European Heart Journal (2023) 44, 3040–3058 SPECIAL ARTICLE

https://doi.org/10.1093/eurheartj/ehad388 Thrombosis and antithrombotic treatment

Management of patients on antithrombotic

therapy with severe infections: a joint clinical
consensus statement of the ESC Working
Group on Thrombosis, the ESC Working Group

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on Atherosclerosis and Vascular Biology,
and the International Society on Thrombosis
and Haemostasis
Bruna Gigante 1*, Jerrold H. Levy 2, Eric van Gorp 3,
Alessandro Bartoloni 4, Marie-Luce Bochaton-Piallat 5, Magnus Bäck 6,7
,
Hugo ten Cate 8,9, Christina Christersson 10, José Luis Ferreiro 11,
Tobias Geisler 12, Esther Lutgens 13,14, Sam Schulman 15,16,
Robert F. Storey 17, Jecko Thachil 18, Gemma Vilahur 19,
Patricia C. Liaw 20†, and Bianca Rocca 21*†
1
Division of Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Solnavägen 30. 17164 and Department of Cardiology, Danderyds Hospital, Entrévägen 2, 182 88,
Stockholm, Sweden; 2Departments of Anesthesiology, Critical Care, and Surgery (Cardiothoracic), Duke University School of Medicine, Durham, United States; 2301 Erwin Road, Durham,
NC 27710, USA; 3Department of Viroscience, Erasmus MC, Rotterdam, PO box 2040 [Room Ee1726], 3000 CA Rotterdam, The Netherlands; 4Department of Experimental and Clinical
Medicine, Infectious Diseases Unit, University of Florence, Largo Brambilla 3, 50100 Florence, Italy; 5Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1
rue Michel-Servet 1, CH-1211 Genève, Switzerland; 6Department of Translational Cardiology, Karolinska Institutet and Karolinska University Hospital, CMM L8:01, 171 76 Stockholm,
Sweden; 7INSERM U1116, University of Lorraine, Nancy University Hospital, 2 rue Jean Lamour, 54505 Vandoeuvre les Nancy Cedex, France; 8Department of Internal medicine,
Thrombosis Expertise Center, Maastricht University Medical Center and CARIM school for cardiovascular diseases, Universiteitsingel 50, PO Box 616, 6200 MD Maastricht, The
Netherlands; 9Center for Thrombosis and Haemostasis, Gutenberg University Medical Center, Langenbeckstr. 1, Bldg. 403, 55131 Mainz, Germany; 10Department of Medical Sciences,
Cardiology, Uppsala University, Akademiska Sjukhuset, 75185, Uppsala, Sweden; 11Department of Cardiology and Bio-Heart Cardiovascular Diseases Research Group; Bellvitge University
Hospital – Bellvitge Biomedical Research Institute (IDIBELL); CIBERCV; L’Hospitalet de Llobregat, Hospital Duran i Reynals - Edifici Terapèutic - 2a planta Gran Via de l’Hospitalet, 199,
08908 Hospitalet de Llobregat Barcelona – Spain; 12Department of Cardiology and Angiology, University Hospital Tübingen, Otfried-Müller-Straße 10, 72076 Tübingen, Germany;
13
Cardiovascular Medicine, Experimental CardioVascular Immunology Laboratory, Mayo Clinic, 200 First St SW, 55905, Rochester, MN, USA; 14Institute for Cardiovascular Prevention
(IPEK), Ludwig-Maximilians Universität, München, Germany & German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Pettenkoferstrasse 9, 80336,
Munich, Germany; 15Department of Medicine and Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, ON, Canada HHS - General Hospital 237, Barton
Street East, Hamilton, ON, L8L 2X2, Canada; 16Department of Obstetrics and Gynecology, I.M. Sechenov First Moscow State Medical University, Bol’shaya Pirogovskaya Ulitsa, 2, стр. 4,
Moscow 119435, Russia; 17Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Pegasus House, 463a Glossop Road, Sheffield, S10 2QD, UK;
18
Department of Haematology, Manchester University Hospitals, Oxford road, Manchester, M13 9WL, UK; 19Institut de Recerca Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau,
CIBERCV, Avda. Sant Antoni Maria Claret 167, 08025 Barcelona, Spain; 20Department of Medicine, Thrombosis & Atherosclerosis Research Institute (TaARI), McMaster University, 237
Barton Street East Hamilton, Ontario L8L 2X2, Canada; and 21Department of Safety and Bioethics, Section on Pharmacology, Catholic University School of Medicine, Largo F. Vito 1, 00168
Rome, Italy

Received 6 October 2022; revised 1 May 2023; accepted 29 May 2023; online publish-ahead-of-print 13 July 2023

* Corresponding authors. Tel/Fax: +39 06 30154253. E-mails: bianca.rocca@unicatt.it; b.rocca@tiscali.it (B.R.); Tel/Fax: +46-(0)8-52487082. E-mail: bruna.gigante@ki.se (B.G.)
†
P.C.L. and B.R. are last co-authors.
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Severe infections and antithrombotic therapy 3041

Graphical Abstract

Sepsis
Induced
Coagulopathy
Score

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Anticoagulants
SAPT DAPT
0 (OAC, Heparins)

Platelets
No change No change No change
149-100x109/L

Platelets
No change No change OAC
<100-30x109/L

Platelets
No change Heparins
29-20x109/L

Platelets
6 <20x109/L

Bacteria and viruses are a common cause of severe infections requiring hospitalization and different degrees of organ support. Patients on single or
combined antithrombotic therapy at high and very high cardiovascular risk are more prone to severe infections and related complications in the
short and long term than the general population. With increasing severity, infections associate with coagulopathy and this imposes modulation
of antithrombotic therapy according to the underlying cardiovascular diseases, indication for treatment, clinical conditions, and patient’s prognosis.
When platelet count is below 100 × 109/L, in patients already on oral anticoagulation (OAC), heparins should be used as described in Tables 3 and 4
and should be stopped when platelet count is below 30 × 109/L. Patients with ongoing dual antiplatelet therapy (DAPT) should be shifted to single
antiplatelet therapy (SAPT) with a P2Y12 inhibitor or low-dose acetylsalicylic acid (ASA). Single antiplatelet therapy with ASA may be more favour­
able in these patients when platelet count is below 30 × 109/L. When platelet count is below 20 × 109/L, antithrombotic therapy should be discon­
tinued, with the possible exception of patients with very recent acute coronary syndrome, i.e. <3 months, in whom low-dose ASA may be
considered, as shown in Tables 3 and 4.

