Arteriosclerosis, Thrombosis, and Vascular Biology

ATVB IN FOCUS:
Thromboinflammation and Infection
Series Editors: Katsue Suzuki-Inoue and Elizabeth Gardiner

Updates in the Incidence, Pathogenesis,

and Management of Cancer and Venous
Thromboembolism
Laura Girardi , Tzu-Fei Wang , Walter Ageno , Marc Carrier

ABSTRACT: Patients with cancer are at higher risk of developing venous thromboembolism (VTE) compared with the general
population. This elevated risk is due to several risk factors and multiple, overlapping thrombotic and hemostatic pathophysiological
pathways that are specific to this patient population. Hence, the management of cancer-associated VTE can be challenging for
clinicians. Patients with cancer-associated VTE are at higher risk of both recurrent events despite anticoagulation and bleeding
complications due to the anticoagulant regimens. Direct oral anticoagulants have recently been shown to be effective, safe, and
more convenient than parenteral low-molecular-weight heparin for the management of cancer-associated VTE. Despite these
recent advances in anticoagulant therapy, many unmet needs remain in these patients (increased risk of bleeding with specific
cancer types, drug-drug interactions, liver dysfunction). Factor XI inhibitors are currently being assessed for the management of
cancer-associated VTE and may help clinicians address these important knowledge gaps.
GRAPHIC ABSTRACT: A graphic abstract is available for this article.
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Key Words: anticoagulants ◼ hemorrhage ◼ neoplasms ◼ venous thromboembolism ◼ venous thrombosis

P
atients with cancer are known to be at high risk
of both arterial and venous thromboembolic (VTE)
events, which is associated with significant mor-
bidity and previously reported as the second leading
cause of death in this patient population.1 VTE is the
most common thrombotic complication in patients with
cancer.2 The risk of developing VTE in patients with
cancer is increased by 12-fold compared with patients
without cancer.3 It is estimated that up to 20% of
patients with cancer will be affected by VTE, with the
highest risk periods associated with hospitalizations
and the development of metastatic disease.4 The pur-
pose of this narrative review is to summarize the inci-
dence and clinical significance of VTE in patients with
cancer, outline the importance of the pathogenesis,
review the evidence on the management of VTE and
highlight unmet needs that will drive further research
in this patient population.
Please see www.ahajournals.org/atvb/atvb-focus for all
articles published in this series.
INCIDENCE AND RISK FACTORS FOR
CANCER-ASSOCIATED VTE
Cancer-associated VTE (CAT), which mainly includes VTE
with upper- or lower-extremity deep vein thrombosis and
pulmonary embolism, is a common complication among
patients with cancer.5 The 6-month VTE risk in patients
with cancer is up to 12-fold higher than in the general
population and up to 23-fold higher in patients with can-
cer receiving chemotherapy or targeted therapy.3 Further-
more, the cumulative incidence of CAT is increasing over
time, from 1.0% in 1997 to 3.4% in 2017, likely due to the
improved survival of patients with cancer and the increased
use of computed tomography scans leading to increased
rates of incidental pulmonary embolism diagnoses.3

Correspondence to: Marc Carrier, MD, MSc, Thrombosis Program, Department of Medicine, Division of Hematology, The Ottawa Hospital General Campus, University of
Ottawa, 501 Smyth Rd, Box 201A, Ottawa, Ontario K1H 8L6, Canada. Email mcarrier@toh.ca
For Sources of Funding and Disclosures, see page 829.
© 2023 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at www.ahajournals.org/journal/atvb

