Received: 14 July 2022 | Revised: 26 December 2022 | Accepted: 24 February 2023

DOI: 10.1002/iid3.807

REVIEW ARTICLE

Adverse events following COVID‐19 mRNA vaccines:

A systematic review of cardiovascular complication,
thrombosis, and thrombocytopenia

Farah Yasmin1 | Hala Najeeb1 | Unaiza Naeem1 | Abdul Moeed1 |

Abdul Raafe Atif1 | Muhammad Sohaib Asghar2 | Nayef Nimri3 |
Maryam Saleem3 | Dhrubajyoti Bandyopadhyay4 | Chayakrit Krittanawong5 |
Mohammed Mahmmoud Fadelallah Eljack6 | Muhammad Junaid Tahir7 |
Fahad Waqar3

1
Department of Internal Medicine, Dow
University of Health Sciences, Karachi, Abstract
Pakistan Background and Objectives: Since publishing successful clinical trial results
2
Division of Nephrology and of mRNA coronavirus disease 2019 (COVID‐19) vaccines in December 2020,
Hypertension, Mayo Clinic, Rochester,
Minnesota, USA multiple reports have arisen about cardiovascular complications following the
3
Department of Cardiovascular Medicine, mRNA vaccination. This study provides an in‐depth account of various
University of Cincinnati, Cincinnati, cardiovascular adverse events reported after the mRNA vaccines' first or
Ohio, USA
second dose including pericarditis/myopericarditis, myocarditis, hypotension,
4
Department of Cardiovascular Medicine,
Westchester Medical Center, Valhalla,
hypertension, arrhythmia, cardiogenic shock, stroke, myocardial infarction/
New York, USA STEMI, intracranial hemorrhage, thrombosis (deep vein thrombosis, cerebral
5
Department of Cardiovascular Medicine, venous thrombosis, arterial or venous thrombotic events, portal vein
Baylor College of Medicine, Houston,
thrombosis, coronary thrombosis, microvascular small bowel thrombosis),
Texas, USA
6 and pulmonary embolism.
Department of Community Medicine,
University of Bakht Alruda, Ed Dueim, Methods: A systematic review of original studies reporting confirmed
Sudan cardiovascular manifestations post‐mRNA COVID‐19 vaccination was per-
7
Department of Radiology, Pakistan formed. Following the PRISMA guidelines, electronic databases (PubMed,
Kidney and Liver Institute and Research
Center, Lahore, Pakistan PMC NCBI, and Cochrane Library) were searched until January 2022. Baseline
characteristics of patients and disease outcomes were extracted from relevant
Correspondence
studies.
Mohammed Mahmmoud Fadelallah
Eljack, Faculty of Medicine and Health Results: A total of 81 articles analyzed confirmed cardiovascular complica-
Sciences, University of Bakht Alruda, Ed tions post‐COVID‐19 mRNA vaccines in 17,636 individuals and reported 284
Dueim, Sudan.
deaths with any mRNA vaccine. Of 17,636 cardiovascular events with any
Email: [email protected]
mRNA vaccine, 17,192 were observed with the BNT162b2 (Pfizer−BioNTech)
vaccine, 444 events with mRNA‐1273 (Moderna). Thrombosis was frequently
reported with any mRNA vaccine (n = 13,936), followed by stroke (n = 758),

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
© 2023 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.

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myocarditis (n = 511), myocardial infarction (n = 377), pulmonary embolism

(n = 301), and arrhythmia (n = 254). Stratifying the results by vaccine type
showed that thrombosis (80.8%) was common in the BNT162b2 cohort, while
stroke (39.9%) was common with mRNA‐1273 for any dose. The time between
the vaccination dosage and the first symptom onset averaged 5.6 and 4.8 days
with the mRNA‐1273 vaccine and BNT162b2, respectively. The mRNA‐1273
cohort reported 56 deaths compared to the 228 with BNT162b2, while the rest
were discharged or transferred to the ICU.
Conclusion: Available literature includes more studies with the BNT162b2
vaccine than mRNA‐1273. Future studies must report mortality and adverse
cardiovascular events by vaccine types.

KEYWORDS
cardiovascular complications, COVID‐19 vaccines, genes, infection, Pfizer−BioNTech,
public health, SARS‐CoV‐2

