Abstract

Patients with severe infections and a pre-existing indication for antithrombotic therapy, i.e. antiplatelet agents, anticoagulant drugs, or their combinations, 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 antithrombotic 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 associated 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 vaccines, if available, are crucial to prevent events or improve outcomes and prognosis.

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 favourable in these patients when platelet count is below 30 × 109/L. When platelet count is below 20 × 109/L, antithrombotic therapy should be discontinued, 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.
Graphical Abstract

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 favourable in these patients when platelet count is below 30 × 109/L. When platelet count is below 20 × 109/L, antithrombotic therapy should be discontinued, 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.

Introduction

Severe bacterial and viral infections are often associated with a coagulopathy that can be defined as any alteration or disturbance of haemostasis resulting in either bleeding, clotting, or both.1 More specifically, a dysregulated balance of thrombosis and fibrinolysis can result in excessive clotting, 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 prescriptions in the European population of ∼15%–20% across different countries.5,6 Thus, the management of antithrombotic treatment in patients suffering from severe infections represents a frequent clinical problem 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 antithrombotic therapy.

The scope of this clinical consensus statement is to review the current evidence on the management of patients with ongoing antithrombotic 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) criteria, defined and scored according to the International Society on Thrombosis and Haemostasis (ISTH) (Table 1).1

Table 1

Scoring for sepsis-induced coagulopathy (SIC)a

Points
012
Prothrombin time (PT-INR)>1.21.2–1.4>1.4
Platelet count (×109/L)>150100–149<100
Total SOFAb (respiratory, cardiovascular, hepatic, and renal)01≥ 2
Points
012
Prothrombin time (PT-INR)>1.21.2–1.4>1.4
Platelet count (×109/L)>150100–149<100
Total SOFAb (respiratory, cardiovascular, hepatic, and renal)01≥ 2

SOFA, Sequential Organ Failure Assessment; INR, international normalized ratio. Modified from Iba et al.  7

Total SIC score ≥4 corresponds to DIC ≥ 5.8

SOFA scoring included in SIC grading does not include the mental status since it is tailored to clinical aspects relevant in sepsis.

Table 1

Scoring for sepsis-induced coagulopathy (SIC)a

Points
012
Prothrombin time (PT-INR)>1.21.2–1.4>1.4
Platelet count (×109/L)>150100–149<100
Total SOFAb (respiratory, cardiovascular, hepatic, and renal)01≥ 2
Points
012
Prothrombin time (PT-INR)>1.21.2–1.4>1.4
Platelet count (×109/L)>150100–149<100
Total SOFAb (respiratory, cardiovascular, hepatic, and renal)01≥ 2

SOFA, Sequential Organ Failure Assessment; INR, international normalized ratio. Modified from Iba et al.  7

Total SIC score ≥4 corresponds to DIC ≥ 5.8

SOFA scoring included in SIC grading does not include the mental status since it is tailored to clinical aspects relevant in sepsis.

Methodology and definitions

The panel of co-authors has been selected because of their complementary expertise in the fields of cardiovascular pharmacology, infectious disease, clinical cardiology, coagulation, and atherosclerosis 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 coagulopathy (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 etiology,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 elements of the SOFA score are included in the SIC criteria (Table 1) to grade the severity of sepsis. Notably, SIC development in patients hospitalized 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 vaccination 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 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) infection was also excluded since it has recently been addressed by dedicated ESC and ISTH guidelines.18,19

Immunothrombosis or thromboinflammation in severe infections?

To describe the prothrombotic and coagulopathic responses induced by the immune and inflammatory reactions to infections, in the last two decades, the literature interchangeably uses the words thromboinflammation and immunothrombosis to describe the link between inflammation and thrombosis.2,3,20 Both terms were first reported by Tanguay et al. in 2004.21

The term thromboinflammation is derived from thrombosis associated with inflammation and is used to describe pathophysiologic perturbations due to vascular endothelial injury and/or loss of antithrombotic 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 respiratory tract and provoking an inflammatory response associated with acute lung injury.22 This thromboinflammatory response became 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 infections. As part of any inflammatory response to attenuate microbial invasion, 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 activation, 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 physiological 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 immunothrombosis per se is a protective, antimicrobial mechanism aimed to locally contain pathogens including bacteria and fungi, its dysregulation and systemic exacerbation, as observed in thromboinflammation, 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 incidence 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 patients are represented in Figure 2 and summarized in Supplementary data online, Table S5.

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 anticoagulants 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 adhesion, 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 thromboinflammation.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.
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 anticoagulants 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 adhesion, 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 thromboinflammation.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.

Modulation of haemostasis by Staphylococcus aureus and Pseudomonas species infections. Severe bacterial infections can modulate haemostasis 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.
Figure 2

Modulation of haemostasis by Staphylococcus aureus and Pseudomonas species infections. Severe bacterial infections can modulate haemostasis 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.

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, neutrophil activation, and release of multiple cellular constituents, such as DNA, histones, and damage-associated molecular patterns, are involved, overwhelming the physiological vascular-protective mechanisms (Figure 1). Endothelial dysfunction is associated with loss of the endogenous vascular-protective mechanisms and contributes to microthrombi.2 Endothelial cells also enhance the synthesis of tissue plasminogen 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 severe 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 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 injury and/or vasoplaegia/shock. Acrocyanosis and ischaemic limbs that are not related to vasopressor use occur in association with SIC and 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 organs, may also be relevant for personalized decisions on antithrombotic drugs.

Moreover, the causative bacterial trigger may not be isolated, and often patients are treated with empiric broad-spectrum or multiple antibiotic agents that may elicit cytochrome P450 (CYP)-based, clinically relevant drug–drug interactions with some antithrombotic agents [clopidogrel, 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 complicate 25%–40% of viral infections. During ICU admittance, secondary infections, 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 animal vectors pose potential global threats,45 as viral haemorrhagic fevers such as dengue have the potential to become pandemic.46 Viral infections trigger coagulation disorders mostly through inflammatory pathways, 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 coagulation 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 coagulation and inflammation.36 In acute infections, macro- and microthromboinflammation 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, including 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 patients requiring mechanical ventilation, extracorporeal life support, and prolonged ICU stays may also develop secondary bacterial infections, such as ventilator-associated pneumonia, and additional haemostatic 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 thromboembolism (VTE) and/or continuation of ongoing antithrombotic therapy.

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 patients 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, promote atherosclerotic plaque progression,54 and may impair the immune 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 inflammatory milieu.57 Whether obesity is an independent risk factor for sepsis,58 sepsis-associated mortality, and severe thromboses in sepsis, including SARS-CoV-2,59–61 remains controversial.58,62–64

The safety and efficacy of continuing low-dose ASA in patients with high-degree thrombocytopenia and severe infections have not been studied in randomized clinical trials (RCTs), since thrombocytopenia is an exclusion criterion in all RCTs on antithrombotic drugs. However, no increased bleeding risk was observed outside the ICU setting in cancer patients with ASCVD with platelet count <100 × 109/L who received 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 exerts its antiinflammatory effects at doses higher than those used for cardiovascular prevention,67 although some data may suggest some indirect antiinflammatory effect at lower doses.68 However, ASA started during hospitalization for viral SARS-CoV-2 infections did not reduce mortality vs. placebo despite significantly shortening hospitalization,69 even though some observational studies and meta-analyses suggested a survival benefit of antiplatelet treatment, mostly ASA, started during hospitalization specifically in patients with severe infections or sepsis (see Supplementary data online, Table S7).

Additional prophylactic anticoagulation, with low-molecular-weight (LMWH) or unfractionated (UFH) heparins, should be considered in all patients with severe infections that are bedridden or have SIC, to reduce the risk of VTE.70 Some settings with a high thrombosis burden, including SARS-CoV-2, may require higher than prophylactic doses (intermediate or therapeutic).19 In each case, the use of heparins at prophylactic or higher doses should be weighed against the bleeding risk in the individual patient (Tables 24).

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 indicatedSevere infections and platelet count ≥20 × 109/LSevere infections and platelet count <20 × 109/LSevere infections and platelet count <20 × 109/L in the presence of multiorgan failure
DuringNo routine antiplatelet therapy, SAPT as pre-existing indicationNo routine antiplatelet therapy, SAPT as pre-existing indicationNo antiplatelet therapyNo antithrombotic treatment
Prophylactic anticoagulationaProphylactic anticoagulationProphylactic anticoagulation in patients at high thromboembolic risk
AfterSAPT as pre-existing indicationSAPT as pre-existing indicationSAPT as pre-existing indicationSAPT as pre-existing indication
No routine prophylactic anticoagulationbNo routine prophylactic anticoagulationbNo routine prophylactic anticoagulationbNo routine prophylactic anticoagulationb
Severe infections where only preventive antithrombotic treatment is indicatedSevere infections and platelet count ≥20 × 109/LSevere infections and platelet count <20 × 109/LSevere infections and platelet count <20 × 109/L in the presence of multiorgan failure
DuringNo routine antiplatelet therapy, SAPT as pre-existing indicationNo routine antiplatelet therapy, SAPT as pre-existing indicationNo antiplatelet therapyNo antithrombotic treatment
Prophylactic anticoagulationaProphylactic anticoagulationProphylactic anticoagulation in patients at high thromboembolic risk
AfterSAPT as pre-existing indicationSAPT as pre-existing indicationSAPT as pre-existing indicationSAPT as pre-existing indication
No routine prophylactic anticoagulationbNo routine prophylactic anticoagulationbNo routine prophylactic anticoagulationbNo routine prophylactic anticoagulationb

ASCVD, atherosclerotic cardiovascular disease; SAPT, single antiplatelet therapy, usually low-dose aspirin.

Therapeutic dose anticoagulation may be considered in patients without high risk of bleeding.

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.

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 indicatedSevere infections and platelet count ≥20 × 109/LSevere infections and platelet count <20 × 109/LSevere infections and platelet count <20 × 109/L in the presence of multiorgan failure
DuringNo routine antiplatelet therapy, SAPT as pre-existing indicationNo routine antiplatelet therapy, SAPT as pre-existing indicationNo antiplatelet therapyNo antithrombotic treatment
Prophylactic anticoagulationaProphylactic anticoagulationProphylactic anticoagulation in patients at high thromboembolic risk
AfterSAPT as pre-existing indicationSAPT as pre-existing indicationSAPT as pre-existing indicationSAPT as pre-existing indication
No routine prophylactic anticoagulationbNo routine prophylactic anticoagulationbNo routine prophylactic anticoagulationbNo routine prophylactic anticoagulationb
Severe infections where only preventive antithrombotic treatment is indicatedSevere infections and platelet count ≥20 × 109/LSevere infections and platelet count <20 × 109/LSevere infections and platelet count <20 × 109/L in the presence of multiorgan failure
DuringNo routine antiplatelet therapy, SAPT as pre-existing indicationNo routine antiplatelet therapy, SAPT as pre-existing indicationNo antiplatelet therapyNo antithrombotic treatment
Prophylactic anticoagulationaProphylactic anticoagulationProphylactic anticoagulation in patients at high thromboembolic risk
AfterSAPT as pre-existing indicationSAPT as pre-existing indicationSAPT as pre-existing indicationSAPT as pre-existing indication
No routine prophylactic anticoagulationbNo routine prophylactic anticoagulationbNo routine prophylactic anticoagulationbNo routine prophylactic anticoagulationb

ASCVD, atherosclerotic cardiovascular disease; SAPT, single antiplatelet therapy, usually low-dose aspirin.

Therapeutic dose anticoagulation may be considered in patients without high risk of bleeding.

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.

