cdc.gov/coronavirus

Updates on Thrombosis with 

Thrombocytopenia Syndrome (TTS)

Advisory Committee on Immunization Practices (ACIP)

Dec 16, 2021

Isaac See, MD

Vaccine Safety Team

CDC COVID-19 Vaccine Task Force

1
Background

2
Thrombosis*

 Thrombosis occurs when blood clots block blood vessels

– 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 replacement therapy or birth control pills, pregnancy, 

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) and blood tests

* Source: https://www.hopkinsmedicine.org/health/conditions-and-diseases/thrombosis 3
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 (μL)

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

injuries

 Thrombocytopenia is a condition in which a person has a low blood platelet 

count (<150,000 per μL)

 Dangerous internal bleeding can occur when the platelet count falls below 

10,000 per μL

 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 4
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

Thrombosis with thrombocytopenia syndrome (TTS): 

new syndrome recognized after adenoviral-vectored 

COVID-19 vaccines

5
Cerebral Venous Sinus Thrombosis (CVST)

Source: Silvis SM et al, Nature Reviews Neurology 13, 555-565 (2017). 6
Features of severe CVST

 CVST is often under-diagnosed due to its nonspecific presentation 

 Short-term death from CVST usually caused by brain herniation

– Resulting from large or multiple hemorrhages (bleed) or from diffuse 

brain edema (swelling)

 Reported prognostic factors for poor short-term outcome include: 

– Anatomical: brain herniation, hemorrhage

– Clinical presentation: seizures, depressed consciousness, altered 

mental status

Idiculla PS et al. Cerebral Venous Thrombosis: a comprehensive review. Eur Neuro 2020;83:369-379.

Saposnik G, et al. AHA/ASA scientific statement. Diagnosis and management of cerebral venous thrombosis. Stroke 2011;42:1158-1192. 7
Timeline for initial U.S. events for TTS following 

Janssen COVID-19 Vaccine, 2021

Feb 27 Mar 2 Apr 13 Apr 23

FDA authorizes 

Janssen COVID19 Vaccine

First post-authorization U.S. 

doses of Janssen COVID-19 

Vaccine

CDC/FDA announce 

pause in use of Janssen 

COVID-19 Vaccine after 

identification of 6 cases 

of CVST with 

thrombocytopenia

ACIP reviews data

Reaffirms recommendation for 

Janssen COVID-19 Vaccine

CDC/FDA lift pause

CDC interim clinical 

considerations and FDA 

EUA fact sheets updated 

with information about 

risk of TTS particularly in 

women <50 years of age

Jul 22

ACIP reviews Janssen 

COVID-19 Vaccine 

benefit/risk data again 

in light of GuillainBarré syndrome (TTS 

data included)

https://www.cdc.gov/media/releases/2021/s0413-JJ-vaccine.html; https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html; 

https://www.fda.gov/media/146304/download; https://www.cdc.gov/mmwr/volumes/70/wr/mm7032e4.htm 8
+ 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

9
7 participating medical 

research centers with 

vaccine safety experts

*More information about clinical consults available at: 

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

Clinical

Immunization

Safety

Assessment 

(CISA) Project 

 clinical consult services*  clinical research

CISA

10
Case finding in VAERS for TTS following COVID-19 

vaccines

 VAERS database search conducted daily for possible TTS reports

– Healthcare providers directly contacted CDC with potential TTS

– CDC initiates an investigation and facilitates submission of a VAERS 

report

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

thrombosis with laboratory evidence of thrombocytopenia, using working 

case definition, reviewed by CDC and FDA medical officers

 CISA experts, including hematology/neurology, confirm clinical syndrome 

consistent with TTS and rule out other causes of thrombosis and 

thrombocytopenia

CISA 11
CDC working case definition for TTS following 

COVID-19 Vaccine

 Reports where only thrombosis is ischemic stroke or myocardial infarction 

are excluded

 Cases with concurrent COVID-19 infection excluded

TTS 

category

Thrombosis location Platelet count Positive PF4 

ELISA* test 

required?