1 | INTRODUCTION Although the pathogenesis behind the CV manifesta-

tions remains unclear, some studies document the
Since the genome sequencing of the severe acute potential mechanism of post‐COVID‐19 vaccine CV
respiratory syndrome coronavirus 2 (SARS‐COV‐2), the adverse events. In genetically predisposed individuals,
etiologic agent of coronavirus disease 2019 (COVID‐19), the mRNA vaccine might trigger an immune response
in January 2020, a global race for the development of resulting in the detection of mRNA as an antigen.
vaccines began. The swift research and development Activation of inflammatory cascades, following the
process has sparked significant concerns about the safety expression of cytokines by dendritic and Toll‐like
profile of novel coronavirus vaccines. According to a receptors, results in an immunomodulatory response
study from August 2020, 70% of the participants had against the mRNA, potentially leading to myocarditis and
safety concerns due to the rapid development of other systemic reactions.6,7 Similarly, postvaccination
vaccines.1 Moreover, a scoping review conducted in immune thrombocytopenic purpura (ITP) might be
September 2021 also highlighted safety concerns as the accredited to increased macrophage activity and reduced
leading predictor of hesitance.2 These perturbations were platelet production in patients with mild “compensated”
further solidified when sporadic adverse events following thrombocytopenia or chronic, hereditary thrombocyto-
immunization were reported as the large‐scale vaccina- penia.8,9 The distinctive feature of ITP after vaccination is
tion programs progressed. the occurrence of thrombosis at uncommon sites,
A study based on the World Health Organization including the splanchnic, adrenal, cerebral, and ophthal-
(WHO) database (VigiBase) documented the highest mic veins, as concluded from the postmortem findings of
number of cardiovascular (CV) adverse events in patients patients with vaccine‐induced thrombotic thrombocyto-
receiving the BNT162b2 (Pfizer−BioNTech) COVID‐19 penia (VITT).10
vaccine. This study categorized 30% and 44% of CV In late April 2021, officials from the Israeli Health
adverse events as severe upon vaccination by BNT162b2 Ministry reported the incidence of myocarditis in people
(Pfizer−BioNTech) and mRNA‐1273 (Moderna), respec- receiving the BNT162b2 (Pfizer−BioNTech) vaccine.11
tively. Palpitations and tachycardia were the common CV Furthermore, the Vaccine Adverse Event Report System
adverse events in both vaccines.3 Apart from this, Simone (VAERS) database of the Food and Drug Administration
et al. reported a very low incidence of myocarditis (FDA) was utilized by Military.com to review the
(n = 15) following mRNA COVID‐19 vaccination in a frequency of adverse events following COVID‐19 immu-
large sample of participants who did not have any prior nization; found a total of 45 cases of myocarditis, with 19
cardiac disease.4 Similarly, another large‐scale study being from BNT162b2 (Pfizer−BioNTech) and 26 from
conducted in the healthcare sector observed a temporal mRNA‐1273 (Moderna).12 To discern the long‐term
relationship of myocarditis in young males following impact of the cardiac complications caused by the two
Pfizer−BioNTech vaccination.5 approved COVID‐19 mRNA vaccines, the Centers for
 20504527, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/iid3.807 by Cochrane Colombia, Wiley Online Library on [23/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
YASMIN ET AL. | 3 of 10

Disease Control and Prevention (CDC) has launched an protein subunit, viral vector, and DNA nucleic acid
investigation by surveying the patients with reported vaccines), and clinical manifestations (non‐
myocarditis after immunization.13 In this systematic CV presentations). A detailed evaluation of 153 studies
review, we aim to summarize the events of cardiac led to the inclusion of 81 studies, as shown in Figure 1,
complications following the mRNA COVID‐19 vaccine, which analyzed confirmed CV, thrombotic, and thrombo-
providing an in‐depth analysis of their occurrences, and cytopenic complications post‐COVID‐19 mRNA vaccina-
their implications. tion. Studies were excluded if adverse events were not
specified as CV events, outcomes were not given by the type
of vaccine, or presented as pregnancy‐related vascular
2 | MATERIALS A ND METHODS complications.

2.1 | Search strategy

3.2 | Characteristics of included studies
This systematic review was performed in conformity with and overall results
the PRISMA guidelines.14 PubMed Central, Cochrane,
Clinicaltrials.gov, and Scopus were searched from incep- The review includes 69 case reports/case series, 4 studies
tion till January 2022 while preprint portals like bioRxiv, with data obtained from electronic medical records
medRxiv, Authorea, and Research Square were also (hospital surveillance data, national database, VAERS/
followed with the following search term: (COVID‐19 VigiBase), and 8 observational studies including prospec-
mRNA vaccines) AND (cardiac OR cardiovascular) AND tive/retrospective cohorts. Of the individuals suffering
(adverse events OR complications) AND (thrombosis OR from CV complications, 286 were lost to treatment.
thrombocytopenia).
Articles were first screened by title, then abstract, and
finally by full text by two independent reviewers (H. N. 3.3 | CV events
and A. R. A.). Data extraction of relevant shortlisted
articles was conducted for the following: study type, age, A total of 17,636 CV events were reported with any
number of males and females, vaccine type, COVID‐19 mRNA vaccines. The most‐reported events in the
status, comorbidities, abnormal lab parameters, CV man- search included pericarditis/myopericarditis, myocar-
ifestations, and clinical outcomes. ditis, hypotension, hypertension, arrhythmia, cardio-
genic shock, stroke, myocardial infarction (MI)/STE-
MI, intracranial hemorrhage, thrombosis (deep vein
2.2 | Inclusion and exclusion criteria thrombosis [DVT], cerebral venous thrombosis [CVT],
arterial or venous thrombotic events, portal vein
The study inclusion criteria were: (a) observational thrombosis, coronary thrombosis, microvascular small
studies and case reports assessing CV complications, (b) bowel thrombosis) and pulmonary embolism. From a
mRNA COVID‐19 vaccine, and (c) no language restric- total of 17,636 CV complications documented, throm-
tion. The exclusion criteria were: (a) reviews, meta‐ bosis was most frequently reported with any mRNA
analysis, protocols, editorials, and conference abstracts, vaccine (n = 13,936), followed by stroke (n = 758),
(b) non‐CV manifestations, and (c) patients with myocarditis (n = 511), MI (n = 377), pulmonary embo-
preexisting CV diseases. Relevant studies were sorted in lism (n = 301), and arrhythmia (n = 254). Cardiogenic
this study based on the inclusion criteria through shock was the least reported outcome with only 1 event,
thematic presentation. while changes in blood pressure were experienced by
39 individuals receiving any mRNA vaccine. Besides
echocardiography, electrocardiogram (ECG) remained
3 | RESUL TS a common diagnostic tool in individuals receiving any
COVID‐19 mRNA vaccine. ST‐elevation was the
3.1 | Literature search results prevalent ECG finding with 0.6% in BNT162b2 (Pfizer
−BioNTech) and 4.1% in mRNA‐1273 (Moderna)
The search strategy and manual search yielded 314 results, vaccine groups. Table 1 gives a detailed stratification
of which 44 studies were removed as duplicates. Of the 256 of CV outcome by type of vaccines, the dosage of
studies screened, 103 were excluded for article types vaccines, and the total reported events in each vaccine
(systematic reviews, reviews, meta‐analyses, protocols, type. Table 2 summarizes the major findings of the
and conference abstracts), vaccine type (whole virus, review for each mRNA vaccine, including abnormal
 20504527, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/iid3.807 by Cochrane Colombia, Wiley Online Library on [23/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
4 of 10 | YASMIN ET AL.