Abstract

Patients with severe infections and a pre-existing indication for antithrombotic therapy, i.e. antiplatelet agents, anticoagulant drugs, or their combi­
nations, require integrated clinical counselling among coagulation, infectious disease, and cardiology specialists, due to sepsis-induced coagulopathy
that frequently occurs. Bacterial and viral pathogens constitute an increasing threat to global public health, especially for patients with ongoing an­
tithrombotic treatment who have a high risk of thrombotic recurrences and high susceptibility to severe infections with increased morbidity and
mortality. Similarly, sepsis survivors are at increased risk for major vascular events. Coagulopathy, which often complicates severe infections, is as­
sociated with a high mortality and obligates clinicians to adjust antithrombotic drug type and dosing to avoid bleeding while preventing thrombotic
complications. This clinical consensus statement reviews the best available evidence to provide expert opinion and statements on the management
of patients hospitalized for severe bacterial or viral infections with a pre-existing indication for antithrombotic therapy (single or combined), in whom
sepsis-induced coagulopathy is often observed. Balancing the risk of thrombosis and bleeding in these patients and preventing infections with vac­
cines, if available, are crucial to prevent events or improve outcomes and prognosis.
.............................................................................................................................................................................................
Keywords Antiplatelet drugs • Anticoagulant drugs • Sepsis • Infections • Sepsis-induced coagulopathy
3042
Introduction
Severe bacterial and viral infections are often associated with a coagulo­
pathy that can be defined as any alteration or disturbance of haemostasis
resulting in either bleeding, clotting, or both.1 More specifically, a dysre­
gulated balance of thrombosis and fibrinolysis can result in excessive clot­
ting, bleeding, or both, depending on the host’s immunological and
inflammatory responses that change over time.2,3 Antithrombotic drugs
are increasingly used worldwide, with a predicted annual growth rate of
nearly 8% between 2022 and 20294 and an estimated prevalence of pre­
scriptions in the European population of ∼15%–20% across different
countries.5,6 Thus, the management of antithrombotic treatment in pa­
tients suffering from severe infections represents a frequent clinical prob­
lem and a challenge. Clinical decisions should balance thrombotic and
bleeding risks associated with severe infections as well as the underlying
history of arterial and/or venous thrombotic disease requiring antithrom­
botic therapy.
The scope of this clinical consensus statement is to review the cur­
rent evidence on the management of patients with ongoing antithrom­
botic therapy (single or combined antiplatelet and/or anticoagulant
agents) who are hospitalized because of a severe infection (Graphical
Abstract). This document focuses on severe infections of bacterial and
viral aetiology and refers to the sepsis-induced coagulopathy (SIC) cri­
teria, defined and scored according to the International Society on
Thrombosis and Haemostasis (ISTH) (Table 1).1
Methodology and definitions
The panel of co-authors has been selected because of their
complementary expertise in the fields of cardiovascular pharmacol­
ogy, infectious disease, clinical cardiology, coagulation, and athero­
sclerosis pathophysiology, as detailed in the Supplementary material
online.
We performed a systematic review of the literature (Supplementary
data online, Table S1) and used the current European Society of
Cardiology (ESC) classification of cardiovascular risk9 (see
Supplementary data online, Table S2). Severe infections were defined
according to the Third International Consensus Definitions for Sepsis
and Septic Shock (see Supplementary data online, Table S3).10 The
SIC score was used to grade the severity of the coagulopathy. This
score has been validated in sepsis patients with coagulopathy and shows
higher specificity compared with disseminated intravascular coagulopa­
thy (DIC) (see Supplementary data online, Table S4).11–14 Furthermore,
anticoagulant therapy has been reported to benefit patients who met
criteria for SIC.14 Finally, since DIC can also be of non-infectious eti­
ology,11 we agreed to use SIC and not to refer to DIC.1,8
We agreed to refer to the Sequential Organ Failure Assessment
(SOFA) score (see Supplementary data online, Table S3),15 since ele­
ments of the SOFA score are included in the SIC criteria (Table 1) to
grade the severity of sepsis. Notably, SIC development in patients hos­
pitalized for sepsis increases mortality from 25.4% to 56.1%.16
We agreed to address the pathophysiology of haemostasis and the
management of patients with ongoing antiplatelet and anticoagulant
therapy during severe infections and the benefits and risks of vaccin­
ation as preventive strategy. Consensus statements for each section
were reached using the Delphi methodology17 as detailed in the
supplementary material online. In clinical consensus statement, advices
for clinical management were classified in four categories, according to
Gigante et al.
the current ESC Scientific Documents policy as detailed in
Supplementary data online, Figure S1.
Patients on mechanical circulatory support were not included.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infec­
tion was also excluded since it has recently been addressed by dedi­
cated ESC and ISTH guidelines.18,19
Immunothrombosis or
thromboinflammation in severe
infections?
To describe the prothrombotic and coagulopathic responses induced
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by the immune and inflammatory reactions to infections, in the last
two decades, the literature interchangeably uses the words thromboin­
flammation and immunothrombosis to describe the link between in­
flammation and thrombosis.2,3,20 Both terms were first reported by
Tanguay et al. in 2004.21
The term thromboinflammation is derived from thrombosis asso­
ciated with inflammation and is used to describe pathophysiologic
perturbations due to vascular endothelial injury and/or loss of antith­
rombotic and antiinflammatory functions.21 As a result, both cellular
and humoral inflammatory mechanisms of immune surveillance are
activated. In acute infections, thromboinflammation may culminate
in microvascular thrombosis, which is the hallmark of the disease,
as has been reported in post-mortem studies of patients with acute
respiratory distress syndrome due to pathogens invading the re­
spiratory tract and provoking an inflammatory response associated
with acute lung injury.22 This thromboinflammatory response be­
came increasingly recognized currently due to coronavirus disease
2019 (COVID-19).23 This response to sepsis also occurs following
ischaemia–reperfusion injury,24 trauma, organ transplant rejection,
and extracorporeal circulation and can progress to DIC.2 In these
thromboinflammatory states, loss of endothelial cell function and
systemic inflammatory responses lead to humoral and cellular injury,
as noted.
Immunothrombosis was again described in 2013 by Engelmann and
Massberg25 to refer to an intrinsic effector pathway of innate (host)
immunity that activates systemic inflammation and haemostasis,
with thrombin and fibrin generation to localize and immobilize infec­
tions. As part of any inflammatory response to attenuate microbial in­
vasion, the microcirculatory thrombosis also produces multiorgan
injury.26,27 These important host defence mechanisms have been
long known, but with the ongoing pandemic and massive numbers
of COVID-19 patients without pre-existing immunity who manifested
lung or multiorgan dysfunction, the concept of immunothrombosis
was increasingly reported. This term describes the microvascular
thrombotic response that facilitates microbe containment and
elimination, a critical component of innate immunity.2,25 Similar to
thromboinflammation, this response requires humoral and cellular ac­
tivation, due to contact activation pathways through factor XII and
complement activation, and subsequent generation of additional
pro-inflammatory mediators that include neutrophil extracellular
traps.26,28 Thus, contact activation pathways likely represent a physio­
logical mechanism of innate immunity and are also crucial in SIC and
acute infections.3,29,30
In summary, thromboinflammation and immunothrombosis have
many similarities, but should not be used interchangeably, even if
they have been used synonymously in the past. Although
Severe infections and antithrombotic therapy
Table 1 Scoring for sepsis-induced coagulopathy (SIC)a
Points
...................................
0 1 2 are not related to vasopressor use occur in association with SIC and
....................................................................................
Prothrombin time (PT-INR) >1.2 1.2–1.4 >1.4
9
Platelet count (×10 /L) >150 100–149 <100
b
Total SOFA (respiratory, 0 1 ≥2
cardiovascular, hepatic, and renal)
SOFA, Sequential Organ Failure Assessment; INR, international normalized ratio.
Modified from Iba et al.7
a
Total SIC score ≥4 corresponds to DIC ≥ 5.8
b
SOFA scoring included in SIC grading does not include the mental status since it is
tailored to clinical aspects relevant in sepsis.
immunothrombosis per se is a protective, antimicrobial mechanism
aimed to locally contain pathogens including bacteria and fungi, its dys­
regulation and systemic exacerbation, as observed in thromboinflam­
mation, may ultimately be harmful to the host.
Haemostasis during severe
infections: pathophysiology and
clinical aspects
Bacterial infections
In recent decades, the incidence of bacterial sepsis has increased: in the
USA, the estimated incidence was 240 cases/100 000 population in
2015,31 while in 2019, a nationwide study in France estimated an inci­
dence of 403/100 000 population.32 Global, climate, and demographic
changes affect infectious disease features and epidemiology.33 Severe
infections caused by gram-positive bacteria34,35 have increased, almost
reaching the incidence observed for gram-negative bacteria. The
thromboinflammatory cascade triggered by infections is summarized
in Figure 1. The mechanisms underlying the coagulopathy39 observed
during the most common severe bacterial infections in hospitalized pa­
tients are represented in Figure 2 and summarized in Supplementary
data online, Table S5.
Coagulopathy and vascular endothelial injury occur following severe
bacterial infections due to inflammatory and thrombotic responses that
include both humoral and cellular components of haemostasis, namely
the coagulation cascade, adhesive proteins, platelets, and inflammatory/
immune cells (e.g. neutrophils, lymphocytes, and monocytes).1,2
Multiple pathways, including enhanced tissue factor expression, neutro­
phil activation, and release of multiple cellular constituents, such as
DNA, histones, and damage-associated molecular patterns, are in­
volved, overwhelming the physiological vascular-protective mechan­
isms (Figure 1). Endothelial dysfunction is associated with loss of the
endogenous vascular-protective mechanisms and contributes to micro­
thrombi.2 Endothelial cells also enhance the synthesis of tissue plas­
minogen activator and plasminogen activator inhibitor-1, with
consequent derangement of the coagulation and fibrinolytic systems,
contributing to SIC1,16 (Table 1), a life-threatening complication of se­
vere infections characterized by consumption of clotting factors and
platelets, co-existence of thrombosis, hypofibrinolysis and bleeding,
and possible progression to DIC and multiorgan failure.1,7,40 The two
major biomarkers of SIC diagnosis (Table 1) are prolonged
3043
prothrombin time (PT) and progressive thrombocytopenia; however,
thrombocytopenia can also be multifactorial in intensive care unit
(ICU) patients. Conversely, patients with SIC often have acute lung in­
jury and/or vasoplaegia/shock. Acrocyanosis and ischaemic limbs that
shock liver.40
Critical to managing these patients is early intervention with
antibiotics, source control, and cardiopulmonary support, as septic
shock can also ensue. The initial site of infection, especially in critical or­
gans, may also be relevant for personalized decisions on antithrombotic
drugs.
Moreover, the causative bacterial trigger may not be isolated, and of­
ten patients are treated with empiric broad-spectrum or multiple anti­
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biotic agents that may elicit cytochrome P450 (CYP)-based, clinically
relevant drug–drug interactions with some antithrombotic agents [clo­
pidogrel, ticagrelor, dabigatran, and vitamin K antagonist (VKA)], as
shown in the Supplementary data online, Table S6.
Viral infections
The incidence of viral sepsis is unknown as often the viral aetiology is
difficult to ascertain.41,42 Depending on the season, sepsis may compli­
cate 25%–40% of viral infections. During ICU admittance, secondary in­
fections, which were not the reason for admittance, and bacterial
infections in severe, primarily airborne viral infections (e.g. influenza
and SARS-CoV-2) can also occur.43 Viral sepsis represents ∼30% of
sepsis in South East Asia.44 Viral infectious diseases transmitted by ani­
mal vectors pose potential global threats,45 as viral haemorrhagic fevers
such as dengue have the potential to become pandemic.46 Viral infec­
tions trigger coagulation disorders mostly through inflammatory path­
ways, similar to bacterial agents.47,48 However, unlike most bacterial
infections treatable with antibiotics, specific antiviral drugs are often
not available and/or have limited efficacy.
Many viruses continue their thromboinflammatory effects until the
host immune system can engage, often including elements of the coagu­
lation and fibrinolytic cascades depending on the infection severity.49
Many enveloped viruses, such as SARS-CoV-2, herpes simplex virus
type 1, and influenza, acquire host-derived constituents such as tissue
factor, which enhance viral infectivity and promote activation of coagu­
lation and inflammation.36 In acute infections, macro- and microthrom­
boinflammation triggered by endothelial injury, leukocyte subset
activation and migration, and complement activation contributes
ultimately to organ failure (Figure 1).1,49 Viral infections, with their
different clinical phenotypes (mild, moderate, and severe) and acute
or chronic evolution, may present different risk profiles with
regard to thrombotic complications.47 Another important distinction
with regard to the clinical phenotype is prothrombotic virus types, in­
cluding influenza, SARS-CoV-2, and human immunodeficiency virus, as
compared with haemorrhagic viruses such as dengue, Ebola, and
Hanta.47
Severe viral infection may initially be complicated by more localized
microthrombi, bleeding, and/or multiorgan failure.1,47 Critically ill pa­
tients requiring mechanical ventilation, extracorporeal life support,
and prolonged ICU stays may also develop secondary bacterial infec­
tions, such as ventilator-associated pneumonia, and additional haemo­
static dysfunction. Understanding and classifying the thromboembolic
risk period are important to balance the risks of bleeding vs. thrombosis
at a given time point with regard to prevention of venous thrombo­
embolism (VTE) and/or continuation of ongoing antithrombotic
therapy.
3044 Gigante et al.