Table 3

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

Patients on SAPTPatients on DAPTPatients on long-term OACPatients on OAC for recentb thromboembolic event
SIC score = 2
Platelet count 100–149 × 109/L
or
PT ratio 1.2–1.4
No change<3 m after PCI or ACS: no change
3–6 m after PCI/ACS: a P2Y12 inhibitor or ASA
≥6 m after PCI/ACS: ASA or a P2Y12 inhibitor
No changeNo change
SIC score = 3
Plateleat count 100–149 × 109/L and PT ratio 1.2–1.4Platelet count ≥20 × 109/L: no change<3 m after PCI or ACS: no change or consider P2Y12 inhibitor or ASAPlatelet count 100–149 × 109/L and PT ratio 1.2–1.4: no changePlatelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change
or
Platelet count <100 × 109/L
or
PT ratio >1.4
Platelet count <20 × 109/L: stop SAPTConsider ASA if platelet count <20 × 109/L
3–6 m after PCI/ACS: P2Y12 inhibitor or ASA
Consider ASA if platelet count <20 × 109/L
≥6 m after PCI/ACS: ASA or clopidogrel
Consider no SAPT if platelet count <20 × 109/L
Platelet count <100 × 109/L
Change VKA/DOAC to heparinc at prophylactic or intermediate dose
Platelet count 50–100 × 109/L
Change VKA/DOAC to therapeutic dosed heparinc, split into two daily doses
SIC score = 5
Platelet count <100 × 109/L and PT ratio >1.4Platelet count ≥20 × 109/L: no change
Platelet count <20 × 109/L: stop SAPT
<1 m after PCI or ACS: no change if platelet count ≥20 × 109/L or consider P2Y12 inhibitor (clopidogrel) or ASA
Consider SAPT-ASA monotherapy if platelets <20 × 109/L
1–3 m after PCI/ACS: P2Y12 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
Platelet count ≥30 × 109/L: no change
Platelet count <30 × 109/L: stop heparinc
Platelet count ≥30 × 109/L: no change
Platelet count 30–50 × 109/L: prophylactic dose heparinc
Platelet count <30 × 109/L: stop heparinc
Patients on SAPTPatients on DAPTPatients on long-term OACPatients on OAC for recentb thromboembolic event
SIC score = 2
Platelet count 100–149 × 109/L
or
PT ratio 1.2–1.4
No change<3 m after PCI or ACS: no change
3–6 m after PCI/ACS: a P2Y12 inhibitor or ASA
≥6 m after PCI/ACS: ASA or a P2Y12 inhibitor
No changeNo change
SIC score = 3
Plateleat count 100–149 × 109/L and PT ratio 1.2–1.4Platelet count ≥20 × 109/L: no change<3 m after PCI or ACS: no change or consider P2Y12 inhibitor or ASAPlatelet count 100–149 × 109/L and PT ratio 1.2–1.4: no changePlatelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change
or
Platelet count <100 × 109/L
or
PT ratio >1.4
Platelet count <20 × 109/L: stop SAPTConsider ASA if platelet count <20 × 109/L
3–6 m after PCI/ACS: P2Y12 inhibitor or ASA
Consider ASA if platelet count <20 × 109/L
≥6 m after PCI/ACS: ASA or clopidogrel
Consider no SAPT if platelet count <20 × 109/L
Platelet count <100 × 109/L
Change VKA/DOAC to heparinc at prophylactic or intermediate dose
Platelet count 50–100 × 109/L
Change VKA/DOAC to therapeutic dosed heparinc, split into two daily doses
SIC score = 5
Platelet count <100 × 109/L and PT ratio >1.4Platelet count ≥20 × 109/L: no change
Platelet count <20 × 109/L: stop SAPT
<1 m after PCI or ACS: no change if platelet count ≥20 × 109/L or consider P2Y12 inhibitor (clopidogrel) or ASA
Consider SAPT-ASA monotherapy if platelets <20 × 109/L
1–3 m after PCI/ACS: P2Y12 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
Platelet count ≥30 × 109/L: no change
Platelet count <30 × 109/L: stop heparinc
Platelet count ≥30 × 109/L: no change
Platelet count 30–50 × 109/L: prophylactic dose heparinc
Platelet count <30 × 109/L: stop heparinc

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.

SIC and SOFA definitions and scores are shown in Table 1 and Supplementary data online, Table S3, respectively.

Recent thromboembolism refers to an event within the previous 3 months.

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.

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.

Table 3

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

Patients on SAPTPatients on DAPTPatients on long-term OACPatients on OAC for recentb thromboembolic event
SIC score = 2
Platelet count 100–149 × 109/L
or
PT ratio 1.2–1.4
No change<3 m after PCI or ACS: no change
3–6 m after PCI/ACS: a P2Y12 inhibitor or ASA
≥6 m after PCI/ACS: ASA or a P2Y12 inhibitor
No changeNo change
SIC score = 3
Plateleat count 100–149 × 109/L and PT ratio 1.2–1.4Platelet count ≥20 × 109/L: no change<3 m after PCI or ACS: no change or consider P2Y12 inhibitor or ASAPlatelet count 100–149 × 109/L and PT ratio 1.2–1.4: no changePlatelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change
or
Platelet count <100 × 109/L
or
PT ratio >1.4
Platelet count <20 × 109/L: stop SAPTConsider ASA if platelet count <20 × 109/L
3–6 m after PCI/ACS: P2Y12 inhibitor or ASA
Consider ASA if platelet count <20 × 109/L
≥6 m after PCI/ACS: ASA or clopidogrel
Consider no SAPT if platelet count <20 × 109/L
Platelet count <100 × 109/L
Change VKA/DOAC to heparinc at prophylactic or intermediate dose
Platelet count 50–100 × 109/L
Change VKA/DOAC to therapeutic dosed heparinc, split into two daily doses
SIC score = 5
Platelet count <100 × 109/L and PT ratio >1.4Platelet count ≥20 × 109/L: no change
Platelet count <20 × 109/L: stop SAPT
<1 m after PCI or ACS: no change if platelet count ≥20 × 109/L or consider P2Y12 inhibitor (clopidogrel) or ASA
Consider SAPT-ASA monotherapy if platelets <20 × 109/L
1–3 m after PCI/ACS: P2Y12 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
Platelet count ≥30 × 109/L: no change
Platelet count <30 × 109/L: stop heparinc
Platelet count ≥30 × 109/L: no change
Platelet count 30–50 × 109/L: prophylactic dose heparinc
Platelet count <30 × 109/L: stop heparinc
Patients on SAPTPatients on DAPTPatients on long-term OACPatients on OAC for recentb thromboembolic event
SIC score = 2
Platelet count 100–149 × 109/L
or
PT ratio 1.2–1.4
No change<3 m after PCI or ACS: no change
3–6 m after PCI/ACS: a P2Y12 inhibitor or ASA
≥6 m after PCI/ACS: ASA or a P2Y12 inhibitor
No changeNo change
SIC score = 3
Plateleat count 100–149 × 109/L and PT ratio 1.2–1.4Platelet count ≥20 × 109/L: no change<3 m after PCI or ACS: no change or consider P2Y12 inhibitor or ASAPlatelet count 100–149 × 109/L and PT ratio 1.2–1.4: no changePlatelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change
or
Platelet count <100 × 109/L
or
PT ratio >1.4
Platelet count <20 × 109/L: stop SAPTConsider ASA if platelet count <20 × 109/L
3–6 m after PCI/ACS: P2Y12 inhibitor or ASA
Consider ASA if platelet count <20 × 109/L
≥6 m after PCI/ACS: ASA or clopidogrel
Consider no SAPT if platelet count <20 × 109/L
Platelet count <100 × 109/L
Change VKA/DOAC to heparinc at prophylactic or intermediate dose
Platelet count 50–100 × 109/L
Change VKA/DOAC to therapeutic dosed heparinc, split into two daily doses
SIC score = 5
Platelet count <100 × 109/L and PT ratio >1.4Platelet count ≥20 × 109/L: no change
Platelet count <20 × 109/L: stop SAPT
<1 m after PCI or ACS: no change if platelet count ≥20 × 109/L or consider P2Y12 inhibitor (clopidogrel) or ASA
Consider SAPT-ASA monotherapy if platelets <20 × 109/L
1–3 m after PCI/ACS: P2Y12 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
Platelet count ≥30 × 109/L: no change
Platelet count <30 × 109/L: stop heparinc
Platelet count ≥30 × 109/L: no change
Platelet count 30–50 × 109/L: prophylactic dose heparinc
Platelet count <30 × 109/L: stop heparinc

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.

SIC and SOFA definitions and scores are shown in Table 1 and Supplementary data online, Table S3, respectively.

Recent thromboembolism refers to an event within the previous 3 months.

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.

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.

Table 4

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

Patients on SAPTPatients on DAPTPatients on long-term OACPatients on OAC due to recentb thromboembolic event
SIC score = 3
Platelet count 100–149 × 109/LorPT ratio 1.2–1.4No change<3 m after PCI or ACS: no change
3–6 m after PCI/ACS: consider P2Y12 inhibitor or ASA (SAPT)
≥6 m after PCI/ACS: SAPT
No changeNo change
SIC score = 4
Platelet count 100–149 × 109/L and PT ratio 1.2–1.4
or
Platelet count <100 × 109/L
or
PT ratio >1.4
Platelet count ≥20 × 109/L: no change
Platelet count <20 × 109/L: stop SAPT
<1 m after PCI/ACS: no change or consider P2Y12 inhibitor (clopidogrel) or ASA (SAPT)
Consider SAPT with ASA if platelet count <20 × 109/L
1–3 m after PCI or ACS: no change or P2Y12 inhibitor or ASA
Consider SAPT with ASA if 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
Platelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change
Platelet count 50–100 × 109/L: change VKA/DOAC to therapeutic dosec heparind, split into two daily doses
Platelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change
Platelet count 50–100 × 109/L: change VKA/DOAC to therapeutic dosec heparind, split into two daily doses
SIC score = 6
Platelet count <100 × 109/L and PT ratio >1.4Platelet count ≥20 × 109/L: no change
Platelet count <20 × 109/L: stop SAPT
<1 m after PCI or ACS: no change if platelets ≥20 × 109/L; consider P2Y12 inhibitor (clopidogrel) or ASA (SAPT) if platelets >20 × 109/L
Consider SAPT with ASA if 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
Platelet count 30–50 × 109/L: prophylactic dose heparind; platelet count <30 × 109/L: stop heparinPlatelet count 30–50 × 109/L: prophylactic dose heparind; platelet count <30 × 109/L: stop heparin
Patients on SAPTPatients on DAPTPatients on long-term OACPatients on OAC due to recentb thromboembolic event
SIC score = 3
Platelet count 100–149 × 109/LorPT ratio 1.2–1.4No change<3 m after PCI or ACS: no change
3–6 m after PCI/ACS: consider P2Y12 inhibitor or ASA (SAPT)
≥6 m after PCI/ACS: SAPT
No changeNo change
SIC score = 4
Platelet count 100–149 × 109/L and PT ratio 1.2–1.4
or
Platelet count <100 × 109/L
or
PT ratio >1.4
Platelet count ≥20 × 109/L: no change
Platelet count <20 × 109/L: stop SAPT
<1 m after PCI/ACS: no change or consider P2Y12 inhibitor (clopidogrel) or ASA (SAPT)
Consider SAPT with ASA if platelet count <20 × 109/L
1–3 m after PCI or ACS: no change or P2Y12 inhibitor or ASA
Consider SAPT with ASA if 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
Platelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change
Platelet count 50–100 × 109/L: change VKA/DOAC to therapeutic dosec heparind, split into two daily doses
Platelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change
Platelet count 50–100 × 109/L: change VKA/DOAC to therapeutic dosec heparind, split into two daily doses
SIC score = 6
Platelet count <100 × 109/L and PT ratio >1.4Platelet count ≥20 × 109/L: no change
Platelet count <20 × 109/L: stop SAPT
<1 m after PCI or ACS: no change if platelets ≥20 × 109/L; consider P2Y12 inhibitor (clopidogrel) or ASA (SAPT) if platelets >20 × 109/L
Consider SAPT with ASA if 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
Platelet count 30–50 × 109/L: prophylactic dose heparind; platelet count <30 × 109/L: stop heparinPlatelet count 30–50 × 109/L: prophylactic dose heparind; platelet count <30 × 109/L: stop heparin

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.

SIC and SOFA definitions and scores are provided in Table 1 and Supplementary data online, Table S3, respectively.

Recent thromboembolism refers to an event within the previous 3 months.

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.

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.

