National Center for Immunization & Respiratory Diseases

Thrombosis with thrombocytopenia syndrome 

(TTS) following Janssen COVID-19 vaccine

Advisory Committee on Immunization Practices (ACIP)

April 23, 2021

Tom Shimabukuro, MD, MPH, MBA

CDC COVID-19 Vaccine Task Force 

Vaccine Safety Team
2

Disclaimer

 The findings and conclusions in this report are those of the authors 

and do not necessarily represent the official position of the Centers for 

Disease Control and Prevention (CDC) or the U.S. Food and Drug 

Administration (FDA)

 Mention of a product or company name is for identification purposes 

only and does not constitute endorsement by CDC or FDA
3

Topics

 Background

 Thrombosis with thrombocytopenia syndrome following 

Janssen COVID-19 vaccine

 Summary
Background
5

Thrombosis*

 Thrombosis occurs when blood clots block blood vessels

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–

–

–

Thromboses can be venous or arterial

Complications include heart attack, stroke, infarctions 

 Causes and risk factors include:

Trauma, immobility, inherited disorders (genetic), autoimmune disease, 

obesity, hormone therapy or birth control pills, pregnancy, smoking, 

cancer, older age, etc.

 Symptoms may include:

Pain and swelling in an extremity, chest pain, numbness or weakness on 

one side of the body, sudden change in mental status

 Diagnosed mainly through imaging (e.g., CT, MRI, ultrasound) and blood tests

* Source: https://www.hopkinsmedicine.org/health/conditions-and-diseases/thrombosis
6

Platelets and thrombocytopenia (low platelets)*

 Platelets (thrombocytes) are colorless blood cells that help blood clot; 

normal platelet count is 150,000–450,000 per microliter

 Platelets stop bleeding by clumping and forming plugs in blood vessel 

injuries

 Thrombocytopenia is a condition in which you have a low blood 

platelet count (<150,000 per microliter)

 Dangerous internal bleeding can occur when your platelet count falls 

below 10,000 platelets per microliter

 Though rare, severe thrombocytopenia can cause bleeding into the 

brain, which can be fatal

* Source: https://www.mayoclinic.org/diseases-conditions/thrombocytopenia/symptoms-causes/syc-20378293
7 https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04/03-COVID-Shimabukuro-508.pdf 8

Originally presented April 14, 2021
9

Cerebral venous sinus anatomy

Silvis SM et al, Nature Reviews Neurology 13, 555-565(2017)
10

VAERS data for cerebral venous sinus thrombosis (CVST) 

reports following COVID-19 vaccines (ACIP April 14, 2021)

https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04/03-COVID-Shimabukuro-508.pdf

Originally presented April 14, 2021
11

CVST with thrombocytopenia following COVID-19 vaccines 

(conclusions from ACIP April 14, 2021)

https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04/03-COVID-Shimabukuro-508.pdf

Originally presented April 14, 2021
https://emergency.cdc.gov/han/2021/han00442.asp 12
13

Vaccine Safety Datalink (VSD) supplementary analysis 

for mRNA vaccines 

 2.7 million doses of Pfizer-BioNTech and 2.5 million doses of 

Moderna COVID-19 vaccine doses administered in VSD as of April 

17, 2021

‒ 10 total cases of CVST identified following mRNA vaccines

• 5 cases ruled out (historical n=2, history of head injury n=2, chronic 

cavernous sinus syndrome n=1)

• 5 cases potentially CVST, but all without thrombocytopenia 

 No confirmed cases of incident CVST with thrombocytopenia after 

5.2 million doses of mRNA COVID-19 vaccines administered in VSD
14

COVID-19 vaccines and CVST with thrombocytopenia

 Safety signal detected for CVST with thrombocytopenia 

following Janssen COVID-19 vaccine

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–

6 cases observed in women aged 18–48 years in early postauthorization monitoring

1 case observed in pre-authorization clinical trials in a 25-

year-old male*

 Currently, there is a lack of evidence of an association 

between mRNA COVID-19 vaccines and CVST with 

thrombocytopenia 

* https://www.nejm.org/doi/full/10.1056/NEJMc2106075; https://www.fda.gov/media/146217/download
15

https://brightoncollaboration.us/wp-content/uploads/2021/04/TTS-Case-

Finding-and-Definition-Process.v9.0-April-16-202115853.pdf

Brighton Collaboration draft case 

finding definition for thrombosis with 

thrombocytopenia syndrome (TTS)  Platelet count <150 X 109/L  In addition to rare thromboses, 

