EXCEPTIONAL CASE REPORT
EXCEPTIONAL CASE REPORT

A case of thrombocytopenia and multiple thromboses after vaccination
with ChAdOx1 nCoV-19 against SARS-CoV-2

Anne Louise Tølbøll Sørensen,1 Magalie Rolland,2 Jacob Hartmann,3 Zitta Barrella Harboe,2,4 Casper Roed,2 Tomas Ø. Jensen,2
Lilian Kolte,2 Daniel El Fassi,1,4 Jens Hillingsø,5 Aneta Radziwon-Balicka,6 Robert Sebastian Soyka,7 Klaus Hansen,8 Nikolai Kirkby,9
Jens P. Goetze,10 Mikkel Gybel-Brask,11 Eva Birgitte Leinøe,1 Anne-Mette Hvas,12,13 Peter Kampmann,1 and Jakob Stensballe11,14

1Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 2Department of Pulmonary Medicine and Infectious Diseases and
3Department of Emergency Medicine, University Hospital of Copenhagen, North Zealand, Denmark; 4Department of Clinical Medicine, University of Copenhagen, Copenhagen,
Denmark; 5Department of Surgery and Transplantation, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 6Department of Clinical Biochemistry and
7Department of Neurology, University Hospital of Copenhagen, North Zealand, Denmark; 8Department of Neurology, 9Department of Clinical Microbiology, 10Department of
Clinical Biochemistry, and 11Section of Transfusion Medicine, Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark;
12Department of Clinical Biochemistry and 13Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; and 14Department of Anaesthesiology, Copenhagen
University Hospital, Rigshospitalet, Copenhagen, Denmark

Key Points

(cid:1) We describe a 30-

year-old woman who
developed thrombocy-
topenia and multiple
thromboses after she
received the
ChAdOx1 nCoV-19
vaccine.

(cid:1) A maximum 4T HIT
score and a positive
immunoassay for anti-
PF4 antibodies
indicated autoimmune
HIT as a potential
pathogenic
mechanism.

Recently, reports of severe thromboses, thrombocytopenia, and hemorrhage in persons

vaccinated with the chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19,

AZD1222, Vaxzevria; Oxford/AstraZeneca) against severe acute respiratory syndrome

coronavirus 2 have emerged. We describe an otherwise healthy 30-year-old woman who

developed thrombocytopenia, ecchymosis, portal vein thrombosis, and cerebral venous

sinus thrombosis the second week after she received the ChAdOx1 nCoV-19 vaccine.

Extensive diagnostic workup for thrombosis predispositions showed heterozygosity for

the prothrombin mutation, but no evidence of myeloproliferative neoplasia or infectious

or autoimmune diseases. Her only temporary risk factor was long-term use of oral

contraceptive pills (OCPs). Although both the prothrombin mutation and use of OCPs

predispose to portal and cerebral vein thrombosis, the occurrence of multiple

thromboses within a short time and the associated pattern of thrombocytopenia and

consumption coagulopathy are highly unusual. A maximum 4T heparin-induced

thrombocytopenia (HIT) score and a positive immunoassay for anti-platelet factor
4/heparin antibodies identified autoimmune HIT as a potential pathogenic mechanism.
Although causality has not been established, our case emphasizes the importance of

clinical awareness. Further studies of this potentially new clinical entity have suggested

that it should be regarded as a vaccine-induced immune thrombotic thrombocytopenia.

Introduction

In the midst of the COVID-19 pandemic, several national health authorities across Europe decided to
the chimpanzee adenovirus-vectored vaccine1 (ChAdOx1nCoV-19,
pause the administration of
AZD1222; Vaxzevria; Oxford/AstraZeneca) for severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2), after sporadic reports of severe cases of thrombocytopenia, bleeding, or thrombosis invacci-
nated individuals.2 We present a likely case and elaborate on the diagnostic and clinical course. This
report is in accordance with the principles of the Declaration of Helsinki.

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Submitted 5 April 2021; accepted 22 April 2021; published online 17 June 2021.
DOI 10.1182/bloodadvances.2021004904.