Table 4

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

Patients on SAPTPatients on DAPTPatients on long-term OACPatients on OAC due to recentb thromboembolic event
SIC score = 3
Platelet count 100–149 × 109/LorPT ratio 1.2–1.4No change<3 m after PCI or ACS: no change
3–6 m after PCI/ACS: consider P2Y12 inhibitor or ASA (SAPT)
≥6 m after PCI/ACS: SAPT
No changeNo change
SIC score = 4
Platelet count 100–149 × 109/L and PT ratio 1.2–1.4
or
Platelet count <100 × 109/L
or
PT ratio >1.4
Platelet count ≥20 × 109/L: no change
Platelet count <20 × 109/L: stop SAPT
<1 m after PCI/ACS: no change or consider P2Y12 inhibitor (clopidogrel) or ASA (SAPT)
Consider SAPT with ASA if platelet count <20 × 109/L
1–3 m after PCI or ACS: no change or P2Y12 inhibitor or ASA
Consider SAPT with ASA if 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
Platelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change
Platelet count 50–100 × 109/L: change VKA/DOAC to therapeutic dosec heparind, split into two daily doses
Platelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change
Platelet count 50–100 × 109/L: change VKA/DOAC to therapeutic dosec heparind, split into two daily doses
SIC score = 6
Platelet count <100 × 109/L and PT ratio >1.4Platelet count ≥20 × 109/L: no change
Platelet count <20 × 109/L: stop SAPT
<1 m after PCI or ACS: no change if platelets ≥20 × 109/L; consider P2Y12 inhibitor (clopidogrel) or ASA (SAPT) if platelets >20 × 109/L
Consider SAPT with ASA if 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
Platelet count 30–50 × 109/L: prophylactic dose heparind; platelet count <30 × 109/L: stop heparinPlatelet count 30–50 × 109/L: prophylactic dose heparind; platelet count <30 × 109/L: stop heparin
Patients on SAPTPatients on DAPTPatients on long-term OACPatients on OAC due to recentb thromboembolic event
SIC score = 3
Platelet count 100–149 × 109/LorPT ratio 1.2–1.4No change<3 m after PCI or ACS: no change
3–6 m after PCI/ACS: consider P2Y12 inhibitor or ASA (SAPT)
≥6 m after PCI/ACS: SAPT
No changeNo change
SIC score = 4
Platelet count 100–149 × 109/L and PT ratio 1.2–1.4
or
Platelet count <100 × 109/L
or
PT ratio >1.4
Platelet count ≥20 × 109/L: no change
Platelet count <20 × 109/L: stop SAPT
<1 m after PCI/ACS: no change or consider P2Y12 inhibitor (clopidogrel) or ASA (SAPT)
Consider SAPT with ASA if platelet count <20 × 109/L
1–3 m after PCI or ACS: no change or P2Y12 inhibitor or ASA
Consider SAPT with ASA if 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
Platelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change
Platelet count 50–100 × 109/L: change VKA/DOAC to therapeutic dosec heparind, split into two daily doses
Platelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change
Platelet count 50–100 × 109/L: change VKA/DOAC to therapeutic dosec heparind, split into two daily doses
SIC score = 6
Platelet count <100 × 109/L and PT ratio >1.4Platelet count ≥20 × 109/L: no change
Platelet count <20 × 109/L: stop SAPT
<1 m after PCI or ACS: no change if platelets ≥20 × 109/L; consider P2Y12 inhibitor (clopidogrel) or ASA (SAPT) if platelets >20 × 109/L
Consider SAPT with ASA if 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
Platelet count 30–50 × 109/L: prophylactic dose heparind; platelet count <30 × 109/L: stop heparinPlatelet count 30–50 × 109/L: prophylactic dose heparind; platelet count <30 × 109/L: stop heparin

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.

SIC and SOFA definitions and scores are provided in Table 1 and Supplementary data online, Table S3, respectively.

Recent thromboembolism refers to an event within the previous 3 months.

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.

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.

Consensus statementsStrength of advice
We advise that in patients who are already on low-dose ASA because of high and very high cardiovascular risk due to multiple risk factors, with no history of symptomatic ASCVD, low-dose ASA should be maintained, but may require adjustment according to the course of the severe infection and degree of SIC and thrombocytopenia (Tables 24).19,71,72graphic
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).73–76graphic
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).graphic
Consensus statementsStrength of advice
We advise that in patients who are already on low-dose ASA because of high and very high cardiovascular risk due to multiple risk factors, with no history of symptomatic ASCVD, low-dose ASA should be maintained, but may require adjustment according to the course of the severe infection and degree of SIC and thrombocytopenia (Tables 24).19,71,72graphic
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).73–76graphic
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).graphic
Consensus statementsStrength of advice
We advise that in patients who are already on low-dose ASA because of high and very high cardiovascular risk due to multiple risk factors, with no history of symptomatic ASCVD, low-dose ASA should be maintained, but may require adjustment according to the course of the severe infection and degree of SIC and thrombocytopenia (Tables 24).19,71,72graphic
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).73–76graphic
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).graphic
Consensus statementsStrength of advice
We advise that in patients who are already on low-dose ASA because of high and very high cardiovascular risk due to multiple risk factors, with no history of symptomatic ASCVD, low-dose ASA should be maintained, but may require adjustment according to the course of the severe infection and degree of SIC and thrombocytopenia (Tables 24).19,71,72graphic
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).73–76graphic
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).graphic

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/septic shock has been associated with a reduction of mortality rates by 7% [95% confidence interval (CI): 2%–12%, P = 0.005] in large observational studies85 while a prospective study reported reduced acute respiratory 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 no significant increases in bleeding up to 90 days (Table 5). Thus, with 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).

Table 5

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

Study (year)DesignPopulationComparison and type of antiplatelet agent(s)EffectivenessSafetyOther remarks
Erlich et al. (2011)81Multicentre observational, prospective study161 hospitalized patients at risk for acute lung injury, ∼30% due to sepsis or infectionPre-hospitalization SAPT–ASA users: 79ASA users: lower acute limb ischaemia OR 0.37 (95% CI: 0.16–0.84) P = 0.02
No difference in mortality or length of hospitalization.
NA
Losche et al. (2012)82Retrospective analysis of two cohortsCohort 1: 224 patients hospitalized for pneumonia
Cohort 2: 615 patients admitted to the ICU for sepsis
Cohort 1, n (%): SAPT–ASA: 38 (17); SAPT–clopidogrel: 9 (4)
Cohort 2, n (%): SAPT–ASA: 129 (21); SAPT or DAPT with clopidogrel: 25 (4)
Cohort 1: ICU admission (%) 9.1 vs. 26.3%
Length of stay 13.9 ± 6.2 vs. 18.2 ± 10.2 days in APT users vs. non-users
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
Cohort 2: no increase of bleeding associated with previous APT useSimilar benefit also after correcting for SOFA score, age, gender, and C-reactive protein levels
Valerio-Rojas et al. (2013)83Retrospective651 ICU patients, 272 (42.8%) on APT
SOFA score day 1: no APT median (IQR) 6 (4–10) and APT 6 (4–9), P = ns
Comparison of prior antiplatelet vs. no antiplatelet
SAPT–ASA: n = 241
SAPT–clopidogrel: n = 4
DAPT with clopidogrel: n = 27
Mortality: (a)OR 0.76 (95% CI: 0.52–1.10)
ARDS: (a)OR 0.50 (95% CI: 0.35–0.71)
Mechanical ventilation (a)OR 0.62 (95% CI: 0.45–0.87)
Red blood cell transfused units: not different among groups
Platelet-transfused patients higher in the no APT group (P = 0.01)
Platelet count significantly higher in the APT group
PT and INR significantly lower in the APT group
Tsai et al. (2015)84Nationwide population-based cohort and nested case–control study683 421 patients hospitalized for sepsisUse of antiplatelet agents before admission
Antiplatelets: aspirin (n = 51 340), clopidogrel or ticlopidine (13 368), prescribed within
1 year before the index date
Mortality: (a)OR 0.82, (95% CI: 0.81–0.83, P = 0.001)NABenefit higher in current users (aOR 0.78, 95% CI 0.76–0.79); non-significant in past users (aOR 1.00, 95% CI 0.98–1.02)
Trauer et al. (2017)85Meta-analysis of 11 observational studiesn = 6823 ICU patients hospitalized for sepsis
Antiplatelet included SAPT–ASA, SAPT clopidogrel, or DAPT aspirin plus clopidogrel
Comparison of prior aspirin or APT usage vs. no usageMortality: ASA users: significant reduction by 7% (95% CI: 2%–12%), P = 0.005
APT users: significantly reduced by 6% (95%CI: 0%–12%), P = 0.004
NA
Ouyang et al. (2019)86Meta-analysis of 10 studies689 897 patients hospitalized for sepsis
121 147 on APT (SAPT–ASA, SAPT–clopidogrel, DAPT clopidogrel, or prasugrel)
SAPT–ASA only used in 5 out of 10 studiesMortality OR: 0.78 (95% CI: 0.77–0.80)
SAPT–ASA: OR 0.60 (95% CI: 0.53–0.68)
NAA subgroup on timing of APT showed benefit for APT administered also after hospitalization
Chow et al. (2021)87Observational, 1:2 propensity score matched for demographics and comorbidities hospital mortality PE17 347 patients hospitalized for COVID-19: 6781 on pre-hospital antiplatelet drugs
Mean platelet count: 210 (160–275) ×103/µL
Pre-hospital antiplatelet therapy vs. no antiplatelet therapy
SAPT–ASA: 83.9%
SAPT–clopidogrel 8.2%
DAPT: 7.4%
In-hospital mortality (%): 18.9 with vs. 21.5 with and without pre-hospital APT (HR 0.81; 95% CI: 0.76–0.87)
PE: 2.2% vs. 3% in users vs. non-users (P = 0.002)
Subgroup analysis: lower mortality in SAPT–ASA only
No mortality reduction for SAPT–clopidogrel or DAPT
Epistaxis (%): 0.9 vs. 0.4 in users vs. no users.
No difference in GI or IC bleeding
Blood transfusion higher in non-users (4% vs. 2.8%, P < 0.001)
Subgroup analysis underpowered to detect differences between SAPT–ASA vs. SAPT–clopidogrel vs. DAPT
Study (year)DesignPopulationComparison and type of antiplatelet agent(s)EffectivenessSafetyOther remarks
Erlich et al. (2011)81Multicentre observational, prospective study161 hospitalized patients at risk for acute lung injury, ∼30% due to sepsis or infectionPre-hospitalization SAPT–ASA users: 79ASA users: lower acute limb ischaemia OR 0.37 (95% CI: 0.16–0.84) P = 0.02
No difference in mortality or length of hospitalization.
NA
Losche et al. (2012)82Retrospective analysis of two cohortsCohort 1: 224 patients hospitalized for pneumonia
Cohort 2: 615 patients admitted to the ICU for sepsis
Cohort 1, n (%): SAPT–ASA: 38 (17); SAPT–clopidogrel: 9 (4)
Cohort 2, n (%): SAPT–ASA: 129 (21); SAPT or DAPT with clopidogrel: 25 (4)
Cohort 1: ICU admission (%) 9.1 vs. 26.3%
Length of stay 13.9 ± 6.2 vs. 18.2 ± 10.2 days in APT users vs. non-users
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
Cohort 2: no increase of bleeding associated with previous APT useSimilar benefit also after correcting for SOFA score, age, gender, and C-reactive protein levels
Valerio-Rojas et al. (2013)83Retrospective651 ICU patients, 272 (42.8%) on APT
SOFA score day 1: no APT median (IQR) 6 (4–10) and APT 6 (4–9), P = ns
Comparison of prior antiplatelet vs. no antiplatelet
SAPT–ASA: n = 241
SAPT–clopidogrel: n = 4
DAPT with clopidogrel: n = 27
Mortality: (a)OR 0.76 (95% CI: 0.52–1.10)
ARDS: (a)OR 0.50 (95% CI: 0.35–0.71)
Mechanical ventilation (a)OR 0.62 (95% CI: 0.45–0.87)
Red blood cell transfused units: not different among groups
Platelet-transfused patients higher in the no APT group (P = 0.01)
Platelet count significantly higher in the APT group
PT and INR significantly lower in the APT group
Tsai et al. (2015)84Nationwide population-based cohort and nested case–control study683 421 patients hospitalized for sepsisUse of antiplatelet agents before admission
Antiplatelets: aspirin (n = 51 340), clopidogrel or ticlopidine (13 368), prescribed within
1 year before the index date
Mortality: (a)OR 0.82, (95% CI: 0.81–0.83, P = 0.001)NABenefit higher in current users (aOR 0.78, 95% CI 0.76–0.79); non-significant in past users (aOR 1.00, 95% CI 0.98–1.02)
Trauer et al. (2017)85Meta-analysis of 11 observational studiesn = 6823 ICU patients hospitalized for sepsis
Antiplatelet included SAPT–ASA, SAPT clopidogrel, or DAPT aspirin plus clopidogrel
Comparison of prior aspirin or APT usage vs. no usageMortality: ASA users: significant reduction by 7% (95% CI: 2%–12%), P = 0.005
APT users: significantly reduced by 6% (95%CI: 0%–12%), P = 0.004
NA
Ouyang et al. (2019)86Meta-analysis of 10 studies689 897 patients hospitalized for sepsis
121 147 on APT (SAPT–ASA, SAPT–clopidogrel, DAPT clopidogrel, or prasugrel)
SAPT–ASA only used in 5 out of 10 studiesMortality OR: 0.78 (95% CI: 0.77–0.80)
SAPT–ASA: OR 0.60 (95% CI: 0.53–0.68)
NAA subgroup on timing of APT showed benefit for APT administered also after hospitalization
Chow et al. (2021)87Observational, 1:2 propensity score matched for demographics and comorbidities hospital mortality PE17 347 patients hospitalized for COVID-19: 6781 on pre-hospital antiplatelet drugs
Mean platelet count: 210 (160–275) ×103/µL
Pre-hospital antiplatelet therapy vs. no antiplatelet therapy
SAPT–ASA: 83.9%
SAPT–clopidogrel 8.2%
DAPT: 7.4%
In-hospital mortality (%): 18.9 with vs. 21.5 with and without pre-hospital APT (HR 0.81; 95% CI: 0.76–0.87)
PE: 2.2% vs. 3% in users vs. non-users (P = 0.002)
Subgroup analysis: lower mortality in SAPT–ASA only
No mortality reduction for SAPT–clopidogrel or DAPT
Epistaxis (%): 0.9 vs. 0.4 in users vs. no users.
No difference in GI or IC bleeding
Blood transfusion higher in non-users (4% vs. 2.8%, P < 0.001)
Subgroup analysis underpowered to detect differences between SAPT–ASA vs. SAPT–clopidogrel vs. 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.

