European Heart Journal (2021) 42, 3995–3999
doi:10.1093/eurheartj/ehab712

ISSUE @ A GLANCE

Thrombosis in peripheral artery
disease and thrombotic
thrombocytopenia after adenoviral
COVID-19 vaccination

Filippo Crea

1,2

1Department of Cardiovascular Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; and 2Department of Cardiovascular and Pulmonary Sciences,
Catholic University of the Sacred Heart, Rome, Italy

With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.

For the podcast associated with this article, please visit https://academic.
oup.com/eurheartj/pages/Podcasts.

balance evolves over time in an individual patient, a regular reassess-
ment of the antithrombotic therapy is of the utmost importance.

This Focus Issue on thrombosis and antithrombotic treatment
starts with the Special Article ‘Antithrombotic therapies in aortic
and peripheral arterial diseases in 2021: a consensus document
from the ESC working group on aorta and peripheral vascular dis-
eases, the ESC working group on thrombosis, and the ESC work-
ing group on cardiovascular pharmacotherapy’ by Victor Aboyans
from the University of Limoges in France, and colleagues.1 The aim
of this collaborative document is to provide an update for clini-
cians on best antithrombotic strategies in patients with aortic and/
or peripheral arterial diseases. Antithrombotic therapy is a pillar of
optimal medical treatment for these patients at very high cardio-
vascular risk (Figure 1).1–3

While the number of trials on antithrombotic therapies in patients
with aortic or peripheral arterial diseases is substantially smaller than
for those with coronary artery disease (CAD), recent evidence
deserves to be incorporated into clinical practice. In the absence of
specific indications for chronic oral anticoagulation due to concomi-
tant cardiovascular disease, a single antiplatelet agent is the basis for
long-term antithrombotic treatment in patients with aortic or periph-
eral arterial diseases. Its association with another antiplatelet agent or
low-dose anticoagulants is also discussed, based on a patient’s ischae-
mic and bleeding risk as well as therapeutic paths (e.g. endovascular
therapy). This consensus document aims to provide guidance on
antithrombotic therapy according to arterial disease localizations and
clinical presentation. It cannot, however, substitute for multidisciplin-
ary team discussions, which are particularly important for patients
with an uncertain ischaemic/bleeding balance. Importantly, since this

ticagrelor

Opioids remain the analgesic agent of choice in managing myocar-
dial ischaemic pain. However, retrospective studies have raised con-
cerns regarding potential
interactions between opioids and oral
P2Y12 inhibitors, which are a cornerstone of therapy in myocardial in-
farction.4,5 In an ESC Fast Track article entitled ‘Effects of ligno-
caine vs. opioids on antiplatelet activity of ticagrelor:
the LOCAL trial’, Himawan Fernando from Monash University in
Melbourne, Australia, and colleagues assessed the impact of intraven-
ous fentanyl and lignocaine on the pharmacokinetics and pharmaco-
dynamics of
in patients with unstable angina and
non-ST-segment elevation myocardial infarction and their procedural
analgesic efficacy and safety.6 Seventy patients undergoing coronary
angiography with ticagrelor loading were included in the pharmacoki-
netic and pharmacodynamic analyses of this randomized trial. Plasma
ticagrelor levels 2 hours post-loading dose were significantly lower in
the fentanyl arm than in the lignocaine treatment arm (598 vs.
1008 ng/mL, P = 0.014). The area under the plasma–time curves for
ticagrelor (1228 vs. 2753 ng h/mL, P < 0.001) and its active metabolite
(201 vs. 447 ng h/mL, P = 0.001) were both significantly lower in the
fentanyl arm. Expression of activated platelet glycoprotein IIb/IIIa re-
ceptor and P-selectin was significantly higher at 60 min in the fentanyl
arm. A higher proportion of patients had high on-treatment platelet
reactivity in the fentanyl arm.

The authors conclude that unlike fentanyl, lignocaine does not im-
pair the bioavailability or delay the antiplatelet effect of ticagrelor.
Both drugs were well tolerated and effective, with a high level of pa-
tient satisfaction for procedural analgesia. Routine procedural anal-
gesia during percutaneous coronary intervention (PCI) should be

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Published on behalf of the European Society of Cardiology. All rights reserved. VC The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.