currently includes more common 

thromboses, such as deep vein 

thrombosis, pulmonary 

thromboembolism, ischemic 

stroke, and myocardial infarction
Data sources and TTS cases
17

+ co-managed by

CDC and FDA

Vaccine Adverse Event 

Reporting System

http://vaers.hhs.gov

VAERS is the nation’s early warning system for vaccine safety
18

7 participating medical 

research centers with 

vaccine safety experts

*More information about clinical consults available at: 

http://www.cdc.gov/vaccinesafety/Activities/CISA.html

CISA 

Clinical

Immunization

Safety

Assessment 

(CISA) Project 

 clinical consult services*  clinical research
19

Case finding for TTS following Janssen COVID-19 vaccine

 Healthcare providers directly contact CDC with potential TTS cases

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‒

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CDC initiates an investigation and facilitates submission of a VAERS report

 FDA physicians review incoming VAERS reports daily to identify potential TTS cases

 VAERS database search for possible TTS reports

MedDRA PTs for large vessel thrombosis and/or embolism (any report)

Did not include the more common thrombosis events*; these events will be 

evaluated in subsequent analyses

 Medical records are requested for all potential TTS cases to confirm thrombosis 

with laboratory evidence of thrombocytopenia 

 CDC and FDA medical officers reviewed TTS reports and available medical records; 

CISA experts including hematologists were consulted 

* e.g., acute myocardial infarction, ischemic stroke, deep vein thrombosis, pulmonary embolism
20

Reporting rates of TTS after Janssen COVID-19 vaccine

Females Males

Age group

TTS

cases Doses admin Reporting rate‡

TTS

cases Doses admin Reporting rate‡

18-49 years old 13 1,866,294 7.0 per million 0 1,977,330 0 per million

50+ years old 2 2,125,239 0.9 per million 0 2,010,144 0 per million

* Source of doses administered: https://covid.cdc.gov/covid-data-tracker/#vaccinations; † One case was excluded from the final analysis: a female aged 

<50 years who had concurrent diagnosis of COVID-19 and TTS following receipt of Janssen vaccine; ‡ Reporting rate = TTS cases per 1 million Janssen 

COVID-19 vaccine doses administered

 7.98 million vaccine doses administered*and 15 confirmed TTS cases† as of April 21, 2021

‒

‒

Some age- and sex-specific doses administered data were imputed

Additional potential TTS cases under review, including potential male cases
21

Confirmed reports of TTS following Janssen COVID-19 

vaccine, by patient age (N=15, all in women) 
22

Reporting rates of TTS after Janssen COVID-19 vaccine in women

Females

Age group TTS cases Doses admin Reporting rate‡

18-29 years old 3 579,709 5.2 per million

30-39 years old 7 594,215 11.8 per million

40-49 years old 3 692,370 4.3 per million

50-64 years old 2 1,367,529 1.5 per million

65+ years old 0 757,710 0 per million

 3.99 million vaccine doses administered to women* with 15 confirmed TTS cases†

as of April 21, 2021

‒ Some age-specific doses administered data were imputed

* Source of doses administered: https://covid.cdc.gov/covid-data-tracker/#vaccinations; † One case was excluded from the final analysis: a female aged 

<50 years who had concurrent diagnosis of COVID-19 and TTS following receipt of Janssen vaccine; ‡ Reporting rate = TTS cases per 1 million Janssen 

COVID-19 vaccine doses administered
23

Characteristics of patients with TTS after Janssen 

COVID-19 vaccine, N=15

 Median age 37 years (range 18–59)

 Median time to symptom onset 8 days (range 6–15 days)

 All cases occurred in females

 12 cases were cerebral venous sinus thrombosis (CVST)

 Pregnant or post-partum* (n=0)

 COVID-19 disease (n=2); both by history, no documentation of serology testing

 Risk factors for thrombosis†

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–

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–

Oral contraceptive use (n=2)

Obesity (n=7)

Hypothyroidism (n=2)

* Within 12 weeks of delivery; † Reference source: https://www.hopkinsmedicine.org/health/conditions-and-diseases/thrombosis

Hypertension (n=2)

Diabetes (n=0)

Coagulation disorders (n=0)
24

0

1

2

3

4

5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Number of confirmed reports

Time from vaccination to symptom onset, days

Confirmed Reports of TTS, by Time to Symptom Onset
25

Signs and symptoms in patients with cerebral venous 

sinus thrombosis after Janssen COVID-19 vaccine, N=12 

 Initial* 

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Headache (all started ≥6 days 

after vaccination)