(cid:1) 2021 by The American Society of Hematology

22 JUNE 2021 (cid:129) VOLUME 5, NUMBER 12

2569

Case description and results

A 30-year-old woman presented with a 3-day history of headache
and general malaise. Her medical history included migraine and her
only regular medication was a third-generation (low thrombosis risk)
estrogen/progestin oral contraceptive pill (OCP) taken for years.
She had no history of autoimmune disease, venous thromboembo-
lism, bleeding, or known genetic predisposition thereto and no prior
exposure to heparin. She was prioritized for vaccination because of
occupational risk of SARS-CoV-2 infection and received the first
dose of ChAdOx1 nCoV-19 8 days before the onset of symptoms.
Findings in her physical examination were unremarkable, and her
body mass index was 22 kg/m2. She tested negative for SARS-
CoV-2. Blood tests revealed thrombocytopenia (51 3 109/L), but
no other remarkable findings (Table 1). Results of noncontrast com-
puted tomography (CT) scan of the head were normal. Migraine
treatment improved her symptoms, and she was discharged with re-
ferral to the hematology outpatient clinic.

Two days later, she was readmitted for persistent headache and oc-
currence of ecchymosis. Blood tests showed thrombocytopenia and
consumption coagulopathy with low levels of fibrinogen, high D-di-
mer, and marginally increased alanine aminotransferase (Figure 1).
Thrombelastography demonstrated normal clot
initiation, but de-
creased clot amplification and strength, reflecting decreased throm-
low levels of fibrinogen, and reduced platelet
bin generation,
function. A peripheral blood smear showed normal red blood cell
morphology without the presence of schistocytes and a normal
white blood cell count, but a reduced number of normal-sized plate-
lets, including a few platelet aggregates.

Magnetic resonance imaging of the head with venogram ruled out
intracranial pathology,
including cerebral venous sinus thrombosis
(CVST). Analysis of the cerebrospinal fluid ruled out meningitis.

On clinical suspicion that the rare prothrombotic disorder being re-
ported was associated with the ChAdOx1 nCoV-19 vaccine, pro-
phylaxis with tinzaparin 4500 IU once daily was initiated.

Because of the coagulopathy, extended examination for thrombosis
was performed. Duplex ultrasonography of the lower extremities and
CT pulmonary angiography produced normal results. In contrast, du-
plex ultrasonography of the abdomen and confirmatory CT abdomi-
nal angiography demonstrated portal vein thrombosis. Anticoagulant
treatment was intensified to tinzaparin 100 IU/kg twice daily, fibrino-
gen substitution targeting 100 mg/dL was given at a single occa-
level of fibrinogen to prevent
sion initially to ensure a noncritical
bleeding, and the patient was transferred to a tertiary hospital,
where extended laboratory workup, including anti-platelet factor 4/
heparin (anti-PF4) antibody testing, was initiated upon arrival.

During the following 2 days, the symptoms improved in parallel with
a gradual increase in platelet counts and improvement of coagulation
parameters (Figure 1). Repeated ultrasonography showed no pro-
gression of the portal vein thrombosis. On the third day after initiation
of therapeutic tinzaparin treatment the headache intensified, and ce-
rebral CT venography demonstrated newly developed CVST. There
were no signs of cerebral venous stasis, infarction, or bleeding. Risk
scoring by the 4T HIT scale gave a maximum score of 8 and thus a
high probability of autoimmune heparin-induced thrombocytopenia
(aHIT).3 Accordingly, tinzaparin was replaced with fondaparinux 7.5
mg once daily, and the dose was increased 2 days later to 5 mg
twice daily, based on anti-factor Xa monitoring.4 The patient was

discharged after 15 days of hospitalization where rivaroxaban was
prescribed upon discharge. Follow-up CT venography demonstrated
regression of the CVST and portal vein thrombosis, and the patient
recovered without major sequelae, although dizziness and light head-
ache persisted.

