Front. Med. 2021, 15(6): 938–941
https://doi.org/10.1007/s11684-021-0895-9

COMMENT

Understanding risk of thrombosis with thrombocytopenia
syndrome after Ad26.COV2.S vaccination

Prathit A. Kulkarni (✉)1,2, Vinay Prasad3

1Infectious Diseases Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; 2Medical Care Line, Michael
E. DeBakey Veterans Affairs Medical Center, Houston, TX 77030, USA; 3Department of Epidemiology and Biostatistics, School of Medicine,
University of California-San Francisco, San Francisco, CA 94143, USA

© Higher Education Press 2021

that

On April 13, 2021, the US Centers for Disease Control and
Prevention (CDC) and the US Food and Drug Adminis-
tration (FDA) recommended a pause in administration of
the Ad26.COV2.S (Johnson & Johnson [Janssen]) cor-
onavirus disease 2019 (COVID-19) vaccine for all persons
[1]. At
time, approximately 6.8 million doses of
vaccine had been administered around the United States.
The pause was prompted by 6 cases of cerebral venous
sinus thrombosis (CVST) in combination with thrombo-
cytopenia, a condition whose nomenclature is in flux but
which we will refer to as thrombosis with thrombocyto-
penia syndrome (TTS), as used by CDC in describing
the condition [2]. All patients were women younger than
50 years. Of note, 2 of 6 patients also had splanchnic and
portal vein thrombosis. As of May 12, 2021, CDC’s
working case definition for TTS after COVID-19 vaccina-
tion divides the condition into two tiers [3]. A case of tier
1 TTS is defined as:
(1) thrombosis in an unusual
location; and (2)
thrombocytopenia with a platelet
count < 150 000/microliter. A positive heparin-platelet
factor 4 (PF4) antibody is supportive but not required. A
tier 2 TTS case is defined as: (1) thrombosis only in a
common location (such as deep vein thrombosis or
pulmonary embolism);
thrombocytopenia with a
platelet count < 150 000/microliter; and (3) positive
heparin-PF4 antibody.

Many in the scientific community were concerned that
this pause was misguided. These concerns were under-
standable given the ongoing COVID-19 pandemic. Some
stated that the risk of “clot” after receiving the Johnson &
Johnson vaccine was less than 1 in 1 million. By looking

(2)

Received May 27, 2021; accepted August 28, 2021
Correspondence: Prathit A. Kulkarni, pakulkar@bcm.edu

at only raw numbers (6 cases out of approximately
6.8 million doses of vaccine given), this is technically
true. However, there are several unique features of the
reported adverse events that supported the initial pause and
need for additional inquiry.

First, the location of the clotting was highly unusual.
CVST is an uncommon diagnosis, with an approximate
annual
incidence rate of 5 per million in the general
population [4]. Treating this clot is challenging because of
the clinical consequences and potential concurrent hemor-
rhage. Current practice is to continue anticoagulation,
though evidence remains scant [4]. Therefore, comparisons
of TTS resulting in CVST to the baseline incidence rate of
all cases of typical venous thromboembolism (VTE), such
as those in the legs associated with oral contraceptive pills
(OCPs), are misleading. It is also likely the case that a
typical treatment for CVST, heparin, might not be usable in
thereby making clinical
these vaccine-related cases,
management even more challenging.

Second, all 6 reported cases were associated with
thrombocytopenia. This was immediately and correctly
recognized as highly unusual, as there are few conditions,
such as heparin-induced thrombocytopenia and thrombosis
(HITT) and thrombotic thrombocytopenic purpura, which
have the unusual association of low platelets and clotting.
HITT, for example, is a state of runaway platelet activation,
which can result in arterial and venous thrombosis. In this
context, analogies to typical VTE again might not be
appropriate.

Third, all 6 cases of CVST initially reported in the
United States were in women aged < 50 years. These
initial data suggested that this was the group at highest risk
for potential TTS after receipt of the Johnson & Johnson
COVID-19 vaccine, not simply all comers. As such, given
the unusual clinical presentation of a novel syndrome with

Prathit A. Kulkarni and Vinay Prasad

939

potentially dire and irreversible consequences in a young,
healthy subpopulation of vaccine recipients, a pause
appears to have been reasonable.

