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RESEARCH ARTICLE
Venous thromboembolism after COVID-19 vaccination
in patients with thrombophilia
Damon E. Houghton
1,2
| Waldemar E. Wysokinski
1,2
| Leslie J. Padrnos
3
|
Surbhi Shah
3
| Ewa Wysokinska
4
| Rajiv Pruthi
2
| Atefeh Ghorbanzadeh
1
|
Aneel Ashrani
2
| Meera Sridharan
2
| Robert D. McBane
1,2
|
Anand Padmanabhan
5
| Ana I. Casanegra
1
1
Department of Cardiovascular Diseases,
Division of Vascular Medicine, Mayo Clinic,
Rochester, Minnesota, United States
2
Department of Internal Medicine, Division of
Hematology, Mayo Clinic, Rochester,
Minnesota, United States
3
Department of Internal Medicine, Division of
Hematology/Oncology, Mayo Clinic, Arizona,
United States
4
Department of Internal Medicine, Division of
Hematology/Oncology, Mayo Clinic, Florida,
United States
5
Department of Laboratory Medicine and
Pathology, Divisions of Hematopathology,
Transfusion Medicine & Experimental
Pathology, Mayo Clinic, Minnesota,
United States
Correspondence
Damon E. Houghton, Division of Vascular
Medicine, Department of Cardiovascular
Diseases Mayo Clinic, 200 1st St, Rochester,
MN 55905, USA.
Email: houghton.damon@mayo.edu
Funding information
Eduardo G. Mestre and Gillian M. Shepherd,
M.D., Clinician Career Development Award
Honoring John T. Shepherd, M.D.,
Grant/Award Number: This publication was
made possible through the sup
Abstract
Patients with thrombophilia remain concerned about venous thromboembolism
(VTE) risk with COVID-19 vaccinations. The aim of this study was to examine VTE
outcomes in patients with inherited or acquired thrombophilia who were vaccinated
for COVID-19. Vaccinated patients ≥18 years between November 1, 2020 and
November 1, 2021 were analyzed using electronic medical records across the Mayo
Clinic enterprise. The primary outcome was imaging confirmed acute VTE occurring
90 days before and after the date of the first vaccine dose. Thrombophilia patients
were identified through laboratory testing results and ICD-10 codes. A total of
792 010 patients with at least one COVID-19 vaccination were identified. Six thou-
sand sixty-seven of these patients were found to have a thrombophilia, among whom
there was a total of 39 VTE events after compared to 51 VTE events before vaccina-
tion (0.64% vs. 0.84%, p=.20). In patients with Factor V Leiden or prothrombin gene
mutation, VTE occurred in 27 patients before and in 29 patients after vaccination
(0.61 vs. 0.65%, p=.79). In patients with antiphospholipid syndrome, VTE occurred
in six patients before and four patients after vaccination (0.59% vs. 0.39%, p=.40).
No difference was observed in the overall VTE rate when comparing the postvaccina-
tion 90 days to the prevaccination 90 days, adjusted hazard ratio 0.81 (95% confi-
dence interval: 0.53–1.23). In this subgroup of COVID-19 vaccinated patients with
thrombophilia, there was no increased risk for acute VTE postvaccination compared
to the prevaccination timeframe. These results are consistent with prior studies and
should offer additional reassurance to patients with inherited or acquired
thrombophilia.
1|BACKGROUND
COVID-19 vaccinations in the United States (Janssen [Ad26.COV2.S],
Moderna [mRNA-1273], and Pfizer [BNT-162b2]) are generally safe
and effective. However, vaccine-induced thrombotic thrombocytope-
nia (VITT) syndrome is a rare but significant thrombotic complication
primarily associated with adenoviral vector-based vaccines.
1,2
Outside
of this rare syndrome, COVID-19 vaccines have not been associated
with increased venous thromboembolism (VTE) risk.
3–5
The safety of
approved vaccines in the United States has also been demonstrated in
high-risk groups such as those with malignancy and those with a
This paper was presented in abstract form at the Thrombosis and Hemostasis Summit of
North America annual meeting, Chicago, IL August 2022.
Received: 29 September 2022 Revised: 11 November 2022 Accepted: 21 December 2022
DOI: 10.1002/ajh.26848
566 © 2023 Wiley Periodicals LLC. Am J Hematol. 2023;98:566–570.wileyonlinelibrary.com/journal/ajh
history of heparin-induced thrombocytopenia. Among patients with
prior VTE, it has been shown that there was actually a lower risk for
VTE after vaccination.