Blood tests showed no signs of hemolysis, repeated peripheral blood
smears were without the presence of schistocytes, a direct anti-globulin
test was negative, and normal activity of ADAMTS13 (1.07 kIU/L) ruled
out thrombotic thrombocytopenic purpura. The blood type was O RhD-
positive. Increased levels of both factor VIII and von Willebrand factor
were detected, consistent with signs of endothelial cell activation.

Assessment for inherited and acquired thrombophilia including mye-
loproliferative neoplasia, analyzed by an in-house myeloid malignancy
gene panel using targeted next-generation sequencing, showed het-
erozygosity for the prothrombin G20210A mutation; otherwise. no
variants were found (Table 1).

Anti-nuclear antibodies and anti-neutrophil cytoplasmatic antibodies
were negative. Complement screening analysis (Complement Sys-
tem Screen WIESLAB; Euro-Diagnostica, Malm€o, Sweden) demon-
strated severely decreased activation of the classic pathway and
slightly decreased activation of the lectin pathway, consistent with
antibody-mediated consumption of complement proteins. Concen-
trations of complement C3 and C4 were within normal range.

Anti-platelet antibodies were detected against glycoprotein GPIIb-
IIIa and GPIa-IIa but were inconclusive regarding human platelet–
specific antibodies (Pak Lx Assay; Immucor, Waukesha, WI).

The HLA-type was A32,33; B14,44; C04,08; DRB1*01,11;
DQB1*03:01,05; and DPB1*02:01,04:01 (polymerase chain reac-
tion; QTYPE SSP; CareDX, Stockholm, Sweden). An extensive in-
fectious disease workup was performed and returned negative
results (Table 1).

At day 22 after vaccination, an enzyme-linked immunosorbent assay
confirmed the presence of IgG antibodies to PF4-polyanion com-
plexes, as indicated by an optical density of 2.2 (upper limit of nor-
mal, %0.4 (LIFECODES PF4 IgG by Immucor, Norcross, Georgia).5
A heparin-induced platelet activation assay was negative. The blood
test for the anti-PF4 assay was performed 36 hours after initiation of
tinzaparin.

Discussion

We report a case of a previously healthy young woman who pre-
sented with thrombocytopenia, ecchymosis, consumption coagulop-
athy, portal vein thrombosis, and a CVST the second week after
administration of the ChAdOx1 nCoV-19 vaccine. An extensive di-
agnostic workup showed heterozygosity for the prothrombin muta-
tion, which increases risk of venous thrombosis by (cid:3)1.5-fold,6 with
a further increase in risk when the vaccine is used in combination
with OCP,7 although this risk decreases with duration of use and
choice of third-generation OCPs.8 We found no evidence of myelo-
proliferative neoplasia or infectious or autoimmune disease. Both
prothrombin mutation and use of OCP predispose to portal vein
thrombosis and CVST, but the occurrence of several thromboses
within a short time, despite therapeutic anticoagulation, and the as-
sociated pattern of thrombocytopenia and consumption coagulop-
athy, are unusual and support the notion of a highly prothrombotic

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TØLBØLL SØRENSEN et al

22 JUNE 2021 (cid:129) VOLUME 5, NUMBER 12

Table 1. Laboratory results of a patient presenting with thrombocytopenia and multiple thromboses after vaccination with ChAdOx1
nCoV-19

Hematology

Hemoglobin, g/dL (ref., 11.8-15.3)

Platelets, 3109/L (ref., 145-390)

Platelets, citrate, 3109/L (ref., 145-390)

Leukocytes, 3109/L (ref., 3.-8.8)

Basophils, 3109/L (ref., 0.01-0.10)

Eosinophils, 3109/L (ref., 0.01-0.5)

Monocytes, 3109/L (ref., 0.2-0,80)

Neutrophils, 3109/L (ref., 1.6-5.9)

Lymphocytes, 3109/L (ref., 1.0-3.5)

D-dimer, mg/L FEU (ref., ,0.5)

CRP, mg/L (ref., ,10)

Hemostasis

INR

Clotting factors II, VII, X (ref., .0.60)

aPTT, s (ref., 25-37)

Plasma fibrinogen, mg/dL (ref., 180-350)

