National Center for Immunization & Respiratory Diseases

Update: Thrombosis with thrombocytopenia 

syndrome (TTS) following COVID-19 vaccination

Advisory Committee on Immunization Practices (ACIP)

May 12, 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 

(TTS) following COVID-19 vaccination

 Summary
Background
5

Thrombosis*

 Thrombosis occurs when blood clots block blood vessels

–

–

–

–

Thromboses can be venous or arterial

Complications include heart attack, stroke, and other 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

 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) with blood tests 

(e.g., D-dimer) * 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 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
https://emergency.cdc.gov/han/2021/han00442.asp 7
8

https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood

https://jamanetwork.com/journals/jama/fullarticle/2779731

https://www.cdc.gov/mmwr/volumes/70/wr/mm7018e2.htm?s_cid=mm7018e2_w
9 https://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7017e4-H.pdf
Update on TTS cases
11

+ 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
12

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
13

Case finding for TTS following COVID-19 vaccines*

 Healthcare providers directly contact CDC about potential TTS cases

 FDA physicians screen incoming VAERS reports daily to identify 

potential TTS cases (i.e., screening of pre-processed reports)

 CDC searches the VAERS database of processed reports daily for 

possible TTS cases

 Medical records requested for all potential TTS case reports to confirm 

thrombosis with laboratory evidence of thrombocytopenia, using 

working case definition 

 CDC and FDA medical officers review TTS case reports and available 

medical records; CISA experts including hematologists consulted 

* Analytic period March 2–May 7, 2021
14

* A blood smear should be evaluated to rule out platelet clumping that 

could indicate a falsely low platelet count

Interim Brighton Collaboration case 

definition for TTS

 New onset thrombocytopenia: platelet 

count <150,000 per microliter*

 No known recent exposure to heparin 

 Presence of venous or arterial thrombosis

 In addition to rare thromboses (e.g., 

cerebral venous thrombosis), currently 

includes more common thromboses (e.g., 

as deep vein thrombosis, pulmonary 

thromboembolism, ischemic stroke, and 

myocardial infarction)

https://brightoncollaboration.us/wp-content/uploads/2021/04/TTS-InterimCase-Definition-v9.2-April22-202116538.docx
15

CDC working case definition for TTS following COVID-19 vaccination

 Tier 1 TTS case

‒

‒

‒

‒

‒

‒

Thrombosis in an unusual location, including cerebral venous sinuses, portal vein, 

splenic vein, and other rare venous and arterial thromboses

• May also concurrently have thrombosis in more common locations (e.g., venous 

thromboembolism, axillary vein thrombosis, deep vein thrombosis, pulmonary embolism)

Platelet count <150,000 per microliter

Positive (+) heparin-PF4 ELISA HIT antibody* result is supportive, but not required

 Tier 2 TTS case

Thrombosis in a common location only (e.g., venous thromboembolism, axillary vein 

thrombosis, deep vein thrombosis, pulmonary embolism, etc.)

• Excludes isolated acute myocardial infarction or ischemic stroke

Platelet count <150,000 per microliter

Positive (+) heparin-PF4 ELISA HIT antibody* result is required

* Heparin platelet factor 4 enzyme-linked immunosorbent assay heparin-induced thrombocytopenia antibody test
16

No confirmed TTS 

reports to VAERS

28 confirmed TTS 

reports to VAERS

No confirmed TTS 

reports to VAERS

†

U.S. COVID-19 vaccine administration by product type and TTS reports to VAERS 

(as of May 7, 2021)*

* Data source: https://covid.cdc.gov/covid-data-tracker/#vaccinations

† One CVST with thrombocytopenia case was observed in Janssen COVID-19 vaccine pre-authorization clinical trials in a 25-year-old male; this case is not included in the VAERS post-authorization confirmed case count
17

Characteristics of U.S. TTS cases after Janssen COVID-19 

vaccination, N=28 (Tier 1=25, Tier 2=3, as of May 7, 2021)

 Median age: 40 years (range 18–59 years)

 Median time from vaccination to symptom onset: 9 days (range 3–15 days)

 All received the Janssen COVID-19 Vaccine before the pause on April 13, 2021

 Female (n=22), male (n=6)

 19 of the 28 TTS cases has a cerebral venous sinus thrombosis (CVST)

 Pregnant or postpartum* (n=0)

 Past SARS-CoV-2 infection (n=5); 3 by history, 2 by nucleocapsid serology testing only

 Risk factors for thrombosis†

–

–

–

–

–

–

–

–

–

Systemic estrogen‡ (n=3)

Obesity (n=12)

Hypertension (n= 7)

Hypothyroidism (n=3)

* Within 12 weeks of delivery; † Reference source: https://www.hopkinsmedicine.org/health/conditions-and-diseases/thrombosis; ‡ 2 patients were taking combined oral contraceptives (COCs), 1 patient was on hormone therapy (HT) estradiol patch

Diabetes (n=3)

Current cigarette smoking (n=2)

Malignancy (n=1)

Fertility treatment (n=1)

