Communication
Thrombotic Events after COVID-19 Vaccination in the Over-50s:
Results from a Population-Based Study in Italy

Ileana Baldi 1,*
Diego Vanuzzo 3,† and Dario Gregori 1

, Danila Azzolina 2, Andrea Francavilla 1, Patrizia Bartolotta 1, Giulia Lorenzoni 1

,

1 Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac Thoracic Vascular Sciences and
Public Health, University of Padova, 35121 Padova, Italy; andrea.francavilla@studenti.unipd.it (A.F.);
patrizia.bartolotta@studenti.unipd.it (P.B.); giulia.lorenzoni@unipd.it (G.L.); dario.gregori@unipd.it (D.G.)

2 Department of Medical Science, University of Ferrara, 44100 Ferrara, Italy; danila.azzolina@unife.it
3 Cardiovascular Prevention Centre, 33100 Udine, Italy; diego50rdc@gmail.com
* Correspondence: ileana.baldi@unipd.it; Tel.: +39-0498275403
†

Former Director, Cardiovascular Prevention Centre.

Abstract: Several European countries suspended or changed recommendations for the use of
Vaxzevria (AstraZeneca) for suspected adverse effects due to atypical blood-clotting. This research
aims to identify a reference point towards the number of thrombotic events expected in the Italian
population over 50 years of age who received Vaxzevria from 22 January to 12 April 2021. The venous
thromboembolism (VT) and immune thrombocytopenia (ITP) event rates were estimated from a
population-based cohort. The overall VT rate was 1.15 (95% CI 0.93–1.42) per 1000 person-years, and
the ITP rate was 2.7 (95% CI 0.7–11) per 100,000 person-years. These figures translate into 83 and
two expected events of VT and ITP, respectively, in the 15 days following the first administration of
Vaxzevria. The number of thrombotic events reported from the Italian Medicines Agency does not
appear to have increased beyond that expected in individuals over 50 years of age.

Keywords: claims data; COVID-19; Vaxzevria; safety; adverse events; Italy

1. Introduction

Starting in March 2021, several European countries suspended or changed recom-
mendations for the use of Vaxzevria (formerly vaccine AstraZeneca), an adenoviral vector
vaccine for preventing coronavirus disease 2019 (COVID-19) due to an increasing number
of unusual blood clots.

After an in-depth analysis, the European Medicines Agency (EMA) drug safety com-
mittee concluded that the vaccine was safe and was not generally associated with a higher
risk of blood-clotting. However, it could not rule out a link with two very rare and severe
clotting conditions and stated these rare side effects should be listed in the vaccine’s side
effects [1].

Shultz and colleagues [2] compared the clinical picture of cases presented with severe
thrombosis and thrombocytopenia after receiving the first dose of Vaxzevria to that of
heparin-induced thrombocytopenia. They proposed that these cases represent a vaccine-
related variant of spontaneous heparin-induced thrombocytopenia, referred to as vaccine-
induced immune thrombotic thrombocytopenia (VITT).

No major safety concerns were identified in the initial trial [3], which involved nearly
24,000 adults. Even side effects that are uncommon during clinical trials may affect a
relatively large number of people once vaccines are widely distributed. Thus, it is not
surprising that new reports of side effects have emerged from the real-world data after
millions of Vaxzevria doses have been administered.

In Italy, the first doses of Vaxzevria arrived in February 2021, and the Italian Medicines
Agency (AIFA) approved administration to individuals 55 years of age and older. Following

Citation: Baldi, I.; Azzolina, D.;

Francavilla, A.; Bartolotta, P.;

Lorenzoni, G.; Vanuzzo, D.;

Gregori, D. Thrombotic Events after

COVID-19 Vaccination in the

Over-50s: Results from a

Population-Based Study in Italy.

Vaccines 2021, 9, 1307. https://

doi.org/10.3390/vaccines9111307

Academic Editor: S. Louise Cosby

Received: 12 September 2021

Accepted: 8 November 2021

Published: 10 November 2021

Publisher’s Note: MDPI stays neutral

with regard to jurisdictional claims in

published maps and institutional affil-

iations.