ADAMTS13 protein, kIU/L (ref., 0.61-1.31)

Thrombophilia

Homocysteine, mmol/L (ref., ,15.0)

Antithrombin, 3103IU/L (ref., 0.83-1.15)

Protein C, 3103 IU/L (ref., 0.70-1.30)

Protein S, 3103 IU/L (ref., 0.57-1.30)

Factor V Leiden R506Q mutation

Prothrombin gene mutation (G20210A)

Lupus anticoagulant

Cardiolipin IgG/IgM, 3103 IU/L (ref., ,10.0)

b-2-GP1 IgG/IgM, kU/L (ref., 0-10)

Organ marker

ALT, U/L (ref., 10-45)

Serology

SARS-CoV-2, spike protein IgG, AU/mL (ref., 34-280)

SARS-CoV-2, nucleoprotein IgG (ref., ,1.0)

Cytomegalovirus IgG/IgM

Ebstein-Barr virus IgG/IgM

Hepatitis A, hepatitis B s-Ab/s-Ag, hepatitis C

HIV1 and HIV2 (Ag1Ab)

Parvovirus B19 IgG /IgM

Polymerase chain reaction

SARS-CoV-2 (oropharyngeal swab)

Influenza type A1B, adenovirus, metapneumovirus, parainfluenza, respiratory
syncytial virus and rhinovirus (oropharyngeal swab)

Bacterial and viral meningitis panel (cerebrospinal fluid)†

11

14

15

16

17

18

19

13.4

13.9

57

39

11.0

0.05

0.27

0.98

6.25

3.42

—

36

1.0

0.91

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

56

46

11.0

0.07

0.20

0.71

4.51

5.61

.20

19

1.0

1.01

38

78

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

Neg

—

Neg

13.7

70

11.0

0.07

0.36

1.13

4.45

4.99

12

14

1.0

1.11

39

85

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

12.3

88

10.3

0.11

0.51

1.10

6.10

4.93

5.9

18

1.0

1.05

36

139

1.07

6.2

0.95

1.20

0.85

Not detected

Heterozygous

NA*

2.2/2.5

,0.6 /,0.9

20.8

,0.070

Pos/neg

Pos/neg

Pos/neg

Neg

Neg

Neg

Neg

—

11.6

119

12.1

0.06

0.71

0.88

4.02

5.26

4.1

21

1.0

0.99

38

176

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

11.5

159

10.8

187

10.1

9.1

1.6

26

1.1

0.90

40

244

1.2

22

1.0

0.97

43

244

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

29

61

134

123

115

95

0.99

1.03

1.04

1.13

1.12

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Ab, antibody, Ag, antigen; ALT, alanine aminotransferase; anti-MPO, anti-myeloperoxidase; anti-PR3, anti-proteinase 3; aPTT, activated partial thromboplastin time; CRP, C-reactive

protein; FEU, fibrinogen equivalent units; INR, international normalized ratio; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

*Lupus anticoagulant could not be assessed because of the heparinization of the blood.
†No growth on cultures, and PCR testing for a panel of 14 pathogens was negative (BioFire FilmArray Meningitis-Encephalitis (ME) Panel; bioM(cid:2)erieux).

22 JUNE 2021 (cid:129) VOLUME 5, NUMBER 12

MULTIPLE THROMBOSES WITH ChAdOx1 nCoV-19 VACCINE 2571

Table 1. (continued)

Immunology

C3, g/L (ref., 0.811-1.570)

C4, g/L (ref., 0.129-0.392)

Antinuclear IgG (ref., ,0.1)

Anti–double-stranded DNA IgG, kIU/L (ref., , 10)

Anti-Smith, anti-(U1) snRNP, anti-SSA, anti-SSB, anti-scl-70, anti-Jo1,
anti-MPO, anti-PR3, anti-glomerular basement membrane,
and immunoglobulin G

11

14

15

16

17

18

19

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

1.42

0.345

0.1

3.7

Neg

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

Ab, antibody, Ag, antigen; ALT, alanine aminotransferase; anti-MPO, anti-myeloperoxidase; anti-PR3, anti-proteinase 3; aPTT, activated partial thromboplastin time; CRP, C-reactive

protein; FEU, fibrinogen equivalent units; INR, international normalized ratio; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

*Lupus anticoagulant could not be assessed because of the heparinization of the blood.
†No growth on cultures, and PCR testing for a panel of 14 pathogens was negative (BioFire FilmArray Meningitis-Encephalitis (ME) Panel; bioM(cid:2)erieux).

state. Finally, the finding of anti-PF4 antibodies in a patient without
prior heparin exposure entails other potential explanations.