3
In the background of VITT, potentially coinci-
dental VTE events occurring after vaccination have been analyzed
with increased scrutiny and even after large studies demonstrated no
generalized increase in VTE risk, published case reports continue to
question the safety in those with thrombophilia
6–9
with calls for defin-
itive research in this area.
10
Patients with inherited or acquired thrombophilia remain con-
cerned about their thrombotic risk with COVID-19 vaccination due to
their unique circumstances, with some avoiding vaccination due to
personal concerns or in some cases medical advice. It is well estab-
lished that COVID-19 infection increases the risk for VTE
11,12
and as
expected, patients with inherited thrombophilia are at further
increased risk for these complications.
13
On September 1, 2022, fol-
lowing the authorization of the Food and Drug Administration, the
Centers for Disease Control and Prevention recommended the
updated COVID-19 booster vaccines by Pfizer-BioNTech and Mod-
erna against Omicron BA.4 and BA.5 variants.
14
In this setting, the
goal of this study was to provide specific evidence on the VTE risk of
COVID-19 vaccines in the United States in patients with known
thrombophilia.
2|METHODS
COVID-19 vaccinated patients ≥18 years of age were identified using
electronic medical records across the Mayo Clinic enterprise between
November 1, 2020 and November 1, 2021. Demographics and medi-
cal comorbidities were extracted using International Classification of
Diseases (ICD) 10th revision and Charlson Comorbidity Scores were
calculated. The primary outcome was time to imaging confirmed
(using a validated natural language processing algorithm) acute VTE
(upper or lower deep vein thrombosis or pulmonary embolism) occur-
ring 90 days before and after the date of the first vaccine dose. Com-
plete methods have been previously described.
3
Laboratory genetic
testing results for Factor V Leiden (FVL) and prothrombin gene muta-
tion (PGM) were extracted, and patients were considered positive if
heterozygous or homozygous mutation(s) were present or if an
ICD-10 code was present (D68.51 or D68.52). Patients with other
congenital (e.g., Protein C, S, or antithrombin deficiencies) or acquired
thrombophilia (e.g., antiphospholipid syndrome) were also identified
using ICD-10 codes (D68.5, D68.51, D68.52, D68.59, D68.61,
D68.62, D68.69) and included if the code was used greater than two
times and more than 90 days apart. Patients positive for more than
one thrombophilia were grouped with the “stronger”thrombophilia
for analysis purposes. Due to the complexities in the diagnosis of anti-
phospholipid antibody syndrome (APS) and the uncertain accuracy of
using ICD-10 codes, a random sample of 100 patients determined to
have APS by the ICD-10 criteria were analyzed by chart review.
Among these patients, the diagnosis of APS was confirmed by chart
review in 78 (i.e., 78% specificity). The most common false positive
was due to patients with a positive lupus anticoagulant without
clinical criteria that would be consistent with APS (coded as “lupus
anticoagulant syndrome”).
The date of first vaccination was the index date for further time-
to-event analyses in the prevaccination and postvaccination 90-day
timeframes. Fischer's exact test was used to compare categorical vari-
ables with few outcomes, otherwise Pearson chi-squared was used.
VTE events were initially compared in the postvaccination timeframe
in patients with any thrombophilia or no thrombophilia. Kaplan–Meier
curves were made showing the time to first VTE in patients with any
versus no thrombophilia in the postvaccination timeframe as well as
among only patients with thrombophilia examining the prevaccination
versus postvaccination timeframes. Cox proportional hazard models
were used to calculate unadjusted and adjusted hazard ratios (HR).
Covariates in the adjusted model included age at index date, sex
(male/female), race (White/non-White), Charlson Comorbidity Score
(without age), history of arterial or VTE, atrial fibrillation, and vaccine
type (Janssen, Pfizer, or Moderna). Anticoagulation status was not
available. Cox proportional hazard models were then used to compare
the prevaccination and postvaccination timeframes within the group
of patients found to have thrombophilia using reversed person-time in
the prevaccination 90 days. Adjusted Cox models were performed
with covariates of surgery, hospital admission, and COVID-19 infec-
tions that might have differed in the prevaccination and postvaccina-
tion timeframes.
3|RESULTS
Among 792 010 patients with at least one COVID-19 vaccination
(Pfizer, n=452 950, Moderna, n=290 607, and Janssen [Johnson &
Johnson], n=48 453), 2189 had abnormal genetic testing for FVL or
PGM; 1765 were hetero/homozygous for FVL, and 484 were hetero/
homozygous for PGM. A total of 3762 patients had ICD-10 diagnostic
codes for FVL or PGM (n=4440 with ICD-10 or genetic testing for
FVL or PGM). A diagnosis of antiphospholipid syndrome (before vacci-
nation) was present in 1021 patients (0.13%) and a diagnosis of pri-
mary or other thrombophilia was present in 686 patients (0.09%).