Copyright: © 2021 by the authors.

Licensee MDPI, Basel, Switzerland.

This article is an open access article

distributed under

the terms and

conditions of the Creative Commons

Attribution (CC BY) license (https://

creativecommons.org/licenses/by/

4.0/).

Vaccines 2021, 9, 1307. https://doi.org/10.3390/vaccines9111307

https://www.mdpi.com/journal/vaccines

(cid:1)(cid:2)(cid:3)(cid:1)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:1)
(cid:1)(cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)

Vaccines 2021, 9, 1307

2 of 5

concerns of a link to blood clots in younger people, Italy now reserves Vaxzevria for
the over-60s.

Nevertheless, elderly patients are poorly represented in COVID-19 clinical trials and
vaccine trials [4]. Hence, there is limited evidence and knowledge about the efficacy and
safety of drugs and vaccines in this population, particularly vulnerable to COVID-19 [5].
This study aims to quantify the order of magnitude of the number of blood clot events,
from ordinary to very rare types, expected in the Italian population over 50 years of age who
received Vaxzevria. To this purpose, age and gender-specific venous thromboembolism
(VT) event rates and overall immune thrombocytopenia (ITP) event rate were estimated
from a population-based cohort with a 37-year follow-up and applied to the vaccinated
with the first dose of Vaxzevria.

2. Materials and Methods
2.1. Data Sources

The “Martignacco project” (MP), promoted by the World Health Organization (WHO),
was started in 1977 to evaluate the impact of health promotion interventions on cardio-
vascular health in middle-aged (40–59 years) subjects within a geographically defined
community in the northeast of Italy. The population-based cohort data for the present
analysis referred to the 3066 subjects enrolled in 1977 and followed up through 31 Decem-
ber 2014, through a computerized record linkage system with administrative sources on
healthcare use (details given elsewhere [6–8]). All Italian citizens have equal access to
health care. Thus, the inequality in health care access is not a matter of insurance status.

The numbers of Vaxzevria administrations stratified by age and gender were retrieved
from the official and freely accessible Italian repository of the COVID-19 vaccine data [9].
The administration period from 22 January to 12 April 2021, was chosen to capture only the
first dose per subject. Thus, in this period, the number of doses coincides with the number
of vaccinated subjects.

The number of side effects was then retrieved from the reports of suspected adverse
reactions to COVID-19 vaccines submitted to the Italian Pharmacovigilance Network [10].
The fourth surveillance report, covering 22 January to 26 April 2021 was used. A 2 week-
difference between the end of Vaxzevria administration period and the release date of the
report was intentionally assumed to ensure a minimum safety follow-up.

2.2. VT and ITP Events Identification

A VT event in the MP cohort is defined as the first occurrence in the study period
of hospitalization with a primary or secondary diagnosis of pulmonary embolism (415.1)
or deep vein thrombosis (451.11, 451.19, 451.2, 451.81, and 453.8), according to the Inter-
national Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). As
reported in a literature review [11], this validated algorithm ensures good predictive values.
An ITP event in the MP cohort is defined as the first occurrence in the study period of
hospitalization with a primary or secondary diagnosis of immune thrombocytopenic pur-
pura (ICD-9-CM 287.31) or primary thrombocytopenia (ICD-9-CM 287.3) [12]. The latter
diagnostic code was used only for hospitalizations that occurred before the ICD-9-CM
update 2007 version.

2.3. Calculation of Rates and Projections

The VT rates (per 1000 person-years) in the MP cohort were calculated by age group
and gender, with 95% confidence intervals (95% CI). For this purpose, age at hospitalization
was split into 10-year increment age groups, from 50 to 80+ years. The rates’ denominators
were computed in years of observation beginning in June 1977 until a VT event or the end
of follow-up.

The ITP number of events and rates was also computed in the MP cohort. Due
to the rarity of the disease, the event rate was reported overall without stratifying by
demographic categories.