FIGURE 1 PRISMA flow chart of studies retrieved, screened, and included in this systematic review.

lab values, treatment methods, onset to first symptom The average time between the vaccination dosage and
postvaccination, and mortality. the onset of the first symptom was 5.6 days. Individuals
requiring hospitalization had a median length of 3.7 days
of hospital stay. The study synthesizes data of abnormal
3.4 | Stratification by vaccine types or elevated lab values; 13 events were reported for
elevated CRP levels, 5 individuals had increased Tropo-
3.4.1 | mRNA‐1273 (Moderna) nin T; whereas 8 cases observed an increase in Troponin
I levels.
A smaller number of studies (n = 18) in the review ECG and cardiac magnetic resonance imaging were
reported 444 CV events in individuals who received the the commonly used diagnostic procedures among hospi-
mRNA‐1273 (Moderna) vaccine at first, second, or both talized patients for any adverse outcomes. Data reveals 16
doses; 4 studies included both types of mRNA vaccines cases of ST‐elevations and 7 PR‐depressions, followed by
were previously published. Figure 2 presents the CV ST‐depressions, T‐wave abnormalities, and bundle
complications in mRNA‐1273 (Moderna) cohort. The branch blocks.
most common complication, stroke, was reported in In studies that reported treatment options steroids
39.9% of cases, followed by 15% of MI and pulmonary (n = 15 cases) including corticosteroids, prednisone,
embolism each, and myocarditis in 11% of the cases methylprednisolone, and dexamethasone frequently
with any dose. The remainder 19.1% of the events opted for. This was followed by IVIG in 10 cases,
comprised 43 cases of thrombosis, and 13 cases of NSAIDs in 7, and colchicine in 6 cases, respectively.
pericarditis after any dose. One event of intracranial Analysis of literature reported mortality in 56 cases
hemorrhage and hypertension each was experienced (12.6%); with the rest being discharged or transferred
after the first dose. to ICU.
 20504527, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/iid3.807 by Cochrane Colombia, Wiley Online Library on [23/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
YASMIN ET AL. | 5 of 10