Bacteria. Lipopolysaccharide (LPS) Viruses. Enveloped viruses such as

(gram-negative) and peptidoglycan SARS-CoV-2 and HSV-1 acquire
(gram-positive) bind to Toll-like receptors endothelial- and monocyte-derived TF
(TLRs)/CD14 on monocytes. This which enhances viral infectivity and also
induces the release of inflammatory activates coagulation. Viruses can also
cytokines and upregulates tissue factor activate platelets (e.g. via SARS-CoV-
(TF) expression. Bacteria can also 2/ACE2 interactions) which results in
activate platelets (e.g. via binding of LPS platelet aggregation and the release of
with platelet TLRs). inflammatory cytokines.

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Thrombin

Figure 1 Common mechanisms of infection-induced thromboinflammation. Bacteria and viruses induce the expression of tissue factor via distinct
mechanisms (described above in boxes). Tissue factor initiates coagulation which results in the generation of thrombin, an enzyme that not only forms
the fibrin clot but also activates platelets and the complement cascade. Inflammatory cytokines such as tumour necrosis factor α, interleukin-6,
interleukin-1, and prostaglandins promote endothelial cell injury. Injured endothelial cells exhibit a prothrombotic phenotype by shedding natural antic­
oagulants such as heparan sulfate and thrombomodulin, releasing plasminogen activator inhibitor-1 which inhibits fibrinolysis, and releasing ultra-large
von Willebrand factor and P-selectin from Weibel–Palade bodies. Ultra-large von Willebrand factor and P-selectin mediate platelet and neutrophil ad­
hesion, respectively. Activated platelets induce the release of neutrophil extracellular traps which provide a scaffold that traps platelets and red blood
cells. Neutrophil extracellular trap components such as extracellular DNA, histones, and damage-associated molecular patterns trigger coagulation
activate platelets and impair fibrinolysis. The net result of severe bacterial and viral infections is vascular occlusion characterized by thromboinflamma­
tion.7,36–38 Created with Biorender.com. TF, tissue factor; HS, heparan sulfate; TM, thrombomodulin; PAI, plasminogen activator inhibitor; ULVWF,
ultra-large von Willebrand factor; NETs, neutrophil extracellular traps; DAMPs, damage-associated molecular patterns.

Patients with severe infections on
antiplatelet therapy
Patients with multiple cardiovascular risk
factors and enhancers
Recent ESC guidelines have classified cardiovascular risk as high or very
high for patients without symptomatic atherosclerotic cardiovascular
disease (ASCVD), according to the presence of multiple risk factors,
high lifetime risk for ASCVD, and documented significant atherosclerotic
plaque burden (see Supplementary data online, Table S2).9 Patients with
history of coronary revascularization without myocardial infarction (MI)
are referred to in the Patients on single antiplatelet therapy section.
Although acetylsalicylic acid (ASA) should not be given routinely to pa­
tients without history of symptomatic ASCVD,9 guidelines indicate that
ASA may be considered in those patients with documented significant
coronary or peripheral artery disease on imaging, or diabetes mellitus
(DM) with organ damage and/or longstanding and/or other multiple
risk factors.9,50,51 Moreover, high coronary artery calcium score (mostly
≥100 Agatston)52 has been suggested as cardiovascular risk enhancer,
useful to re-assess and stratify cardiovascular risk and identify patients
who may derive a net benefit from low-dose ASA prophylaxis.52,53
Cardiovascular risk factors amplify prothrombotic diathesis, pro­
mote atherosclerotic plaque progression,54 and may impair the im­
mune response during severe infections. Due to immune dysfunction
and high prevalence of antibiotic resistance, patients with type 2 DM
have a high risk for infections and two to six times higher incidence
of sepsis vs. matched non-type 2 DM subjects.55,56
Obesity is also characterized by a prothrombotic and low-grade in­
flammatory milieu.57 Whether obesity is an independent risk factor for
Severe infections and antithrombotic therapy 3045

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Figure 2 Modulation of haemostasis by Staphylococcus aureus and Pseudomonas species infections. Severe bacterial infections can modulate haemo­
stasis via multiple mechanisms. Long-chain polyphosphates (≥500 phosphate units) produced by bacteria promote FXIIa-mediated activation of blood
coagulation. Polyphosphates also incorporate into fibrin clots and render the clots resistant to fibrinolysis. Staphylococcus aureus secretes coagulase and
von Willebrand binding protein which activate prothrombin to thrombin in a non-enzymatic manner. Staphylococcus aureus also secretes fibronectin-
binding protein A and clumping factor A which activate platelets. With respect to NETosis, Staphylococcus aureus secretes pore-forming toxins (such as
Panton–Valentine leucocidin) which induces a unique and rapid (5–60 min) form of NETosis that occurs in an oxidant-independent mechanism.
Elastase, a major virulence factor in Pseudomonas species, activates FXII in the coagulation cascade. Pseudomonas species also secrete protease IV which
inhibits fibrinolysis via the degradation of plasminogen and fibrinogen. The result of severe infections of Staphylococcus aureus and Pseudomonas species is
immunothrombosis, whose dysregulation may lead to vascular occlusion and thromboinflammation. Created with Biorender.com. vWbp, von
Willebrand binding protein; FnbpA, fibronectin-binding protein A; ClfA, clumping factor A; NETs, neutrophil extracellular traps.