Vaccines 2021, 9, 1307

3 of 5

Age and gender-specific VT rates were applied to the Italian population vaccinated
with Vaxzevria from 22 January to 12 April 2021 to estimate the number of expected cases
in the 15 days following vaccination. The same operation was carried out to estimate the
ITP events expected in the whole vaccinated population.

Expected side effects were computed by multiplying the number of vaccinated people
for each demographic category (age, gender) by the VT and ITP rates (calculated in the MP
cohort) and by 0.041 (the result of 15 days/365 days) and divided by 1000. The prediction
intervals for the expected number of events were computed via a 10,000 bootstrap resam-
pling procedure. The expected number of events were iteratively resampled from a Poisson
random variable whose parameters were given by the expected event rate calculated for
the Martignacco reference cohort. The 95% prediction interval bounds were derived by
considering the 0.025 and 0.975 quantiles of the resampled distribution.

3. Results
3.1. VT and ITP Rates in the Martignacco Project Cohort

The overall VT rate in the MP cohort was 1.15 (95% CI 0.93–1.42) events per
1000 person-years. The VT rates increased with age for both genders. A lower VT rate was
observed in females under 69 years in comparison with males. The situation was reversed
in the over-70s (Table 1).

Table 1. Number of first hospitalizations for venous thromboembolism (VT), person-years (PY), the rates (×1000), and 95%
confidence intervals (95% CI) according to gender and age classes. Number of administered doses of Vaxzevria in Italy as of
12 April 2021. Expected VT events in the 15 days following vaccination with 95% prediction intervals (95% PI).

Martignacco Cohort

COVID-19 Vaccinated Cohort

VT

PY

(95%CI)

Doses

Expected VTs

(95% PI)

Gender

Female

Male

Overall

Age

50–59
60–69
70–79
≥80

50–59
60–69
70–79
≥80

2
10
22
10

5
13
15
6

83

6405
13,460
12,802
6275

6422
12,393
10,418
4117

72,293

Rate

0.312
0.743
1.718
1.594

0.779
1.049
1.440
1.458

1.148

(0.078–1.248)
(0.400–1.381)
(1.131–2.610)
(0.857–2.962)

(0.324–1.871)
(0.609–1.807)
(0.868–2.388)
(0.655–3.244)

350,064
215,887
404,790
36,940

228,011
148,207
358,223
25,159

4.49
6.59
28.58
2.42

7.30
6.39
21.20
1.51

(3.69–5.33)
(5.58–7.63)
(26.40–30.63)
(1.85–3.03)

(6.23–8.41)
(5.37–7.38)
(19.35–23.00)
(1.03–2.01)

(0.926–1.424)

1,767,281

83.38 *

(79.58–86.88)

* The global expected number of events was computed by considering the overall estimated incidence rate 1.148.

Two ITP events were observed in the MP cohort over 72,293 person-years, resulting in

an ITP rate of 2.7 (95% CI 0.7–11) cases over 100,000 person-years.

3.2. Expected VT and ITP Events in the Vaccinated with Vaxzevria

From 22 January to 12 April, 2,702,730 doses of the Vaxzevria were administered.
Among them, 65.4% (1,767,281 doses) were delivered in those over 50 years old. During
this time interval, based on the extracted VT and ITP rates from the Martignacco data
(Table 1), the overall expected cases of VT and ITP were 83 (Table 1) and 1.8 (95% CI
0.46–6.68), respectively.

4. Discussion

Blood clots are more common in older people and might not trigger the same attention
and in-depth investigation that blood clots in younger Vaxzevria recipients have had.
This study quantifies the order of magnitude of a very rare blood clot type, ITP, and a
common one, VT, expected in the Italian population aged over 50 years of age following
the administration of Vaxzevria.

Vaccines 2021, 9, 1307

4 of 5

To our knowledge, this is one of the few studies that has assessed VT and ITP rates
within a population-based cohort and not through hospital episode-based statistics. Ac-
cording to rate projections calculated in those over-50s in the Martignacco cohort, on a
national basis a total of 83 VT (54% in women) and two ITP events is expected in the
15 days following vaccination in those over 50 years old.