3996

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Figure 1 Graphical Abstract (from Aboyans V, Bauersachs R, Mazzolai L, Brodmann M, Palomares JFR, Debus S, Collet JP, Drexel H, Espinola-
Klein C, Lewis BS, Roffi M, Sibbing D, Sillesen H, Stabile E, Schlager O, De Carlo M. Antithrombotic therapies in aortic and peripheral arterial diseases
in 2021: a consensus document from the ESC working group on aorta and peripheral vascular diseases, the ESC working group on thrombosis, and
the ESC working group on cardiovascular pharmacotherapy. See pages 4013–4024).

reconsidered and, if performed, lignocaine is a beneficial alternative
to fentanyl. The manuscript is accompanied by an Editorial by
Dominick Angiolillo and Mattia Galli from the University of Florida
College of Medicine in Jacksonville, FL, USA.7 The authors conclude
that although the available evidence on the use of non-opioid analge-
sics in patients undergoing coronary angiography and PCI are thus far
promising, whether they can be safely and effectively used as a main-
stream treatment in this setting remains to be seen.

Peripheral artery disease (PAD) is a progressive atherosclerotic
it can be asymptomatic, but often results in profound
disorder;
functional limitation, acute limb-threatening ischaemia, and amputa-
tion.8–12 More than 235 million individuals worldwide are afflicted,
and age is one of the most important risk factors for PAD. Despite an
elevated risk for major adverse limb events and major adverse cardio-
vascular events, patients with PAD are less likely to be treated with
antithrombotic therapy compared with their CAD counterparts, In
another ESC Fast Track article entitled ‘Low-dose rivaroxaban
plus aspirin in older patients with peripheral artery disease
undergoing acute limb revascularization: insights from the
VOYAGER PAD trial’, Mori Krantz from the University of
Colorado School of Medicine in Aurora, CO, USA, and colleagues in-
dicate that in their secondary analysis of the VOYAGER trial, rivarox-
aban 2.5 mg twice a day plus aspirin 100 mg a day vs aspirin only was
assessed in older adults. Advanced age is associated with elevated
bleeding risk and unfavourable net benefit for dual antiplatelet ther-
apy in chronic CAD.13 The risk–benefit of low-dose rivaroxaban in

...............................................................................

patients >_75 years old with PAD after lower extremity revasculariza-
tion (LER) has not been described. The primary endpoint was a com-
posite of acute limb ischaemia, major amputation, myocardial
infarction, ischaemic stroke, or cardiovascular death. The principal
safety outcome was thrombolysis in myocardial
infarction (TIMI)
major bleeding analysed by the pre-specified age cut-off of 75 years.
Of 6564 patients randomized, 1330 (20%) were >75 years. Absolute
3-year Kaplan–Meier cumulative incidence rates for primary efficacy
(23% vs. 19%) and safety (3.5% vs. 1.5%) endpoints were higher in
elderly vs. non-elderly patients. The efficacy (P-interaction 0.83) and
safety (P-interaction 0.38) of rivaroxaban were consistent irrespect-
ive of age. The combination of intracranial and fatal bleeding was not
increased in patients >75 years. Overall, benefits (absolute risk re-
duction 3.8%, number needed to treat 26 for the primary endpoint)
exceeded risks (absolute risk increase 0.81%, number needed to
harm 123 for TIMI major bleeding).

The authors conclude that patients >_75 years old with PAD are at
both heightened ischaemic and bleeding risk after LER. No excess
harm with respect to major, intracranial, or fatal bleeding was seen in
older patients, yet numerically greater absolute benefits were
observed. This suggests that low-dose rivaroxaban combined with as-
pirin should be considered in PAD after LER regardless of age. The
manuscript is accompanied by an Editorial by Greg Lip, S.R.
Vallabhaneni, and Juqian Zhang from the Liverpool Centre for
Cardiovascular Science, University of Liverpool and Liverpool Heart
& Chest Hospital in the UK.14 The authors conclude that one priority