Table 5

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

Study (year)DesignPopulationComparison and type of antiplatelet agent(s)EffectivenessSafetyOther remarks
Erlich et al. (2011)81Multicentre observational, prospective study161 hospitalized patients at risk for acute lung injury, ∼30% due to sepsis or infectionPre-hospitalization SAPT–ASA users: 79ASA users: lower acute limb ischaemia OR 0.37 (95% CI: 0.16–0.84) P = 0.02
No difference in mortality or length of hospitalization.
NA
Losche et al. (2012)82Retrospective analysis of two cohortsCohort 1: 224 patients hospitalized for pneumonia
Cohort 2: 615 patients admitted to the ICU for sepsis
Cohort 1, n (%): SAPT–ASA: 38 (17); SAPT–clopidogrel: 9 (4)
Cohort 2, n (%): SAPT–ASA: 129 (21); SAPT or DAPT with clopidogrel: 25 (4)
Cohort 1: ICU admission (%) 9.1 vs. 26.3%
Length of stay 13.9 ± 6.2 vs. 18.2 ± 10.2 days in APT users vs. non-users
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
Cohort 2: no increase of bleeding associated with previous APT useSimilar benefit also after correcting for SOFA score, age, gender, and C-reactive protein levels
Valerio-Rojas et al. (2013)83Retrospective651 ICU patients, 272 (42.8%) on APT
SOFA score day 1: no APT median (IQR) 6 (4–10) and APT 6 (4–9), P = ns
Comparison of prior antiplatelet vs. no antiplatelet
SAPT–ASA: n = 241
SAPT–clopidogrel: n = 4
DAPT with clopidogrel: n = 27
Mortality: (a)OR 0.76 (95% CI: 0.52–1.10)
ARDS: (a)OR 0.50 (95% CI: 0.35–0.71)
Mechanical ventilation (a)OR 0.62 (95% CI: 0.45–0.87)
Red blood cell transfused units: not different among groups
Platelet-transfused patients higher in the no APT group (P = 0.01)
Platelet count significantly higher in the APT group
PT and INR significantly lower in the APT group
Tsai et al. (2015)84Nationwide population-based cohort and nested case–control study683 421 patients hospitalized for sepsisUse of antiplatelet agents before admission
Antiplatelets: aspirin (n = 51 340), clopidogrel or ticlopidine (13 368), prescribed within
1 year before the index date
Mortality: (a)OR 0.82, (95% CI: 0.81–0.83, P = 0.001)NABenefit higher in current users (aOR 0.78, 95% CI 0.76–0.79); non-significant in past users (aOR 1.00, 95% CI 0.98–1.02)
Trauer et al. (2017)85Meta-analysis of 11 observational studiesn = 6823 ICU patients hospitalized for sepsis
Antiplatelet included SAPT–ASA, SAPT clopidogrel, or DAPT aspirin plus clopidogrel
Comparison of prior aspirin or APT usage vs. no usageMortality: ASA users: significant reduction by 7% (95% CI: 2%–12%), P = 0.005
APT users: significantly reduced by 6% (95%CI: 0%–12%), P = 0.004
NA
Ouyang et al. (2019)86Meta-analysis of 10 studies689 897 patients hospitalized for sepsis
121 147 on APT (SAPT–ASA, SAPT–clopidogrel, DAPT clopidogrel, or prasugrel)
SAPT–ASA only used in 5 out of 10 studiesMortality OR: 0.78 (95% CI: 0.77–0.80)
SAPT–ASA: OR 0.60 (95% CI: 0.53–0.68)
NAA subgroup on timing of APT showed benefit for APT administered also after hospitalization
Chow et al. (2021)87Observational, 1:2 propensity score matched for demographics and comorbidities hospital mortality PE17 347 patients hospitalized for COVID-19: 6781 on pre-hospital antiplatelet drugs
Mean platelet count: 210 (160–275) ×103/µL
Pre-hospital antiplatelet therapy vs. no antiplatelet therapy
SAPT–ASA: 83.9%
SAPT–clopidogrel 8.2%
DAPT: 7.4%
In-hospital mortality (%): 18.9 with vs. 21.5 with and without pre-hospital APT (HR 0.81; 95% CI: 0.76–0.87)
PE: 2.2% vs. 3% in users vs. non-users (P = 0.002)
Subgroup analysis: lower mortality in SAPT–ASA only
No mortality reduction for SAPT–clopidogrel or DAPT
Epistaxis (%): 0.9 vs. 0.4 in users vs. no users.
No difference in GI or IC bleeding
Blood transfusion higher in non-users (4% vs. 2.8%, P < 0.001)
Subgroup analysis underpowered to detect differences between SAPT–ASA vs. SAPT–clopidogrel vs. DAPT
Study (year)DesignPopulationComparison and type of antiplatelet agent(s)EffectivenessSafetyOther remarks
Erlich et al. (2011)81Multicentre observational, prospective study161 hospitalized patients at risk for acute lung injury, ∼30% due to sepsis or infectionPre-hospitalization SAPT–ASA users: 79ASA users: lower acute limb ischaemia OR 0.37 (95% CI: 0.16–0.84) P = 0.02
No difference in mortality or length of hospitalization.
NA
Losche et al. (2012)82Retrospective analysis of two cohortsCohort 1: 224 patients hospitalized for pneumonia
Cohort 2: 615 patients admitted to the ICU for sepsis
Cohort 1, n (%): SAPT–ASA: 38 (17); SAPT–clopidogrel: 9 (4)
Cohort 2, n (%): SAPT–ASA: 129 (21); SAPT or DAPT with clopidogrel: 25 (4)
Cohort 1: ICU admission (%) 9.1 vs. 26.3%
Length of stay 13.9 ± 6.2 vs. 18.2 ± 10.2 days in APT users vs. non-users
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
Cohort 2: no increase of bleeding associated with previous APT useSimilar benefit also after correcting for SOFA score, age, gender, and C-reactive protein levels
Valerio-Rojas et al. (2013)83Retrospective651 ICU patients, 272 (42.8%) on APT
SOFA score day 1: no APT median (IQR) 6 (4–10) and APT 6 (4–9), P = ns
Comparison of prior antiplatelet vs. no antiplatelet
SAPT–ASA: n = 241
SAPT–clopidogrel: n = 4
DAPT with clopidogrel: n = 27
Mortality: (a)OR 0.76 (95% CI: 0.52–1.10)
ARDS: (a)OR 0.50 (95% CI: 0.35–0.71)
Mechanical ventilation (a)OR 0.62 (95% CI: 0.45–0.87)
Red blood cell transfused units: not different among groups
Platelet-transfused patients higher in the no APT group (P = 0.01)
Platelet count significantly higher in the APT group
PT and INR significantly lower in the APT group
Tsai et al. (2015)84Nationwide population-based cohort and nested case–control study683 421 patients hospitalized for sepsisUse of antiplatelet agents before admission
Antiplatelets: aspirin (n = 51 340), clopidogrel or ticlopidine (13 368), prescribed within
1 year before the index date
Mortality: (a)OR 0.82, (95% CI: 0.81–0.83, P = 0.001)NABenefit higher in current users (aOR 0.78, 95% CI 0.76–0.79); non-significant in past users (aOR 1.00, 95% CI 0.98–1.02)
Trauer et al. (2017)85Meta-analysis of 11 observational studiesn = 6823 ICU patients hospitalized for sepsis
Antiplatelet included SAPT–ASA, SAPT clopidogrel, or DAPT aspirin plus clopidogrel
Comparison of prior aspirin or APT usage vs. no usageMortality: ASA users: significant reduction by 7% (95% CI: 2%–12%), P = 0.005
APT users: significantly reduced by 6% (95%CI: 0%–12%), P = 0.004
NA
Ouyang et al. (2019)86Meta-analysis of 10 studies689 897 patients hospitalized for sepsis
121 147 on APT (SAPT–ASA, SAPT–clopidogrel, DAPT clopidogrel, or prasugrel)
SAPT–ASA only used in 5 out of 10 studiesMortality OR: 0.78 (95% CI: 0.77–0.80)
SAPT–ASA: OR 0.60 (95% CI: 0.53–0.68)
NAA subgroup on timing of APT showed benefit for APT administered also after hospitalization
Chow et al. (2021)87Observational, 1:2 propensity score matched for demographics and comorbidities hospital mortality PE17 347 patients hospitalized for COVID-19: 6781 on pre-hospital antiplatelet drugs
Mean platelet count: 210 (160–275) ×103/µL
Pre-hospital antiplatelet therapy vs. no antiplatelet therapy
SAPT–ASA: 83.9%
SAPT–clopidogrel 8.2%
DAPT: 7.4%
In-hospital mortality (%): 18.9 with vs. 21.5 with and without pre-hospital APT (HR 0.81; 95% CI: 0.76–0.87)
PE: 2.2% vs. 3% in users vs. non-users (P = 0.002)
Subgroup analysis: lower mortality in SAPT–ASA only
No mortality reduction for SAPT–clopidogrel or DAPT
Epistaxis (%): 0.9 vs. 0.4 in users vs. no users.
No difference in GI or IC bleeding
Blood transfusion higher in non-users (4% vs. 2.8%, P < 0.001)
Subgroup analysis underpowered to detect differences between SAPT–ASA vs. SAPT–clopidogrel vs. 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.

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 thrombocytopenia, 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 increase 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 treatment is preventable by gastroprotectant drugs including proton pump inhibitors (PPIs),93,94 which should be used in sepsis, SIC, thrombocytopenia, 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 enzymes,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 relevant 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 suggested that in ICU patients, gastric acid suppression may further increase the risk of penumonia.102 However, in the case of coagulopathy, as for SIC, the benefit of reducing major gastrointestinal bleeding seems higher than the risk of pneumonia, and PPIs seemed more effective than histamine H2 receptor antagonists, although more randomized trials are needed.94,103 If a PPI is administered, especially in severely thrombocytopenic patients on clopidogrel, omeprazole and esomeprazole should be avoided due to potential and clinically relevant drug–drug interactions (see Supplementary data online, Table S6).104–107

Consensus statementsStrength of advice
We advise to continue SAPT in patients with a clear, pre-existing indication in secondary cardiovascular prevention during new-onset sepsis or severe infections, unless severe SIC with platelet count ≤20 × 109/L occurs.71,86,88graphic
We advise to check for clinically relevant drug interactions with antimicrobials when clopidogrel or ticagrelor is used and with PPIs when clopidogrel is used.107,108graphic
We advise to treat patients with high degree of SIC, including thrombocytopenia, with gastroprotective agents, preferably PPIs.19,93,99,102,103graphic
Consensus statementsStrength of advice
We advise to continue SAPT in patients with a clear, pre-existing indication in secondary cardiovascular prevention during new-onset sepsis or severe infections, unless severe SIC with platelet count ≤20 × 109/L occurs.71,86,88graphic
We advise to check for clinically relevant drug interactions with antimicrobials when clopidogrel or ticagrelor is used and with PPIs when clopidogrel is used.107,108graphic
We advise to treat patients with high degree of SIC, including thrombocytopenia, with gastroprotective agents, preferably PPIs.19,93,99,102,103graphic
Consensus statementsStrength of advice
We advise to continue SAPT in patients with a clear, pre-existing indication in secondary cardiovascular prevention during new-onset sepsis or severe infections, unless severe SIC with platelet count ≤20 × 109/L occurs.71,86,88graphic
We advise to check for clinically relevant drug interactions with antimicrobials when clopidogrel or ticagrelor is used and with PPIs when clopidogrel is used.107,108graphic
We advise to treat patients with high degree of SIC, including thrombocytopenia, with gastroprotective agents, preferably PPIs.19,93,99,102,103graphic
Consensus statementsStrength of advice
We advise to continue SAPT in patients with a clear, pre-existing indication in secondary cardiovascular prevention during new-onset sepsis or severe infections, unless severe SIC with platelet count ≤20 × 109/L occurs.71,86,88graphic
We advise to check for clinically relevant drug interactions with antimicrobials when clopidogrel or ticagrelor is used and with PPIs when clopidogrel is used.107,108graphic
We advise to treat patients with high degree of SIC, including thrombocytopenia, with gastroprotective agents, preferably PPIs.19,93,99,102,103graphic