3.5 | BNT162b2 (Pfizer−BioNTech) Excluding studies that reported median days for the
onset of symptoms and vaccine dosage, the average time
A major proportion of studies (n = 59) in the review to the first CV symptom was 4.8 days, while the average
reported 17,192 confirmed CV events in individuals who hospital stay was recorded to be 6 days in individuals
received the BNT162b2 (Pfizer−BioNTech) vaccine, and requiring hospitalization. Of the studies reporting
4 studies reporting both types of mRNA vaccines were elevated lab parameters postvaccination, increased CRP
found in published literature. With 13,893 events (80.8%),
any type of thrombosis remained the most common CV
outcome in this cohort. Stroke was observed in 581 cases TABLE 2 Overall summary of literature by vaccine types.
(3.4%), and myocarditis in 462 events (2.7%), compared mRNA‐1273 BNT162b2
with 68 events of pericarditis with the first or second dose (Pfizer−
of BNT162b2 (Pfizer−BioNTech) vaccine. Observed with Characteristics (Moderna) BioNTech)
BNT162b2 (Pfizer−BioNTech) vaccine only, arrhythmia, Total events 444 17,192
MI, and pulmonary embolism accounted for 1.5%, 1.8%,
Sex
and 1.4% of events, respectively. Eight events of hyper-
tension were reported after the first BNT162b2 (Pfizer Males 178 8042
−BioNTech) vaccine dose. Hypotension and hyper- Females 193 6102
tension were observed after the second dosage in 10 Unidentified 73 3048
individuals each. Cardiogenic shock (n = 1) was the least
Case management
reported outcome in the cohort. Figure 3 summarizes the
CV events in the cohort. Colchicine 6 30
NSAIDsa 7 39
b
TABLE 1 Adverse events stratified by COVID‐19 vaccine type. Steroids 15 38
c
BNT162b2 ACE inhibitors or ARB 4 8
(Pfizer− mRNA‐1273 d
Beta blockers 6 13
BioNTech) (Moderna)
e
Anticoagulant & Xa inhibitors 5 13
Cardiac events
f
Antiplatelet 0 3
Pericarditis 68 13
Platelet transfusion 4 15
Myocarditis 462 49
IVIG 10 30
Myocardial infarction 310 67
Diureticsg 3 4
Arrythmia 254 0
Mean time between vaccine and 5.6 4.8
Cardiogenic shock 1 0
symptom onset (days)
Thrombotic events 13,893 43
Mean length of 3.7 6.0
Thrombocytopenia events 1346 28 hospitalization (days)
Vascular events Mortality (n)h 56 228
Hypertension Laboratory findings (n with highest values)
First dose 8 1 D‐Dimer level >500 (ng/mL) 5 12
Second dose 10 0 CK‐MB (ng/mL) 0 9
Hypotension Troponin‐I 8 27
First dose 0 0 Troponin‐T 5 21
Second dose 10 CRP levels >10 mg/L 13 50
Stroke 581 177 ECG findings
Pulmonary embolism 236 65 ST elevation 16 70
Intracranial hemorrhage ST depression 1 7
First dose 13 1 PR depression 7 10
Second dose 0 T‐wave abnormality 2 17
Abbreviation: COVID‐19, coronavirus disease 2019. (Continues)
 20504527, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/iid3.807 by Cochrane Colombia, Wiley Online Library on [23/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6 of 10 | YASMIN ET AL.

TABLE 2 (Continued)

mRNA‐1273 BNT162b2
(Pfizer−
Characteristics (Moderna) BioNTech)
Bundle branch block 1 2
Sinus tachycardia 2 9
Abbreviation: ECG, electrocardiogram.
a
NSAIDs used in treatment include ibuprofen, aspirin, acetylsalicylic acid,
ketorolac.
b
Steroids listed: corticosterone, prednisone, methylprednisolone,
dexamethasone.
c
ARB/ACE inhibitors: lisinopril, ramipril, candesartan.
d
Beta blockers: bisoprolol, metoprolol, carvedilol.
e
Anticogulants/Xa inhibitors: rivaroxaban, apixaban, warfarin, enoxaparin,
heparin, clexane dabigatran, lovenox.
f
Antiplateletes: clopidogrel, eptifibatide, ticagrelor. F I G U R E 3 Cardiac and vascular events observed with
g
Diuretics: acetazolamide, furosemide, mineralocorticoid antagonist. BNT162b2 (Pfizer−BioNTech) vaccine with any dose.
h
n = 2 vaccine types unspecified.

F I G U R E 4 Treatment options of cardiovascular complications

F I G U R E 2 Cardiac and vascular events observed with mRNA‐ in COVID‐19 mRNA‐1273 (Moderna) vaccine cohort. COVID‐19,
1273 (Moderna) vaccine with any dose. coronavirus disease 2019.

levels were observed in 50 individuals. Abnormal (1.3%), with the rest of the population being discharged
Troponin‐I and Troponin‐T levels were recorded in 27 or transferred to critical care.
and 21 cases, respectively. Elevated D‐dimer levels
(>500 ng/L) were reported in 12 cases, followed by
9 cases of increased CK‐MB levels. 3.6 | Treatment options and diagnostics
The most prevalent ECG finding was ST elevation
in 70 individuals, followed by a T‐wave abnormality in Treatment options for postvaccination critical cases
17 individuals. Bundle branch blocks and sinus comprised steroids including corticosteroids, prednisone,
tachycardia were the least observed findings in methyl prednisone, and dexamethasone (25% for mRNA‐
individuals receiving the BNT162b2 (Pfizer−BioN- 1273; 19.6% for BNT162b2), NSAIDs such as Ibuprofen,
Tech) vaccine. Critical cases were managed mostly aspirin, acetylsalicylic acid, and ketorolac (11.6% for
with NSAIDS (n = 39) and steroids (n = 38). Colchicine mRNA‐1273; 20% for BNT162b2), colchicine (10%
and IVIG were reported to be used in 30 cases each. for mRNA‐1273; 15.5% for BNT162b2), IVIGs (16.7% for
Antiplatelet therapy and diuretics were the least used mRNA‐1273; 15.5% for BNT162b2) as shown in
treatment options. Mortality was reported in 228 cases Figures 4 and 5.
 20504527, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/iid3.807 by Cochrane Colombia, Wiley Online Library on [23/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
YASMIN ET AL. | 7 of 10