As to VT estimates, other studies relying on episode-based statistics, reported similar
findings based on pre-pandemic incidence rates from the entire Danish population [13].
Regarding ITP, the estimated rate of 2.7 per 100,000 person-years is in line with the results
of population-based studies in France, UK, and Japan, reporting an ITP incidence ranging
from 2.2 to 3.9 per 100,000 person-years [14].

On 10 May the AIFA has published the fourth COVID-19 Vaccine Surveillance Re-
port [10]. The report includes suspected adverse reactions registered in the National
Pharmacovigilance Network between 27 December 2020 and 26 April 2021 for the four
vaccines used in the current vaccination campaign. Twenty-nine cases of cerebral venous
thrombosis and five cases of venous thrombosis of atypical location following Vaxzevria
administration were reported. Of these, 22 cases (65%) affected women with an average
age of about 48 years, and 12 (35%) affected men with an average age of about 52 years.
The mean time to onset was approximately 8 days after administration of the first dose of
Vaxzevria vaccine.

The lack of public disclosure of adverse reaction attributes at the individual level (i.e.,
age, gender, diagnostic subtypes, severity) captured by the National Pharmacovigilance
Network hampers the comparison between these figures (n = 34) and the expected events
(n = 85). However, caution should be observed in making this comparison because report-
ing of side effects is susceptible to biases and misclassifications. For example, a complex
syndrome such as VITT could be misclassified, particularly before European regulators
expressed concerns about a possible link between rare blood clots and Vaxzevria. Now
that the concern about this potential association has become public, clinicians will be on
the lookout for it, and reporting could increase.

Nevertheless, study findings suggest that the number of thrombotic events following
Vaxzevria administration does not appear to have increased beyond that expected in those
over 50 years of age.

In a press release dated 8 April 2021, the EMA stated that a causal relationship
between the vaccination with Vaxzevria and VITT could be a reasonable possibility. The
regulatory agency also declared that other studies will be conducted to identify the exact
pathophysiological mechanism for these thrombotic events and define the precise extent of
the risk [15].

The prompt development of a safe and effective vaccine to reduce the spread of

COVID-19 and establish higher levels of herd immunity is a global imperative.

In light of the above results, it must be underlined that thrombotic events were not
uncommon in the pre-pandemic era—especially with increasing age—as appears in the
Martignacco cohort.

Therefore, it should be expected that these kinds of events will occur in the older pop-
ulation who get vaccinated, representing the result of a physio-pathological phenomenon
that naturally takes place rather than the direct consequence of the vaccine administration.
In conclusion, it is safe to say that thrombosis occurs relatively often and that the
incident cases following the vaccine should not be considered a priori as adverse effects of
the vaccine itself.

Although our findings should be interpreted in the context of the strengths and
limitations of the use of claims in outcome research [11], there is a reason to be optimistic
about the safety of Vaxzevria in a population usually under-represented in vaccine trials.
These findings contribute to the ongoing discussion on vaccine safety, particularly for
vaccines that rely on adenoviruses where occurrence of severe blood clotting and VITT
constitute a significant concern.

Vaccines 2021, 9, 1307

5 of 5

Author Contributions: Conceptualization, I.B. and D.G.; methodology, I.B. and D.A.; formal analysis,
D.A.; data curation, D.V., A.F. and P.B.; writing—original draft preparation, I.B. and D.A.; writing-
review and editing, D.G., G.L., D.V. and I.B.; supervision, I.B. All authors have read and agreed to
the published version of the manuscript.

Funding: The authors did not receive any funding for this study.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Conflicts of Interest: The authors declare no conflict of interest.

References

1. Mallapaty, S.; Callaway, E. What scientists do and don’t know about the Oxford–AstraZeneca COVID vaccine. Nature 2021, 592,

2.

3.

4.