Patients on dual antiplatelet therapy

When a patient develops severe infection while on dual antiplatelet therapy (DAPT) consisting of ASA and a P2Y12 inhibitor, large observational studies support the safety of continuing DAPT in this setting (Table 5), but evidence from randomized studies about the balance of efficacy and safety, especially as SIC progresses, is lacking.87,109,110

Few observational and post hoc analyses suggested that DAPT with clopidogrel may be associated with an increased risk of infection vs. ASA alone after coronary artery bypass surgery,111 and that DAPT with ticagrelor may be associated with a lower risk of bacterial lung infection.112–115 A weak off-target clopidogrel effect with a minor decrease on leucocyte count has been described, but without any impact on rates of neutropenia.116,117 On the other hand, platelet P2Y12 inhibition has been inconsistently reported to reduce systemic inflammatory response in animal and human models of endotoxemia,118–121 but the clinical relevance remains unknown. Furthermore, SAPT with either ticagrelor or clopidogrel, in addition to standard anticoagulant therapy, failed to improve clinical outcomes in non-critically ill hospitalized COVID-19 patients.122

For most patients treated with ASA and clopidogrel, ASA or clopidogrel123,124 may be stopped, and SAPT was used starting from 3 to 6 months after percutaneous coronary intervention (PCI) and/or acute coronary syndrome (ACS), without significant stent thrombosis risk (Tables 3 and 4).123–126

For DAPT-treated patients who develop an indication for full-dose 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 drug may offer a safer strategy, even early after PCI and/or ACS,127 provided a normal platelet count or a mild degree of thrombocytopenia, although this strategy has never been tested in severe infection developing SIC. Moreover, the safety vs. efficacy of a dual antithrombotic therapy with ASA, as compared with clopidogrel or ticagrelor, has not been tested in a contemporary setting nor in severe infections and sepsis with or without SIC. Thus, in patients with sepsis or severe 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 (Table 5), although this strategy has never been tested in sepsis and/or in severely thrombocytopenic patients (Tables 3 and 4).

Importantly, in patients with severe sepsis on ticagrelor or clopidogrel, potential clinically relevant drug–drug interactions with antimicrobial agents should always be considered due to their CYP450-dependent biotransformation (see Supplementary data online, Table S7).128 Moreover, ∼25% of patients on ticagrelor develop drug-related dyspnoea,129,130 which may require differential diagnosis.130 Caution is required with clopidogrel if hepatic dysfunction develops during severe infection as this can reduce its antiplatelet effect.107 Ticagrelor is also contraindicated in severe hepatic impairment due to risk of accumulation and bleeding.108

Since thrombin is also a potent platelet activator, anticoagulants may also diminish platelet activation,131,132 on top of impairing secondary haemostasis (see Supplementary data online, Figure S2). Consequently, antithrombotic therapy should be carefully tailored in DAPT-treated patients with severe infection who require therapeutic anticoagulation or develop coagulopathy.

Current ESC guidelines9,51 recommend PPIs94 in patients on DAPT to reduce the risk of gastrointestinal bleeding19,99; however, caution should be used in critically ill patients,102 as detailed in the previous section.

Consensus statementsStrength of advice
We advise to continue DAPT following recent (i.e. up to 6 months) ACS with or without PCI, in patients with platelet count >50 × 109/L.81–87graphic
Continuing DAPT if platelet count is 30–50 × 109/L may be appropriate unless coagulation is severely impaired, or there is a high bleeding risk. In the latter cases, we advise to switch to SAPT with clopidogrel or low-dose ASA.69,81–87,133–136graphic
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.66,81–87graphic
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.graphic
We advise to check for relevant drug–drug interactions for ticagrelor and clopidogrel and ongoing antiviral or antibiotic agents.107,108graphic
We advise to treat patients with gastroprotective agents, preferably PPIs.19,93,99,102,103graphic
Consensus statementsStrength of advice
We advise to continue DAPT following recent (i.e. up to 6 months) ACS with or without PCI, in patients with platelet count >50 × 109/L.81–87graphic
Continuing DAPT if platelet count is 30–50 × 109/L may be appropriate unless coagulation is severely impaired, or there is a high bleeding risk. In the latter cases, we advise to switch to SAPT with clopidogrel or low-dose ASA.69,81–87,133–136graphic
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.66,81–87graphic
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.graphic
We advise to check for relevant drug–drug interactions for ticagrelor and clopidogrel and ongoing antiviral or antibiotic agents.107,108graphic
We advise to treat patients with gastroprotective agents, preferably PPIs.19,93,99,102,103graphic
Consensus statementsStrength of advice
We advise to continue DAPT following recent (i.e. up to 6 months) ACS with or without PCI, in patients with platelet count >50 × 109/L.81–87graphic
Continuing DAPT if platelet count is 30–50 × 109/L may be appropriate unless coagulation is severely impaired, or there is a high bleeding risk. In the latter cases, we advise to switch to SAPT with clopidogrel or low-dose ASA.69,81–87,133–136graphic
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.66,81–87graphic
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.graphic
We advise to check for relevant drug–drug interactions for ticagrelor and clopidogrel and ongoing antiviral or antibiotic agents.107,108graphic
We advise to treat patients with gastroprotective agents, preferably PPIs.19,93,99,102,103graphic
Consensus statementsStrength of advice
We advise to continue DAPT following recent (i.e. up to 6 months) ACS with or without PCI, in patients with platelet count >50 × 109/L.81–87graphic
Continuing DAPT if platelet count is 30–50 × 109/L may be appropriate unless coagulation is severely impaired, or there is a high bleeding risk. In the latter cases, we advise to switch to SAPT with clopidogrel or low-dose ASA.69,81–87,133–136graphic
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.66,81–87graphic
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.graphic
We advise to check for relevant drug–drug interactions for ticagrelor and clopidogrel and ongoing antiviral or antibiotic agents.107,108graphic
We advise to treat patients with gastroprotective agents, preferably PPIs.19,93,99,102,103graphic

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 coagulopathy.1 In a meta-analysis of 24 trials (14 767 patients) addressing various 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 significant 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

Table 6

Studies in patients with anticoagulant therapy during severe infections or sepsis

Study (year)Study typePopulationComparison or interventionEfficacy outcomeSafety outcomeOther remarks
Umemura et al. (2016)137Meta-analysis of 24 RCTs14 767 patients with sepsis, treated with any anticoagulant, of those 3206 had DICAnticoagulants vs. controlMortality overall, RR 0.97 (95% CI: 0.92–1.02)Subgroup with DIC, RR 0.72 (95% CI: 0.62–0.85)Bleeding complications overall, RR 1.33 (95% CI: 1.12–1.57)
Subgroup with DIC, RR 1.26 (95% CI: 0.86–1.85)
Only three of the studies used heparins
Wang et al. (2014)138Meta-analysis of nine controlled trialsPatients with sepsis (592) or severe sepsis (3011)UFH or LMWH vs. control28-day mortality, OR 0.66 (95% CI: 0.56–0.77)Bleeding complications, OR 1.06 (95% CI: 0.83–1.36)A variety of heparin dose regimens were used
Li et al. (2021)139Meta-analysis of 10 RCTs684 adult patients with sepsisLMWH at mainly intermediate dose vs. control28-day mortality, RR 0.52 (95% CI: 0.38–0.70)
APACHE II score mean difference −4.42 (95% CI: −5.50 to −3.33
Bleeding complications, RR 1.29 (95% CI: 0.76–2.17)All studies were small with 32–159 patients
Søgaard et al. (2017)140Nationwide healthcare database. Inverse probability of treatment weighting3030 patients with AF on warfarin vs. 55 721 patients without AF and warfarin, all admitted for sepsisWarfarin at the time of sepsis diagnosis vs. no warfarin. Warfarin effect will remain 3–5 days after stopping90-day all-cause mortality, HR 0.64 (95% CI: 0.58–0.69); thromboembolism, 1.25 (95% CI: 0.89–1.76)Bleeding complications, 1.19 (95% CI: 1.00–1.41)No information on how anticoagulation was managed during hospitalization. No data on sepsis severity
Study (year)Study typePopulationComparison or interventionEfficacy outcomeSafety outcomeOther remarks
Umemura et al. (2016)137Meta-analysis of 24 RCTs14 767 patients with sepsis, treated with any anticoagulant, of those 3206 had DICAnticoagulants vs. controlMortality overall, RR 0.97 (95% CI: 0.92–1.02)Subgroup with DIC, RR 0.72 (95% CI: 0.62–0.85)Bleeding complications overall, RR 1.33 (95% CI: 1.12–1.57)
Subgroup with DIC, RR 1.26 (95% CI: 0.86–1.85)
Only three of the studies used heparins
Wang et al. (2014)138Meta-analysis of nine controlled trialsPatients with sepsis (592) or severe sepsis (3011)UFH or LMWH vs. control28-day mortality, OR 0.66 (95% CI: 0.56–0.77)Bleeding complications, OR 1.06 (95% CI: 0.83–1.36)A variety of heparin dose regimens were used
Li et al. (2021)139Meta-analysis of 10 RCTs684 adult patients with sepsisLMWH at mainly intermediate dose vs. control28-day mortality, RR 0.52 (95% CI: 0.38–0.70)
APACHE II score mean difference −4.42 (95% CI: −5.50 to −3.33
Bleeding complications, RR 1.29 (95% CI: 0.76–2.17)All studies were small with 32–159 patients
Søgaard et al. (2017)140Nationwide healthcare database. Inverse probability of treatment weighting3030 patients with AF on warfarin vs. 55 721 patients without AF and warfarin, all admitted for sepsisWarfarin at the time of sepsis diagnosis vs. no warfarin. Warfarin effect will remain 3–5 days after stopping90-day all-cause mortality, HR 0.64 (95% CI: 0.58–0.69); thromboembolism, 1.25 (95% CI: 0.89–1.76)Bleeding complications, 1.19 (95% CI: 1.00–1.41)No information on how anticoagulation was managed during hospitalization. No 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.

Table 6

Studies in patients with anticoagulant therapy during severe infections or sepsis

Study (year)Study typePopulationComparison or interventionEfficacy outcomeSafety outcomeOther remarks
Umemura et al. (2016)137Meta-analysis of 24 RCTs14 767 patients with sepsis, treated with any anticoagulant, of those 3206 had DICAnticoagulants vs. controlMortality overall, RR 0.97 (95% CI: 0.92–1.02)Subgroup with DIC, RR 0.72 (95% CI: 0.62–0.85)Bleeding complications overall, RR 1.33 (95% CI: 1.12–1.57)
Subgroup with DIC, RR 1.26 (95% CI: 0.86–1.85)
Only three of the studies used heparins
Wang et al. (2014)138Meta-analysis of nine controlled trialsPatients with sepsis (592) or severe sepsis (3011)UFH or LMWH vs. control28-day mortality, OR 0.66 (95% CI: 0.56–0.77)Bleeding complications, OR 1.06 (95% CI: 0.83–1.36)A variety of heparin dose regimens were used
Li et al. (2021)139Meta-analysis of 10 RCTs684 adult patients with sepsisLMWH at mainly intermediate dose vs. control28-day mortality, RR 0.52 (95% CI: 0.38–0.70)
APACHE II score mean difference −4.42 (95% CI: −5.50 to −3.33
Bleeding complications, RR 1.29 (95% CI: 0.76–2.17)All studies were small with 32–159 patients
Søgaard et al. (2017)140Nationwide healthcare database. Inverse probability of treatment weighting3030 patients with AF on warfarin vs. 55 721 patients without AF and warfarin, all admitted for sepsisWarfarin at the time of sepsis diagnosis vs. no warfarin. Warfarin effect will remain 3–5 days after stopping90-day all-cause mortality, HR 0.64 (95% CI: 0.58–0.69); thromboembolism, 1.25 (95% CI: 0.89–1.76)Bleeding complications, 1.19 (95% CI: 1.00–1.41)No information on how anticoagulation was managed during hospitalization. No data on sepsis severity
Study (year)Study typePopulationComparison or interventionEfficacy outcomeSafety outcomeOther remarks
Umemura et al. (2016)137Meta-analysis of 24 RCTs14 767 patients with sepsis, treated with any anticoagulant, of those 3206 had DICAnticoagulants vs. controlMortality overall, RR 0.97 (95% CI: 0.92–1.02)Subgroup with DIC, RR 0.72 (95% CI: 0.62–0.85)Bleeding complications overall, RR 1.33 (95% CI: 1.12–1.57)
Subgroup with DIC, RR 1.26 (95% CI: 0.86–1.85)
Only three of the studies used heparins
Wang et al. (2014)138Meta-analysis of nine controlled trialsPatients with sepsis (592) or severe sepsis (3011)UFH or LMWH vs. control28-day mortality, OR 0.66 (95% CI: 0.56–0.77)Bleeding complications, OR 1.06 (95% CI: 0.83–1.36)A variety of heparin dose regimens were used
Li et al. (2021)139Meta-analysis of 10 RCTs684 adult patients with sepsisLMWH at mainly intermediate dose vs. control28-day mortality, RR 0.52 (95% CI: 0.38–0.70)
APACHE II score mean difference −4.42 (95% CI: −5.50 to −3.33
Bleeding complications, RR 1.29 (95% CI: 0.76–2.17)All studies were small with 32–159 patients
Søgaard et al. (2017)140Nationwide healthcare database. Inverse probability of treatment weighting3030 patients with AF on warfarin vs. 55 721 patients without AF and warfarin, all admitted for sepsisWarfarin at the time of sepsis diagnosis vs. no warfarin. Warfarin effect will remain 3–5 days after stopping90-day all-cause mortality, HR 0.64 (95% CI: 0.58–0.69); thromboembolism, 1.25 (95% CI: 0.89–1.76)Bleeding complications, 1.19 (95% CI: 1.00–1.41)No information on how anticoagulation was managed during hospitalization. No 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.