Coagulation disorders (n=0)
18

0

1

2

3

4

16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64

Number of confirmed reports

Patient age, years

Confirmed U.S. case reports of TTS following Janssen COVID-19 

vaccination by patient age as of May 7, 2021 (N=28)

Median
19

0

1

2

3

4

5

6

7

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 U.S. case reports of TTS following Janssen COVID-19 

vaccination by time to symptom onset as of May 7, 2021 (N=28)
20

U.S. reporting rates of TTS after Janssen COVID-19 

vaccination (as of May 7, 2021)

Females Males

Age group

TTS

cases 

Doses 

admin

Reporting rate†

(per million)

TTS

cases 

Doses

admin

Reporting rate†

(per million)

18-29 yrs old 3 641,510 4.7 2 714,458 2.8

30-39 yrs old 8 642,745 12.4 1 728,699 1.4

40-49 yrs old 7 743,256 9.4 1 775,390 1.3

50-64 yrs old 4 1,463,416 2.7 2 1,505,505 1.3

65+ yrs old 0 814,947 0 0 697,925 0

* Source of doses administered: https://covid.cdc.gov/covid-data-tracker/#vaccinations; † Reporting rate = TTS cases per 1 million Janssen COVID-19 vaccine doses administered

 8.73 million total Janssen COVID-19 Vaccine doses administered*
21

Females Males

Age group

TTS

cases 

Doses 

admin

Reporting rate†

(per million)

TTS

cases 

Doses

admin

Reporting rate†

(per million)

18-29 yrs old 3 641,510 4.7 2 714,458 2.8

30-39 yrs old 8 642,745 12.4 1 728,699 1.4

40-49 yrs old 7 743,256 9.4 1 775,390 1.3

50-64 yrs old 4 1,463,416 2.7 2 1,505,505 1.3

65+ yrs old 0 814,947 0 0 697,925 0

U.S. reporting rates of TTS after Janssen COVID-19 

vaccination (as of May 7, 2021)

* Source of doses administered: https://covid.cdc.gov/covid-data-tracker/#vaccinations; † Reporting rate = TTS cases per 1 million Janssen COVID-19 vaccine doses administered

 8.73 million total Janssen COVID-19 Vaccine doses administered*
22

Females Males

Age group

TTS

cases 

Doses 

admin

Reporting rate†

(per million)

TTS

cases 

Doses

admin

Reporting rate†

(per million)

18-29 yrs old 3 641,510 4.7 2 714,458 2.8

30-39 yrs old 8 642,745 12.4 1 728,699 1.4

40-49 yrs old 7 743,256 9.4 1 775,390 1.3

50-64 yrs old 4 1,463,416 2.7 2 1,505,505 1.3

65+ yrs old 0 814,947 0 0 697,925 0

U.S. reporting rates of TTS after Janssen COVID-19 

vaccination (as of May 7, 2021)

* Source of doses administered: https://covid.cdc.gov/covid-data-tracker/#vaccinations; † Reporting rate = TTS cases per 1 million Janssen COVID-19 vaccine doses administered

 8.73 million total Janssen COVID-19 Vaccine doses administered*
23

Locations of thromboses in U.S. TTS cases following 

Janssen COVID-19 vaccination, N=28 

(as of May 7, 2021; not mutually exclusive) 

 Cerebral venous sinuses*

 Anterior cerebral artery

 Internal carotid artery

 Femoral vein and artery

 Hepatic vein

 Iliac artery

 Internal jugular vein

*10 of 19 patients with cerebral venous sinus thrombosis experienced an intracerebral hemorrhage: temporo-parietal junction, temporal 

lobe, frontal lobe, occipital lobe, cerebellum, intraventricular, subarachnoid

 Lower extremity veins

 Portal vein

 Pulmonary artery

 Superior mesenteric 

vein and artery

 Splenic vein

 Upper extremity veins
24

Selected laboratory findings in U.S. TTS cases following 

Janssen COVID-19 vaccination, N=28 (as of May 7, 2021)

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

‒

‒

‒

‒

‒

‒

<50,000..................(n=18)

50–<100,000.......... (n=6)

100,000–149,000... (n=4)

 Heparin-PF4 ELISA HIT antibody results

Positive (+)..............(n=24)†

Negative (-).............(n=2)

Not available.......... (n=2)

* Platelet nadir range: 9,000-127,000 per microliter

† Tier 2 TTS required a positive (+) heparin-PF4 ELISA antibody test as part of definition
25

SARS-CoV-2 testing results in U.S. TTS cases following 

Janssen COVID-19 vaccination, N=28 (as of May 7, 2021)

 SARS-CoV-2 nucleic acid or 

antigen viral assay 

–

–

–

Negative (n=25)

Positive (n=0)

Not available (n=3)

 SARS-CoV-2 serology by 

nucleocapsid antibody

–

–

–

Negative (n=4)

Positive (n=2)*

Not available/not specified (n=22)†

* Neither of these patients reported a history of COVID-19. †

Three had a negative serology, the report did not specify whether nucleocapsid or spike protein antibody 
26