Tier 1 Unusual location, e.g., CVST, 

abdominal venous or arterial 

thrombosis

<150,000 cells/μL No

Tier 2 Only in ‘typical’ location(s), e.g., 

pulmonary embolism, deep vein 

thrombosis of extremity

<150,000 cells/μL Yes

*PF4 ELISA: platelet factor 4 enzyme-linked immunosorbent assay 12
Analytic periods

 Descriptive epidemiology and reporting rates for TTS cases receiving 

Janssen COVID-19 Vaccine March 2–August 31, 2021

 Summarize information about all deaths among TTS cases following 

Janssen COVID-19 Vaccine confirmed by December 9, 2021

 Reporting rates for TTS deaths receiving Janssen COVID-19 Vaccine March 

2–August 31, 2021

13
Epidemiology of U.S. TTS cases following Janssen 

COVID-19 vaccination (March 2–August 31, 2021)

14
Characteristics of U.S. TTS cases after Janssen COVID-19 

vaccination*, N=54 (Tier 1=46, Tier 2=8)

 Median age: 44.5 years (range 18–70 years)

 Female (n=37), male (n=17)

 26 (48%) are women aged <50 years 

 83% in white non-Hispanic persons

 29 of the TTS cases (54%) have a cerebral venous sinus thrombosis (CVST)

 Pregnant or postpartum (n=0)

 Known or newly diagnosed thrombophilia (n=0)

 Past SARS-CoV-2 infection (n=7); 5 by history, 2 by nucleocapsid serology 

testing only

15 *Vaccinated March 2–August 31, 2021
Characteristics of U.S. TTS cases after Janssen COVID-19 

vaccination*, N=54 (continued)

 Median time from vaccination to symptom onset: 9 days (range 0–18 days)

 Median time from symptom onset to admission: 5 days (range: 0–30 days)

 39 (72%) received the Janssen COVID-19 Vaccine before the pause on April 

13, 2021

 All after dose 1 of Janssen COVID-19 Vaccine (i.e., none after booster 

doses)

16 *Vaccinated March 2–August 31, 2021
Number of TTS cases following Janssen COVID-19 

vaccination, by month of vaccination* (N=54)

0

5

10

15

20

25

March April May June July August

Number of cases

Month of vaccination (2021)

After pause

Before pause

17 *Vaccinated March 2–August 31, 2021
U.S. TTS cases, by time from Janssen COVID-19 

vaccination to symptom onset, (N=53*)

*Exact symptom onset could not be determined for one case but known to be ≤12 days after vaccination. Vaccinations March 2–August 31, 2021

0

1

2

3

4

5

6

7

8

9

0 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

18
Venous thrombosis risk factors in U.S. TTS cases 

following Janssen COVID-19 vaccination*, N=54

* Vaccinated March 2–August 31, 2021

** Venous thrombosis risk factors as described in Lijfering WM et al, Br J Haemtol 2020; and Crous-Bou M et al, Semin Thromb Hemost 2016.

† 2 receiving combined oral contraceptives and 1 on estradiol patch for hormone replacement therapy

‡Other venous thrombosis risk factors include cirrhosis, malignancy, fertility treatment, venous catheter at thrombosis site; one case had both venous catheter at 

thrombosis site and malignancy

Risk factor** (not mutually exclusive) n (%)

Obesity 25 (46)

Hypertension 16 (30)

Diabetes 7 (13)

Systemic estrogen therapy† 3 (6)

Other venous thrombosis risk factor‡ 3 (6)

None of the above risk factors 21 (39)

19
Outcomes among U.S. TTS cases following Janssen 

COVID-19 vaccination, N=54*

 All hospitalized

 ICU admission (n=36)

 Length of stay for patients surviving 

hospitalization

– Median 9 days

– Range: 1–132 days

– Interquartile range: 6–17 days

 Outcome of hospitalization

– Death (n=8)

– Discharged to post-acute care 

facility (n=9)

– Discharged home (n=37)

20 *Vaccinated March 2–August 31, 2021
Reporting rates of TTS after Janssen COVID-19 vaccine, 

vaccination through August 31, 2021 (N=54)