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 complications were marginally higher, and mortality was lower in the AF group, but interpretation is hampered by the 90-day observation period, thus well beyond 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 anticoagulants (DOAC) in AF and SIC is limited. Oral anticoagulations are generally unsuitable for patients in ICU due to vomiting, gastroparesis, unpredictable absorption, and need for frequent cessation due to invasive procedures. International normalized ratio (INR) values are specifically intended for VKA monitoring and are not informative for other anticoagulants. The PT ratio thresholds in the SOFA score are not helpful for decision-making when OACs are used.

There is a paucity of data reporting management of patients with severe infections on long-term VKA. Further, with the high mortality, morbidity, and coagulopathy associated with sepsis and severe infections, interpretation of the few reports based on single-centre observational experience is challenging. A systematic review identified eight cases of SARS-CoV-2–related prosthetic heart valve thrombosis, without evidence for non-adherence to the VKA regimen.71 Intensified monitoring of INR or switch to intravenous heparin during hospitalization 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 benefit of full-dose anticoagulation probably outweighs the bleeding risk. By 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 antimycotics, some antivirals,142 while caution should be exerted with clarithromycin.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 critically ill patients102 as stated above.

Consensus statementsStrength 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).138,139graphic
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.66graphic
For patients with VTE within 1 month, it may be appropriate to remain on full anticoagulation, preferably with LMWH, split into two daily doses.graphic
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.148graphic
We advise to treat patients with high degree of SIC with gastroprotective agents, preferably PPIs.19,93,99,102,103graphic
In patients with a long-term VKA indication, we advise to intensify INR monitoring or switch to heparin during hospitalization.71,141graphic
Consensus statementsStrength 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).138,139graphic
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.66graphic
For patients with VTE within 1 month, it may be appropriate to remain on full anticoagulation, preferably with LMWH, split into two daily doses.graphic
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.148graphic
We advise to treat patients with high degree of SIC with gastroprotective agents, preferably PPIs.19,93,99,102,103graphic
In patients with a long-term VKA indication, we advise to intensify INR monitoring or switch to heparin during hospitalization.71,141graphic
Consensus statementsStrength 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).138,139graphic
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.66graphic
For patients with VTE within 1 month, it may be appropriate to remain on full anticoagulation, preferably with LMWH, split into two daily doses.graphic
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.148graphic
We advise to treat patients with high degree of SIC with gastroprotective agents, preferably PPIs.19,93,99,102,103graphic
In patients with a long-term VKA indication, we advise to intensify INR monitoring or switch to heparin during hospitalization.71,141graphic
Consensus statementsStrength 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).138,139graphic
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.66graphic
For patients with VTE within 1 month, it may be appropriate to remain on full anticoagulation, preferably with LMWH, split into two daily doses.graphic
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.148graphic
We advise to treat patients with high degree of SIC with gastroprotective agents, preferably PPIs.19,93,99,102,103graphic
In patients with a long-term VKA indication, we advise to intensify INR monitoring or switch to heparin during hospitalization.71,141graphic

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 observation period, reduced the risk of hospitalization for stroke, heart failure,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 vaccine in preventing cardiovascular and pulmonary diseases at a population level is under investigation in a randomized, registry-based trial in elderly Finnish citizens.153 In patients with recent ACS, influenza vaccine reduced the risk for all-cause and cardiovascular mortality,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 patients with chronic coronary syndrome, a trend towards a reduction in cardiovascular mortality and incidence of cardiovascular complications was observed.154,158,159 The ESC guidelines recommend influenza 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 studies, 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, different mechanisms underlie vaccine-induced immune thrombotic thrombocytopenia vs. other thromboembolic complications during SARS-CoV-2 infection.170

Consensus statementsStrength of advice
We advise to vaccinate against influenza patients at high and very high risk of ASCVD or with previous ASCVD.51,160,171graphic
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.graphic
Consensus statementsStrength of advice
We advise to vaccinate against influenza patients at high and very high risk of ASCVD or with previous ASCVD.51,160,171graphic
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.graphic
Consensus statementsStrength of advice
We advise to vaccinate against influenza patients at high and very high risk of ASCVD or with previous ASCVD.51,160,171graphic
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.graphic
Consensus statementsStrength of advice
We advise to vaccinate against influenza patients at high and very high risk of ASCVD or with previous ASCVD.51,160,171graphic
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.graphic

Conclusions and future directions

The clinical course of coagulopathy associated with severe infections should guide the management of patients with a previous clear indication 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 maintained throughout the hospitalization, taking into account the progression 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 condition in sepsis patients in ICU, and patients requiring acute revascularization. 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 considerations of clinical management due to the complex inflammatory and other immunomodulatory effects of sepsis.

Beyond early therapy of the underlying causative infection, the unmet need is the task of improving therapeutic modalities, specifically focusing 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 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 interest 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.

References

1

Iba
 
T
,
Levi
 
M
,
Levy
 
JH
.
Sepsis-induced coagulopathy and disseminated intravascular coagulation
.
Semin Thromb Hemost
 
2020
;
46
:
89
95
. https://doi.org/10.1055/s-0039-1694995

2

Jackson
 
SP
,
Darbousset
 
R
,
Schoenwaelder
 
SM
.
Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms
.
Blood
 
2019
;
133
:
906
918
. https://doi.org/10.1182/blood-2018-11-882993

3

Delabranche
 
X
,
Helms
 
J
,
Meziani
 
F
.
Immunohaemostasis: a new view on haemostasis during sepsis
.
Ann Intensive Care
 
2017
;
7
:
117
. https://doi.org/10.1186/s13613-017-0339-5

4

Data Bridge Market Research. Global Antithrombotic Drugs Market—industry trends and forecast to 2029.
 https://www.databridgemarketresearch.com/reports/global-antithrombotic-drugs-market
.

5

Adelborg
 
K
,
Grove
 
EL
,
Sundbøll
 
J
,
Laursen
 
M
,
Schmidt
 
M
.
Sixteen-year nationwide trends in antithrombotic drug use in Denmark and its correlation with landmark studies
.
Heart
 
2016
;
102
:
1883
1889
. https://doi.org/10.1136/heartjnl-2016-309402

6

García Rodríguez
 
LA
,
Cea Soriano
 
L
,
de Abajo
 
FJ
,
Valent
 
F
,
Hallas
 
J
,
Gil
 
M
, et al.  
Trends in the use of oral anticoagulants, antiplatelets and statins in four European countries: a population-based study
.
Eur J Clin Pharmacol
 
2022
;
78
:
497
504
. https://doi.org/10.1007/s00228-021-03250-6

7

Iba
 
T
,
Umemura
 
Y
,
Wada
 
H
,
Levy
 
JH
.
Roles of coagulation abnormalities and microthrombosis in sepsis: pathophysiology, diagnosis, and treatment
.
Arch Med Res
 
2021
;
52
:
788
797
. https://doi.org/10.1016/j.arcmed.2021.07.003

8

Iba
 
T
,
Levy
 
JH
,
Warkentin
 
TE
,
Thachil
 
J
,
van der Poll
 
T
,
Levi
 
M
.
Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation
.
J Thromb Haemost
 
2019
;
17
:
1989
1994
. https://doi.org/10.1111/jth.14578

9

Visseren
 
FLJ
,
Mach
 
F
,
Smulders
 
YM
,
Carballo
 
D
,
Koskinas
 
KC
,
Bäck
 
M
, et al.  
2021 ESC guidelines on cardiovascular disease prevention in clinical practice
.
Eur Heart J
 
2021
;
42
:
3227
3337
. https://doi.org/10.1093/eurheartj/ehab484

10

Singer
 
M
,
Deutschman
 
CS
,
Seymour
 
CW
,
Shankar-Hari
 
M
,
Annane
 
D
,
Bauer
 
M
, et al.  
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)
.
JAMA
 
2016
;
315
:
801
810
. https://doi.org/10.1001/jama.2016.0287

11

Iba
 
T
,
Arakawa
 
M
,
Di Nisio
 
M
,
Gando
 
S
,
Anan
 
H
,
Sato
 
K
, et al.  
Newly proposed sepsis-induced coagulopathy precedes international society on thrombosis and haemostasis overt-disseminated intravascular coagulation and predicts high mortality
.
J Intensive Care Med
 
2020
;
35
:
643
649
. https://doi.org/10.1177/0885066618773679

12

Iba
 
T
,
Arakawa
 
M
,
Levy
 
JH
,
Yamakawa
 
K
,
Koami
 
H
,
Hifumi
 
T
, et al.  
Sepsis-induced coagulopathy and Japanese association for acute medicine DIC in coagulopathic patients with decreased antithrombin and treated by antithrombin
.
Clin Appl Thromb Hemost
 
2018
;
24
:
1020
1026
. https://doi.org/10.1177/1076029618770273

13

Yamakawa
 
K
,
Yoshimura
 
J
,
Ito
 
T
,
Hayakawa
 
M
,
Hamasaki
 
T
,
Fujimi
 
S
.
External validation of the two newly proposed criteria for assessing coagulopathy in sepsis
.
Thromb Haemost
 
2019
;
119
:
203
212
. https://doi.org/10.1055/s-0038-1676610

14

Ding
 
R
,
Wang
 
Z
,
Lin
 
Y
,
Liu
 
B
,
Zhang
 
Z
,
Ma
 
X
, et al.  
Comparison of a new criteria for sepsis-induced coagulopathy and International Society on Thrombosis and Haemostasis disseminated intravascular coagulation score in critically ill patients with sepsis 3.0: a retrospective study
.
Blood Coagul Fibrinolysis
 
2018
;
29
:
551
558
. https://doi.org/10.1097/mbc.0000000000000755

15

Vincent
 
JL
,
Moreno
 
R
,
Takala
 
J
,
Willatts
 
S
,
De Mendonça
 
A
,
Bruining
 
H
, et al.  
The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine
.
Intensive Care Med
 
1996
;
22
:
707
710
. https://doi.org/10.1007/bf01709751

16

Lyons
 
PG
,
Micek
 
ST
,
Hampton
 
N
,
Kollef
 
MH
.
Sepsis-associated coagulopathy severity predicts hospital mortality
.
Crit Care Med
 
2018
;
46
:
736
742
. https://doi.org/10.1097/CCM.0000000000002997

17

Rowe G
 
TWG
.
The Delphi technique as a forecasting tool: issues and analysis
.
Int J Forecasting
 
1999
;
15
:
353
375
. https://doi.org/10.1016/S0169-2070(99)00018-7

18

Task Force for the management of COVID-19 of the European Society of Cardiology.
 
ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 2—care pathways, treatment, and follow-up
.
Eur Heart J
 
2021
;
43
:
1059
1103
. https://doi.org/10.1093/eurheartj/ehab697

19

Schulman
 
S
,
Sholzberg
 
M
,
Spyropoulos
 
AC
,
Zarychanski
 
R
,
Resnick
 
HE
,
Bradbury
 
CA
, et al.  
ISTH guidelines for antithrombotic treatment in COVID-19
.
J Thromb Haemost
 
2022
;
20
:
2214
2225
. https://doi.org/10.1111/jth.15808

20

Martinod K
 
CD
.
Immunothrombosis and thromboinflammation in host defense and disease
.
Platelets
 
2021
;
32
:
314
324
. https://doi.org/10.1080/09537104.2020.1817360

21

Tanguay
 
JF
,
Geoffroy
 
P
,
Sirois
 
MG
,
Libersan
 
D
,
Kumar
 
A
,
Schaub
 
R
, et al.  
Prevention of in-stent restenosis via reduction of thrombo-inflammatory reactions with recombinant P-selectin glycoprotein ligand-1
.
Thromb Haemost
 
2004
;
91
:
1186
1193
. https://doi.org/10.1160/th03-11-0701

22

Tomashefski
 
JF
 Jr,
Davies
 
P
,
Boggis
 
C
,
Greene
 
R
,
Zapol
 
WM
,
Reid
 
L
.
The pulmonary vascular lesions of the adult respiratory distress syndrome
.
Am J Pathol
 
1983
;
112
:
112
126
.