Treatment and outcomes among U.S. TTS cases following 

Janssen COVID-19 vaccination, N=28 (as of May 7, 2021)

 Treatment

‒

‒

‒

‒

‒

‒

‒

‒

‒

‒

Heparin (n=12)

9/11 (82%) admitted before HAN*

3/17 (18%) admitted after HAN*

Non-heparin anticoagulants (n=26)

Platelet transfusion (n=7)

Intravenous immunoglobulin (n=18)

* CDC Health Alert Network (HAN) notification released on April 13, 2021

† As of May 7, 2021

§ None of the patients who died received heparin; all had signs of severe CVST (hemorrhage + mass effect) on initial imaging and died within 2 days of presentation

 Outcomes†

Death (n=3)§

Remain hospitalized (n=4)

• Intensive care unit (n=1)

Discharged to post-acute 

care facility (n=2)

Discharged home (n=19)
27

VSD

Vaccine

Safety

Datalink

 9 participating integrated healthcare organizations

 Data on over 12 million persons per year
28

VSD: Cerebral venous sinus thrombosis (CVST) 

after mRNA COVID-19 vaccination

 3.3 million doses of Pfizer-BioNTech and 3.0 million doses of Moderna

COVID-19 vaccinations administered in VSD as of April 24, 2021

‒ 11 total ICD-10 coded CVST diagnoses identified following mRNA vaccines 

(3 after Pfizer-BioNTech and 8 after Moderna vaccination) 

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

sinus syndrome n=1)

• 6 potential CVST incident cases, but all without thrombocytopenia 

 No confirmed cases of incident CVST with thrombocytopenia after 6.3 

million doses of mRNA COVID-19 vaccines administered in VSD
29

VSD: Thrombosis events after Janssen COVID-19 vaccination

 159,885 Janssen COVID-19 Vaccine doses administered in VSD through April 24, 2021

‒

‒

No statistical signals detected for any prespecified Rapid Cycle Analysis outcomes

No CVST cases identified

 32 VTE/PE cases identified in the 1–42 days following vaccination (including 3 cases 

diagnosed with both VTE and PE) 

‒ 29 of the cases have been quick reviewed to date (3 in progress)

• 6 were ruled out as not VTE/PE

• 23 were confirmed VTE/PE cases







4 were determined to have symptom onset prior to vaccination

1 had an indeterminate symptom onset

18 are potential VTE/PE cases with incidence following vaccination

» 10 female (5 PE, 5 VTE), 8 males (4 PE, 4 VTE)

» Ages ranged from 30–79

» None with history of COVID-19 infection 

» None with thrombocytopenia noted at time of VTE/PE

VTE = venous thromboembolism

29 PE = pulmonary embolism 

23

18
Summary and next steps
31

Summary

 TTS is a rare, clinically serious and potentially life-threatening condition; current evidence 

suggests a plausible causal association with the Janssen COVID-19 Vaccine

 Symptom onset appears to occur from several days after vaccination to up to 2 weeks, 

with most cases having symptom onset around 1–2 weeks after vaccination

 Most cases are in women, with most aged 18-49 years old 

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

is being observed following AstraZeneca COVID-19 vaccination in Europe

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

‒ Do not treat cases of thrombosis with thrombocytopenia with heparin unless heparin-PF4 

ELISA HIT antibody testing is negative

 TTS does not appear to be associated with mRNA COVID-19 vaccines

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

following vaccination and quickly assess safety signals

 CDC is committed to open and transparent communication of vaccine safety information
32

Next steps

 Continue enhanced monitoring in VAERS and conduct surveillance in 

other vaccine safety systems (e.g., VSD, Centers for Medicare & Medicaid 

Services data, Veterans Affairs electronic health record data)

 Update ACIP and the public as addition information becomes available
33

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
Adolescent vaccination 

and v-safe enrollment
35

http://cdc.gov/vsafe

Smartphone-based active safety monitoring

4
36

Use of v-safe for adolescent COVID-19 vaccination

 CDC encourages parents and guardians to enroll their vaccinated 

adolescents into v-safe

 Parents and guardians can complete health surveys on behalf of their 

adolescents, describing symptoms and health events after vaccination

‒

‒

CDC encourages completing health surveys even if vaccinated persons are feeling 

well and have no side effects

 Participation in v-safe will help CDC continue to monitor the safety of 

COVID-19 vaccines as use is expanded into younger populations

 Promote v-safe participation at vaccination locations 

Take advantage of the post-vaccination observation period to encourage v-safe 

participation
37

Acknowledgments

Centers for Disease Control and Prevention

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:
38

v-safe VAERS VSD CISA Project

Full list of U.S. COVID-19 vaccine safety monitoring systems

https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety.html

 Authorized COVID-19 vaccines are being administered under the most 

intensive vaccine safety monitoring effort in U.S. history

 Strong, complementary systems are in place―both new and established 

Vaccine safety in the United States
Back-up Slides
40

Proposed VAERS MedDRA PT and text string search terms for TTS

 MedDRA PTs for large vessel thrombosis and embolism in unusual locations 

‒

‒

‒

‒

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 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