event reported concerning the vaccination phase. We

presume that a thorough analysis of all adverse events
arising with mRNA vaccination is necessary to know the
details of these events and adopt measures to mitigate the
difficulties accordingly. Recent studies analyzing compli-
cations occurring post‐mRNA vaccination have focused
on a single or few complications while our study has
extensively reviewed literature published so far and has
considered all potential studies. For the short‐term
knowledge regarding adverse effects of mRNA vaccina-
tion,16 our findings provide a comprehensive insight into
the unfavorable sequel that has been reported and
stratify them based on the different types of mRNA
vaccines. This can be possibly helpful in better under-
standing and predicting the intricacies of mRNA vaccine
inoculation.
F I G U R E 5 Treatment options of cardiovascular complications
in COVID‐19 mRNA‐BNT162b2 (Pfizer−BioNTech) vaccine
Thrombotic events were the most common complica-
cohort. COVID‐19, coronavirus disease 2019. tion from our data for both vaccines overall and affected
individuals displayed symptoms such as severe headache,
dizziness, visual disturbances, fever, and shortness of
4 | DISCUS SION breath.17 Previous studies have identified cerebral venous
sinus thrombosis, splanchnic venous system thrombosis,
This systematic review evaluated the rare CV complica- pulmonary embolism, DVT, or acute arterial thrombosis
tions that have occurred due to mRNA vaccines and as sites of thrombosis.17 As recent literature shows, these
revealed that the highest complication reported com- lipid nanoparticles‐mRNA‐based vaccines (Pfizer/BioN-
bined for both mRNA vaccines was thrombosis. Throm- Tech and Moderna) have caused rare cases of DVT, and
bocytopenia has also been widely recorded and was the generally, healthy individuals have presented with acute
second‐highest adverse event to occur. Our analysis also atypical thrombi. Combined descriptive analysis for the
demonstrated a moderate frequency of vascular adverse vaccines BNT162b2, mRNA‐1273, and ChAdOx1 nCov‐
events among which, stroke was most reported and was 19 (AstraZeneca) was reported to the WHO Global
overall, the third‐highest event to be documented. Database for Individual Case Safety Reports (VigiBase)
Myocarditis was the next commonly occurring complica- from December 13, 2020 to March 16, 2021, stated a rate
tion and had the highest cases reported among all cardiac of 0.21 cases of thrombotic events including CVT per 1
events. Other cardiac events included MI, arrhythmia, million individual vaccinated days.18 Our results are
pericarditis, and cardiogenic shock. Cardiogenic shock comparable to an analysis of safety surveillance data
was the lowest reported adverse effect among all events. involving various US health plans for the mRNA
The mRNA vaccines have been graded as the most vaccine.19
effective (approximately 94%) due to their strong Thrombocytopenia, the second most reported com-
immunogenicity and effective presentation of SARS‐ plication in our review, has also been reported in recent
CoV‐2 antigens to the immune system. Real‐world studies. Atypical manifestations of thrombocytopenia
incidence of adverse reactions after mRNA vaccines has presented alongside thrombosis, collectively termed
also remained lower than that concluded from clinical VITT, have been found. Following mRNA immunization,
trials. Several systematic reviews have been published incidence rates of VITT have been reported to be within
since the onset of the SARS‐CoV‐2 infection evaluating anticipated, background levels. Our findings, however,
the relation between CV conditions and COVID‐19 further this knowledge by revealing a great frequency of
outcomes. Cardiac complications have been observed to thrombosis and thrombocytopenia occurring, higher
be the most frequently occurring complication while than any other complication.17 The time of presentation
CV disease is the most common comorbidity.15 A few of thrombus and concurrent thrombocytopenia is 6−24
studies have explored the incidence of thrombosis, days after the administration of the first dose mRNA
thrombocytopenia, and various vascular events. How- (Pfizer/BioNTech and Moderna) vaccines, which corre-
ever, the evolving situation with the emergence of new sponds with the time length presumed for the onset of
SARS‐CoV‐2 variants requires that the focus of health- the first symptom of the respective complications for the
care experts be on investigating the course of any adverse two vaccines in our paper. Elrashdy et al. propose that
 20504527, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/iid3.807 by Cochrane Colombia, Wiley Online Library on [23/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
8 of 10 | YASMIN ET AL.