824   June 2023 Arterioscler Thromb Vasc Biol. 2023;43:824–831. DOI: 10.1161/ATVBAHA.123.318779
 Girardi et al
Nonstandard Abbreviations and Acronyms
CAT  cancer-associated venous
thromboembolism
DOAC direct oral anticoagulant
IL interleukin
LMWH low-molecular-weight heparin
PAI-1 plasminogen activator inhibitor 1
RR relative risk
sCLEC-2 soluble C-type lectin-like receptor 2
TF tissue factor
TNF tumor necrosis factor
VTE venous thromboembolism
A large observational cohort study published in 2017
has estimated the incidence of first and recurrent VTE
among patients with active cancer to be 5.8 (95% CI, 5.7–
6.0) and 9.6 (95% CI, 8.8–10.4) per 100 person-years,
respectively.6 The rates of recurrent events were indepen-
dent of the type of the index event (ie, pulmonary embo-
lism or deep vein thrombosis). The mortality risk after VTE
was also considerable, with most deaths (64.5%) occur-
ring within the first year following the CAT diagnosis.
The pathogenesis of CAT is multifactorial, and mul-
tiple risk factors have been identified, including cancer-
associated risk factors, therapy-related risk factors,
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patient-related risk factors, and the presence of certain
biomarkers.7,8 Cancer-related risk factors include can-
cer site, stage, and time since cancer diagnosis.5,9–12
The highest risk is reported to be associated with pan-
creas, brain, stomach, lung, and ovarian cancers.9,13–15 In
patients with pancreas and brain cancers, the incidences
of VTE were reported to be as high as 59 and 48 per
1000 person-years, respectively.11 Patients with breast
and prostate cancers have lower incidences with only 10
per 1000 person-years for both tumor types.11 This was
confirmed in an observational cohort study using the Cali-
fornia Cancer Registry, which also reported that the high-
est 2-year cumulative incidence of VTE was in patients
with cancers of the pancreas (12%), brain (12%), ova-
ries (9.3%), and lung (7.6%).16 Many studies have dem-
onstrated that metastatic disease was an important risk
factor for CAT.13,17 The presence of metastatic disease
has been reported to be associated with a 1.9 increased
risk (relative risk [RR], 1.9 [95% CI, 1.6–2.3]) of VTE in
patients with different tumor types.17
Patient- and treatment-related factors also play impor-
tant roles in the development of CAT. Several traditional
risk factors for VTE have been identified in many patients
with cancer such as older age,6 ethnicity,18 history or
family history of VTE,19 comorbidities (eg, renal failure,
respiratory disease, acute infection, and obesity14), and
prolonged immobility.12 For example, Hispanic and Asian
Arterioscler Thromb Vasc Biol. 2023;43:824–831. DOI: 10.1161/ATVBAHA.123.318779
Cancer-Associated Thrombosis
Highlights
ATVB IN FOCUS - T
• Patients with cancer are at higher risk of developing
venous thromboembolism.
• The management of cancer-associated thrombosis
is challenging due to both higher risk of thrombotic
recurrences and bleeding complications compared
with general population.
• Pathophysiology of cancer-associated thrombosis is
complex but can also be a source of identifiable bio-
markers for both prevention and precision therapies.
patients with cancer have a lower 1-year incidence of VTE
complication compared with White or Black patients.20
Furthermore, concomitant prothrombotic genetic risk
factors such as factor V Leiden and non-O blood types
are also associated with CAT events.21 Chemotherapy is
also an important risk factor for CAT.21 Cisplatin-based
chemotherapy has been widely reported to increase
the risk of CAT.22 Many other systematic chemotherapy
agents (including L-asparaginase, thalidomide, lenalido-
mide) have been shown to increase the risk of arterial
and venous thrombosis.23,24 Targeted therapies including
antiangiogenic agents (eg, bevacizumab) and immune
checkpoint inhibitors have also been shown to increase
the risk of thromboembolism.25,26 It remains unclear
whether the underlying risk of thrombotic complication in
patients receiving targeted therapies is higher than for
those receiving chemotherapy.26 In addition to chemo-
therapy, other cancer and supportive treatment modalities
are proved to substantially increase the thrombotic poten-
tial. Surgery, hormonal therapy, erythropoiesis-stimulating
agents, blood transfusions, and central venous catheters
are all reported to be associated with an increased risk.1,7
Although VTE incidence varies per cancer type and
stage, it seems to be associated with an increased risk of
mortality independent of the cancer characteristics.16,27
A population-based case-control study has reported that
the 1-year survival was significantly lower in patients
with CAT compared with patients with cancer without
VTE (12% versus 36%).27 Another observational study
has also reported a significant increase in mortality (haz-
ard ratio, 1.6–4.2; P<0.01) in patients with different
tumor types and CAT after adjusting for age, sex, can-
cer stage, and additional comorbidities.13 The heightened
underlying risk of death might be due to fatal pulmonary
embolism, major bleeding complications associated with