14.1 million total Janssen COVID-19 vaccine doses administered*

Females Males

Age group

TTS

cases 

Doses 

admin

Reporting rate†

(per million)

TTS

cases 

Doses

admin

Reporting rate†

(per million)

18-29 yrs old 5 1,089,649 4.59 3 1,565,212 1.92

30-39 yrs old 11 1,037,386 10.60 3 1,443,900 2.08

40-49 yrs old 10 1,108,495 9.02 6 1,392,990 4.30

50-64 yrs old 9 2,002,984 4.49 5 2,338,263 2.14

65+ yrs old 2 1,096,923 1.82 0 1,004,285 0

21 *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

Overall reporting rate: 3.83 cases per million Janssen doses
Reporting rates of TTS after Janssen COVID-19 vaccine, 

vaccination March 2–August 31, 2021 (N=54)

14.1 million total Janssen COVID-19 vaccine doses administered*

Females Males

Age group

TTS

cases 

Doses 

admin

Reporting rate†

(per million)

TTS

cases 

Doses

admin

Reporting rate†

(per million)

18-29 yrs old 5 1,089,649 4.59 3 1,565,212 1.92

30-39 yrs old 11 1,037,386 10.60 3 1,443,900 2.08

40-49 yrs old 10 1,108,495 9.02 6 1,392,990 4.30

50-64 yrs old 9 2,002,984 4.49 5 2,338,263 2.14

65+ yrs old 2 1,096,923 1.82 0 1,004,285 0

22

Overall reporting rate: 3.83 cases per million Janssen doses

Highest 

rates

*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
Reporting rates of TTS after Janssen COVID-19 vaccine, 

vaccination March 2–August 31, 2021 (N=54)

14.1 million total Janssen COVID-19 vaccine doses administered*

Females Males

Age group

TTS

cases 

Doses 

admin

Reporting rate†

(per million)

TTS

cases 

Doses

admin

Reporting rate†

(per million)

18-29 yrs old 5 1,089,649 4.59 3 1,565,212 1.92

30-39 yrs old 11 1,037,386 10.60 3 1,443,900 2.08

40-49 yrs old 10 1,108,495 9.02 6 1,392,990 4.30

50-64 yrs old 9 2,002,984 4.49 5 2,338,263 2.14

65+ yrs old 2 1,096,923 1.82 0 1,004,285 0

23

Overall reporting rate: 3.83 cases per million Janssen doses Similar 

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

females: data presented to ACIP Jul 2021 vs Dec 2021

Females (Jul ACIP*) Females (Dec ACIP**)

Age group

TTS

cases 

Doses

admin

Reporting rate†

(per million)

TTS

cases 

Doses 

admin

Reporting rate†

(per million)

18-29 yrs old 4 946,358 4.22 5 1,089,649 4.59

30-49 yrs old 17 1,934,574 8.79 21 2,145,881 9.79

50-64 yrs old 7 1,865,372 3.75 9 2,002,984 4.49

65+ yrs old 0 1,028,190 0 2 1,096,923 1.82

Total 28 5,774,494 4.85 37 6,335,437 5.84

24

* Jul ACIP: vaccination through Jul 8, 2021 https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-07/05-COVID-Rosenblum-508.pdf

** Current data: vaccination through August 31, 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
Reporting rates of TTS after Janssen COVID-19 vaccine, 

males: data presented to ACIP Jul 2021 vs Dec 2021

Males (Jul ACIP*) Males (Dec ACIP**)

Age group

TTS

cases 

Doses

admin

Reporting rate†

(per million)

TTS

cases 

Doses 

admin

Reporting rate†

(per million)

18-29 yrs old 3 1,281,479 2.34 3 1,565,212 1.92

30-49 yrs old 4 2,440,773 1.64 9 2,836,890 3.17

50-64 yrs old 3 2,130,473 1.41 5 2,338,263 2.14

65+ yrs old 0 943,098 0 0 1,004,285 0

Total 10 6,795,823 1.47 17 7,744,650 2.20

25

* Jul ACIP: vaccination through Jul 8, 2021 https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-07/05-COVID-Rosenblum-508.pdf