Patients with thrombophilia were more likely to be white (95.4%
vs. 86.8%, p< .001; Table 1), female (61.8% vs. 55.1%, p< .001), older
(mean age 59.0 vs. 56.8, p< .001), and had higher Charlson Comorbid-
ities Scores (2.62 vs. 1.35, p< .001).
In the 90 days after COVID-19 vaccination, VTE occurred more
frequently in patients with any thrombophilia compared to patients
without thrombophilia (0.64% vs. 0.10%, p< .001) (Figure 1). The
unadjusted HR comparing patients with any thrombophilia to those
without thrombophilia was 6.72 (95% confidence interval [CI]: 4.87–
9.27) which varied by type of thrombophilia (APS: HR: 4.08, 95% CI:
1.53–10.90; FVL of PGM: HR: 6.72, 95% CI: 4.61–9.79; other throm-
bophilia: HR: 10.71, 95% CI: 5.09–22.54) Comparing patients with
any thrombophilia to those without in an adjusted analysis including
age, sex, race, the Charlson Comorbidity Index (without age), type of
vaccine, atrial fibrillation, and history of venous or arterial thrombo-
embolism decreased the HR to 2.58 (95% CI: 1.83–3.64)
HOUGHTON ET AL.567
demonstrating an inherently higher risk for VTE in this population
(due to their thrombophilia). The adjusted HRs for specific types of
thrombophilias also demonstrated an increased rate of VTE compared
to patients without thrombophilia (APS HR: 1.33, 95% CI: 0.49–3.59;
FVL or PGM HR: 3.12, 95% CI: 2.11–4.63; other thrombophilia 2.20,
95% CI: 1.03–4.70). In the multivariable Cox models comparing those
with thrombophilia to those without thrombophilia in the postvacci-
nation 90 days, atrial fibrillation was associated with a lower risk for
VTE (HR: 0.74, CI: 0.59–0.92), presumably due to anticoagulation
effect. A history of VTE on the other hand was associated with an
increased risk for VTE (HR: 2.47, CI: 1.92–3.18).
To understand whether COVID-19 vaccination itself increased
the risk of VTE in patients with thrombophilia, we compared the rates
of VTE in the 90 days after vaccination to the 90 days before vaccina-
tion only among patients with thrombophilia (Figure 2). There was a
total of 39 VTE events after vaccination compared to 51 VTE events
before vaccination (0.64% vs. 0.84%, p=.20). In patients with FVL or
PGM, VTE occurred in 27 patients in the 90 days before vaccination
and in 29 patients after vaccination (0.61% vs. 0.65%, p=.79). Among
those with confirmed FVL or PGM genetic testing, VTE occurred in
16 patients (0.73%) prior to vaccination and in 16 patients (0.73%)
after vaccination (p=1.0). In patients with APS, VTE occurred in six
patients before vaccination and four patients after vaccination (0.59%
vs. 0.39%, p=.40). In patients with other thrombophilia VTE occurred
in 20 patients (2.3%) before vaccination and 9 patients (1.3%) after
vaccination (p=.04). Among patients with any type of thrombophilia,
the unadjusted Cox proportional hazard model comparing the rate of
VTE in the postvaccination 90 days was compared to the prevaccina-
tion 90 days and demonstrated no increased risk of VTE postvaccina-
tion (HR: 0.77, 95% CI: 0.51–1.17). Adjusting for surgeries, hospital
TABLE 1 Baseline characteristics of COVID-19 vaccinated patients with and without thrombophilia diagnosis.
Any thrombophilia (n=6067) No thrombophilia (n=785 943) pValue
Age, mean (SD) 59.0 (16.5) 56.8 (18.3) <.0001
Female, n(%) 3748 (61.8) 432 640 (55.1) <.0001
Race, White, n(%) 5785 (95.4) 682 156 (86.8) <.0001
COVID-19 vaccine type .001
Janssen (J&J) 303 (5.0) 48 150 (6.1)
Moderna 2246 (37.0) 288 361 (37.0)
Pfizer 3518 (58.0) 449 432 (57.2)
Charlson Comorbidity Index, mean (SD) 2.62 (3.01) 1.35 (2.24) <.0001
Cancer, n(%) 1184 (19.5) 106 015 (13.5) <.0001
Cancer w/ metastasis, n(%) 151 (2.5) 13 010 (1.66) <.0001
Cerebrovascular accident, n(%) 845 (13.9) 25 742 (3.3) <.0001
Myocardial infarction, n(%) 246 (4.1) 13 357 (1.7) <.0001
Atrial fibrillation, n(%) 825 (13.6) 49 054 (6.24) <.0001
Prior arterial thromboembolism, n(%) 225 (3.7) 3022 (0.38) <.0001
Prior venous thromboembolism, n(%) 2560 (42.2) 22 736 (2.9) <.0001
FIGURE 1 Rates of venous thromboembolism in patients with
(solid line) and without (dotted line) thrombophilia. FIGURE 2 Rates of venous thromboembolism in patients with
thrombophilia before (dotted line) and after (solid line) COVID-19
vaccination.