sepsis,58 sepsis-associated mortality, and severe thromboses in sepsis, all patients with severe infections that are bedridden or have SIC, to re­
including SARS-CoV-2,59–61 remains controversial.58,62–64 duce the risk of VTE.70 Some settings with a high thrombosis burden,
The safety and efficacy of continuing low-dose ASA in patients with including SARS-CoV-2, may require higher than prophylactic doses
high-degree thrombocytopenia and severe infections have not been (intermediate or therapeutic).19 In each case, the use of heparins at
studied in randomized clinical trials (RCTs), since thrombocytopenia is prophylactic or higher doses should be weighed against the bleeding
an exclusion criterion in all RCTs on antithrombotic drugs. However, risk in the individual patient (Tables 2–4).
no increased bleeding risk was observed outside the ICU setting in can­
cer patients with ASCVD with platelet count <100 × 109/L who re­
ceived ASA (median platelet count in thrombocytopenic patients 32 ×
109/L), suggesting a favourable risk/benefit profile of ASA even in patients
with low-to-moderate degree thrombocytopenia.65,66 Interestingly, ASA Consensus statements Strength of advice
....................................................................................
exerts its antiinflammatory effects at doses higher than those used for
We advise that in patients who are already on
cardiovascular prevention,67 although some data may suggest some indir­
low-dose ASA because of high and very
ect antiinflammatory effect at lower doses.68 However, ASA started high cardiovascular risk due to multiple risk
during hospitalization for viral SARS-CoV-2 infections did not reduce factors, with no history of symptomatic
mortality vs. placebo despite significantly shortening hospitalization,69 ASCVD, low-dose ASA should be
even though some observational studies and meta-analyses suggested maintained, but may require adjustment
a survival benefit of antiplatelet treatment, mostly ASA, started during according to the course of the severe
hospitalization specifically in patients with severe infections or sepsis infection and degree of SIC and
(see Supplementary data online, Table S7). thrombocytopenia (Tables 2–4).19,71,72
Additional prophylactic anticoagulation, with low-molecular-weight Continued
(LMWH) or unfractionated (UFH) heparins, should be considered in
3046 Gigante et al.

Table 2 Management of antithrombotic therapy in patients with multiple cardiovascular risk factors and enhancers and
no history of symptomatic ASCVD

Severe infections where only
preventive antithrombotic
treatment is indicated
......................................................................................................................................................................................
During No routine antiplatelet therapy, SAPT
as pre-existing indication
Prophylactic anticoagulationa
Severe infections and
platelet count ≥20 ×
109/L
No routine antiplatelet
therapy, SAPT as
pre-existing indication
Prophylactic anticoagulation
Severe infections and Severe infections and platelet
platelet count <20 × 109/L count <20 × 109/L in the
presence of multiorgan failure
No antiplatelet therapy No antithrombotic treatment
Prophylactic anticoagulation in
patients at high
thromboembolic risk

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After SAPT as pre-existing indication SAPT as pre-existing SAPT as pre-existing indication SAPT as pre-existing indication
indication
No routine prophylactic No routine prophylactic No routine prophylactic No routine prophylactic
anticoagulationb anticoagulationb anticoagulationb anticoagulationb

ASCVD, atherosclerotic cardiovascular disease; SAPT, single antiplatelet therapy, usually low-dose aspirin.
a
Therapeutic dose anticoagulation may be considered in patients without high risk of bleeding.
b
Thromboprophylaxis may be considered in high-risk patients (persistent immobility, history of venous thromboembolism, advanced age, obesity, cancer, thrombophilia, increased
D-dimer concentrations, and high inflammatory activity) and low risk of bleeding.

no significant increases in bleeding up to 90 days (Table 5). Thus, with

Continued
Consensus statements Strength of advice
....................................................................................
Additional parenteral anticoagulation at
prophylactic or at higher doses depending
on the individual bleeding risk may be
appropriate in patients with high and very
high cardiovascular risk as needed
according to SIC severity (Tables 3
and 4).73–76
Temporary switching to parental
anticoagulation may be appropriate in
some situations where combination is not
justifiable (e.g. SIC with low platelet count
and/or high bleeding risk).
Patients on single antiplatelet therapy
According to current guidelines, single antiplatelet therapy (SAPT),
mainly with low-dose ASA, is used for prevalent stable symptomatic
ASCVD or previous revascularization in the absence of history of
MI.9,51 ASCVD patients have a high susceptibility to viral77 and bacterial
infections78 and worse sepsis outcomes.79 Moreover, sepsis survivors
appear at increased risk for future major vascular events.80
Observational studies on sepsis report that SAPT is associated with a
better outcome (Table 5). Acetylsalicylic acid started before sepsis/sep­
tic shock has been associated with a reduction of mortality rates by 7%
[95% confidence interval (CI): 2%–12%, P = 0.005] in large observation­
al studies85 while a prospective study reported reduced acute respira­
tory distress syndrome with no mortality reduction.88 Expectedly,
pre-sepsis ASA usage was largely associated with previous
ASCVD.85,88 A meta-analysis, including 10 large studies totalling 689
897 patients hospitalized for sepsis,86 showed reduced mortality with
SAPT (mostly ASA) started before sepsis. Available safety data report
the limitations of observational studies, current evidence does not
show harm and supports continuing SAPT during new-onset sepsis
or severe infections (Tables 5 and S7).
Sepsis-induced coagulopathy is associated with high mortality and may
benefit from prophylactic LMWH (Tables 3 and 4).40 Prophylactic
LMWH does not contraindicate SAPT in patients with previous
ASCVD. However, bleeding increases with the degree of thrombocyto­
penia, especially for platelet counts <25 × 109/L, with bleeding rates of
∼15%/year in thrombocytopenic patients89 vs. ∼0.07%/year in healthy
subjects.90 Evidence of efficacy and safety of SAPT in thrombocytopenic
cardiovascular patients is limited since these patients are excluded from
cardiovascular trials. Acute ischaemic and bleeding events in patients
with thrombocytopenia of various origin are associated with four- to
five-fold increased mortality vs. non-thrombocytopenic subjects.89,91
Acetylsalicylic acid used for secondary prevention did not significantly in­
crease major bleeding with platelet counts >20 × 109/L92 while with
≤20 × 10/9/L platelets, data do not support continuing SAPT (Tables 3
and 4). However, data on SAPT in severe thrombocytopenia and sepsis
are not available. Gastrointestinal bleeding during antithrombotic treat­
ment is preventable by gastroprotectant drugs including proton pump
inhibitors (PPIs),93,94 which should be used in sepsis, SIC, thrombocyto­
penia, and/or prophylactic LMWH while on SAPT.66 Moreover, multiple
drugs (vasoactive, antibiotics, antivirals, and corticosteroids) are
co-administered during sepsis, potentially generating clinically relevant
drug interactions.95 Since ASA is not biotransformed by the CYP450 en­
zymes,96 no interactions are reported or can be anticipated, while the
P2Y12 inhibitor clopidogrel, a pro-drug with multiple CYP-dependent
bioactivation steps and low bioavailability, is subjected to clinically rele­
vant interactions that may modify its antiplatelet effect (see
Supplementary data online, Table S6).97,98
Recent ESC guidelines9,51 recommend PPIs in patients on SAPT (IA)
to reduce gastrointestinal bleeding.93,99–101 Some studies have sug­
gested that in ICU patients, gastric acid suppression may further in­
crease the risk of penumonia.102 However, in the case of
coagulopathy, as for SIC, the benefit of reducing major gastrointestinal
Severe infections and antithrombotic therapy 3047

Table 3 Management of antithrombotic drugs in patients with ongoing antithrombotic treatment, SOFA score of 1a,
and increasing SICa score

Patients on SAPT Patients on DAPT Patients on Patients on OAC

long-term OAC for recentb
thromboembolic
event
......................................................................................................................................................................................
SIC score = 2
Platelet count 100– No change <3 m after PCI or ACS: no No change No change
149 × 109/L change
or 3–6 m after PCI/ACS: a
PT ratio 1.2–1.4 P2Y12 inhibitor or ASA

