μL
at an outpatient visit and she was referred to the ED, where an
ultrasound of the abdomen revealed portal vein thrombosis with
mild retroperitoneal, intraperitoneal, and pelvic hemorrhage.
Lower extremity ultrasound revealed deep vein thrombosis of
the right posterior tibial and peroneal veins.

• Seventeen days after vaccination, she reported a headache in the
posterior occipital area and mild nausea; CT of the head showed
thrombosis of the right transverse sinus and straight sinus; a few
days later, intracranial hemorrhage was noted on CT of the head.

Abbreviations: CT, computed tomography; ED, emergency department.

patient platelet counts was April 21, 2021. There was 1 addi-
tional report of a patient hospitalized for COVID-19 pneumo-
nia after Ad26.COV2.S vaccination followed by a hospitaliza-
tion with CVST and pneumonia; because thrombosis is a known
complication of COVID-19,12 this patient is not included in this
case series report.

The first 6 cases of CVST and thrombocytopenia that led
to the pause in Ad26.COV2.S vaccination all occurred in women
younger than 60 years; all but 1 initially presented with head-
ache. Initial clinical presentations for these first 6 reported US
cases are provided in the Box.

(continued)

Summary of Clinical Case Data and Outcomes of the 12 Cases
Following the identification of the first 6 cases of CVST with
thrombocytopenia, an additional 6 cases were identified. Char-
acteristics of these 12 cases are described below. Ten met the

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Research Original Investigation

Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination

Table 2. Immunologic and Functional HIT Assays

Test

Purpose

Method

Heparin-platelet factor 4 (PF4)
enzyme-linked immunosorbent
assay (ELISA)

Immunologic HIT assay that
measures the amount of HIT
antibodies directed against PF4
(detects functional and
nonfunctional antibodies)

Patient serum is added to a microtiter plate coated with
PF4 (or heparin-PF4 complex)
Alkaline-phosphatase linked secondary anti–human IgG
antibody is added and incubated with the test samples
After washing, a colorimetric substrate is added and the
optical density of the colored product is measured after a
30-min incubation

Serotonin release assay (SRA)

Latex immunoturbidimetric
assay (LIA)

p-Selectin expression assay
(PEA)

Functional HIT assay that
measures serotonin release from
dense granules in platelets as a
marker for platelet activation in
the presence of high and low
doses of heparin

Patient serum is added to donor platelets labeled with
14C-serotonin in the presence of low (0.1 U/mL) and high
(100 U/mL) concentrations of heparin (and in some
specialized reference laboratories, buffer control)
Platelet activation is determined by the amount of
14C-serotonin released into the reaction supernatant

Functional immunologic HIT
assay that detects the presence
of PF4 HIT antibodies based on
their ability to competitively
inhibit agglutination of HIT-like
monoclonal antibodies bound to
latex particles

Functional HIT assay that
measures platelet surface
p-selectin expression as a
marker of platelet activation in
the presence and absence of
high-dose heparin

Patient plasma is added to latex particles coated with
a HIT-like monoclonal antibody and PF4 molecules
conjugated with fluorescent marker
With negative plasma (those without HIT antibodies), the
latex/monoclonal antibody particles and PF4 molecules
agglutinate, which will increase detectable fluorescence
Positive plasma will compete with the latex/monoclonal
antibody particles leading to less agglutination and lower
fluorescence

Patient serum is incubated with platelets pretreated with
PF4 purified from normal donor platelets ± high (100
U/mL) concentration of heparin
Platelet activation is determined by measuring the
presence of p-selectin (CD62p) by flow cytometry

Abbreviation: HIT, heparin-induced thrombocytopenia.

Reference range

Optical density values 0-0.499
(of note, each integer unit
increase equals a 10-fold increase
in signal intensity)

<20% Platelet activation
difference between the low and
high concentrations of heparin
Saline buffer is not generally
tested; if performed, there will
not be significant serotonin
release in buffer for classic HIT

≥1.0 U/mL

Percent release with PF4 vs PF4 +
high-dose heparin, reported as
positive, negative, or borderline

interim (version 9.2) case definition according to the Brighton
Collaboration for TTS (2 did not have evidence of review of a
peripheral smear to rule out platelet clumping); all had radio-
graphic evidence of CVST satisfying level 1 criteria, indicating
the highest level of certainty.