568 HOUGHTON ET AL.
admissions, and COVID-19 infections in each timeframe did not
change the results (HR: 0.81, 95% CI: 0.53–1.23).
Sensitivity analyses were performed in the prevaccination versus
postvaccination timeframes among those with any thrombophilia
excluding patients with any history of venous or arterial thromboem-
bolism (not including myocardial infarction or ischemic CVA). Three
thousand eleven patients with any thrombophilia were evaluated and
there were 25 VTE events pre and 20 VTE events postvaccination
(0.83 vs. 0.66%, p=.56). Next, VTE events were examined only in
those with any thrombophilia and a history of VTE (n=2560) and
there were 24 VTE events pre and 16 VTE events postvaccination
(0.94 vs. 0.63%, p=.20). In patients with atrial fibrillation and any
thrombophilia, five VTE events occurred prevaccination and seven
VTE events occurred postvaccination (0.85% vs. 0.61%, p=.56). In
4877 patients with any thrombophilia but no cancer, the rates of VTE
remained similar in the prevaccination and postvaccination time-
frames (0.64% vs. 0.70%, p=.71). Within the subcohort of Janssen
vaccinated patients (n=48 453), 606 were found to have inherited or
acquired thrombophilia with 2 VTE events occurring before vaccina-
tion and 1 VTE event occurring after vaccination (p=1.0).
4|DISCUSSION
In this study we examined a subgroup of patients at higher risk for
VTE from inherited or acquired thrombophilia and found that there
was no increased risk for VTE that could be attributed to COVID-19
vaccination. Our findings are consistent with the results from the pre-
viously published overall cohort analysis and other published studies
that have examined VTE risk. While these results are perhaps not sur-
prising to many, patients with thrombophilia are understandably more
anxious about factors that may increase their thrombotic risk and may
require a higher burden of proof before accepting treatments/inter-
ventions. In general, patients with inherited or acquired thrombophi-
lias are more difficult to study due to their relative infrequency in the
general population, but the size of our overall cohort allowed us to
identify many patients for analysis. Since patients with thrombophilia
are by definition at higher risk for VTE, the pre/post vaccination anal-
ysis utilized in this study allowed us to account for these subgroups
unique risk by using the patients as their own control over a narrow
window of observation.
One group of particularly concern has been patients with antipho-
spholipid syndrome
15
as cases reported in some patients after vacci-
nation were found to have/or develop a lupus anticoagulant with
associated thrombosis.
16
In a survey of 161 patients with “triple-posi-
tive”APS, 146 were vaccinated and experienced no significant or
unexpected adverse events. Among patients that did not receive a
vaccination 1 was due to medical advice and 10 were due to fear of
the vaccination.
17
A study of 44 patients in Brazil with primary APS
vaccinated with Sinovac-CoronaVac had no postvaccination complica-
tions within 6 months with no evidence of significant changes in their
antiphospholipid antibodies.
18
A study in China with BBIBPCorV
among 39 patients with primary APS also showed stable antibodies
with no thrombotic events within 12 weeks.
19
In patients without
APS, there has also been no evidence that COVID-19 vaccinations are
inducing production of antiphospholipid antibodies.
20
Our data from
1021 patients with APS provides a robust assessment of VTE risk in a
larger sample and is consistent with these smaller studies indicating
no elevated VTE risk for COVID-19 vaccination in APS patients.