Chills 

Fever 

Nausea/vomiting

Malaise/lethargy

Abdominal pain

 Later in clinical course*

Severe headache, several with 

neck pain or stiffness

Nausea/vomiting

Abdominal pain

Unilateral weakness

Speech difficulty

Gaze deviation

Loss of consciousness

Seizure 

* Occurring in ≥2 patients 
26

Locations of thromboses in TTP patients, N=15 

(not mutually exclusive) 

 Cerebral venous sinus locations (n=12)*

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Transverse sinuses

Sigmoid sinuses

Confluence of sinuses

Straight sinus

Superior sagittal sinus

Inferior sagittal sinus

Cortical veins

 Other locations (n=11)

‒ Portal vein†

‒ Hepatic vein

‒ Superior mesenteric artery†

‒ Splenic artery†

‒ Pulmonary artery†

‒ Lower extremity vein†

‒ Internal jugular vein

‒ Carotid artery†

‒ Brachial vein†

‒ Femoral vein and artery†

‒ Iliac artery†

* 7 patients with cerebral venous sinus thrombosis experienced an intracerebral hemorrhage: temporoparietal junction, temporal lobe, frontal lobe, occipital lobe, cerebellum, intraventricular, subarachnoid

†

Patients without CVST had thrombosis in these locations
27

Selected laboratory findings in TTS patients, N=15

 Platelet levels (normal levels: 150,000–450,000 per mm3)*

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<50,000..................(n=10)

50–<100,000.......... (n=3)

100,000–149,000...(n=2)

 PF4 HIT† ELISA antibody results

Positive (+)..............(n=11)

Negative (-).............(n=0)

Not available.......... (n=4)

* Platelet nadir range: 9,000-127,000; † Platelet factor 4 heparin-induced thrombocytopenia 
28

SARS-CoV-2 testing results in TTS patients, N=15

 SARS-CoV-2 viral assay 

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–

–

–

–

–

Negative (n=10)

Positive (n=0)

Not available (n=5)

 SARS-CoV-2 serology

Negative (n=4)

Positive (n=0)

Not available (n=11)
29

Treatment and outcomes among TTS patients, N=15

 Treatment*

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Heparin (n=6)‡

Nonheparin anticoagulants (n=12)

Platelet transfusion (n=7)

Intravenous immunoglobulin (n=8)

* Based on 14 patients

† As of April 21, 2021

‡ All patients who received heparin were hospitalized before HAN release 

§ None of the patients who died received heparin

 Outcomes†

Death (n=3)§

Remain hospitalized (n=7)

• Intensive care unit (n=4)

Discharged home (n=5)
30

VSD

Vaccine

Safety

Datalink

 9 participating integrated healthcare organizations

 Data on over 12 million persons per year
31

VSD: Thrombosis events after Janssen COVID-19 vaccine

 142,122 Janssen COVID-19 vaccine doses administered in VSD through April 17, 2021

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No statistical signals detected for any prespecified Rapid Cycle Analysis outcomes

 No CVST cases identified

 22 VTE/PE cases identified in the 1–42 days following vaccination and quick reviewed 

(including 2 with both VTE and PE)

6 ruled out as not VTE

16 were confirmed VTE/PE cases

• 4 (3 PE, 1 VTE) had symptom onset prior to vaccination

 Including 1 case with thrombocytopenia documented prior to vaccination

• 1 had an indeterminate symptom onset

• 11 were incident cases following vaccination

 6 female (2 PE, 4 VTE), 5 male (1 PE, 4 VTE)

 Ages ranged from 50-79 years

 None with history of COVID-19 infection 

 None with thrombocytopenia at time of VTE/PE

VTE = venous thromboembolism

PE = pulmonary embolism 
Summary and next steps
33

Summary

 TTS is a rare, but clinically serious and potentially life-threatening adverse event that has 

been observed in association with the Janssen COVID-19 vaccine

 Symptom onset appears to occur at least several days after vaccination, typically around 

1–2 weeks after vaccination

 The clinical features of TTS following Janssen COVID-19 vaccine appear similar to what is 

being observed following the AstraZeneca COVID-19 vaccine in Europe

 It is important to recognize TTS early and initiate appropriate treatment

‒ Do not treat TTS with heparin, unless HIT testing is negative

 The U.S. vaccine safety monitoring system is able to rapidly detect rare adverse events 

following immunization and quickly assess safety signals

 Safety surveillance and research on TTS continues 

 CDC is committed to open and transparent communication of vaccine safety information
34