the mechanism underlying VITT might be the interac- IVIG. Das et al. also report NSAIDs alone to be primarily
tion between RNA molecules and platelets/platelet factor used, and NSAIDS with colchicine and NSAIDs with
4 (PF4). Other host conditions such as the history of steroids to be the next resort for treating CV events such as
thrombosis, susceptibility to thrombi, smoking, and myocarditis.23 Analogous to our analysis, ST‐segment
taking medications that can cause autoimmunity have elevation was the most common abnormal parameter, as
previously resulted in VITT.20 Recent studies assessing stated by a study evaluating myocarditis post‐RNA
thrombocytopenia arising with mRNA vaccines found vaccination.23 Diffuse ST changes and echocardiographic
the cases to be reported in less than 2 weeks after dysfunction are observed in our results and studies
vaccination.18 This period between vaccination and elsewhere.23
complication to surface overlaps with the time of When differentiating adverse events for each mRNA
symptom onset divulged in our results for all complica- vaccine, stroke was the highest reported complication
tions; 4.8 and 5.6 days for Moderna and Pfizer−BioN- after any dose for individuals receiving mRNA‐1273
Tech, respectively. Moreover, preliminary data on the (Moderna) vaccination. MI, pulmonary embolism, and
relation between thrombocytopenia and mRNA vaccines myocarditis were the next commonly reported events.
had not signified any association.18 Given the outcome of While COVID‐19 itself is a risk factor for stroke, current
the high incidence of thrombocytopenia in our results, it literature delineates the phenomenon of CVT and ische-
warrants further investigation to detect any correlation. mic stroke associated with VITT occurring.26 Young
A high number of outcome events during the 21‐day patients with ischemic stroke have mostly presented,
risk interval have been inferred for ischemic stroke—the post‐ChAdOx1 nCoV‐19 vaccine,27 while our findings,
next most frequent complication.19 Additionally, an that reported stroke after mRNA‐1273 vaccination, are
observational study that prospectively analyzed indivi- new considering current evidence. There is a paucity of
duals who had recently received mRNA‐1273 (Moderna) literature that details stroke‐related events following
or BNT162b2 (Pfizer−BioNTech) (n = 1,398,074) re- mRNA‐1273 inoculation, and while our results might
ported 246 cases of acute ischemic stroke among patients indicate an underlying link, Koh et al.21 report acute
who developed cerebrovascular disorders (n = 286).21 ischemic stroke post‐mRNA vaccination to be coinciden-
Myocarditis, which is the fourth most common event in tal. Moreover, the authors when discerning a plausible
our study, has been increasingly reported in studies link between RNA‐based vaccines including mRNA‐
evaluating the safety of mRNA‐1273 (Moderna) and 1273, and acute ischemic stroke by assessing patients
BNT162b2 (Pfizer−BioNTech), and most cases occur least likely to develop the condition found no pattern
after the second dose of these vaccines.22 COVID‐19 related to stroke etiology.21 For BNT162b2 (Pfizer
vaccine‐associated myocarditis usually is transient and −BioNTech) vaccine, the highest number of CV compli-
self‐limiting.23 Postvaccination cases of myocarditis/ cations was thrombosis followed by thrombocytopenia,
pericarditis are reported by Klein et al.19 of which 82% stroke, myocarditis, and pericarditis. The results are
required hospitalization at a median length of 1 day. A contrary to current statistics; incidences of VITT have
meta‐analysis evaluating real‐world data from the occurred between 1 in 125,000 and 1 in 1 million, mainly
VAERS, managed by the CDC and FDA of the United linked to the ChAdOx1‐nCoV‐19 vaccine, while only
States of America, found 2−3 cases per million doses of 1 reported case of DVT linked with the BNT162b2 mRNA
myocarditis/pericarditis as adverse drug reaction in COVID‐19 vaccine.28 Unlike the DNA‐borne adenoviral
RNA‐based vaccines.24 The European Medicines Agency vaccines, low rates of VITT could be due to the changes
has officially reported myocarditis as a side effect post‐ in mRNA vaccines that diminish dampen pathogen‐
RNA vaccination, which is predominantly found among associated molecular pattern sensing mechanisms low-
males, corresponding to 1.60 cases/million doses for ering the immunogenic risk.17 However, there might be a
Pfizer−BioNTech and 3.04 cases/million doses for need to revisit this proposed mechanism as other factors
Moderna in the region.25 might be at play, resulting in a high incidence of
Certain events, notably thromboembolism and myo- thrombosis and thrombocytopenia. Our findings are
carditis/pericarditis, may result in death.24 In our analysis, comparable to phase 3 clinical trial results for the
the overall mortality for each vaccine type is relatively BNT162b2 (Pfizer–BioNTech) vaccine that has indicated
very low in comparison to the number of events reported a slight imbalance between the vaccinated and placebo
for the corresponding mRNA vaccine. For management of groups with several events, including acute MI and
patients with damaging effects postvaccination, NSAIDs cerebrovascular accidents (stroke).29 Stroke was also a
(Ibuprofen, aspirin, acetylsalicylic acid, ketorolac) were recurring event in our analysis, however, a study based
most used, followed by steroids (corticosteroids, predni- on the Scottish National Registry having recorded 0.82
sone, methyl prednisone, dexamethasone), colchicine, and million people who received BNT162b2 concluded no
 20504527, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/iid3.807 by Cochrane Colombia, Wiley Online Library on [23/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
YASMIN ET AL. | 9 of 10