A limitation of our study was that the primary outcome of VTE
did not include venous thrombosis at atypical sites (cerebral vein
thrombosis or splanchnic vein thrombosis, for example) as the NLP
algorithms and imaging studies used were specific for outcomes acute
upper or lower extremity DVT and acute PE. The analysis is also lim-
ited by ICD-10 identification of patients with thrombophilia; however,
measures were employed to increase the specificity of these codes
which we favored in this analysis rather than sensitivity. We did show
in an analysis of patients with thrombophilia compared to without
thrombophilia that we did successfully identify a population of
patients with an inherently higher risk for VTE. Manual chart review
did confirm reasonable specificity for the diagnosis of APS. Due to the
smaller sample size of patients vaccinated with Janssen vaccine,
robust subgroup analyses of various thrombophilias were not possible,
but in multivariable models the specific vaccine manufacturer was not
associated with VTE outcomes. It is likely that most patients with APS
and other strong thrombophilias were on anticoagulation whereas
many patients with FVL or PGM were not. The anticoagulation status
of the patient unfortunately was not known and could not be included
in multivariable analyses. This would potentially explain why in the
multivariable model's patients with FVL or PGM had higher HRs than
the other “stronger”thrombophilias. A higher number of homozygous
and compound heterozygous patients in the sample would also be
likely compared to population-based prevalence and could also
explain the higher HR seen compared to other studies.
13
Unfortu-
nately, ICD-10 codes of these mutations do not differentiate between
homozygous and heterozygous mutations.
Due to the methods of cohort identification, methods of outcome
identification, and potential influence of anticoagulation effects, a
direct comparison of the crude rates of VTE in this study to epidemio-
logic population-based studies is limited. In our primary analysis com-
paring the postvaccination timeframe to the prevaccination timeframe
in patients with thrombophilia, the adjusted HR was 0.81 with confi-
dence intervals that crossed 1, indicating no statistically significant
difference. The lower HR in the postvaccination timeframe is similar
to the statistically significant reduction in VTE in patients with a his-
tory of VTE that has been observed in our prior analyses.
3
The smaller
sample size of patients with thrombophilia limits the statistically
power in this analysis, but we believe that these results should be
viewed favorably and may indicate a lower risk for VTE within this
subpopulation as well. It is most likely that any VTE reduction from
the vaccination would be on the account of preventing and limiting
the severity of COVID-19 infection and it is unclear if this will apply
to ongoing variants of the disease or if infection rates become very
low. Nonetheless, with updated COVID-19 vaccine boosters now
available in the United States, it is important for patients and physi-
cians to know the data to meet questions of uncertainty.
HOUGHTON ET AL.569
5|CONCLUSIONS
Given the rapid development of COVID-19 vaccinations and COVID-19
infectious related thrombotic complications as well as subsequent iden-
tification of VITT syndrome (all of which have received significant media
attention), it is understandable for some, especially patients with prior
thrombosis and/or thrombophilias, to fear COVID-19 vaccination and
want additional data. In this large group of COVID-19 vaccinated
patients with inherited or acquired thrombophilia, there was no
increased risk for acute VTE postvaccination compared to the prevacci-
nation timeframe with any of the approved vaccines in the
United States. These results are consistent with prior studies and should
offer significant reassurance to patients with thrombophilia.
AUTHOR CONTRIBUTIONS
All authors were involved in the conception and design or analysis
and interpretation of the data, drafting of the manuscript or revising it
critically, and read and approved the final manuscript.
ACKNOWLEDGMENTS
This publication was made possible through the support of the
Eduardo G. Mestre and Gillian M. Shepherd, MD, Clinician Career
Development Award Honoring John T. Shepherd, MD.
CONFLICT OF INTEREST STATEMENT
Anand Padmanabhan reports financial relationships with: Equity own-
ership (Retham Technologies), Advisory board (Veralox Therapeutics),
Patents/Royalty (Mayo Clinic, Versiti, Retham Technologies). Meera
Sridharan has received consultant fees as part of an advisory board
for Alexion Pharmaceutical. Other authors declare no conflict of
interest.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.
ORCID
Damon E. Houghton https://orcid.org/0000-0002-6065-9523
Waldemar E. Wysokinski https://orcid.org/0000-0002-8119-6206
Leslie J. Padrnos https://orcid.org/0000-0002-1788-4944
Surbhi Shah https://orcid.org/0000-0003-0978-5687
Ewa Wysokinska https://orcid.org/0000-0003-4351-8734
Meera Sridharan https://orcid.org/0000-0001-7225-8228
Robert D. McBane https://orcid.org/0000-0001-8727-8029
Anand Padmanabhan https://orcid.org/0000-0003-2519-4377
Ana I. Casanegra https://orcid.org/0000-0001-6114-4284
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How to cite this article: Houghton DE, Wysokinski WE,
Padrnos LJ, et al. Venous thromboembolism after COVID-19
vaccination in patients with thrombophilia. Am J Hematol.
2023;98(4):566‐570. doi:10.1002/ajh.26848
570 HOUGHTON ET AL.