Next Steps

 Continue enhanced monitoring in VAERS and surveillance in other 

vaccine safety systems (e.g., VSD, CMS, VA electronic health record)

 Expand VAERS database search strategy for TTS reports (proposed)

‒

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MedDRA PTs for large vessel thrombosis and embolism (all reports regardless 

of presence of thrombocytopenia)

MedDRA PTs for more common thrombotic events AND MedDRA PTs for 

thrombocytopenia OR text string for “thrombocytopenia” or “low platelets”

Medical record review for all potential TTS cases reports to confirm 

thrombosis with thrombocytopenia 
35

How to report an adverse event to VAERS

 Go to vaers.hhs.gov

 Submit a report online

 For help:

Call 1-800-822-7967

Email info@VAERS.org

video instructions 

https://youtu.be/sbCWhcQADFE

 Please send records to VAERS 

ASAP if contacted and asked

‒ HIPAA permits reporting of 

protected health information 

to public health authorities 

including CDC and FDA
36

Acknowledgments

Centers for Disease Control and Prevention

COVID-19 Vaccine Task Force

COVID-19 Vaccine Task Force, Vaccine Safety Team

Immunization Safety Office

Division of Healthcare Quality Promotion

Clinical Immunization Safety Assessment Project

Vaccine Safety Datalink

Food and Drug Administration

Center for Biologics Evaluation and Research 

We wish to acknowledge the contributions of investigators from the following organizations:
Questions
Back-up Slides
39

One report of TTS excluded from case count

 Female aged <50 years with COVID-19 (PCR positive) and TTS with complex clinical course:

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–

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Received Janssen vaccine

Hospitalization 1 (admitted 22 days after vaccination): for COVID-19 pneumonia

• Presented with nausea, hematemesis, shortness of breath; date of symptom onset 

unclear

• Normal platelet count

Hospitalization 2 (readmitted 28 days after vaccination): 

• Presented with nausea, hematemesis, abdominal pain, shortness of breath, cough 

• Platelet 100,000

• Imaging studies showed CVST, lower leg venous thromboembolism, pulmonary 

embolism

• Died during hospitalization*

*Reported cause of death: respiratory failure, shock, COVID-19 pneumonia 
40

Proposed VAERS MedDRA PT and text string search terms for TTS

 MedDRA PTs for large vessel thrombosis and embolism 

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Aortic embolus, aortic thrombosis, aseptic cavernous sinus thrombosis, brain stem embolism, brain stem thrombosis, carotid 

arterial embolus, carotid artery thrombosis, cavernous sinus thrombosis, cerebral artery thrombosis, cerebral venous sinus 

thrombosis, cerebral venous thrombosis, superior sagittal sinus thrombosis, transverse sinus thrombosis, mesenteric artery 

embolism, mesenteric artery thrombosis, mesenteric vein thrombosis, splenic artery thrombosis, splenic embolism, splenic 

thrombosis, thrombosis mesenteric vessel, visceral venous thrombosis, hepatic artery embolism, hepatic artery thrombosis, 

hepatic vein embolism, hepatic vein thrombosis, portal vein embolism, portal vein thrombosis, portosplenomesenteric venous 

thrombosis, splenic vein thrombosis, spontaneous heparin-induced thrombocytopenia syndrome, femoral artery embolism, 

iliac artery embolism, jugular vein embolism, jugular vein thrombosis, subclavian artery embolism, subclavian vein thrombosis, 

obstetrical pulmonary embolism, pulmonary artery thrombosis, pulmonary thrombosis, pulmonary venous thrombosis, renal 

artery thrombosis, renal embolism, renal vein embolism, renal vein thrombosis, brachiocephalic vein thrombosis, vena cava 

embolism, vena cava thrombosis, truncus coeliacus thrombosis

 MedDRA PTs for more common thrombotic events

Axillary vein thrombosis, deep vein thrombosis, pulmonary embolism, MedDRA PTs for acute myocardial infarction*, MedDRA 

PTs for stroke*

 MedDRA PTs for thrombocytopenia 

Autoimmune heparin-induced thrombocytopenia, Heparin-induced thrombocytopenia, Immune thrombocytopenia, Nonimmune heparin associated thrombocytopenia, Spontaneous heparin-induced thrombocytopenia syndrome, 

Thrombocytopenia, Thrombocytopenic purpura

 Text string for

“thrombocytopenia” or “low platelets” in symptom text

* https://www.cdc.gov/vaccinesafety/pdf/VAERS-v2-SOP.pdf