Importantly, the relevant comparison for understanding
risk of TTS associated with the Johnson & Johnson
COVID-19 vaccine is not the baseline rate of all VTE in
the general population or even the baseline rate of CVST in
women less than age 50. The most accurate comparison of
risk is the baseline incidence rate of CVST associated with
thrombocytopenia in women aged < 50 years of age who
have not received a heparin product. In a study that
evaluated a cohort of 865 patients with CVST from 7
countries around the world from 1987 through March
2018, 73 (8.4%) were found to have concomitant
thrombocytopenia [5]. The cause of thrombocytopenia
was known in 64% of these patients. One patient was
found to have positive heparin-PF4 antibody diagnosed as
part of routine care. This patient had received low-
molecular weight heparin as part of her care. Among 93
frozen plasma samples subsequently evaluated for pre-
sence of heparin-PF4 antibodies, none were found to be
positive. Overall, the incidence of CVST occurring in
conjunction with thrombocytopenia mediated via heparin-
PF4 antibodies was exceedingly rare in this cohort of
patients with CVST from the general population (0.1% of
patients), and in fact only occurred in a patient who had
received a heparin product. Therefore, risk of CVST with
potentially antibody-mediated thrombocytopenia related to
the Johnson & Johnson COVID-19 vaccine is, by
definition, excess above an almost negligible baseline.

After the initial pause in national administration of the
Johnson & Johnson vaccine on April 13, 2021, an
additional 9 cases of TTS were publicly reported. The
total of 15 cases, 12 of which included CVST, were
discussed at a meeting of the US Advisory Committee on
Immunization Practices (ACIP) on April 23, 2021 [6].
Thirteen of the 15 cases were in women younger than age
50. With approximately 1.9 million doses of vaccine given
in this age group, the reporting rate of TTS was noted to be
7.0 per million. Simultaneously,
the mortality rate of
COVID-19 for women less than age 50 was reported to be
less than 1 in 100 000. Therefore, the risk of developing
TTS after administration of the Johnson & Johnson
vaccine was roughly similar to the risk of mortality from
COVID-19 in the same age and sex demographic. As
described during the meeting, for women aged 18–49
years, for every 1 million doses of vaccine given with
current
risk of exposure to severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) in the United
States, there would be 13 expected cases of TTS, and 12
deaths related to COVID-19 would be prevented.

With regard to the potential pathophysiological basis for
vaccine-related TTS, a description of the first 12 patients in
the United States with the condition was published in late
April 2021 [7]. All patients were women between the ages

of 18 and 60. Eleven of 12 patients were younger than age
50, and 8/12 additionally had thromboses in locations other
than the cerebral circulation. A total of 11 patients had
positive heparin-PF4 antibodies, and 1 patient did not have
the testing performed. However, 8/11 had negative
functional platelet antibody results with 6 having under-
gone serotonin release assay testing only and 2 having
undergone both serotonin release assay testing and latex
immunoturbidimetric assay testing. Other thrombophilia
testing was negative in these 11 patients.

Just prior to the initial reports of TTS occurring after
vaccination with the Johnson & Johnson COVID-19
thrombotic thrombocytopenia
vaccine, descriptions of
related to the ChAdOx1 nCov-19 (AstraZeneca) COVID-
19 vaccine (which also uses Adenovirus-vector vaccine
technology) were published [8]. The initial report of 11
patients from Germany and Austria suggested that the
clotting observed in a condition termed vaccine-induced
immune thrombotic thrombocytopenia (VITT)—and
remarkably similar
in description to cases of TTS
described in the United States—might also be mediated
by antibody-driven activation of PF-4. This would make
the condition most similar to HITT. A report simulta-
neously published on the same day described 5 additional
patients from Norway, all younger than age 60, with CVST
and thrombocytopenia [9]. All patients had strongly
positive anti-heparin-PF4 antibodies. Another report of
22 patients with acute thrombosis in unusual locations
along with thrombocytopenia confirmed the presence of
anti-heparin-PF4 antibodies as well [10]. In contrast to the
series of patients described in the United States, the vast
majority of patients described in these European reports
had positive functional platelet antibody assays. As
described by See et al., the reason for this difference
could be due to false-negative test results or potentially
different types of functional platelet antibody tests that
were used in different settings [7]. Indeed, a detailed
discussion of anti-PF4 antibodies describes how rapid tests
typically used for diagnosis of HITT might not be positive
in patients with VITT [11]. In addition, standard serotonin
release assays that do not include the presence of PF4 were
turned positive when PF4 was
often negative but
introduced into the mixture. Specifically, the authors of
this study related to PF4 immunoassays recommend use of
a “sensitive, quantitative, immunologic test” for diagnosis
of VITT [11].