A description of selected tests used in the diagnosis of HIT

is included in Table 2.

Of the 12 patients with CVST and thrombocytopenia re-
ported to VAERS as of April 21, 2021, the patients’ ages ranged
from 18 to younger than 60 years, all were White women, and
ethnicity was reported as non-Hispanic for 11 and unknown for
1 (Table 1). Eleven women were younger than 50 years. Re-
ports came from 11 states. The median interval from vaccina-
tion to symptom onset was 8 days (range, 6-15 days). The me-
dian interval from vaccination to hospitalization was 16 days
(range, 10-25 days). Median time from symptom onset to hos-
pitalization was 7 days (range, 2-13 days).

At least 1 risk factor for CVST was identified in 7 patients:
obesity (n = 6; body mass index range, 30.9-39.9 [calculated
as weight in kilograms divided by height in meters squared]),
hypothyroidism (n = 1), and use of combined oral contracep-
tives (n = 1). None of the patients was pregnant or within 12
weeks postpartum, had prior thrombosis, a personal or fam-
ily history of thrombophilia, or documented prior exposure
to heparin.

In addition to CVST, 7 patients had intracerebral hemor-
rhage and 8 had non-CVST thromboses (Table 1). Platelet
nadirs ranged from 9 ×103/μL to 127 ×103/μL (Table 3).
D-dimer or fibrinogen values were abnormal in all patients.
Heparin-platelet factor 4 (PF4) HIT antibody ELISA results
were positive in 11 patients; 1 was not tested. Of the 11
patients with positive PF4 HIT antibody ELISA results, func-

tional platelet HIT antibody results were as follows: 1 positive
(both serotonin release assay and P-selectin assay); 8 nega-
tive (6 serotonin release assay only, 2 both serotonin release
assay and latex immunoturbidimetric assay); and 2 without
testing reported. Additional thrombophilia testing was con-
ducted in 11 patients and was negative (Table 4), including
tests for antiphospholipid antibody syndrome using 1 or
more assays (anticardiolipin antibodies, β2 glycoprotein 1
antibody, and lupus anticoagulant).

One patient reported a history of SARS-CoV-2 infection ap-
proximately 4 months prior to vaccination; in that patient,
SARS-CoV-2 viral testing and serology was not performed dur-
ing the admission for CVST. For the other 11 patients, 10 had
negative SARS-CoV-2 nucleic acid amplification results dur-
ing their hospital admission; 1 had a negative SARS-CoV-2 an-
tigen test result. For these 11 patients without a reported his-
tory of SARS-CoV-2, serologic testing results were as follows:
4 patients tested negative and 7 were not tested (Table 3).

All patients were hospitalized and 10 were admitted to an
intensive care unit (ICU). Six patients initially received hepa-
rin for thromboses, all initially admitted to the hospital be-
fore public notification of CVST and thrombocytopenia events
(April 13, 2021)2,14; all were subsequently changed to a non-
heparin anticoagulant. Two patients did not receive antico-
agulation. Four patients received nonheparin anticoagula-
tion initially for CVST treatment (argatroban, n = 2; bivalirudin,
n = 2). In addition to anticoagulation, 7 patients received
intravenous immunoglobulin (IVIG) and 3 of these also re-
ceived systemic corticosteroids; 4 had platelet transfusions.
At the time of the last follow-up, the patient outcomes were
death (n = 3), continued ICU care (n = 3), continued non-ICU
hospitalization (n = 2), and discharge home (n = 4). Of the 9

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Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination

Original Investigation Research

1

2

3

4

5

6

7

8

9

10

11

12

1

2

3

4

5

6

7

8

9

10

11

12

Table 3. Results From Hematology and SARS-CoV-2 Testing for Initial 12 Patients With Cerebral Venous Sinus Thrombosis and Thrombocytopenia
Following Emergency Authorization Receipt of Ad26.COV2.S Vaccine—US, 2021a

Patient
No.