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≥6 m after PCI/ACS: ASA
or a P2Y12 inhibitor
SIC score = 3
Plateleat count 100– Platelet count ≥20 × <3 m after PCI or ACS: no Platelet count 100– Platelet count 100–
149 × 109/L and PT 109/L: no change change or consider P2Y12 149 × 109/L and PT 149 × 109/L and
ratio 1.2–1.4 inhibitor or ASA ratio 1.2–1.4: no PT ratio 1.2–1.4:
change no change
or Platelet count <20 × Consider ASA if platelet count Platelet count <100 × Platelet count 50–
Platelet count 109/L: stop SAPT <20 × 109/L 109/L 100 × 109/L
<100 × 109/L 3–6 m after PCI/ACS: P2Y12 Change VKA/ Change VKA/
or inhibitor or ASA DOAC to heparinc DOAC to
PT ratio >1.4 Consider ASA if platelet at prophylactic or therapeutic dosed
count <20 × 109/L intermediate dose heparinc, split into
≥6 m after PCI/ACS: ASA two daily doses
or clopidogrel
Consider no SAPT if platelet
count <20 × 109/L
SIC score = 5
Platelet count <100 × Platelet count ≥20 × <1 m after PCI or ACS: no Platelet count ≥30 × Platelet count ≥30 ×
109/L and PT ratio 109/L: no change change if platelet count ≥20 × 109/L: no change 109/L: no change
>1.4 Platelet count <20 × 109/L or consider P2Y12 Platelet count <30 × Platelet count 30–
109/L: stop SAPT inhibitor (clopidogrel) or ASA 109/L: stop heparinc 50 × 109/L:
Consider SAPT-ASA prophylactic dose
monotherapy if platelets heparinc
<20 × 109/L Platelet count <30 ×
1–3 m after PCI/ACS: P2Y12 109/L: stop heparinc
inhibitor (clopidogrel) or ASA
Consider SAPT–ASA
monotherapy if platelets
<20 × 109/L
≥3 m after PCI/ACS: ASA or
clopidogrel
Consider no APT if platelet
count <20 × 109/L

These treatment proposals should be considered in light of individual patient characteristics and may not be appropriate if the risk of life-threatening stent thrombosis is high or other
patient characteristics suggest that bleeding risk of DAPT or a more effective P2Y12 inhibitor (ticagrelor or prasugrel) outweighs the thrombotic risk.
ACS, acute coronary syndrome; APT, antiplatelet therapy; DAPT, dual antiplatelet therapy; OAC, oral anticoagulant; PT, prothrombin time; SAPT, single antiplatelet therapy; VKA, vitamin
K antagonist.
a
SIC and SOFA definitions and scores are shown in Table 1 and Supplementary data online, Table S3, respectively.
b
Recent thromboembolism refers to an event within the previous 3 months.
c
Heparins: low-molecular weight heparin (LMWH) at indicated dose for creatinine clearance >30 mL/min, with dose adjustment for creatinine clearance 15–30 mL/min; unfractionated
heparin (UFH) if creatinine clearance <15 mL/min.
d
Therapeutic dose LMWH should be reduced when the calculated creatinine clearance is <30–40 mL/min according to product monograph, or changed to UFH. If creatinine clearance
<15 mL/min, use only UFH.
3048 Gigante et al.

Table 4 Management of antithrombotic drugs in patients with ongoing antithrombotic treatment, SOFAa score of at
least 2, and increasing SICa score

Patients on SAPT Patients on DAPT Patients on Patients on OAC

long-term OAC due to recentb
thromboembolic
event
......................................................................................................................................................................................
SIC score = 3
Platelet count 100– No change <3 m after PCI or ACS: no No change No change
149 × 109/L change
or 3–6 m after PCI/ACS: consider
PT ratio 1.2–1.4 P2Y12 inhibitor or ASA (SAPT)

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≥6 m after PCI/ACS: SAPT
SIC score = 4
Platelet count 100– Platelet count ≥20 × <1 m after PCI/ACS: no Platelet count 100– Platelet count 100–
149 × 109/L and PT 109/L: no change change or consider P2Y12 149 × 109/L and PT 149 × 109/L and PT
ratio 1.2–1.4 Platelet count <20 × inhibitor (clopidogrel) or ASA ratio 1.2–1.4: no ratio 1.2–1.4: no
or 109/L: stop SAPT (SAPT) change change
Platelet count Consider SAPT with ASA if Platelet count 50– Platelet count 50–
<100 × 109/L platelet count <20 × 109/L 100 × 109/L: change 100 × 109/L: change
or 1–3 m after PCI or ACS: no VKA/DOAC to VKA/DOAC to
PT ratio >1.4 change or P2Y12 inhibitor or therapeutic dosec therapeutic dosec
ASA heparind, split into two heparind, split into
Consider SAPT with ASA if daily doses two daily doses
platelet count <20 × 109/L
3–6 m after PCI/ACS: P2Y12
inhibitor or ASA
Consider SAPT with ASA if
platelets <20 × 109/L
≥6 m after PCI/ACS: SAPT
Consider no SAPT if platelet
count <20 × 109/L
SIC score = 6
Platelet count Platelet count ≥20 × <1 m after PCI or ACS: no Platelet count 30– Platelet count 30–
<100 × 109/L and PT 109/L: no change change if platelets ≥20 × 109/ 50 × 109/L: 50 × 109/L:
ratio >1.4 Platelet count <20 × L; consider P2Y12 inhibitor prophylactic dose prophylactic dose
109/L: stop SAPT (clopidogrel) or ASA (SAPT) if heparind; platelet heparind; platelet
platelets >20 × 109/L count <30 × 109/L: count <30 × 109/L:
Consider SAPT with ASA if stop heparin stop heparin
platelets <20 × 109/L
1–3 m after PCI/ACS: P2Y12
inhibitor (clopidogrel) or ASA
Consider SAPT with ASA if
platelet count <20 × 109/L
≥3 m after PCI/ACS: SAPT
Consider no SAPT if platelet
count <20 × 109/L

These treatment proposals should be considered in light of individual patient characteristics and may not be appropriate if the risk of life-threatening stent thrombosis is high or other
patient characteristics suggest that bleeding risk of DAPT or a more effective P2Y12 inhibitor (ticagrelor or prasugrel) outweighs the thrombotic risk.
ACS, acute coronary syndrome; APT, antiplatelet therapy; DAPT, dual antiplatelet therapy; OAC, oral anticoagulant; PT, prothrombin time; SAPT, single antiplatelet therapy; VKA, vitamin
K antagonist.
a
SIC and SOFA definitions and scores are provided in Table 1 and Supplementary data online, Table S3, respectively.
b
Recent thromboembolism refers to an event within the previous 3 months.
c
Therapeutic dose LMWH should be reduced when the calculated creatinine clearance is <30–40 mL/min according to product monograph, or changed to UFH. If creatinine clearance
<15 mL/min, use only UFH.
d
Heparins: low-molecular weight heparin (LMWH) at indicated dose for creatinine clearance >30 mL/min, with dose adjustment for creatinine clearance 15–30 mL/min; unfractionated
heparin (UFH) if creatinine clearance <15 mL/min.
Severe infections and antithrombotic therapy 3049

Table 5 Studies in patients on single or dual antiplatelet therapy before hospitalization for severe infections or sepsis

Study (year) Design Population Comparison and Effectiveness Safety Other remarks
type of antiplatelet
agent(s)
......................................................................................................................................................................................
Erlich et al. Multicentre 161 hospitalized Pre-hospitalization ASA users: lower NA
(2011)81 observational, patients at risk for SAPT–ASA users: acute limb ischaemia
prospective study acute lung injury, 79 OR 0.37 (95% CI:
∼30% due to sepsis 0.16–0.84) P = 0.02
or infection No difference in
mortality or length
of hospitalization.