Issue @ a Glance

3997

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Figure 2 Graphical Abstract (from Hwang J, Park SH, Lee SW, Lee SB, Lee MH, Jeong GH, Kim MS, Kim JY, Koyanagi A, Jacob L, Jeong SY, Song
JW, Yon DK, Shin JI, Smith L. Predictors of mortality in thrombotic thrombocytopenia after adenoviral COVID-19 vaccination: the FAPIC score. See
pages 4053–4063).

is improving clinical risk stratification of PAD patients so rivaroxaban
combined with aspirin could potentially benefit those with ‘true’ high
risk but at an acceptable level of major but non-fatal bleeding.

implications of

In the past 18 months, we have published several studies on the
cardiovascular
the coronavirus disease 2019
(COVID-19) pandemic.15–17 The COVID-19 pandemic can only be
overcome through a global effort leading to mass vaccination. Yet,
only recently, Norway and Denmark stopped the ChAdOx1 nCoV-
19 vaccination after several cases of vaccine-induced syndrome of se-
vere thrombosis and thrombocytopenia with fatal outcome were
reported. The clinical manifestation and outcomes of thrombosis
with thrombocytopenia syndrome (TTS) after adenoviral COVID-19
vaccine administration are largely unknown due to the rare nature of
the disease. In a Fast Track article entitled ‘Predictors of mortality
in thrombotic thrombocytopenia after adenoviral COVID-
19 vaccination: the FAPIC score’, Jae Il Shin from the Yonsei
University College of Medicine in Korea, and colleagues aimed to ana-
lyse the clinical presentation, treatment modalities, outcomes, and
prognostic factors of adenoviral TTS, as well as identify predictors for
mortality.18 PubMed, Scopus, Embase, and Web of Science databases
were searched, and the resulting articles were reviewed. A total of 6
case series and 13 case reports (64 patients) of TTS after ChAdOx1
nCoV-19 vaccination were included. The authors performed a
pooled analysis and developed a novel scoring system to predict
mortality. The overall mortality of TTS after ChAdOx1 nCoV-19
vaccination was 36%. In this study, age at or under 60, platelet count
below 25 (cid:2) 103/lL, fibrinogen below 150 mg/dL, the presence of

..................................................................................

intracerebral haemorrhage (ICH), and the presence of cerebral ven-
ous thrombosis (CVT) were significantly associated with death and
were selected as predictors for mortality (1 point each). Shin et al.
named this novel scoring system FAPIC (fibrinogen, age, platelet
count, ICH, and CVT), and the C-statistic for the FAPIC score was
0.837. Expected mortality increased with each point increase in the
FAPIC score, ranging from 2.08% to 90.05% (Figure 2). The FAPIC
scoring model was internally validated through cross-validation and
bootstrapping, then externally validated on a panel of TTS patients
after Ad26.COV2.S administration. The authors conclude that fi-
brinogen levels, age, platelet counts, and the presence of ICH and
CVT are significantly associated with mortality in patients with TTS,
and the FAPIC score constituting these risk factors could predict
mortality.

In a Fast Track manuscript entitled ‘Immune complexes, in-
nate immunity, and NETosis in ChAdOx1 vaccine-induced
thrombocytopenia’, Sverre Holm from the Oslo University
Hospital in Norway, and colleagues reported five cases of vaccine-
induced immune thrombotic thrombocytopenia (VITT) 7–10 days
after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral
vector vaccine against COVID-19.19 They aimed to investigate the
pathogenic immunological responses operating in these patients. The
authors assessed circulating inflammatory markers by immune assays
and immune cell phenotyping by flow cytometry analyses, and per-
formed immunoprecipitation with antiplatelet factor 4 (PF4) antibody
in plasma samples from all five patients followed by mass spectrom-
etry. A thrombus was retrieved from the sinus sagittal superior of

3998

Issue @ a Glance

one patient and analysed by immunohistochemistry and flow cytome-
try. Precipitated immune complexes revealed multiple innate im-
mune pathway triggers for platelet and leucocyte activation. Plasma
contained increased levels of innate immune response cytokines and
markers of systemic inflammation, extensive degranulation of neutro-
phils, and tissue and endothelial damage. Blood analyses showed acti-
vation of neutrophils and increased levels of circulating H3Cit,
double-stranded DNA, and myeloperoxidase–DNA complex. The
thrombus had extensive infiltration of neutrophils, formation of neu-
trophil extracellular traps (NETs), and IgG deposits. The authors
conclude that their results show that anti-PF4/polyanion IgG-medi-
ated thrombus formation in VITT patients is accompanied by a mas-
sive innate immune activation and particularly by the fulminant
activation of neutrophils including NETosis. These results provide
novel data on the immune response in this rare adenoviral vector-
induced VITT.