Platelet
nadir,
×103/μLb
12

Fibrinogen
nadir,
mg/dLb
93

Initial

SARS-CoV-2

aPTT, s

Serology

Viral assay

Not done

Negative (PCR)

Heparin-PF4
ELISA test
(optical density)b,c
Not done

Functional platelet
assay test resultsc
Not done

D-dimer
peak,
μg/mLb
>20.0

1.1

112.07

8.46

5.45

7.05

7.84

6.7

>4

13.47

41.71

45.57

166

82

240

141

59

77

239

332

128

206

149

69

18

127

10

13

64

90

15

9

102

20

INR

1.4

1.2

1.5

1.1

1.1

1.3

1.2

0.9

1.1

1.2

1.2

–f

31

22.3

31.1

31.2

18.1

34.5

–e

28

26.9

24.1

30.2

Nucleocapsid
antibody
negative

Not done

Not done

Antibody
negatived
Spike antibody
negative

Not done

Not done

Nucleocapsid
antibody
negative

Not done

Not done

Negative (PCR)

Positive (1.2)

Negative SRA

Negative (PCR)

Positive (2.7)

Negative (PCR)

Positive (3.0)

Negative (PCR)

Positive (1.6)

Negative (PCR)

Positive (3.2)

Negative SRA

Negative SRA

Negative SRA

Negative SRA,
negative LIA

Not done

Positive (1.4)

Not done

Negative (antigen)

Positive (2.3)

Negative (PCR)

Positive (2.5)

Negative SRA

Negative SRA

Negative (PCR)

Positive (2.2)

Not done

Negative (PCR)

Positive (2.6)

26.4

Not done

Negative (PCR)

Positive (2.1)

Negative SRA,
negative LIA

Positive SRA and PEA,
negative LIA

Abbreviations: aPTT, activated partial thromboplastin time; CVST, cerebral
venous sinus thrombosis; DVT, deep vein thrombosis; ELISA, enzyme-linked
immunosorbent assay; INR, international normalized ratio; LIA, latex
immunoturbidimetric assay; PCR, polymerase chain reaction; PEA, P-selectin
expression assay; PF4, platelet factor 4; SRA, serotonin release assay.

Conversion factors: To convert platelet counts to cells/μL, multiply values
by 1000.
a Data are as of April 21, 2021. No patient received heparin prior to the detection

of thrombocytopenia.

b Reference range may vary by laboratory; representative ranges include the
following: D-dimer, <0.5 μg/mL; fibrinogen, 200-400 mg/dL; heparin-PF4

ELISA optical density, 0-0.499 (each integer unit equals a 10-fold increase in
signal intensity); platelets, 150- 450 ×103/μL.

c See Table 2 for more details.
d Information was not available to distinguish whether antinucleocapsid or

anti-spike SARS-CoV-2 antibodies were assessed.

e The initial PTT value in this patient was obtained when the patient had already

received anticoagulation.

received anticoagulation.

f The initial INR value in this patient was obtained when the patient had already

Table 4. Results of Selected Testing for Hypercoagulable States in Initial 12 Patients With Cerebral Venous Sinus Thrombosis and Thrombocytopenia
Following Emergency Authorization Receipt of Ad26.COV2.S Vaccine—US, 2021a

Antiphospholipid antibody testing

Patient
No.

Anticardiolipin antibody

β2 Glycoprotein 1 antibody

Lupus anticoagulant assay

Homocysteine
level

Antithrombin
activity

Negative IgM, IgG

Negative IgM, IgG

Negative IgM, IgG

Weak positive IgM (17.9 mg/dL),
negative IgGb
Indeterminate IgM (16.0 mg/dL),
negative IgGc
Negative IgM, IgG