therapeutic anticoagulation, and is likely a measure of
biological aggressiveness of the cancer.27,28
PATHOGENESIS OF CAT
Multiple overlapping and interacting pathways explain the
increased incidence of arterial and venous thrombosis in
June 2023   825
 Girardi et al
patients with cancers. The pathogenesis of CAT seems
to be different compared with the development of VTE in
ATVB IN FOCUS - T
patients without cancer. The underlying mechanisms of
CAT include activation of the coagulation, dysregulation
of fibrinolytic systems, inflammation, and cytokine pro-
duction (Figure 1).29,30
TF (tissue factor) seems to be an important trigger of
the hypercoagulability associated with CAT.31 TF is a pro-
coagulant protein that initiates the extrinsic pathway of
the coagulation cascade by creating complexes with fac-
tor VII, which will promote the activation of factor X and
the formation of factor Xa. Tumor cells can constitutively
express TF and release extracellular vesicles expressing
TF leading to thrombin and fibrin formation.32–34 Multiple
studies have reported elevated plasma level of TF in
patients with different cancer types (eg, pancreas, brain,
gastric).1 The fibrinolytic system is also altered in patients
with cancer. PAI-1 (plasminogen activator inhibitor 1) is a
serine protease that inhibits tissue plasminogen activator
and urokinase promoting the formation and deposition
of fibrin.1 Elevated plasma level of PAI-1 can be found
in different tumor types (eg, brain, lung, pancreas).35,36
Furthermore, cancer cells are capable of secreting
platelet-activating factors (eg, adenosine diphosphate,
thromboxane A2, CD40 ligand).1,37,38 In addition, tumor
cytokines can activate endothelial cells. Moreover, neu-
trophil extracellular traps formed from activated neutro-
phils are an important mediator in the development of
CAT. Stimulation of neutrophils (eg, IL [interleukin]-8,
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IL-1β, IL-17, activated endothelial cells) can induce
NETosis, which is used as a scaffold for platelets and
other procoagulants.39 The histones present in neutrophil
826   June 2023 Arterioscler Thromb Vasc Biol. 2023;43:824–831. DOI: 10.1161/ATVBAHA.123.318779
Cancer-Associated Thrombosis
extracellular traps can directly activate platelets and lead
to the further thrombin generation.40 Finally, cytokine pro-
duction from cancer cells (TNF [tumor necrosis factor]-α,
IL-1β, IL-6, IL-17), aggregated platelets, and activated
leukocytes also contributes to endothelium damage and
thrombus formation (Figure 1). All these overlapping
pathways can also lead to the development of dissemi-
nated intravascular coagulation, which can be another
important contributor to thromboembolic complications.
The current data suggest that there may be cancer type–
specific pathways of VTE.41 Therefore, the understanding
of the pathogenesis of CAT is important and can lead to
the identification of biomarkers helping clinicians to iden-
tify patients with cancer at high risk of VTE and poten-
tially eligible for primary prevention42–44 and those with
CAT at high risk of recurrent events.45 For example, a
correlation between sCLEC-2 (soluble C-type lectin-like
receptor 2) levels and podoplanin expression has recently
been established in patients with high-grade gliomas.42
A relevant relationship between sCLEC-2 levels and
the occurrence of CAT was demonstrated among these
patients suggesting that podoplanin could be a potential
marker to predict CAT in this patient population.42
MANAGEMENT OF CAT
Given the overlapping altered thrombotic and hemo-
static pathways in patients with cancer, the management
of CAT can be challenging. The risk of recurrent VTE
despite appropriate anticoagulant therapy and the risk of
bleeding on anticoagulation are higher among patients
with cancer compared with those without cancer.28 This
Figure 1. Multiple mechanisms in
cancer-associated thrombosis.
FVII indicates factor VII; FXa, factor Xa; IL,
interleukin; NETs, neutrophil extracellular
traps; PAI-1, plasminogen activator
inhibitor 1; TF, tissue factor; TNFα,
tumor necrosis factor alpha; and TxA2,
thromboxane A2.
 Girardi et al
leads to an increase in the rates of hospitalization and
health care costs and a significant decrease in the quality
of life in these patients.43 Furthermore, multiple qualita-
tive studies have demonstrated that CAT is traumatic and
distressing for patients and their families, highlighting
the lack of support and awareness for its diagnosis and
treatment.44 Hence, it is imperative to urgently start an
effective and safe anticoagulant regimen in patients with
CAT to avoid any potential adverse events.
Several anticoagulant regimens, including vitamin K
antagonists, low-molecular-weight heparins (LMWHs),
and direct oral anticoagulants (DOACs), have been eval-
uated for the management of CAT. LMWH monotherapy
has been the standard of care for the management of
CAT for many years.46,47 A meta-analysis has reported
that the use of LMWH (compared with vitamin K antago-
nists) was associated with a significant reduction in the
risk of recurrent events (RR, 0.58 [95% CI, 0.43–0.77])