23

Levy
 
JH
,
Iba
 
T
,
Olson
 
LB
,
Corey
 
KM
,
Ghadimi
 
K
,
Connors
 
JM
.
COVID-19: thrombosis, thromboinflammation, and anticoagulation considerations
.
Int J Lab Hematol
 
2021
;
43
:
29
35
. https://doi.org/10.1111/ijlh.13500

24

Stark
 
K
,
Massberg
 
S
.
Interplay between inflammation and thrombosis in cardiovascular pathology
.
Nat Rev Cardiol
 
2021
;
18
:
666
682
. https://doi.org/10.1038/s41569-021-00552-1

25

Engelmann
 
B
,
Massberg
 
S
.
Thrombosis as an intravascular effector of innate immunity
.
Nat Rev Immunol
 
2013
;
13
:
34
45
. https://doi.org/10.1038/nri3345

26

Meyers
 
S
,
Crescente
 
M
,
Verhamme
 
P
,
Martinod
 
K
.
Staphylococcus aureus and neutrophil extracellular traps: the master manipulator meets its match in immunothrombosis
.
Arterioscler Thromb Vasc Biol
 
2022
;
42
:
261
276
. https://doi.org/10.1161/atvbaha.121.316930

27

Iba
 
T
,
Levy
 
JH
.
Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis
.
J Thromb Haemost
 
2018
;
16
:
231
241
. https://doi.org/10.1111/jth.13911

28

Zhu
 
Y
,
Chen
 
X
,
Liu
 
X
.
NETosis and neutrophil extracellular traps in COVID-19: immunothrombosis and beyond
.
Front Immunol
 
2022
;
13
:
838011
. https://doi.org/10.3389/fimmu.2022.838011

29

Wuillemin
 
WA
,
Fijnvandraat
 
K
,
Derkx
 
BH
,
Peters
 
M
,
Vreede
 
W
,
ten Cate
 
H
, et al.  
Activation of the intrinsic pathway of coagulation in children with meningococcal septic shock
.
Thromb Haemost
 
1995
;
74
:
1436
1441
. https://doi.org/10.1055/s-0038-1649961

30

Jansen
 
PM
,
Pixley
 
RA
,
Brouwer
 
M
,
de Jong
 
IW
,
Chang
 
AC
,
Hack
 
CE
, et al.  
Inhibition of factor XII in septic baboons attenuates the activation of complement and fibrinolytic systems and reduces the release of interleukin-6 and neutrophil elastase
.
Blood
 
1996
;
87
:
2337
2344
. https://doi.org/10.1182/blood.V87.6.2337.bloodjournal8762337

31

Martin
 
GS
,
Mannino
 
DM
,
Eaton
 
S
,
Moss
 
M
.
The epidemiology of sepsis in the United States from 1979 through 2000
.
N Engl J Med
 
2003
;
348
:
1546
1554
. https://doi.org/10.1056/NEJMoa022139

32

Pandolfi
 
F
,
Guillemot
 
D
,
Watier
 
L
,
Brun-Buisson
 
C
.
Trends in bacterial sepsis incidence and mortality in France between 2015 and 2019 based on National Health Data System (Systeme National des donnees de Sante (SNDS)): a retrospective observational study
.
BMJ Open
 
2022
;
12
:
e058205
. https://doi.org/10.1136/bmjopen-2021-058205

33

Baker
 
RE
,
Mahmud
 
AS
,
Miller
 
IF
,
Rajeev
 
M
,
Rasambainarivo
 
F
,
Rice
 
BL
, et al.  
Infectious disease in an era of global change
.
Nat Rev Microbiol
 
2022
;
20
:
193
205
. https://doi.org/10.1038/s41579-021-00639-z

34

Mayr
 
FB
,
Yende
 
S
,
Angus
 
DC
.
Epidemiology of severe sepsis
.
Virulence
 
2014
;
5
:
4
11
. https://doi.org/10.4161/viru.27372

35

Vincent
 
JL
,
Rello
 
J
,
Marshall
 
J
,
Silva
 
E
,
Anzueto
 
A
,
Martin
 
CD
, et al.  
International study of the prevalence and outcomes of infection in intensive care units
.
JAMA
 
2009
;
302
:
2323
2329
. https://doi.org/10.1001/jama.2009.1754

36

Pryzdial
 
ELG
,
Sutherland
 
MR
,
Lin
 
BH
,
Horwitz
 
M
.
Antiviral anticoagulation
.
Res Pract Thromb Haemost
 
2020
;
4
:
774
788
. https://doi.org/10.1002/rth2.12406

37

Li
 
C
,
Li
 
J
,
Ni
 
H
.
Crosstalk between platelets and microbial pathogens
.
Front Immunol
 
2020
;
11
:
1962
. https://doi.org/10.3389/fimmu.2020.01962

38

Zhang
 
S
,
Liu
 
Y
,
Wang
 
X
,
Yang
 
L
,
Li
 
H
,
Wang
 
Y
, et al.  
SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19
.
J Hematol Oncol
 
2020
;
13
:
120
. https://doi.org/10.1186/s13045-020-00954-7

39

Ramachandran
 
G
.
Gram-positive and gram-negative bacterial toxins in sepsis: a brief review
.
Virulence
 
2014
;
5
:
213
218
. https://doi.org/10.4161/viru.27024

40

Iba
 
T
,
Levy
 
JH
,
Raj
 
A
,
Warkentin
 
TE
.
Advance in the management of sepsis-induced coagulopathy and disseminated intravascular coagulation
.
J Clin Med
 
2019
;
8
:
728
. https://doi.org/10.3390/jcm8050728

41

Lin
 
G-L
,
McGinley
 
JP
,
Drysdale
 
SB
,
Pollard
 
AJ
.
Epidemiology and immune pathogenesis of viral sepsis
.
Front Immunol
 
2018
;
9
:
2147
. https://doi.org/10.3389/fimmu.2018.02147

42

Anesi
 
GL
. COVID-19: epidemiology, clinical features, and prognosis of the critically ill adult. In. Up To Date. accessed 06222022; 2022.

43

Timsit
 
JF
,
Ruppé
 
E
,
Barbier
 
F
,
Tabah
 
A
,
Bassetti
 
M
.
Bloodstream infections in critically ill patients: an expert statement
.
Intensive Care Med
 
2020
;
46
:
266
284
. https://doi.org/10.1007/s00134-020-05950-6

44

Southeast Asia Infectious Disease Clinical Research Network
.
Causes and outcomes of sepsis in Southeast Asia: a multinational multicentre cross-sectional study
.
Lancet Glob Health
 
2017
;
5
:
e157
e167
. https://doi.org/10.1016/S2214-109X(17)30007-4

45

FitzGerald
 
GA
,
Patrono
 
C
.
The coxibs, selective inhibitors of cyclooxygenase-2
.
N Engl J Med
 
2001
;
345
:
433
442
. https://doi.org/10.1056/NEJM200108093450607

46

World Health Organization
.
Integrating Neglected Tropical Diseases Into Global Health and Development: Fourth WHO Report on Neglected Tropical Diseases
:
World Health Organization
. https://apps.who.int/iris/handle/10665/255011.
License: CC BY-NC-SA 3.0 IGO. 2017.

47

Goeijenbier
 
M
,
van Wissen
 
M
,
van de Weg
 
C
,
Jong
 
E
,
Gerdes
 
VEA
,
Meijers
 
JCM
, et al.  
Review: viral infections and mechanisms of thrombosis and bleeding
.
J Med Virol
 
2012
;
84
:
1680
1696
. https://doi.org/10.1002/jmv.23354

48

Raadsen
 
M
,
Du Toit
 
J
,
Langerak
 
T
,
van Bussel
 
B
,
van Gorp
 
E
,
Goeijenbier
 
M
, et al.  
Thrombocytopenia in virus infections
.
J Clin Med
 
2021
;
10
:
877
. https://doi.org/10.3390/jcm10040877

49

Goeijenbier
 
M
,
van Gorp
 
EC
,
Van den Brand
 
JM
,
Stittelaar
 
K
,
Bakhtiari
 
K
,
Roelofs
 
JJTH
, et al.  
Activation of coagulation and tissue fibrin deposition in experimental influenza in ferrets
.
BMC Microbiol
 
2014
;
14
:
134
. https://doi.org/10.1186/1471-2180-14-134

50

Cosentino
 
F
,
Grant
 
PJ
,
Aboyans
 
V
,
Bailey
 
CJ
,
Ceriello
 
A
,
Delgado
 
V
, et al.  
2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD
.
Eur Heart J
 
2020
;
41
:
255
323
. https://doi.org/10.1093/eurheartj/ehz486

51

Knuuti
 
J
,
Wijns
 
W
,
Saraste
 
A
,
Capodanno
 
D
,
Barbato
 
E
,
Funck-Brentano
 
C
, et al.  
2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes
.
Eur Heart J
 
2020
;
41
:
407
477
. https://doi.org/10.1093/eurheartj/ehz425

52

Akintoye
 
E
,
Afonso
 
L
,
Bengaluru Jayanna
 
M
,
Bao
 
W
,
Briasoulis
 
A
,
Robinson
 
J
.
Prognostic utility of risk enhancers and coronary artery calcium score recommended in the 2018 ACC/AHA multisociety cholesterol treatment guidelines over the pooled cohort equation: insights from 3 large prospective cohorts
.
J Am Heart Assoc
 
2021
;
10
:
e019589
. https://doi.org/10.1161/JAHA.120.019589

53

Golub I
 
S
,
Termeie Orly
 
G
,
Kristo
 
S
,
Schroeder
 
LP
,
Lakshmanan
 
S
,
Shafter
 
AM
, et al.  
Major global coronary artery calcium guidelines
.
JACC Cardiovasc Imaging
 
2023
;
16
:
98
117
. https://doi.org/10.1016/j.jcmg.2022.06.018

54

Oikonomou
 
E
,
Leopoulou
 
M
,
Theofilis
 
P
,
Antonopoulos
 
AS
,
Siasos
 
G
,
Latsios
 
G
, et al.  
A link between inflammation and thrombosis in atherosclerotic cardiovascular diseases: clinical and therapeutic implications
.
Atherosclerosis
 
2020
;
309
:
16
26
. https://doi.org/10.1016/j.atherosclerosis.2020.07.027

55

Schuetz
 
P
,
Castro
 
P
,
Shapiro
 
NI
.
Diabetes and sepsis: preclinical findings and clinical relevance
.
Diabetes Care
 
2011
;
34
:
771
778
. https://doi.org/10.2337/dc10-1185

56

Shah
 
BR
,
Hux
 
JE
.
Quantifying the risk of infectious diseases for people with diabetes
.
Diabetes Care
 
2003
;
26
:
510
513
. https://doi.org/10.2337/diacare.26.2.510

57

Vilahur
 
G
,
Ben-Aicha
 
S
,
Badimon
 
L
.
New insights into the role of adipose tissue in thrombosis
.
Cardiovasc Res
 
2017
;
113
:
1046
1054
. https://doi.org/10.1093/cvr/cvx086

58

Wang
 
S
,
Liu
 
X
,
Chen
 
Q
,
Liu
 
C
,
Huang
 
C
,
Fang
 
X
.
The role of increased body mass index in outcomes of sepsis: a systematic review and meta-analysis
.
BMC Anesthesiol
 
2017
;
17
:
118
. https://doi.org/10.1186/s12871-017-0405-4

59

Friedman
 
AN
,
Guirguis
 
J
,
Kapoor
 
R
,
Gupta
 
S
,
Leaf
 
DE
,
Timsina
 
LR
, et al.  
Obesity, inflammatory and thrombotic markers, and major clinical outcomes in critically ill patients with COVID-19 in the US
.
Obesity (Silver Spring)
 
2021
;
29
:
1719
1730
. https://doi.org/10.1002/oby.23245

60

Aghili
 
SMM
,
Ebrahimpur
 
M
,
Arjmand
 
B
,
Shadman
 
Z
,
Pejman Sani
 
M
,
Qorbani
 
M
, et al.  
Obesity in COVID-19 era, implications for mechanisms, comorbidities, and prognosis: a review and meta-analysis
.
Int J Obes (Lond)
 