Negative IgM, IgG

Negative IgM, IgG

Negative IgM, IgG

Negative IgM, IgG

Weak positive IgM (15.3 mg/dL),
negative IgGb
Negative IgM, IgG

Negative IgM, IgG

Negative IgM, IgG

dRVVT negative

dRVVT negative

dRVVT negative

Normal

Normal

Normal

dRVVT negative

Normal

dRVVT negative

dRVVT negative

dRVVT 86 (≤45 seconds)d
hex confirmation pending

Negative IgM, IgG

Negative IgM, IgG

dRVVT negative

Negative IgM, IgG

Negative IgM, IgG

Negative IgM, IgG

Negative IgM, IgG

RVVT ratio negative

RVVT ratio negative

Normal

Normal

Normal

Normal

Normal

Normal

Abbreviations: dRVVT, dilute Russell viper venom time. Blank cells indicate that
testing was not found in the medical records.
a Additional testing performed in at least 1 patient includes for protein C and
protein S activity, antinuclear antibodies, flow cytometry for paroxysmal
nocturnal hemoglobinuria, serum protein electrophoresis, and heparinase
testing; all results were normal. Testing for selected inherited causes of
hypercoagulability were negative in all patients where results were available.

b Reference range: <15.0 mg/dL = negative, 15.0-39.9 mg/dL = weak positive.
c Reference range in IgM phospholipid (MPL) units: 0-12 = negative,

13-19 = indeterminate, 20-80 = low to moderately positive,
and (cid:2)81 = high positive.
d The patient was receiving anticoagulation so the elevated value is not

considered abnormal.

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Research Original Investigation

Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination

patients who were still alive at last follow-up, 6 had a platelet
count within normal range (150 ×103/μL to 450 ×103/μL); all
had last known platelet counts higher than 100 ×103/μL.

Of the patients who died, all had intraparenchymal hem-
orrhage and evidence of mass effect on initial head CT con-
ducted in the emergency department. Two were obese; none
had other CVST risk factors. Median time from admission to
death was 1 day (range, 1-2 days). In addition to supportive ICU
care, 1 received argatroban and IVIG; the other 2 did not re-
ceive anticoagulation or IVIG before dying.

Additional CVST Cases
Since April 21, 2021, 2 additional US reports to VAERS of CVST
with thrombocytopenia following administration of
Ad26.COV2.S have been confirmed as of April 25. One is a man
younger than 40 years; the other is a woman aged between 40
and 59 years. Investigation is ongoing.

Discussion

This case series describes the first 12 reported cases of CVST
with thrombocytopenia following Ad26.COV2.S vaccination
in the US. In many respects, the clinical presentation and
laboratory features were similar to those seen in Europe after
ChAdOx1 nCoV-19 vaccine, another adenoviral vector
COVID-19 vaccine.9-11

Similar to the initially described European cases of CVST
with thrombocytopenia following ChAdOx1 nCoV-19 vaccina-
tion, the US cases of this condition also occurred primarily in
women younger than 40 years and in patients without diag-
nosed thrombophilia.9,11 The European patients had a me-
dian platelet nadir count of 19 ×103/μL9,10 (US patients were
also 19 ×103/μL), and several had non-CVST large-vessel throm-
bosis (30% of initially reported CVST cases following ChAdOx1
nCoV-19 vaccination9-11 vs 75% following Ad26.COV2.S
vaccination).9-11 In the European cases of CVST with throm-
bocytopenia following ChAdOx1 nCoV-19 vaccination, 50% of
patients died,9-11 compared with 25% of US patients who had
CVST with thrombocytopenia.

Similar to the TTS cases (including CVST) described in
Europe following receipt of ChAdOx1 nCoV-19 vaccine, the US
cases of CVST with thrombocytopenia also had positive hep-
arin-PF4 HIT antibody ELISA tests in the absence of prior ex-
posure to heparin, as would be seen in autoimmune HIT.8 How-
ever, in the initial European CVST reports, 88% of patients
tested with functional platelet HIT antibody tests had posi-
tive results9-11; in contrast, functional platelet HIT antibody test
results were positive in only 1/9 (11%) of the US cases with re-
sults available. The heparin-PF4 ELISA detects presence of anti-
PF4 antibodies; functional platelet HIT antibody assays de-
termine the extent to which these antibodies activate platelets
in the presence of heparin, leading to aggregation.20