without a significant increase in the risk of major bleed-
ing (RR, 1.09 [95% CI, 0.55–2.12]).48 Despite the fact
that LMWHs have several advantages over vitamin K
antagonists (fewer drug-drug interactions, dependable
pharmacokinetics, shorter half-life), its need for once- or
twice-daily injections and higher costs are associated
with lower adherence and persistence by patients.49
DOACs have become a valid, effective, safe, and more
convenient alternative for the management of acute VTE
in the general population. DOACs are now recommended
as first-line therapy in this setting as their risk-benefit
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ratio is favorable compared with vitamin K antago-
nists.50,51 Based on these findings and on their promising
features, DOACs and, more specifically, the direct fac-
tor Xa inhibitors apixaban, edoxaban, and rivaroxaban
have been compared with LMWH for the management
of CAT.52–55 A meta-analysis combining the results of
all randomized controlled trials has shown that patients
receiving DOACs had significantly lower risk of recur-
rent VTE events (RR, 0.67 [95% CI, 0.52–0.84]) without
a significant increased major bleeding events (RR, 1.17
[95% CI, 0.82–1.67]) but with a significant increase in
clinically relevant nonmajor bleeding (RR, 1.66 [95% CI,
1.31–2.09]) when compared with LMWH.56 Randomized
controlled trials comparing edoxaban and rivaroxaban
with LMWH have reported a higher risk of major bleed-
ing episodes in patients receiving DOACs.53,55 These
findings seem to be due to an excess of gastrointesti-
nal bleedings occurring mostly in patients with gastro-
intestinal cancers.57 A different result is shown by the
trial that compared apixaban to LMWH, which showed
that DOAC was associated with a similar risk of gastro-
intestinal bleeding when compared with LMWH (hazard
ratio, 1.05 [95% CI, 0.44–2.50]).52 The reasons for the
discrepancy in the risk of gastrointestinal bleeding are
unclear and may be related to heterogeneity in the base-
line characteristics of included patients or to the differ-
ences in the DOAC properties (eg, once versus twice a
Arterioscler Thromb Vasc Biol. 2023;43:824–831. DOI: 10.1161/ATVBAHA.123.318779
Cancer-Associated Thrombosis
day). In addition, DOAC is associated with a higher risk
of clinically relevant nonmajor bleeding compared with
ATVB IN FOCUS - T
LMWH in patients with CAT. These events seem to be
more commonly related to gastrointestinal bleeding, epi-
staxis, hematuria, or abnormal uterine bleeding. Given the
lack of direct head-to-head comparisons and significant
heterogeneity among the clinical trials, it is not possible
to recommend one DOAC over another. Based on these
findings, recent guidelines mostly suggest that either
apixaban, edoxaban, rivaroxaban, or LMWH can be used
for the management of CAT (Table).58–63 Anticoagulation
should be tailored based on patient characteristics and
preferences and should be adapted and reassessed on a
regular basis, as the patient’s cancer status and manage-
ment change over time (Figure 2).64
FUTURE
Despite the multiple anticoagulation regimens available
to manage CAT, there are still numerous unmet needs.
Treatment with LMWH requires once- or twice-daily
subcutaneous injection and seems to be associated
with shorter persistence compared with oral anticoagu-
lants.49 Although DOACs may be an attractive alterna-
tive to LMWH, they are associated with higher risk of
bleeding complications (major and clinically relevant
nonmajor bleeding) in specific tumor types (eg, unre-
sected gastrointestinal and genitourinary cancers),64
and there are little data supporting their use in patients
with additional risk factors for bleeding (eg, primary brain
tumor, thrombocytopenia), for whom adjusted doses of
LMWHs remain the treatment of choice. Furthermore,
the use of DOACs should be avoided in patients taking
other medications (including anticancer and supportive
therapies) with possible drug-drug interactions.65 All
DOACs are substrates of P-glycoprotein, and apixaban
and rivaroxaban are also substrates of CYP3A4. There-
fore, treatments that affect P-glycoprotein or CYP3A4
metabolism have the potential to interact with DOACs
and should preferentially be avoided. Finally, renal and
liver dysfunction are common in patients with cancer
and can lead to higher plasma concentration of DOACs
and bleeding concerns. Hence, new anticoagulants that
are safe and effective for the management of CAT but
that are also addressing these unmet needs are desper-
ately needed to optimize the care of patients with cancer
and VTE (Figure 2).64
As mentioned previously, multiple mechanisms lead
to activation of the coagulation cascade and excess
thrombin generation in patients with cancer (Figure 1).
Furthermore, extracellular vesicles from various cancer
cell lines have been shown to activate FXII and initiate
the intrinsic pathway.66 Thrombin and factor XIIa activate
factor XI, leading to the further amplification of the coag-
ulation cascade. Hence, inhibition of factor XI maybe
be an innovative and effective pathway to address the
June 2023   827
 Girardi et al Cancer-Associated Thrombosis