To note, two other COVID-19 vaccines which utilize
Adenovirus-vector technology have received authorization
in different parts of the world but not in the United States.
These are the Gam-COVID-Vac (Sputnik V) vaccine from
Russia, which uses 2 components, a recombinant adeno-
virus type 26 vector and a recombinant adenovirus type 5
vector in a heterologous prime-boost fashion, and the
CanSinoBIO vaccine from China, which also uses an
adenovirus type 5 vector. However, there have not been to

940

Understanding risk of thrombosis with thrombocytopenia syndrome

date any public reports of serious episodes of thrombosis
associated with either of these vaccines. Additionally, there
is one other vaccine that currently has approval for use in
Europe which utilizes Adenovirus-vector
technology,
Ad26.ZEBOV, also a Johnson & Johnson product
incorporating adenovirus type 26. This vaccine,
for
prevention of Ebola virus disease, has not been reported
in the literature to be linked to serious clotting disorders.
By the time of a follow-up meeting of ACIP on May 12,
2021, a total of 28 cases of TTS had been confirmed by
CDC, with 25/28 cases being in the Tier 1 category [3].
Among the 28 cases, 19 cases included CVST. At a
subsequent ACIP meeting on July 22, 2021, the number of
cases of confirmed reports of TTS had risen to 38, with
28/38 cases occurring in females [12]. The reporting rate of
TTS among females aged 30–49 years was 8.8 per million;
in women aged 18–29 years, it was 4.2 per million. As
noted during that meeting, based upon average exposure
risk and hospitalization rates in the United States from June
19, 2021, for every million doses of Johnson & Johnson
vaccine given, for women aged 18–29, 4–5 cases of TTS
would be expected, and 5 deaths would be prevented. For
women aged 30–49, a total of 8–10 cases of TTS would be
expected, and 20 deaths would be averted.

their

A crucial point in a risk-benefit analysis is that risk of
acquiring SARS-CoV-2 infection is not static, and also
differs from one individual to another. For example, if
someone has an occupation and lifestyle that allow them to
avoid interaction with others and they adhere strictly to
recommended public health guidance,
risk of
acquiring SARS-CoV-2 infection might be extremely
low. Risk is also affected by viral
transmission rates,
which are constantly changing in different geographical
areas. In addition, mRNA vaccine options are now widely
available throughout the United States; therefore, it is not
the case that no form of protection would be available for
patients if they opted not to receive the Johnson & Johnson
to note that population-based
vaccine. It
recommendations in countries around the world where
vaccine supply could be different would have a different
risk-benefit analysis.

is important

it

The current approach for use of the Johnson & Johnson
COVID-19 vaccine in the United States is that
is
recommended under emergency use authorization (EUA)
for all persons greater than age 18. However, EUA was
amended on April 23, 2021, and now includes a warning
label regarding the possibility of TTS related to the
vaccine. To note, certain countries in Europe have opted to
restrict use of Adenovirus-vector vaccines to certain age
the Joint
groups only. As an example,
Committee on Vaccination and Immunisation in the UK
advised the following: “in addition to those aged under 30,
unvaccinated adults aged 30–39 years who are not in a
clinical priority group at higher risk of severe COVID-19
disease, should preferentially be offered an alternative to

in May 2021,

the AstraZeneca COVID-19 (AZD1222) vaccine” assum-
ing no delay in vaccination occurs [13]. Therefore,
clinicians might have continued concerns about recom-
mending or administering the Johnson & Johnson vaccine
than age 50, particularly when
to women younger
alternatives (mRNA vaccines) are now widely available.
As noted by the ACIP Work Group on benefits and risks of
COVID-19 vaccination on July 22, 2021, reported adverse
events from vaccination are “potentially serious and should
be transparently communicated with the public” [14]. The
work group also noted the “importance of patient choice in
vaccine product” and that “patients and providers should
be aware of both the benefits and risks of COVID-19
vaccination when choosing a vaccine product.” The
authors agree with these sentiments. Ultimately, a clear
risks and benefits, and an individual
articulation of
discussion with each patient, will be needed as clinicians
help patients select a vaccine product.

Compliance with ethics guidelines

Prathit A. Kulkarni discloses the following: Research funding:
Vessel Health, Inc.; Michael E. DeBakey VA Medical Center
Research Service Line; Department of Veterans Affairs Office of
Research and Development; Speaking: National AIDS Education &
Training Center.

Vinay Prasad discloses the following: Research funding: Arnold
Ventures; Royalties: Johns Hopkins Press, Medscape, MedPage
Today; Consulting: UnitedHealthcare; Speaking: Evicore, New
Century Health; Other: Patreon backers for Plenary Session podcast.
involve reporting of primary data
obtained from studies of human or animal subjects. It is solely a
comment manuscript.