Functional platelet HIT antibody assays have higher speci-
ficity than the heparin-PF4 ELISA and are typically positive in
patients with strongly positive (eg, optical density >1) ELISA
tests.20 Because of this, functional platelet HIT antibody as-
says are generally considered to be the criterion standard test

for verification of classic and autoimmune HIT.20 In contrast,
the utility of these functional platelet assays for confirming TTS
is unclear. It is possible, given the clinical scenario of these pa-
tients, that the negative functional platelet assay results may
represent false negatives. Lack of standardization in func-
tional platelet HIT antibody assays may lead to differences in
results by different laboratories.21,22 For example, in the ini-
tial European studies, the functional platelet HIT antibody as-
says included the use of a saline buffer,9-11 which is not al-
ways included when assessing for classic HIT.8 The European
studies also did not use the serotonin release assay that was
most commonly used in the US cases.9-11 It may be important
to notify testing laboratories that postvaccination TTS is being
evaluated, so that testing methods can be adjusted if needed.8
Given that the number of CVST with thrombocytopenia cases
following Ad26.COV2.S vaccination in the US is still small, ob-
taining additional information about functional platelet HIT
antibody assay results could help with investigations into the
mechanism of CVST and thrombocytopenia following
Ad26.COV2.S vaccination.

The results described in this US investigation suggest that
CVST with thrombocytopenia following Ad26.COV2.S vacci-
nation is a rare syndrome with timing that appears to cluster
around 1 to 2 weeks following vaccination. The biological
mechanism for this new syndrome of CVST with thrombocy-
topenia (and other types of TTS) is an active area of investiga-
tion globally. The FDA has stated that a causal relationship be-
tween Ad26.COV2.S vaccine and TTS is plausible and has
updated its EUA with a warning about rare clotting events af-
ter Ad26.COV2.S vaccination, primarily among women aged
18 to 49 years.23 The clinical course and laboratory test re-
sults suggest that the pathogenesis of TTS may be similar to
autoimmune HIT. Autoimmune HIT is thought to be trig-
gered by the formation of antibodies directed against PF4, a
constituent of platelet alpha granules released during plate-
let activation. In contrast to classic HIT in which exogenous
heparin triggers antibody formation, in autoimmune HIT, an
endogenous polyanion such as polyphosphates and chondroi-
tin sulfate triggers PF4 antibody formation.24

However, while it has been proposed that a component of
the ChAdOx1 nCoV-19 vaccine could take the place of heparin
or an endogenous polyanion,9 the precise mechanism of TTS
in relation to COVID-19 vaccination has not yet been estab-
lished. The Global Advisory Committee on Vaccine Safety
(GACS) has stated that a platform-specific mechanism related
to adenovirus vector vaccines cannot be excluded.5 Al-
though the Ad26.COV2.S vaccine and ChAdOx1 nCoV-19 vac-
cine both use an adenoviral vector, the viral vectors are dif-
ferent (human vs chimpanzee).25 CVST and thrombocytopenia
following SARS-CoV-2 infection has been reported in at least
2 cases26; HIT testing was not done in these cases. As of April
21, 2021, no reports of CVST with thrombocytopenia follow-
ing authorized mRNA COVID-19 vaccines had been reported
to VAERS and confirmed.

These findings have important clinical and public health
implications. CDC has updated its interim clinical consider-
ations for use of authorized COVID-19 vaccines to indicate that
women aged 18 to 49 years should be aware of the increased

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Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination

Original Investigation Research

risk of TTS after receipt of Ad26.COV2.S vaccine.27 The pre-
ponderance of patients with positive heparin-PF4 ELISA tests
supports the recommendations in the CDC’s Health Alert Net-
work to avoid heparin when TTS is suspected and to strongly
consider anticoagulation with a nonheparin agent.2 Clini-
cians should consult with a hematologist when managing pa-
tients with TTS and report such cases to VAERS.2,23,27 The
American Society of Hematology has posted additional clini-
cal information and resources for clinicians caring for pa-
tients with TTS after Ad26.COV2.S vaccination.28