Table. Summary of the Clinical Practice Guidelines Recommendations for the Management of Cancer-Associated Thrombosis

Recommendation
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Guideline Initial treatment Long-term treatment

ASCO LMWH, UFH, fondaparinux, or rivaroxaban. LMWH, edoxaban, or rivaroxaban for ≥6 mo is preferred.
(2019)58
For patients initiating treatment with parenteral anticoagulation, LMWH is
preferred over UFH.
ASH DOAC (apixaban or rivaroxaban) or LMWH should be used for initial treat- For patients requiring long-term anticoagulation (>6 mo), DOACs
(2021)59 ment of VTE for patients with cancer. or LMWH.
For the short-term treatment of VTE (3–6 mo), DOAC (apixaban, edoxaban,
or rivaroxaban) is recommended over LMWH and over VKA.
DOACs should be used carefully for patients with GI cancers.
ESMO LMWH, UFH, fondaparinux, apixaban, and rivaroxaban are recommended Long-term anticoagulation for at least 6 mo includes LMWH, apix-
(2022)60 treatments for the acute phase. aban, edoxaban, or rivaroxaban, which are preferred over VKAs.
LMWH is preferred over UFH or fondaparinux.
UFH may be considered in patients with severe renal impairment (defined
as CrCl <30 mL/min).
ITAC LMWH is recommended when CrCl is ≥30 mL/min. LMWH or DOACs should be used for a minimum of 6 mo.
(2022)61
For patients without high risk of GI or GU bleeding, rivaroxaban, apixaban, After 6 mo, therapy should be based on individual evaluation.
or edoxaban can also be used when CrCl is ≥30 mL/min.
UFH can also be used when LMWH or DOACs are contraindicated.
NCCN Apixaban, edoxaban, or rivaroxaban is preferred for patients without gastric
(2020)62 or gastroesophageal lesions.
LMWH is preferred for patients with gastric or gastroesophageal lesions.