relationship exists between this vaccine type and this review merits more comprehensive studies to
stroke.21 Conversely, a study retrieving statistics from investigate factors that increase the susceptibility to
the English National Immunization (NIMS) Database of develop deleterious CV events after mRNA vaccination.
COVID‐19 constituting a cohort of more than 10 million Vaccine recommendations can be reviewed considering
people having received first dose of BNT162b2 deduced a our analysis, highlighting the need for robust post‐
positive association with BNT162b2 vaccine and hemor- marketing surveillance, especially for such events that
rhagic stroke.30 Myocarditis was a common complication can generate findings pivotal for future evaluations that
after the aforementioned CV events and Israel, which has establish the safety profile of the mRNA‐1273 (Moderna)
led the vaccination race worldwide, has reported cases of and BNT162b2 (Pfizer−BioNTech). Mortality and
myocarditis post‐BNT162b2 (Pfizer−BioNTech) vaccina- adverse CV events require the attention of researchers
tion; this represents 0.001% of its population that to prevent complications in immunocompromised in-
received the second dose and was markedly high in the dividuals. However, the total doses administered are
16−35 years age group.25 insufficient to draw a definitive conclusion. Future
The effect of COVID‐19 mRNA vaccines is eminent studies must report adverse events by vaccine types and
from our results; however, identifying the number of changes in lab parameters of relevant outcomes pre‐ and
dosages eliciting each stratified complication and time postvaccination.
for symptom resolution for the respective occurrence is
imperative for reviewing vaccine delivery plans. Due to A U T H O R C O N TR I B U T I O N S
the studies' variable reporting, this could not be Farah Yasmin: Conceptualization. Hala Najeeb: For-
distinguished in this review. Furthermore, more studies mal analysis. Unaiza Naeem: Writing—original draft.
focusing on lab parameters and biomarkers are required Abdul Moeed: Writing—original draft. Abdul Raafe
to employ strategies to mitigate complications and Atif: Writing—original draft. Muhammad Sohaib
observe disease courses. Only a small proportion of our Asghar: Formal analysis. Nayef Nimri: Writing—
selected publications mentioned these lab findings, review & editing. Maryam Saleem: Writing—review &
which, considering the number of events reported, are editing. Dhrubajyoti Bandyopadhyay: Writing—
insufficient to establish a criterion for detecting abnor- review & editing. Chayakrit Krittanawong: Writing—
malities. Prior research has revealed myocarditis to be review & editing. Mohammed Mahmmoud Fadelal-
more common in the younger population22; it elucidates lah Eljack: Visualization. Muhammad Junaid Tahir:
that dividing each condition based on age group can help Validation. Fahad Waqar: Supervision.
discern predisposing factors and correlate vaccination
and CV health. This key finding would allow strategizing C O NF L I C T O F I N T E R E S T S TA T E M E N T
vaccination in vulnerable population groups. A note- The authors declare no conflict of interest.
worthy limitation is the number of excluded studies as
data was inconsistently presented in those and could not DATA AVAILABILITY STATEMENT
be categorized under our desired outcomes. Adding to No new data were created or analyzed in this study. Data
this is the low to moderate quality of included studies sharing is not applicable to this article.
since most are case series/case reports. However, data
from electronic medical records offsets this potential ORC ID
constraint with a larger population size to conclude. Muhammad Sohaib Asghar http://orcid.org/0000-
0001-6705-2030
Mohammed Mahmmoud Fadelallah Eljack http://or-
5 | CONCLUSION cid.org/0000-0002-2370-9368

This systematic review provides essential data for REFER ENCES

immunization providers when evaluating the risk versus 1. Dror AA, Eisenbach N, Taiber S, et al. Vaccine hesitancy: the
benefits of COVID‐19 mRNA vaccines on the CV system. next challenge in the fight against COVID‐19. Eur J Epidemiol.
CV events such as thrombosis, thrombocytopenia, stroke, 2020;35(8):775‐779.
2. Alshurman BA, Khan AF, Mac C, Majeed M, Butt ZA. What
and myocarditis frequently occur with the mRNA
demographic, social, and contextual factors influence the
vaccines studied. A significant number of studies intention to use covid‐19 vaccines: a scoping review. Int
included in our review reported BNT162b2 events, which J Environ Res Public Health. 2021;18:9342.
presses the need to conduct more research into the 3. Kaur R, Dutta S, Charan J, et al. Cardiovascular adverse events
CV implications of mRNA‐1273 (Moderna) vaccine. reported from covid‐19 vaccines: a study based on who
Vaccines have a potentially life‐saving advantage, and database. Int J Gen Med. 2021;14:3909‐3927.
 20504527, 2023, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/iid3.807 by Cochrane Colombia, Wiley Online Library on [23/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
10 of 10 | YASMIN ET AL.