With the exception of hematologic findings (thrombocy-
topenia, extracranial thrombosis), the clinical presentation of
the US patients with CVST and thrombocytopenia following
Ad26.COV2.S vaccination is similar to typical CVST pa-
tients.7,29 Eleven of the 12 US patients in this series presented
initially with headaches; as illustrated by the vignettes of
some of the initial 6 US patients with CVST and thrombocyto-
penia, headaches occurring with CVST may wax and wane
and even improve with over-the-counter treatments. A sub-
acute presentation of headache is present in 90% of patients
with typical CVST.7,29 An advisory released by the American
Heart Association on April 15, 2021, describes symptoms
including headache that should increase concern for CVST or
other thrombosis.30 In the phase 3 study of Ad26.COV2.S vac-
cine, headaches occurred in 44% of patients younger than 60
years in the first week following vaccination; most patients’
symptoms appeared within 2 days and resolved within 2
days.12 In the US cases of CVST with thrombocytopenia fol-
lowing Ad26.COV2.S vaccination, symptoms began at least 6

days after vaccination and persisted for at least a week for
most. Urgent consultation with a neurologist is prudent
when a patient is suspected or confirmed to have CVST. In
addition, since the median time from symptom onset to hos-
pitalization was 7 days in the US CVST case series, patient and
clinician education might shorten the time to clinical evalua-
tion and therefore treatment. The US patients who died had
had features known to be associated with poor outcomes in
CVST, notably hemorrhage.31

Limitations
This case series has several limitations. First, VAERS is a pas-
sive surveillance system, so even with public notification of
CVST and thrombocytopenia following Ad26.COV2.S vacci-
nation, cases of CVST with thrombocytopenia may be under-
reported. Second, most data were obtained by retrospective
medical record review, and information might not be docu-
mented. Third, some laboratory investigations were not per-
formed in all patients.

Conclusions

The initial 12 US cases of CVST with thrombocytopenia after
Ad26.COV2.S vaccination represent serious events. This case
series may inform clinical guidance as Ad26.COV2.S vaccina-
tion resumes in the US as well as investigations into the po-
tential relationship between Ad26.COV2.S vaccine and CVST
with thrombocytopenia.

ARTICLE INFORMATION

Accepted for Publication: April 26, 2021.

Published Online: April 30, 2021.
doi:10.1001/jama.2021.7517

Author Contributions: Drs Lale and See had full
access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: See, Lale, Guh, Shimabukuro,
Wheeler, Edwards, Creech, Clark, DeStefano,
Broder.
Acquisition, analysis, or interpretation of data: See,
Su, Lale, Woo, Guh, Shimabukuro, Streiff, Rao,
Wheeler, Beavers, Durbin, Miller, Mba-Jonas, Nair,
Nguyen, Talaat, Urrutia, Creech, Clark, Broder.
Drafting of the manuscript: See, Lale, Woo, Guh,
Rao, Nguyen, Broder.
Critical revision of the manuscript for important
intellectual content: See, Su, Guh, Shimabukuro,
Streiff, Wheeler, Beavers, Durbin, Edwards, Miller,
Mba-Jonas, Nair, Talaat, Urrutia, Creech, Clark,
DeStefano, Broder.
Statistical analysis: See, Su, Lale, Guh.
Administrative, technical, or material support: Su,
Lale, Guh, Shimabukuro, Streiff, Rao, Wheeler,
Miller, Nair, Nguyen, Talaat, Creech, Clark, Broder.
Supervision: See, Shimabukuro, Edwards, Nair,
Clark, DeStefano, Broder.
Other - neurological expertise: Urrutia.
Other - clinical expertise: Wheeler.
Other - reading all serious reports: Woo.

Conflict of Interest Disclosures: Dr Streiff
reported receiving grants from Janssen for the