HIT is an acquired prothrombotic disorder characterized by throm-
bocytopenia, coagulopathy, and a high risk of thrombosis9,10 that is
induced by antibodies targeting neoepitopes formed by the binding
of PF4 to heparin.11,12 Binding of these immune complexes to plate-
let FcgRIIa receptors leads to platelet activation, degranulation, NE-
Tosis, and endothelial activation, further aggravated by activation of
the complement system.13

Autoimmune HIT, or spontaneous HIT, refers to a disorder clinically
and serologically indistinguishable from HIT, but without prior expo-
sure to heparin.14-16 The pathophysiological background is incom-
pletely understood, but it is hypothesized to be caused by other
polyanions complexing with PF4-forming antigens to which anti-
PF4/polyanion antibodies can bind. Several case reports have de-
scribed aHIT caused by nonheparin triggers.17-19

A maximum 4T HIT risk score gave a high predicted probability of
HIT, and the demonstration of anti-PF4 antibodies by an

Third visit to E D w/headache + ecchy m osis
RI-H ead with veno gra m without C V S T
S econd visit to E D w/headache
First visit to E D w/headache
A d mitted to hospital,

A b d o mianal U S and C T angio sho w p ortal
thro m b osis. Pt(cid:2) transferred to tertiary facility
C T-H ead with veno gra m sho w s C V S T
Increasing headache,

A nti-P F 4/heparin antib o dy E LIS A p ositive
regression of C V S T and p ortal thro m b osis
C T-head/sho w s unchanged C V S T and
sp ontaneous bleeding fro m oral cavity 
Discharged in g oo d condition with
HIP A negative (collected day 1 7)
Visit to E D due to self-limiting
regression of p ortal thro m b osis

R ead mittied to prim ary hospital w/headache
C T-H ead sho w s further regression of C V S T
O ut-patient ap p ointm ent
w/headache and dizziness

35

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30

25

20

15

10

5

0

-5

Tinzaparin
4500 IU (cid:2)(cid:3)1

Tinzaparin
100 IU/kg (cid:2)(cid:3)2

Fondaparinux
7,5 mg (cid:2)(cid:3)1

Fondaparinux
5 mg (cid:2)(cid:3)2

Rivaroxaban 15 mg (cid:2) 2 for 21 days,
followed by 20 mg (cid:2)(cid:3)1

11 12 13 14 15 16 17 18 19 20 21 22 23

24 25 26 27 28 29 30 31 32 33 34 35 36

Days after vaccination

Platele count

Fibrinogen

D-dimer

Figure 1. Timeline from presentation of first symptoms 8 days after vaccination with the ChAdOx1 nCoV-19 vaccine to outpatient postvaccination follow-
up day 35. Serial coagulation test results are shown: platelet counts, D-dimer, and fibrinogen. Time points for the result of the anti-PF4 antibody test and key clinical events,
including timing of thrombosis events and changes in anticoagulant treatment, are also shown. ED, emergency department; MRI, magnetic resonance imaging; ELISA,
enzyme-linked immunosorbent assay; HIPA, heparin-induced platelet activation; FEU, fibrinogen equivalent units.