This manuscript did not

References

1. U.S. Centers for Disease Control & Prevention. Joint CDC and FDA
statement on Johnson & Johnson COVID-19 vaccine. Press release
on April 13, 2021. 2021. https://www.cdc.gov/media/releases/2021/
s0413-JJ-vaccine.html (accessed April 24, 2021)

2. U.S. Centers for Disease Control & Prevention. Health Alert
Network Advisory on April 13, 2021. 2021. https://emergency.cdc.
gov/han/2021/han00442.asp (accessed April 24, 2021)

3. U.S. Centers for Disease Control & Prevention. ACIP presentation
slides: May 12, 2021 meeting. 2021. https://www.cdc.gov/vaccines/
acip/meetings/downloads/slides-2021-05-12/07-COVID-Shimabu-
kuro-508.pdf (accessed August 2, 2021)

4. Saposnik G, Barinagarrementeria F, Brown RD Jr, Bushnell CD,
Cucchiara B, Cushman M, deVeber G, Ferro JM, Tsai FY. Diagnosis
and management of cerebral venous thrombosis: a statement for
healthcare professionals from the American Heart Association/
American Stroke Association. Stroke 2011; 42(4): 1158–1192
5. Sánchez van Kammen M, Heldner MR, Brodard J, Scutelnic A,
Silvis S, Schroeder V, Kremer Hovinga JA, Middeldorp S, Levi M,

Prathit A. Kulkarni and Vinay Prasad

941

Hiltunen S, Lindgren E, Mansour M, Arauz A, Barboza MA,
Zuurbier SM, Aguiar de Sousa D, Ferro JM, Fischer U, Field TS,
Jood K, Tatlisumak T, Putaala J, Arnold M, Coutinho JM.
Frequency of
factor 4/heparin
antibodies in patients with cerebral venous sinus thrombosis prior
to the COVID-19 pandemic. JAMA 2021; 326(4): 332–338

thrombocytopenia and platelet

6. U.S. Centers for Disease Control & Prevention. ACIP presentation
slides: April 23, 2021 meeting. 2021. https://www.cdc.gov/
vaccines/acip/meetings/slides-2021-04-23.html (accessed April 24,
2021)

7. See I, Su JR, Lale A, Woo EJ, Guh AY, Shimabukuro TT, Streiff
MB, Rao AK, Wheeler AP, Beavers SF, Durbin AP, Edwards K,
Miller E, Harrington TA, Mba-Jonas A, Nair N, Nguyen DT, Talaat
KR, Urrutia VC, Walker SC, Creech CB, Clark TA, DeStefano F,
Broder KR. US case reports of cerebral venous sinus thrombosis
with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to
April 21, 2021. JAMA 2021; 325(24): 2448–2456

8. Greinacher A, Thiele T, Warkentin TE, Weisser K, Kyrle PA,
Eichinger S. Thrombotic thrombocytopenia after ChAdOx1 nCov-
19 vaccination. N Engl J Med 2021; 384(22): 2092–2101

9. Schultz NH, Sárvoll IH, Michelsen AE, Munthe LA, Lund-Johansen
F, Ahlen MT, Wiedmann M, Aamodt AH, Skattør TH, Tjønnfjord
GE, Holme PA. Thrombosis and thrombocytopenia after ChAdOx1
nCov-19 vaccination. N Engl J Med 2021; 384(22): 2124–2130

10. Scully M, Singh D, Lown R, Poles A, Solomon T, Levi M, Goldblatt
D, Kotoucek P, Thomas W, Lester W. Pathologic antibodies to
platelet factor 4 after ChAdOx1 nCoV-19. N Engl J Med 2021; 384
(23): 2202–2211

11. Vayne C, Rollin J, Gruel Y, Pouplard C, Galinat H, Huet O, Mémier
V, Geeraerts T, Marlu R, Pernod G, Mourey G, Fournel A,
Cordonnier C, Susen S. PF4 immunoassays in vaccine-induced
thrombotic thrombocytopenia. N Engl J Med 2021; 385(4): 376–
378

12. U.S. Centers for Disease Control & Prevention. ACIP presentation
slides: July 22, 2021 meeting. 2021. https://www.cdc.gov/vaccines/
acip/meetings/downloads/slides-2021-07/05-COVID-Rosenblum-
508.pdf (accessed August 2, 2021)

13. United Kingdom Joint Committee on Vaccination and Immunisa-
tion. Use of the AstraZeneca COVID-19 (AZD1222) vaccine:
Updated JCVI statement, 7 May 2021. 2021. https://www.gov.uk/
government/publications/use-of-the-astrazeneca-covid-19-vaccine-
jcvi-statement-7-may-2021/use-of-the-astrazeneca-covid-19-
azd1222-vaccine-updated-jcvi-statement-7-may-2021 (accessed
August 2, 2021)

14. U.S. Centers for Disease Control & Prevention. ACIP presentation
slides: July 22, 2021 meeting. 2021. https://www.cdc.gov/vaccines/
acip/meetings/downloads/slides-2021-07/06-COVID-Mbaeyi-508.
pdf (accessed August 2, 2021)