ASCO indicates American Society of Clinical Oncology; ASH, American Society of Hematology; CrCl, creatinine clearance; DOAC, direct oral anticoagulant; ESMO,
European Society for Medical Oncology; GI, gastrointestinal; GU, genitourinary; ITAC, International Initiative on Thrombosis and Cancer; LMWH, low-molecular-weight
heparin; NCCN, National Comprehensive Cancer Network; UFH, unfractionated heparin; VKA, vitamin K antagonist; and VTE, venous thromboembolism.

current unmet needs for the management of CAT. Pre- Four phase II randomized controlled trials have evalu-
vious studies have shown that factor XI deficiency (ie, ated different factor XI inhibitors and found them to be
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hemophilia C) or inhibition of factor XI seems to protect
against thrombotic complications with little or no bleed-
ing.67,68 However, patients with elevated plasma factor XI
levels were found to be at higher risk of thromboembo-
lism.69 The role of factor XI in the contact system and
the intrinsic pathway appears to be essential for throm-
bosis formation, stabilization, and growth but not hemo-
stasis.70,71 Hence, factor XI inhibitors could potentially be
effective anticoagulants to manage VTE without bleed-
ing complications.
noninferior or superior to enoxaparin for the prevention of
VTE after knee replacement surgery without increasing
bleeding risks.72–75 One of the factor XI inhibitors, abel-
acimab, is a monoclonal antibody that binds factor XI and
locks it in its inactive precursor form, preventing its activa-
tion by factor XIIa or thrombin. Administration of abelaci-
mab yields rapid and dose-dependent factor XI inhibition.
Because the half-life of abelacimab is 20 days, this drug
can be administered monthly.70 Given that it is adminis-
tered parenterally, it is not dependent on P-glycoprotein

Figure 2. Treatment algorithm in

cancer-associated thrombosis (CAT).
DOAC indicates direct oral anticoagulant;
GI, gastrointestinal; GU, genitourinary;
and LMWH, low-molecular-weight heparin.

828   June 2023 Arterioscler Thromb Vasc Biol. 2023;43:824–831. DOI: 10.1161/ATVBAHA.123.318779
 Girardi et al
or CYP3A4 metabolism, and, probably also for this, it
does not accumulate in patients with severe renal or
hepatic dysfunction.70 Therefore, abelacimab could poten-
tially address most of the previously identified unmet
needs in the management of CAT. Two ongoing phase
III multicenter randomized controlled trials (ASTER and
MAGNOLIA trials) are evaluating the efficacy and safety
of abelacimab in the management of CAT. The ASTER
trial is comparing abelacimab and apixaban, whereas the
MAGNOLIA trial is comparing abelacimab to LMWH in
patients with gastrointestinal or genitourinary cancer,
in whom DOACs may be associated with higher risk of
bleeding complications. Although potential disadvantages
for using abelacimab in patients with CAT include paren-
teral administration (intravenous at first and subcutane-
ous thereafter) and its longer half-life, the results of these
2 trials will address the important knowledge gaps faced
by clinicians managing CAT and allow a new addition to
the treatment armamentarium for these patients.
CONCLUSIONS
VTE is a frequent complication among patients with
cancer and is associated with significant morbidity and
mortality. The management of CAT is challenging due to
complex pathophysiological interacting pathways spe-
cific for this patient population. Although the different
anticoagulant options provide clinicians with the opportu-
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nity to tailor anticoagulation based on the patients’ char-
acteristics and preferences, many unmet needs remain.
The factor XI inhibitors may provide a unique opportunity
to optimize the management of CAT.
ARTICLE INFORMATION
Received March 1, 2023; accepted April 17, 2023.
Affiliations
Department of Medicine and Surgery, University of Insubria, Varese, Italy (L.G.,
W.A.). Department of Medicine, Ottawa Hospital Research Institute, University of
Ottawa, Ontario, Canada (T.-F.W., M.C.).
Sources of Funding
M. Carrier is the recipient of a Tier 1 Research Chair in Cancer and Thrombosis
from the Department and Faculty of Medicine at the University of Ottawa.
Disclosures
T.-F. Wang reports advisory board honoraria from Servier and Valeo and research
funding to the institution from Leo Pharma. W. Ageno reports advisory board hon-
oraria from Bayer, Boehringer Inghelheim, Daiichi Sankyo, Bristol-Myers Squibb
(BMS)/Pfizer, Sanofi, and Portola and reports research funding and personal
fees from Bayer and personal fees from BMS/Pfizer, Daiichi Sankyo, Sanofi, As-
pen, Janssen, and Portola, outside the submitted work. M. Carrier has received
research funding from BMS, Pfizer, and Leo Pharma and honoraria from Bayer,
Pfizer, BMS, Servier, and Leo Pharma. The other author reports no conflicts.
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