Cassini clinical trial of rivaroxaban for prevention of
cancer-associated thrombosis; personal fees from
Janssen for serving on the advisory board for the
Cassini trial; from Bayer, Bristol Myers Squibb, and
Dispersol for providing consultative advice; from
Bayer for CME lectures; and from Pfizer for CME
lectures and serving on the advisory board.
Dr Strieff also reported receiving grants from NHLBI
for a study on missed doses in VTE prophylaxis,
from AHRQ for work on individualized feedback on
VTE prophylaxis practices, and from PCORI for
research on patient education to improve
acceptance of VTE prophylaxis. Dr Durbin reported
receiving grants from Pfizer as an investigator for
the Pfizer COVID-19 vaccine trial and grants from
NIH for serving as the site principal investigator for
the AstraZeneca COVID-19 vaccine trial; receiving
personal fees from Merck for consultative advice on
dengue vaccine development; and serving on the
scientific advisory board for Valneva. Dr Edwards
reported receiving grants from NIH and providing
consultative advice to BioNet and IBM; she also
reported serving on data and safety monitoring
boards of Pfizer, Moderna, Merck, Sanofi, Roche,
X-4 Pharma, and Seqirus. Dr Talaat reported
receiving grants from Pfizer for serving as the site
principal investigator for the phase 3 adult
COVID-19 vaccine study and the phase 1-3 pediatric
(under 12) COVID-19 vaccine study, both at Johns
Hopkins University; she also reported receiving
grants from the NIH-Coronavirus Prevention
Network for serving as a co-investigator on the
phase 3 AstraZeneca COVID-19 vaccine trial in
adults. Dr Urratia reported receiving grants from
Genentech Inc for serving as the site principal

investigator on the TIMELESS trial and his work on
the investigator-sponsored OPTIMIST main trial.
Dr Creech reported receiving grants from Merck as
well as personal fees from Altimmune, Horizon,
Karius, Premier, and Astellas for providing
consultative advice. No other disclosures were
reported.

Funding/Support: This work was supported by the
Centers for Disease Control and Prevention (CDC)
Clinical Immunization Safety Assessment (CISA)
Project contracts 200-2012-53664 to Johns
Hopkins University and 200-2012-50430 to
Vanderbilt University Medical Center.

Role of the Funder/Sponsor: CDC provided
funding to Drs Creech, Durbin, Edwards, Streiff,
Talaat, Urrutia, Walker, and Wheeler. CDC, including
CDC authors along with non-CDC coauthors,
conducted the investigations; performed
collection, management, analysis, and
interpretation of the data; was involved in
preparation, review, and approval of the
manuscript; and made the decision to submit the
manuscript for publication.

Disclaimer: The findings and conclusions in this
report are those of the authors and do not
necessarily represent the official position of the
CDC or the Food and Drug Administration (FDA).
Mention of a product or company name is for
identification purposes only and does not
constitute endorsement by the CDC and FDA.

Additional Contributions: We thank the following
CDC staff who contributed to this article without
compensation aside from their salaries. For data

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Research Original Investigation

Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination

collection: Kathy Byrd, MD, MPH (CDC COVID-19
Response), Margaret Cortese, MD (CDC COVID-19
Response), Amelia Jazwa, MSPH (CDC COVID-19
Response), Anamika Khatri-Dua, MD (CDC
COVID-19 Response), Susan Lukacs, DO, MSPH
(CDC COVID-19 Response), Mike McNeil, MD, MPH
(CDC COVID-19 Response), Monica Parise, MD (CDC
COVID-19 Response), Allan Taylor, MD, MPH (CDC
COVID-19 Response). For leadership and support:
Denise Cardo, MD (CDC COVID-19 Response). We
also thank the following individuals who
contributed to this article with funding support
through the CISA Project. For programmatic
support: Paula Campbell, MS, MPH (Vanderbilt
University) and Braxton Hern, BS (Vanderbilt
University). For vaccine safety expertise: Elizabeth
Barnett, MD (Boston University), Neal Halsey, MD
(Johns Hopkins University), Thomas Kickler, MD
(Johns Hopkins University), Nicola Klein, MD, PhD
(Kaiser Permanente Northern California), Philip
LaRussa, MD (Columbia University), Stephen
Pelton, MD (Boston University), Elizabeth
Schlaudecker, MD, MPH (Cincinnati Children’s
Hospital Medical Center), Michael Smith, MD, MSCE
(Duke University), Mary Staat, MD, MPH (Cincinnati
Children’s Hospital Medical Center), Melissa
Stockwell (Columbia University), Emmanuel “Chip”
Walter, MD, MPH (Duke University), and Jennifer
Yui, MD, MS (Johns Hopkins University). We also
thank the clinical staff who have cared for these
patients and who reported these events to VAERS..

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