2572

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22 JUNE 2021 (cid:129) VOLUME 5, NUMBER 12

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300

250

200

150

100

50

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immunoassay supported the diagnosis aHIT. The HLA-types
DRB1*11 and DQB1*03:01 are associated with an increased risk
of thrombocytopenic thrombotic purpura, and DRB1*11 is tightly
linked to DRB3*01:01, identified as a potential risk factor for the de-
velopment of HIT.20

Anticoagulant treatment with tinzaparin (100 IU/kg twice daily) was
continued from day 17 to 19 after vaccination, despite suspicion of
aHIT, as the clinical condition improved. Laboratory analyses in paral-
lel showed normalization of platelet counts and improvement of the
coagulopathy, and ultrasonography demonstrated no progression of
the portal vein thrombosis (Figure 1). Tinzaparin was prioritized over al-
ternatives (argatroban, fondaparinux, or direct oral factor Xa inhibitors)
because of the estimated high risk of hemorrhage. Hence, use of an
anticoagulant with a short half-life in combination with ease of adminis-
tration outside of an intensive care unit was preferable. At the time of
CVST diagnosis on day 19 after vaccination, monitoring of anti-factor
Xa activity demonstrated levels in the lower therapeutic range, tinza-
parin was deemed insufficient, and anticoagulant
treatment was
promptly switched to fondaparinux with a higher anti-Xa potency and
casuistic use in HIT.4,21 The presence of anti-PF4 antibodies was con-
firmed on day 22 after vaccination by an immunoassay.

Intravenous immunoglobulin has been proposed to be a potentially
beneficial treatment of aHIT.15 Given the small
increased risk of
thromboembolism associated with intravenous immunoglobulin,22
the predominantly prothrombotic state of the patient, and a recover-
ing platelet count, this treatment was withheld.

Our data demonstrate activation of the classic pathway of the com-
plement system. Complement cascade activation has been de-
scribed as pathogenic in HIT,13 and modulation thereof by inhibition
of C1 or C5 could represent a putative target for therapeutic inter-
vention in refractory aHIT.23

Although causality has not been established, our case emphasizes
the importance of undertaking further studies to characterize this po-
tentially new clinical entity recently described with the suggested
name of vaccine-induced immune thrombotic thrombocytope-
nia.24,25 It is important that clinicians be alert to this syndrome

References

characterized by thrombosis at unusual sites, thrombocytopenia,
and coagulopathy with risk of bleeding needing prompt attention.

Authorship

Contribution: A.L.T.S., M.R., J.H., Z.B.H., C.R., T.Ø.J., D.E.F., E.B.L.,
M.G-B., and J.S. analyzed and interpreted the data and wrote the
manuscript; and L.K. J.H., A.R.-B., R.S.S., K.H., N.K., J.P.G., A.-M.H.,
and P.K. analyzed and interpreted the data.

Conflict-of-interest disclosure: A.L.T.S. is a former employee of
Novo Nordisk Biopharm and has received honoraria for lecture from
Takeda and advisory board honoraria from SOBI (both not related
to the present case). Z.B.H. received an unrestricted research grant
from the Independent Research Fund Denmark (not related to the
present case), and received travel expenses for attending a medical
conference from Pfizer. C.R. has received travel expenses for at-
tending medical conferences from Pfizer and MSD. L.K. has re-
ceived an honorarium for a lecture on pneumococcal disease from
MSD. J.H. receives consulting fees for Novo Nordisk on drug deliv-
ery. E.B.L. has received honoraria from Amgen for a lecture on im-
mune thrombocytopenia (not related to present case). A.-M.H. has
received an unrestricted research grant from CSL Behring (not relat-
ed to the present case) and has received honoraria for lectures
from CSL Behring, Bayer, Astellas, and Boehringer-Ingelheim. P.K.
has received honoraria for lectures from uniQure and Takeda and
travel expenses for attendance at medical conferences from uni-
Qure. The remaining authors declare no competing financial
interests.

ORCID profiles: A.L.T.S., 0000-0003-4537-2505; J.H., 0000-
0003-0829-2645; Z.B.H., 0000-0001-5552-0095; T.Ø.J., 0000-
0003-0398-4431; D.E.F., 0000-0001-8226-1658; A.R.-B., 0000-
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Correspondence: Casper Roed, Department of Pulmonary Medi-
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North Zealand, Dyrehavevej 29, 3400 Hillerod, Denmark; e-mail:
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