15–17. [CrossRef] [PubMed]
Schultz, N.H.; Sørvoll, I.H.; Michelsen, A.E. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N. Engl. J.
Med. 2021, 384, 2124–2130. [CrossRef] [PubMed]
Voysey, M.; Clemens, S.A.C.; Madhi, S.A.; Weckh, Y.L.; Folegatti, M.P.; Aley, P.K.; Angus, B.; Ballie, L.V.; Barnabas, S.N.;
Bhorat, E.Q.; et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: An interim analysis of
four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021, 397, 99–111. [CrossRef]
Helfand, B.K.I.; Webb, M.; Gartaganis, S.L.; Fuller, L.; Kwon, C.S.; Inouye, S.K. The Exclusion of Older Persons From Vaccine and
Treatment Trials for Coronavirus Disease 2019—Missing the Target. JAMA Intern. Med. 2020, 180, 1546. [CrossRef] [PubMed]

6.

7.

5. Magnani, C.; Azzolina, D.; Gallo, E.; Ferrante, D.; Gregori, D. How Large Was the Mortality Increase Directly and Indirectly
Caused by the COVID-19 Epidemic? An Analysis on All-Causes Mortality Data in Italy. Int. J. Environ. Res. Public Health 2020, 17,
1557. [CrossRef] [PubMed]
Lorenzoni, G.; Azzolina, D.; Lanera, c.; Brianti, g.; Gregori, D.; Vanuzzo, D.; Baldi, I. Time trends in first hospitalization for heart
failure in a community-based population. Int. J. Cardiol. 2018, 271, 195–199. [CrossRef] [PubMed]
Puska, P.; Leparski, E. (Eds.) Comprehensive Cardiovascular Community Control Programmes in Europe; World Health Organization,
Regional Office for Europe: Copenhagen, Denmark; WHO Publications Center: Albany, NY, USA, 1988.
Vanuzzo, D.; Pilotto, L.; Lombardi, R.; Lazzerini, G.; Carluccio, M.; Diviacco, S.; Quadrifoglio, F.; Danek, G.; Gregori, D.;
Fioretti, P.; et al. Both vitamin B6 and total homocysteine plasma levels predict long-term atherothrombotic events in healthy
subjects. Eur. Heart J. 2007, 28, 484–491. [CrossRef] [PubMed]
Italia/Covid19-Opendata-Vaccini. Developers Italia 2021. Available online: https://github.com/italia/covid19-opendata-vaccini
(accessed on 13 April 2021).
Fourth AIFA Report on COVID-19 Vaccine Surveillance. Available online: https://www.aifa.gov.it/documents/20142/1289678/
Comunicato_AIFA_644_EN.pdf (accessed on 25 May 2021).

10.

8.

9.

11. Tamariz, L.; Harkins, T.; Nair, V. A systematic review of validated methods for identifying venous thromboembolism using

12.

administrative and claims data. Pharmacoepidemiol. Drug Saf. 2012, 21, 154–162. [CrossRef] [PubMed]
Segal, J.B.; Powe, N.R. Accuracy of identification of patients with immune thrombocytopenic purpura through administrative
records: A data validation study. Am. J. Hematol. 2004, 75, 12–17. [CrossRef] [PubMed]

13. Østergaard, S.D.; Schmidt, M.; Horváth-Puhó, E.; Thomsen, R.W.; Sørensen, H.T. Thromboembolism and the Oxford-AstraZeneca

COVID-19 vaccine: Side-effect or coincidence? Lancet 2021, 397, 1441–1443. [CrossRef]

14. Wu, S.-C.; Lin, S.; Fang, C.-W.; Tsai, I.J.; Yang, W.C. Immune thrombocytopenic purpura increased risk of subsequent pancreatitis:

A Nationwide population cohort study. Sci. Rep. 2019, 9, 16923. [CrossRef] [PubMed]

15. European Medicine Agency. Signal Assessment Report on Embolic and Thrombotic Events (SMQ) with COVID-19 Vaccine (ChAdOx1-S
[recombinant])—Vaxzevria (Previously COVID-19 Vaccine AstraZeneca) (Other Viral Vaccines); European Medicine Agency: Amster-
dam, The Netherlands, 2021.