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Losche et al. Retrospective Cohort 1: 224 patients Cohort 1, n (%): Cohort 1: ICU Cohort 2: no increase Similar benefit also
(2012)82 analysis of two hospitalized for SAPT–ASA: 38 (17); admission (%) 9.1 vs. of bleeding after correcting
cohorts pneumonia SAPT–clopidogrel: 9 26.3% associated with for SOFA score,
Cohort 2: 615 patients (4) Length of stay 13.9 previous APT use age, gender, and
admitted to the ICU Cohort 2, n (%): ± 6.2 vs. 18.2 ± 10.2 C-reactive
for sepsis SAPT–ASA: 129 (21); days in APT users vs. protein levels
SAPT or DAPT non-users
with clopidogrel: 25 (4) Cohort 2: OR for
total mortality 0.19
(95% CI: 0.12–0.33)
for APT use vs.
non-use; OR 0.20
(95% CI: 0.12–0.33)
for ASA users vs.
non users
Valerio-Rojas Retrospective 651 ICU patients, 272 Comparison of prior Mortality: (a)OR 0.76 Red blood cell Platelet count
et al. (42.8%) on APT antiplatelet vs. no (95% CI: 0.52–1.10) transfused units: not significantly
(2013)83 SOFA score day 1: antiplatelet ARDS: (a)OR 0.50 different among higher in the APT
no APT median SAPT–ASA: n = 241 (95% CI: 0.35–0.71) groups group
(IQR) 6 (4–10) and SAPT–clopidogrel: Mechanical Platelet-transfused PT and INR
APT 6 (4–9), P = ns n=4 ventilation (a)OR patients higher in significantly
DAPT with 0.62 (95% CI: 0.45– the no APT group lower in the APT
clopidogrel: n = 27 0.87) (P = 0.01) group
Tsai et al. Nationwide 683 421 patients Use of antiplatelet Mortality: (a)OR 0.82, NA Benefit higher in
(2015)84 population-based hospitalized for agents before (95% CI: 0.81–0.83, current users
cohort and nested sepsis admission P = 0.001) (aOR 0.78, 95%
case–control Antiplatelets: aspirin CI 0.76–0.79);
study (n = 51 340), non-significant in
clopidogrel or past users (aOR
ticlopidine (13 368), 1.00, 95% CI
prescribed within 0.98–1.02)
1 year before the
index date
Trauer et al. Meta-analysis of 11 n = 6823 ICU patients Comparison of prior Mortality: ASA users: NA
(2017)85 observational hospitalized for aspirin or APT usage significant reduction
studies sepsis vs. no usage by 7% (95% CI: 2%–
Antiplatelet 12%), P = 0.005
included SAPT– APT users:
ASA, SAPT significantly reduced
clopidogrel, or by 6% (95%CI: 0%–
DAPT aspirin plus 12%), P = 0.004
clopidogrel
Ouyang et al. Meta-analysis of 10 689 897 patients SAPT–ASA only used Mortality OR: 0.78 NA A subgroup on
(2019)86 studies hospitalized for in 5 out of 10 studies (95% CI: 0.77–0.80) timing of APT
sepsis SAPT–ASA: OR showed benefit
121 147 on APT for APT
Continued
3050 Gigante et al.

Table 5 Continued

Study (year) Design Population Comparison and Effectiveness Safety Other remarks
type of antiplatelet
agent(s)
......................................................................................................................................................................................
(SAPT–ASA, SAPT– 0.60 (95% CI: 0.53– administered
clopidogrel, DAPT 0.68) also after
clopidogrel, or hospitalization
prasugrel)
Chow et al. Observational, 1:2 17 347 patients Pre-hospital In-hospital mortality Epistaxis (%): 0.9 vs. 0.4 Blood transfusion
(2021)87 propensity score hospitalized for antiplatelet therapy (%): 18.9 with vs. in users vs. no users. higher in
matched for COVID-19: 6781 on vs. no antiplatelet 21.5 with and No difference in GI non-users (4%

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demographics and pre-hospital therapy without or IC bleeding vs. 2.8%, P <
comorbidities antiplatelet drugs SAPT–ASA: 83.9% pre-hospital APT 0.001)
hospital mortality PE Mean platelet count: SAPT–clopidogrel (HR 0.81; 95% CI: Subgroup
210 (160–275) 8.2% 0.76–0.87) analysis
×103/µL DAPT: 7.4% PE: 2.2% vs. 3% in underpowered
users vs. non-users to detect
(P = 0.002) differences
Subgroup analysis: between SAPT–
lower mortality in ASA vs. SAPT–
SAPT–ASA only clopidogrel vs.
No mortality DAPT
reduction for
SAPT–clopidogrel
or DAPT

APT, antiplatelets; ASA, acetylsalicylic acid; ARDS, acute respiratory distress syndrome; CI, confidence interval; DAPT, dual antiplatelet therapy; HR, hazard ratio; GI, gastrointestinal; IC,
intracerebral; ICU, intensive care unit; INR, international normalized ratio; IQR, interquartile range; (a)OR, (adjusted) odds ratio; NA, not available; PE, pulmonary embolism; PT,
prothrombin time; SAPT, single antiplatelet therapy.

bleeding seems higher than the risk of pneumonia, and PPIs seemed Patients on dual antiplatelet therapy
more effective than histamine H2 receptor antagonists, although When a patient develops severe infection while on dual antiplatelet
more randomized trials are needed.94,103 If a PPI is administered, espe­ therapy (DAPT) consisting of ASA and a P2Y12 inhibitor, large observa­
cially in severely thrombocytopenic patients on clopidogrel, omepra­ tional studies support the safety of continuing DAPT in this setting
zole and esomeprazole should be avoided due to potential and
(Table 5), but evidence from randomized studies about the balance of
clinically relevant drug–drug interactions (see Supplementary data
efficacy and safety, especially as SIC progresses, is lacking.87,109,110
online, Table S6).104–107
Few observational and post hoc analyses suggested that DAPT with clo­
pidogrel may be associated with an increased risk of infection vs. ASA
alone after coronary artery bypass surgery,111 and that DAPT with tica­
grelor may be associated with a lower risk of bacterial lung infec­
tion.112–115 A weak off-target clopidogrel effect with a minor decrease
Consensus statements Strength of advice
.................................................................................... on leucocyte count has been described, but without any impact on rates
We advise to continue SAPT in patients with a of neutropenia.116,117 On the other hand, platelet P2Y12 inhibition has
clear, pre-existing indication in secondary been inconsistently reported to reduce systemic inflammatory response
cardiovascular prevention during new-onset in animal and human models of endotoxemia,118–121 but the clinical rele­
sepsis or severe infections, unless severe SIC
vance remains unknown. Furthermore, SAPT with either ticagrelor or clo­
with platelet count ≤20 × 109/L occurs.71,86,88
pidogrel, in addition to standard anticoagulant therapy, failed to improve
We advise to check for clinically relevant drug clinical outcomes in non-critically ill hospitalized COVID-19 patients.122
interactions with antimicrobials when For most patients treated with ASA and clopidogrel, ASA or clopido­
clopidogrel or ticagrelor is used and with grel123,124 may be stopped, and SAPT was used starting from 3 to 6
PPIs when clopidogrel is used.107,108 months after percutaneous coronary intervention (PCI) and/or acute
coronary syndrome (ACS), without significant stent thrombosis risk
We advise to treat patients with high degree of
SIC, including thrombocytopenia, with (Tables 3 and 4).123–126
gastroprotective agents, preferably For DAPT-treated patients who develop an indication for full-dose
PPIs.19,93,99,102,103 anticoagulant therapy during sepsis, triple antithrombotic therapy
(DAPT plus an anticoagulant drug) carries a high bleeding risk, while
dual antithrombotic therapy with clopidogrel and one anticoagulant
Severe infections and antithrombotic therapy 3051

Table 6 Studies in patients with anticoagulant therapy during severe infections or sepsis

Study (year) Study type Population Comparison or Efficacy outcome Safety Other remarks
intervention outcome
......................................................................................................................................................................................
Umemura Meta-analysis of 14 767 patients Anticoagulants vs. Mortality overall, RR 0.97 Bleeding Only three of the
et al. 24 RCTs with sepsis, control (95% CI: 0.92–1.02) complications studies used
(2016)137 treated with any Subgroup with DIC, overall, RR heparins
anticoagulant, of RR 0.72 (95% CI: 0.62– 1.33 (95% CI:
those 3206 had 0.85) 1.12–1.57)
DIC Subgroup with
DIC, RR 1.26
(95% CI: 0.86–