** Current data: vaccination through August 31, 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
U.S. TTS deaths following Janssen COVID-19 

vaccination

26
Epidemiology of TTS deaths following Janssen COVID19 vaccination through December 9, 2021 (N=9*)

 All after dose 1 of Janssen COVID-19 Vaccine

 Median age: 45 years (range: 28–62)

 Sex: female (n=7), male (n=2)

 Race/ethnicity: all non-Hispanic white

 Underlying medical conditions:

– Obesity (n=7)

– Hypertension (n=3)

– Diabetes (n=2)

– None of the above (n=2)

– Iron deficiency anemia (n=2)

– Hypothyroidism (n=2)

– Other** (n=4)

* One TTS death confirmed in a person vaccinated with Janssen COVID-19 Vaccine after August 31, 2021

** Other includes (n=1 each) asthma, gastroesophageal reflux disease, obstructive sleep apnea, hyperlipidemia, seizure disorder; one patient with both 

hyperlipidemia and seizure disorder 27
Clinical description of TTS deaths following Janssen 

COVID-19 vaccination through December 9, 2021 (N=9)

 All have features of severe CVST: large or multiple cerebral hemorrhages; 

evidence of intracranial edema and/or mass effect; depressed 

consciousness and/or seizure

 7 with confirmed CVST

 None received IV heparin for treatment

 Four received craniectomy/craniotomy for brain hemorrhage

 Median time from symptom onset to admission: 3 days (range: 0-5)

 Median time from admission to death: 1 day (range: 0-2)

28
Revisit TTS updates to ACIP 2021

Date of 

meeting

Purpose of 

discussion

Cut-off for 

data

No. Janssen 

doses given

Total TTS 

cases

Total TTS 

deaths

Apr 23 Discuss resolution of 

Janssen pause

Apr 21 7.98 million 15 3

May 12 General follow-up 

on TTS

May 7 8.73 million 28 3

Jul 22 Updated benefit-risk 

discussion (including 

Guillain-Barré)

Jul 8 12.5 million 38 4

29
Revisit TTS updates to ACIP 2021: comparing previously 

presented data with data as of Dec 9, 2021

Date of 

meeting

Purpose of 

discussion

Cut-off for 

data

No. Janssen 

doses given

Total TTS 

cases

Total TTS 

deaths

Apr 23 Discuss resolution of 

Janssen pause

Apr 21 7.98 million 15

39

3

5

May 12 General follow-up 

on TTS

May 7 8.73 million 28

43

3

6

Jul 22 Updated benefit-risk 

discussion (including 

Guillain-Barré)

Jul 8 12.5 million 38

50

4

6

Dec 16 TTS update Aug 31 14.1 million 54 8

30
TTS death reporting rate with Janssen COVID-19 

vaccination by August 31, 2021 (N=8 confirmed deaths)

Overall death reporting rate: 0.57 per million Janssen COVID-19 Vaccine doses

Females Males

Age group

TTS

deaths 

Doses 

admin

Reporting rate†

(per million)

TTS

deaths 

Doses

admin

Reporting rate†

(per million)

18-29 yrs old 0 1,089,649 0 1 1,565,212 0.64

30-39 yrs old 2 1,037,386 1.93 0 1,443,900 0

40-49 yrs old 2 1,108,495 1.80 1 1,392,990 0.72

50-64 yrs old 2 2,002,984 1.00 0 2,338,263 0

65+ yrs old 0 1,096,923 0 0 1,004,285 0

31 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
TTS death reporting rate with Janssen COVID-19 

vaccination by August 31, 2021 (N=8 confirmed deaths)

Overall death reporting rate: 0.57 per million Janssen COVID-19 Vaccine doses

Females Males

Age group

TTS

deaths 

Doses 

admin

Reporting rate†

(per million)

TTS

deaths 

Doses

admin

Reporting rate†

(per million)