The two manuscripts by Shin et al. and Holm et al. are accompa-
nied by a double Editorial by Jean Connors from the Harvard
Medical School in Boston, MA, USA.20 Connors concludes that what
is clear is that VITT is a rare occurrence that we can now diagnose
with identifiable clinical and laboratory features and can be treated
appropriately, resulting in lower mortality. Although use of the
adenoviral vector vaccines was put on temporary hold in some coun-
tries, use by most has understandably resumed given the >4 million
deaths that have resulted from severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) infection. Continued investigation to
unravel the aetiological triggers of VITT using clinical and laboratory
findings is warranted, not only to understand the pathophysiology of
VITT and improve treatment, but also to identify critical knowledge
that can be used in the future—with 3.9 billion doses of vaccine
administered around the world to date, there is hope that this pan-
demic will soon be over.

Mental stress substantially contributes to the initiation and pro-
gression of human disease, including cardiovascular conditions. In a
Translational Research article entitled ‘Acute mental stress
drives vascular inflammation and promotes plaque desta-
bilization in mouse atherosclerosis’, Julia Hinterdobler from the
Technical University Munich in Germany, and colleagues aimed to in-
vestigate the underlying mechanisms of these contributions since
they remain largely unclear.21 Here, they show in humans and mice
that leucocytes deplete rapidly from the blood after a single episode
of acute mental stress. Using cell-tracking experiments in animal
models of acute mental stress, the authors found that stress expos-
ure leads to prompt uptake of inflammatory leucocytes from the
blood to distinct tissues including the heart, lung, skin, and, if present,
atherosclerotic plaques. Mechanistically, they found that acute stress
enhances leucocyte influx into mouse atherosclerotic plaques by
modulating endothelial cells. Specifically, acute stress increases adhe-
sion molecule expression and chemokine release through locally
derived norepinephrine. Both chemical and surgical disruption of
norepinephrine signalling diminished stress-induced leucocyte migra-
tion into mouse atherosclerotic plaques.

The authors conclude that their data show that acute mental
stress rapidly amplifies inflammatory leucocyte expansion inside
mouse atherosclerotic lesions and promotes plaque vulnerability.
The contribution is accompanied by an Editorial by Amir
Lerman from the Mayo Clinic in Rochester, MN, USA, and

.............................................................................................................................................................................

colleagues.22 Lerman and colleagues point out that the study by
Hinterdobler et al. helps to identify several key challenges and
next steps in our attempt to learn more about this intriguing and
relevant area, by shedding light on the central role of the endo-
thelium as the effector cells of the neuroimmune response to
mental stress.

The issue is also complemented by a Discussion Forum contribu-
In a commentary entitled ‘The neutrophil–lymphocyte
tion.
ratio and incident atherosclerotic events: the impact of ra-
cial differences?’, Philippe Giral from the Sorbonne Universite´
UMRS 1166 in France and colleagues comment on the recent publi-
cation ‘The neutrophil–lymphocyte ratio and incident ath-
erosclerotic events: analyses from five contemporary
randomized trials’ by Nicholas H. Adamstein from Harvard
Medical School in Boston, MA, USA.23,24

The editors hope that this issue of the European Heart Journal will

be of interest to its readers.

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c
a
d
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m
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.
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u
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c
o
m
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/

/

l

/

/

/

/

a
r
t
i
c
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4
2
3
9
3
9
9
5
6
3
9
7
1
7
5
b
y
 
g
u
e
s
t
 

 

 

 

o
n
0
5
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c
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2
0
2
2