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1.85)
Wang et al. Meta-analysis of Patients with sepsis UFH or LMWH vs. 28-day mortality, OR Bleeding A variety of heparin
(2014)138 nine controlled (592) or severe control 0.66 (95% CI: 0.56– complications, dose regimens
trials sepsis (3011) 0.77) OR 1.06 (95% were used
CI: 0.83–1.36)
Li et al. Meta-analysis of 684 adult patients LMWH at mainly 28-day mortality, RR 0.52 Bleeding All studies were small
(2021)139 10 RCTs with sepsis intermediate dose (95% CI: 0.38–0.70) complications, with 32–159
vs. control APACHE II score RR 1.29 (95% patients
mean difference −4.42 CI: 0.76–2.17)
(95% CI: −5.50 to
−3.33
Søgaard Nationwide 3030 patients with Warfarin at the time 90-day all-cause Bleeding No information on
et al. healthcare AF on warfarin of sepsis diagnosis mortality, HR 0.64 complications, how
(2017)140 database. vs. 55 721 vs. no warfarin. (95% CI: 0.58–0.69); 1.19 (95% CI: anticoagulation
Inverse patients without Warfarin effect thromboembolism, 1.00–1.41) was managed
probability of AF and warfarin, will remain 3–5 1.25 (95% CI: 0.89– during
treatment all admitted for days after stopping 1.76) hospitalization. No
weighting sepsis data on sepsis
severity

APT, antiplatelet drugs; ASA, acetylsalicylic acid; ARDS, acute respiratory distress syndrome; CI, confidence interval; DAPT, dual antiplatelet therapy; DIC, disseminated intravascular
coagulation; HR, hazard ratio; GI, gastrointestinal; IC, intracerebral; ICU, intensive care unit; INR, international normalized ratio; IQR, interquartile range; LMWH,
low-molecular-weight heparin; NA, not available; (a)OR, (adjusted) odds ratio; PE, pulmonary embolism; PT, prothrombin time; RCT, randomized clinical trial; RR, relative risk;
SAPT, single antiplatelet therapy; UFH, unfractionated heparin.