18-29 yrs old 0 1,089,649 0 1 1,565,212 0.64

30-39 yrs old 2 1,037,386 1.93 0 1,443,900 0

40-49 yrs old 2 1,108,495 1.80 1 1,392,990 0.72

50-64 yrs old 2 2,002,984 1.00 0 2,338,263 0

65+ yrs old 0 1,096,923 0 0 1,004,285 0

32 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

Highest 

rates
TTS death reporting rate with Janssen COVID-19 

vaccination by August 31, 2021 (N=8 confirmed deaths)

Overall death reporting rate: 0.57 per million Janssen COVID-19 Vaccine doses

Females Males

Age group

TTS

deaths 

Doses 

admin

Reporting rate†

(per million)

TTS

deaths 

Doses

admin

Reporting rate†

(per million)

18-29 yrs old 0 1,089,649 0 1 1,565,212 0.64

30-39 yrs old 2 1,037,386 1.93 0 1,443,900 0

40-49 yrs old 2 1,108,495 1.80 1 1,392,990 0.72

50-64 yrs old 2 2,002,984 1.00 0 2,338,263 0

65+ yrs old 0 1,096,923 0 0 1,004,285 0

33

% of TTS cases with death: Vaccinated before pause**: 5/39 (13%)

Vaccinated after pause**: 3/15 (20%)

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
In addition: two possible TTS deaths with Janssen 

COVID-19 vaccination*

 Features shared with confirmed TTS deaths after Janssen COVID-19 vaccine

– Symptoms beginning within 7–14 days of vaccination

– Large cerebral hemorrhage with mass effect and thrombocytopenia

– Rapid progression from admission to death (1–2 days)

 Difference: no definitive imaging for CVST; no imaging for other thrombosis

 Reviewed with CISA investigators

– Difficult to confirm as TTS cases because of lack of documented 

thrombosis

– Clinically concerned that TTS with CVST is underlying cause of 

hemorrhage

*Of these two possible TTS deaths following Janssen COVID-19 vaccination, one is in a woman between 50–64 years of age and 

the other in a man 40–49 years. Both vaccinated before the pause in Janssen COVID-19 vaccination. 34
0

1

2

3

4

5

Mar Apr May Jun Jul Aug Sep Oct

Number of deaths

Month (2021)

Known at July 2021 ACIP meeting

Confirmed after July 2021 ACIP

Possible but unconfirmed

Confirmed and possible TTS deaths following Janssen 

COVID-19 Vaccine, by month of vaccination as of Dec 9, 

2021*

*8 TTS deaths confirmed in persons with Janssen COVID-19 vaccination by August 31, 2021; 1 TTS death confirmed with Janssen COVID-19 vaccination after August 31, 2021

35

All vaccinated before Janssen 

pause (Apr 13, 2021)
Limitations

 Possible underdiagnosis of CVST and TTS

 VAERS is passive surveillance system

 Therefore, case and death reporting rates might be underestimates

36
Summary

 U.S. TTS case reporting rate (3.8 per million doses) following Janssen COVID19 vaccination higher than previously presented

– Case reporting rates for men 40–49 years and women 50–64 years 

similar to women 18–29 years (~4–5 per million doses)

 U.S. TTS deaths following Janssen COVID-19 vaccination:

– Have typical features of severe CVST: clinical course from symptoms to 

admission, and admission to death is rapid

– Are more common than known during previous presentations to ACIP 

(TTS death reporting rate following Janssen: ~2 per million doses in 

women 30–49 years)

– Proportion of TTS cases with death did not decrease after Janssen pause 

on April 13 37
Acknowledgements

 VAERS (CDC and FDA teams) 

 CISA Project and Investigators

 COVID-19 Vaccine Task Force

 COVID-19 Vaccine Task Force, Vaccine Safety Team 

 Immunization Safety Office

 People reporting to VAERS

38
For more information, contact CDC

1-800-CDC-INFO (232-4636)

TTY: 1-888-232-6348 www.cdc.gov

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.

Thank you!

Mention of a product or company name is for identification purposes only and does not constitute endorsement by CDC or FDA. 39