4. Simone A, Herald J, Chen A, et al. Acute myocarditis 20. Elrashdy F, Tambuwala MM, Hassan SS, et al. Autoimmunity
following COVID‐19 mRNA vaccination in adults aged 18 roots of the thrombotic events after COVID‐19 vaccination.
years or older. JAMA Internal Med. 2021;181(12):1668‐1670. Autoimmun Rev. 2021;20(11):102941.
doi:10.1001/jamainternmed.2021.5511 21. Koh JS, Hoe RHM, Yong MH, et al. Hospital‐based
5. Witberg G, Barda N, Hoss S, et al. Myocarditis after Covid‐19 observational study of neurological disorders in patients
vaccination in a Large Health Care Organization. N Engl J recently vaccinated with COVID‐19 mRNA vaccines.
Med. 2021;385:2132‐2139. J Neurol Sci. 2021;430:120030.
6. Karikó K, Buckstein M, Ni H, Weissman D. Suppression of 22. Bozkurt B, Kamat I, Hotez PJ. Myocarditis with COVID‐19
RNA recognition by toll‐like receptors: the impact of nucleo- mRNA vaccines. Circulation. 2021;144:471‐484.
side modification and the evolutionary origin of RNA. 23. Das BB, Moskowitz WB, Taylor MB, Palmer A. Myocarditis
Immunity. 2005;23(2):165‐175. and pericarditis following mRNA COVID‐19 vaccination:
7. Caso F, Costa L, Ruscitti P, et al. Could Sars‐coronavirus‐2 trigger what do we know so far? Children. 2021;8(7):607.
autoimmune and/or autoinflammatory mechanisms in genetically 24. Cai C, Peng Y, Shen E, et al. A comprehensive analysis of the
predisposed subjects? Autoimmun Rev. 2020;19(5):102524. efficacy and safety of COVID‐19 vaccines. Mol Ther.
8. Rinaldi M, Perricone C, Ortega‐Hernandez OD, Perricone R, 2021;29(9):2794‐2805.
Shoenfeld Y. Immune thrombocytopaenic purpura: an auto- 25. Lazaros G, Klein AL, Hatziantoniou S, Tsioufis C, Tsakris A,
immune cross‐link between infections and vaccines. Lupus. Anastassopoulou C. The novel platform of mRNA COVID‐19
2014;23(6):554‐567. vaccines and myocarditis: clues into the potential underlying
9. Perricone C, Ceccarelli F, Nesher G, et al. Immune mechanism. Vaccine. 2021;39:4925‐4927.
thrombocytopenic purpura (ITP) associated with vaccinations: 26. Markus HS. Ischaemic stroke can follow COVID‐19 vaccina-
a review of reported cases. Immunol Res. 2014;60(2‐3):226‐235. tion but is much more common with COVID‐19 infection
10. Pomara C, Sessa F, Ciaccio M, et al. Post‐mortem findings in itself. J Neurol, Neurosurg Psychiatr. 2021;92:1142.
vaccine‐induced thrombotic thombocytopenia. Haematologica. 27. Al‐Mayhani T, Saber S, Stubbs MJ, et al. Ischaemic stroke as a
2021;106:2291‐2293. presenting feature of ChAdOx1 nCoV‐19 vaccine‐induced
11. Israel examines heart inflammation cases after Pfizer immune thrombotic thrombocytopenia [Internet]. J Neurol,
Covid shot [Internet]. Accessed January 30, 2022. https:// Neurosurg Psychiatr. 2021;92:1247‐1248. https://jnnp.bmj.
www.bloombergquint.com/onweb/israel-examines-heart- com/content/92/11/1247
inflammation-cases-after-pfizer-covid-shot 28. Al‐Maqbali JS, Al Rasbi S, Kashoub MS, et al. A 59‐year‐old
12. Kime P. Pentagon tracking 14 cases of heart inflammation in woman with extensive deep vein thrombosis and pulmonary
troops after COVID‐19 shots [internet] Military.com. 2021. https:// thromboembolism 7 days following a first dose of the pfizer‐
www.military.com/daily-news/2021/04/26/pentagon-tracking-14- biontech bnt162b2 mrna covid‐19 vaccine. Am J Case Rep.
cases-of-heart-inflammation-troops-after-covid-19-shots.html 2021;22(1):e932946‐1.
13. CDC. Investigating long‐term effects of myocarditis [Internet]. 29. Barda N, Dagan N, Ben‐Shlomo Y, et al. Safety of the
https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/ BNT162b2 mRNA Covid‐19 Vaccine in a Nationwide Setting.
myo-outcomes.html 2021;385(12):1078‐1090. https://pubmed.ncbi.nlm.nih.gov/
14. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items 34432976/
for systematic reviews and meta‐analyses: the PRISMA 30. Patone M, Handunnetthi L, Saatci D, et al. Neurological
statement. Open Med. 2009;3(3):e123‐30. complications after first dose of COVID‐19 vaccines and
15. Ma L, Song K, Huang Y. Coronavirus disease‐2019 (COVID‐ SARS‐CoV‐2 infection. Nat Med. 2021;27(12):2144‐2153.
19) and cardiovascular complications. J Cardiothorac Vasc https://www.nature.com/articles/s41591-021-01556-7
Anesth. 2021;35(6):1860‐1865.
16. Haaf P, Kuster GM, Mueller C, et al. The very low risk of
myocarditis and pericarditis after mRNA COVID‐19 vaccination SU PPOR T ING INF OR MATI ON
should not discourage vaccination. Swiss Med Wkly 2021 41 Additional supporting information can be found online
[Internet]. 2021;151(41):w30087. https://smw.ch/article/doi/smw. in the Supporting Information section at the end of this
2021.w30087/ article.
17. Chen PW, Tsai ZY, Chao TH, Li YH, Hou CJ, Liu PY.
Addressing vaccine‐induced immune thrombotic thrombocy-
topenia (Vitt) following covid‐19 vaccination: a mini‐review of
practical strategies. Acta Cardiol Sin. 2021;37(4):355‐364. How to cite this article: Yasmin F, Najeeb H,
18. Novak N, Tordesillas L, Cabanillas B. Adverse rare events to Naeem U, et al. Adverse events following
vaccines for COVID‐19: from hypersensitivity reactions to COVID‐19 mRNA vaccines: a systematic review of
thrombosis and thrombocytopenia. Int Rev Immunol. cardiovascular complication, thrombosis, and
2022;41(4):438‐447. doi:10.1080/08830185.2021.1939696
thrombocytopenia. Immun Inflamm Dis.
19. Klein NP, Lewis N, Goddard K, et al. Surveillance for adverse
events after COVID‐19 mRNA vaccination. JAMA. 2021;
2023;11:e807. doi:10.1002/iid3.807
326(14):1390‐1399.