drug may offer a safer strategy, even early after PCI and/or ACS,127 pro­ secondary haemostasis (see Supplementary data online, Figure S2).
vided a normal platelet count or a mild degree of thrombocytopenia, Consequently, antithrombotic therapy should be carefully tailored in
although this strategy has never been tested in severe infection devel­ DAPT-treated patients with severe infection who require therapeutic
oping SIC. Moreover, the safety vs. efficacy of a dual antithrombotic anticoagulation or develop coagulopathy.
therapy with ASA, as compared with clopidogrel or ticagrelor, has Current ESC guidelines9,51 recommend PPIs94 in patients on DAPT to
not been tested in a contemporary setting nor in severe infections reduce the risk of gastrointestinal bleeding19,99; however, caution should
and sepsis with or without SIC. Thus, in patients with sepsis or severe be used in critically ill patients,102 as detailed in the previous section.
infections with an indication for DAPT, who need full anticoagulant
doses, it is safe to stop DAPT and continue with one antiplatelet agent,
either clopidogrel or aspirin depending on the severity of SIC,
thrombocytopenia, and co-medication, also earlier after PCI or ACS Consensus statements Strength of advice
(Table 5), although this strategy has never been tested in sepsis and/ ....................................................................................
or in severely thrombocytopenic patients (Tables 3 and 4). We advise to continue DAPT following recent (i.e.
Importantly, in patients with severe sepsis on ticagrelor or clopidogrel, up to 6 months) ACS with or without PCI, in
potential clinically relevant drug–drug interactions with antimicrobial patients with platelet count >50 × 109/L.81–87
agents should always be considered due to their CYP450-dependent bio­
transformation (see Supplementary data online, Table S7).128 Moreover,
Continuing DAPT if platelet count is 30–50 ×
∼25% of patients on ticagrelor develop drug-related dyspnoea,129,130
109/L may be appropriate unless coagulation is
which may require differential diagnosis.130 Caution is required with clopi­
severely impaired, or there is a high bleeding
dogrel if hepatic dysfunction develops during severe infection as this can risk. In the latter cases, we advise to switch
reduce its antiplatelet effect.107 Ticagrelor is also contraindicated in severe to SAPT with clopidogrel or low-dose
hepatic impairment due to risk of accumulation and bleeding.108 ASA.69,81–87,133–136
Since thrombin is also a potent platelet activator, anticoagulants
Continued
may also diminish platelet activation,131,132 on top of impairing
3052
Continued
Consensus statements Strength of advice
....................................................................................
Continuing SAPT with ASA may be appropriate
in patients with more severe
thrombocytopenia and at higher risk of major
vascular event recurrence, on a case-by-case
basis.66,81–87
Continue with one antiplatelet agent (ASA or a
P2Y12 inhibitor, preferably clopidogrel) may be
appropriate when patients receive therapeutic
dose of anticoagulation or develop higher
degree of SIC (>3) with PT >1.4.
We advise to check for relevant drug–drug
interactions for ticagrelor and clopidogrel and
ongoing antiviral or antibiotic agents.107,108
We advise to treat patients with gastroprotective
agents, preferably PPIs.19,93,99,102,103
Patients on oral anticoagulants
Anticoagulants, including antithrombin and soluble thrombomodulin
(see Supplementary data online, Figure S3), may improve outcomes in
SIC by reducing organ dysfunction, especially with pre-existing coagulo­
pathy.1 In a meta-analysis of 24 trials (14 767 patients) addressing vari­
ous anticoagulants in sepsis, reduced mortality was only observed in
those with sepsis-associated DIC.137 However, there was an increased
risk for bleeding, and only five studies used heparin as anticoagulant. A
meta-analysis of nine studies with prophylactic dose UFH or LMWH in
sepsis demonstrated a significant reduction in mortality without a sig­
nificant increase in bleeding risk.138 Furthermore, in a meta-analysis
of 10 trials of specifically LMWH, in 8 of which at intermediate dose
(684 patients), reduced 28-day mortality was again observed without
increased bleeding (Table 6).139
Outcomes for patients with atrial fibrillation (AF) receiving warfarin and
diagnosed with sepsis were analysed from a Danish national database, using
non-anticoagulated patients without AF as controls.140 Bleeding complica­
tions were marginally higher, and mortality was lower in the AF group, but
interpretation is hampered by the 90-day observation period, thus well be­
yond the phase of critical care. A retrospective cohort study addressed the
anticoagulant management of 115 septic patients with AF in the ICU, of
whom 34 continued warfarin or heparin during hospitalization.141 Time
in therapeutic range with warfarin was <50% (Table 6).
Anticoagulated patients had similar survival rates and more bleeding
complications. Current knowledge of risk/benefit of direct oral anticoa­
gulants (DOAC) in AF and SIC is limited. Oral anticoagulations are gen­
erally unsuitable for patients in ICU due to vomiting, gastroparesis,
unpredictable absorption, and need for frequent cessation due to inva­
sive procedures. International normalized ratio (INR) values are specif­
ically intended for VKA monitoring and are not informative for other
anticoagulants. The PT ratio thresholds in the SOFA score are not help­
ful for decision-making when OACs are used.
Gigante et al.
There is a paucity of data reporting management of patients with se­
vere infections on long-term VKA. Further, with the high mortality,
morbidity, and coagulopathy associated with sepsis and severe infec­
tions, interpretation of the few reports based on single-centre observa­
tional experience is challenging. A systematic review identified eight
cases of SARS-CoV-2–related prosthetic heart valve thrombosis, with­
out evidence for non-adherence to the VKA regimen.71 Intensified
monitoring of INR or switch to intravenous heparin during hospitaliza­
tion might reduce this risk (Tables 3 and 4).
There is a lack of studies on patients with recent VTE and sepsis.
Generally, the risk of recurrent VTE decreases with time. For those
with VTE within 1 month, especially with pulmonary embolism, the bene­
fit of full-dose anticoagulation probably outweighs the bleeding risk. By
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splitting the therapeutic dose of LMWH into two daily doses, high
peak concentrations are avoided. With longer intervals from the VTE,
intermediate-dose LMWH is probably sufficient (Tables 3 and 4).
Clinically relevant drug–drug interaction should be considered with each
OAC, either VKA or DOAC, based on P-glycoprotein- and/or
CYP450-related biotransformation (see Supplementary data online,
Table S7). Drugs that compete as substrates, inhibitors, or enhancers of
their activity may affect warfarin efficacy and/or safety; thus, INR monitoring
should be more frequent to adjust dosing (Graphical Abstract). Dabigatran
is contraindicated with strong P-glycoprotein inhibitors including azole anti­
mycotics, some antivirals,142 while caution should be exerted with clarithro­
mycin.142 Edoxaban dosing should be reduced with strong P-glycoprotein
inhibitors,143 and rivaroxaban144 and apixaban145 are not recommended
with drugs that are strong inhibitors of both P-glycoprotein and CYP3A4
(azole antimycotics and HIV protease inhibitors).
Current ESC guidelines9,51 recommend the use of PPIs94 in patients
treated with OAC (IA)146,147; however, caution should be used in crit­
ically ill patients102 as stated above.
Consensus statements Strength of advice
....................................................................................
For patients on oral anticoagulation for stroke
prophylaxis in AF in case of severe infection,
we advise to switch to low- or intermediate-
dose LMWH when platelets drop between
100 and 30 × 109/L (only if INR is <2.0 for
those on a VKA).138,139
We advise to interrupt anticoagulant treatment
for platelet count <30 × 109/L. For patients
with VTE, the dose of heparin should be
based on the severity of the infection and
whether the indication is a recent
thromboembolic event.66
For patients with VTE within 1 month, it may be
appropriate to remain on full anticoagulation,
preferably with LMWH, split into two daily
doses.
We advise to check for clinically relevant drug–
drug interactions in patients treated with
OAC based on ongoing antimicrobial
treatment and on the specific anticoagulant
drug in use.148
Continued
Severe infections and antithrombotic therapy
Continued
Consensus statements Strength of advice
....................................................................................
We advise to treat patients with high degree of
SIC with gastroprotective agents, preferably
PPIs.19,93,99,102,103
In patients with a long-term VKA indication, we
advise to intensify INR monitoring or switch
to heparin during hospitalization.71,141
Vaccination in patients at high and
very high cardiovascular risk
Vaccinations decrease the risk of ASCVD, though with different
effectiveness. Influenza vaccine, regardless of formulation and obser­
vation period, reduced the risk of hospitalization for stroke, heart fail­
ure,149 ACS, peripheral artery disease,122,150 all-cause, and
cardiovascular mortality149,151,152 in high-risk patients. The relative
effectiveness of high vs. standard dose of quadrivalent influenza vac­
cine in preventing cardiovascular and pulmonary diseases at a popu­
lation level is under investigation in a randomized, registry-based
trial in elderly Finnish citizens.153 In patients with recent ACS, influ­
enza vaccine reduced the risk for all-cause and cardiovascular mortal­
ity,154,155 regardless of vaccine formulation.150 An early vaccination
with double-dose influenza vaccination does not seem to add benefits
in terms of prognosis in ACS patients156 and, in a small clinical trial,
the risk of hospitalization for ACS, heart failure, and stroke.157 In pa­
tients with chronic coronary syndrome, a trend towards a reduction
in cardiovascular mortality and incidence of cardiovascular complica­
tions was observed.154,158,159 The ESC guidelines recommend influ­
enza vaccine in elderly patients with chronic coronary syndromes
(IB).51 In a recent meta-analysis, influenza vaccine reduced the risk
of ASCVD, cardiovascular, and all-cause mortality in patients with
ASCVD.160 The addition of pneumococcal polysaccharide vaccine
to influenza vaccine reduced the incidence of ACS, ischaemic stroke,
and heart failure hospitalization.161 However, in observational stud­
ies, no consistent benefits of pneumococcal polysaccharide vaccine
alone have been observed,133,162,163 with a possible beneficial effect
on the risk for ACS, but not ischaemic stroke.164 No clinical trial or
large longitudinal study has assessed the effect of influenza vaccine
on the risk of incident VTE or AF. Recently, SARS-CoV-2 vaccines
have been given worldwide and long follow-up may reveal long-term
cardiovascular effects. Vaccine-induced immune thrombotic
thrombocytopenia is a rare (1:50 000–100 000)165 but often fatal
autoimmune adverse reactions to SARS-CoV-2 vaccinations
(ChAdOx1 and Ad26.COV2.S) characterized by coagulopathy, acute
arterial and venous thrombosis, and bleeding.166–169 Notably, differ­
ent mechanisms underlie vaccine-induced immune thrombotic
thrombocytopenia vs. other thromboembolic complications during
SARS-CoV-2 infection.170
3053
Consensus statements Strength of advice
....................................................................................
We advise to vaccinate against influenza
patients at high and very high risk of ASCVD
or with previous ASCVD.51,160,171
It may be appropriate to reinforce the use of
vaccinations for patients at high and very high
risk of ASCVD or with previous ASCVD to
reduce the risk of severe infections and the
consequent possible associated SIC.
Downloaded from https://academic.oup.com/eurheartj/article/44/32/3040/7223688 by guest on 28 August 2023
Conclusions and future directions
The clinical course of coagulopathy associated with severe infections
should guide the management of patients with a previous clear indi­
cation for single or combined antithrombotic agents due to previous
thrombotic disorders or at high thrombotic risk (Tables 3 and 4
and Graphical Abstract). Antithrombotic therapy should be main­
tained throughout the hospitalization, taking into account the pro­
gression toward SIC and the degree of thrombocytopenia
(Graphical Abstract).
Some limitations need to be acknowledged. This document does not
consider patients on mechanical circulatory devices, a common condi­
tion in sepsis patients in ICU, and patients requiring acute revasculari­
zation. It does not include management of antithrombotic therapy
during severe fungal and parasite infections.
However, in patients on antithrombotic therapy who develop severe
infections or sepsis, mortality remains high despite multiple considera­
tions of clinical management due to the complex inflammatory and
other immunomodulatory effects of sepsis.
Beyond early therapy of the underlying causative infection, the un­
met need is the task of improving therapeutic modalities, specifically fo­
cusing on novel methods for attenuating thromboinflammation in this
critically ill patient population.
Supplementary data
Supplementary data are available at European Heart Journal online.
Declarations
Disclosure of Interest
A.B.: consultant fee from MSD Italy, investigator-initiated grant to the
institution from GSK Spa, research grant from Nordic Pharma Srl,
and travel grant from Pfizer srl.
C.C.: speaker fees from Astra Zeneca, Boehringer Ingelheim, Bayer,
Bristol Myers Squibb, and Orion Pharma outside the submitted work.
J.L.F.: speaker fees from Eli Lilly Co, Daiichi Sankyo, Inc., AstraZeneca,
Roche Diagnostics, Pfizer, Abbott, Ferrer, Rovi, Boehringer Ingelheim,
and Bristol-Myers Squibb; consulting fees from AstraZeneca, Eli Lilly
3054
Co., Ferrer, Boston Scientific, Pfizer, Boehringer Ingelheim, Daiichi
Sankyo, and Bristol-Myers Squibb; and research grant from AstraZeneca.
T.G.: personal fees from AstraZeneca, Boehringer Ingelheim, Pfizer,
Boston Scientific, and Abbott; grants and personal fees from Bayer
Healthcare, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, and
Medtronic outside of the submitted work; supported by the German
Research Foundation (DFG) KFO-274-Project number 190538538,
by the German Research Foundation (DFG)-Project number
374031971-TRR 240, and funded by the German Research
Foundation (DFG)-Project number 335549539-GRK2381.
J.H.L.: steering or advisory committees for Octapharma, Merck, and
Werfen.
E.L.: speaker’s fees from Novartis and Novo Nordisk.
B.R.: speaker fee from Sobi (Sweden), consultant fee from Aboca
(Italy), and investigator-initiated grant to the institution from Bayer
AG for a study on rivaroxaban.
S.S.: research grant from Octapharma and honoraria from Bayer,
Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, and Sanofi.
R.F.S.: research grants and personal fees from AstraZeneca,
Cytosorbents, GlyCardial Diagnostics, and Thromboserin and personal
fees from Alnylam, Bayer, Bristol Myers Squibb/Pfizer, Chiesi, CSL
Behring, Daiichi Sankyo, HengRui, Idorsia, Intas Pharmaceuticals,
Medscape, Novartis, PhaseBio, Portola, and Sanofi Aventis.
J.T.: speaker honoraria from Bayer, BMS Pfizer, Boehringer, and
Daichii Sankyo.
H.t.C.: research support from Bayer; consultancy fees from
AstraZeneca, Leo, Galapagos, Novostia, and Alveron; shareholder
Coagulation Profile; and all revenues deposited at the CARIM School
for Cardiovascular Diseases, Maastricht University.
B.G., M.-L.B.-P., M.B., G.V., E.v.G., and P.C.L. have no conflict of inter­
est to report.
Data Availability
No new data were generated or analysed in support of this research.
Funding
All authors declare no funding for this contribution.
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