2021
;
45
:
998
1016
. https://doi.org/10.1038/s41366-021-00776-8

61

Hendren
 
NS
,
de Lemos
 
JA
,
Ayers
 
C
,
Das
 
SR
,
Rao
 
A
,
Carter
 
S
, et al.  
Association of body mass index and age with morbidity and mortality in patients hospitalized with COVID-19: results from the American Heart Association COVID-19 Cardiovascular Disease Registry
.
Circulation
 
2021
;
143
:
135
144
. https://doi.org/10.1161/CIRCULATIONAHA.120.051936

62

El-Solh
 
A
,
Sikka
 
P
,
Bozkanat
 
E
,
Jaafar
 
W
,
Davies
 
J
.
Morbid obesity in the medical ICU
.
Chest
 
2001
;
120
:
1989
1997
. https://doi.org/10.1378/chest.120.6.1989

63

Jagan
 
N
,
Morrow
 
LE
,
Walters
 
RW
,
Plambeck
 
RW
,
Wallen
 
TJ
,
Patel
 
TM
, et al.  
Sepsis and the obesity paradox: size matters in more than one way
.
Crit Care Med
 
2020
;
48
:
e776
e782
. https://doi.org/10.1097/ccm.0000000000004459

64

Pepper
 
DJ
,
Sun
 
J
,
Welsh
 
J
,
Cui
 
X
,
Suffredini
 
AF
,
Eichacker
 
PQ
.
Increased body mass index and adjusted mortality in ICU patients with sepsis or septic shock: a systematic review and meta-analysis
.
Crit Care
 
2016
;
20
:
181
. https://doi.org/10.1186/s13054-016-1360-z

65

Sarkiss
 
MG
,
Yusuf
 
SW
,
Warneke
 
CL
,
Botz
 
G
,
Lakkis
 
N
,
Hirch-Ginsburg
 
C
, et al.  
Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes
.
Cancer
 
2007
;
109
:
621
627
. https://doi.org/10.1002/cncr.22434

66

Falanga
 
A
,
Leader
 
A
,
Ambaglio
 
C
,
Bagoly
 
Z
,
Castaman
 
G
,
Elalamy
 
I
, et al.  
EHA guidelines on management of antithrombotic treatments in thrombocytopenic patients with cancer
.
Hemasphere
 
2022
;
6
:
e750
. https://doi.org/10.1097/HS9.0000000000000750

67

Patrono
 
C
,
Rocca
 
B
.
Nonsteroidal antiinflammatory drugs: past, present and future
.
Pharmacol Res
 
2009
;
59
:
285
289
. https://doi.org/10.1016/j.phrs.2009.01.011

68

Chiang
 
N
,
Bermudez
 
EA
,
Ridker
 
PM
,
Hurwitz
 
S
,
Serhan
 
CN
.
Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial
.
Proc Natl Acad Sci U S A
 
2004
;
101
:
15178
15183
. https://doi.org/10.1073/pnas.0405445101

69

RECOVERY Collaborative Group
.
Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
.
Lancet
 
2022
;
399
:
143
151
. https://doi.org/10.1016/s0140-6736(21)01825-0

70

Kahn
 
SR
,
Lim
 
W
,
Dunn
 
AS
,
Cushman
 
M
,
Dentali
 
F
,
Akl
 
EA
, et al.  
Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
.
Chest
 
2012
;
141
:
e195S
e226S
. https://doi.org/10.1378/chest.11-2296

71

Trieu
 
TK
,
Birkeland
 
K
,
Kimchi
 
A
,
Kedan
 
I
.
Comprehensive collection of COVID-19 related prosthetic valve failure: a systematic review
.
J Thromb Thrombolysis
 
2022
:
55
:
474
489
. https://doi.org/10.1007/s11239-022-02746-x

72

Su
 
W
,
Miao
 
H
,
Guo
 
Z
,
Chen
 
Q
,
Huang
 
T
,
Ding
 
R
.
Associations between the use of aspirin or other antiplatelet drugs and all-cause mortality among patients with COVID-19: a meta-analysis
.
Front Pharmacol
 
2022
;
13
:
989903
. https://doi.org/10.3389/fphar.2022.989903

73

Rentsch
 
CT
,
Beckman
 
JA
,
Tomlinson
 
L
,
Gellad
 
WF
,
Alcorn
 
C
,
Kidwai-Khan
 
F
, et al.  
Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: cohort study
.
BMJ
 
2021
;
372
:
n311
. https://doi.org/10.1136/bmj.n311

74

Poulakou
 
G
,
Dimakakos
 
E
,
Kollias
 
A
,
Kyriakoulis
 
KG
,
Rapti
 
V
,
Trontzas
 
I
, et al.  
Beneficial effects of intermediate dosage of anticoagulation treatment on the prognosis of hospitalized COVID-19 patients: the ETHRA study
.
In Vivo
 
2021
;
35
:
653
661
. https://doi.org/10.21873/invivo.12305

75

Nadkarni
 
GN
,
Lala
 
A
,
Bagiella
 
E
,
Chang
 
HL
,
Moreno
 
PR
,
Pujadas
 
E
, et al.  
Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19
.
J Am Coll Cardiol
 
2020
;
76
:
1815
1826
. https://doi.org/10.1016/j.jacc.2020.08.041

76

Tang
 
N
,
Bai
 
H
,
Chen
 
X
,
Gong
 
J
,
Li
 
D
,
Sun
 
Z
.
Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy
.
J Thromb Haemost
 
2020
;
18
:
1094
1099
. https://doi.org/10.1111/jth.14817

77

Zhang
 
Y
,
Wang
 
M
,
Zhang
 
X
,
Liu
 
T
,
Libby
 
P
,
Shi
 
G-P
.
COVID-19, the pandemic of the century and its impact on cardiovascular diseases
.
Cardiol Discov
 
2021
;
1
:
233
258
. https://doi.org/10.1097/CD9.0000000000000038

78

Wang
 
Y
,
Ouyang
 
Y
,
Liu
 
B
,
Ma
 
X
,
Ding
 
R
.
Platelet activation and antiplatelet therapy in sepsis: a narrative review
.
Thromb Res
 
2018
;
166
:
28
36
. https://doi.org/10.1016/j.thromres.2018.04.007

79

Merx
 
MW
,
Weber
 
C
.
Sepsis and the heart
.
Circulation
 
2007
;
116
:
793
802
. https://doi.org/10.1161/circulationaha.106.678359

80

Ou
 
SM
,
Chu
 
H
,
Chao
 
PW
,
Lee
 
Y-J
,
Kuo
 
S-C
,
Chen
 
T-J
, et al.  
Long-term mortality and major adverse cardiovascular events in sepsis survivors. A nationwide population-based study
.
Am J Respir Crit Care Med
 
2016
;
194
:
209
217
. https://doi.org/10.1164/rccm.201510-2023OC

81

Erlich
 
JM
,
Talmor
 
DS
,
Cartin-Ceba
 
R
,
Gajic
 
O
,
Kor
 
DJ
.
Prehospitalization antiplatelet therapy is associated with a reduced incidence of acute lung injury: a population-based cohort study
.
Chest
 
2011
;
139
:
289
295
. https://doi.org/10.1378/chest.10-0891

82

Losche
 
W
,
Boettel
 
J
,
Kabisch
 
B
,
Winning
 
J
,
Claus
 
RA
,
Bauer
 
M
, et al.  
Do aspirin and other antiplatelet drugs reduce the mortality in critically ill patients?
 
Thrombosis
 
2012
;
2012
:
720254
. https://doi.org/10.1155/2012/720254

83

Valerio-Rojas
 
JC
,
Jaffer
 
IJ
,
Kor
 
DJ
,
Gajic
 
O
,
Cartin-Ceba
 
R
.
Outcomes of severe sepsis and septic shock patients on chronic antiplatelet treatment: a historical cohort study
.
Crit Care Res Pract
 
2013
;
2013
:
782573
. https://doi.org/10.1155/2013/782573

84

Tsai
 
MJ
,
Ou
 
SM
,
Shih
 
CJ
,
Chao
 
P-W
,
Wang
 
L-F
,
Shih
 
Y-N
, et al.  
Association of prior antiplatelet agents with mortality in sepsis patients: a nationwide population-based cohort study
.
Intensive Care Med
 
2015
;
41
:
806
813
. https://doi.org/10.1007/s00134-015-3760-y

85

Trauer
 
J
,
Muhi
 
S
,
McBryde
 
ES
,
Al Harbi
 
SA
,
Arabi
 
YM
,
Boyle
 
AJ
, et al.  
Quantifying the effects of prior acetyl-salicylic acid on sepsis-related deaths: an individual patient data meta-analysis using propensity matching
.
Crit Care Med
 
2017
;
45
:
1871
1879
. https://doi.org/10.1097/CCM.0000000000002654

86

Ouyang
 
Y
,
Wang
 
Y
,
Liu
 
B
,
Ma
 
X
,
Ding
 
R
.
Effects of antiplatelet therapy on the mortality rate of patients with sepsis: a meta-analysis
.
J Crit Care
 
2019
;
50
:
162
168
. https://doi.org/10.1016/j.jcrc.2018.12.004

87

Chow
 
JH
,
Yin
 
Y
,
Yamane
 
DP
,
Davison
 
D
,
Keneally
 
RJ
,
Hawkins
 
K
, et al.  
Association of prehospital antiplatelet therapy with survival in patients hospitalized with COVID-19: a propensity score-matched analysis
.
J Thromb Haemost
 
2021
;
19
:
2814
2824
. https://doi.org/10.1111/jth.15517

88

Wiewel
 
MA
,
de Stoppelaar
 
SF
,
van Vught
 
LA
,
Frencken
 
JF
,
Hoogendijk
 
AJ
,
Klein Klouwenberg
 
PMC
, et al.  
Chronic antiplatelet therapy is not associated with alterations in the presentation, outcome, or host response biomarkers during sepsis: a propensity-matched analysis
.
Intensive Care Med
 
2016
;
42
:
352
360
. https://doi.org/10.1007/s00134-015-4171-9

89

Adelborg
 
K
,
Corraini
 
P
,
Darvalics
 
B
,
Frederiksen
 
H
,
Ording
 
A
,
Horváth-Puhó
 
E
, et al.  
Risk of thromboembolic and bleeding outcomes following hematological cancers: a Danish population-based cohort study
.
J Thromb Haemost
 
2019
;
17
:
1305
1318
. https://doi.org/10.1111/jth.14475

90

Antithrombotic Trialists C
,
Baigent
 
C
,
Blackwell
 
L
,
Collins
 
R
,
Emberson
 
J
,
Godwin
 
J
, et al.  
Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials
.
Lancet
 
2009
;
373
:
1849
1860
. https://doi.org/10.1016/S0140-6736(09)60503-1

91

Hakim
 
DA
,
Dangas
 
GD
,
Caixeta
 
A
,
Nikolsky
 
E
,
Lansky
 
AJ
,
Moses
 
JW
, et al.  
Impact of baseline thrombocytopenia on the early and late outcomes after ST-elevation myocardial infarction treated with primary angioplasty: analysis from the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial
.
Am Heart J
 
2011
;
161
:
391
396
. https://doi.org/10.1016/j.ahj.2010.11.001

92

Feher
 
A
,
Kampaktsis
 
PN
,
Parameswaran
 
R
,
Stein
 
EM
,
Steingart
 
R
,
Gupta
 
D
, et al.  
Aspirin is associated with improved survival in severely thrombocytopenic cancer patients with acute myocardial infarction
.
Oncologist
 
2017
;
22
:
213
221
. https://doi.org/10.1634/theoncologist.2016-0110

93

Moayyedi
 
P
,
Eikelboom
 
JW
,
Bosch
 
J
,
Connolly
 
SJ
,
Dyal
 
L
,
Shestakovska
 
O
, et al.  
Pantoprazole to prevent gastroduodenal events in patients receiving rivaroxaban and/or aspirin in a randomized, double-blind, placebo-controlled trial
.
Gastroenterology
 
2019
;
157
:
403
412
 
e405
. https://doi.org/10.1053/j.gastro.2019.04.041

94

Scally
 
B
,
Emberson
 
JR
,
Spata
 
E
,
Reith
 
C
,
Davies
 
K
,
Halls
 
H
, et al.  
Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials
.
Lancet Gastroenterol Hepatol
 
2018
;
3
:
231
241
. https://doi.org/10.1016/S2468-1253(18)30037-2

95

Bakker
 
T
,
Dongelmans
 
DA
,
Nabovati
 
E
,
Eslami
 
S
,
Keizer
 
NF
,
Abu-Hanna
 
A
, et al.  
Heterogeneity in the identification of potential drug-drug interactions in the intensive care unit: a systematic review, critical appraisal, and reporting recommendations
.
J Clin Pharmacol
 
2022
;
62
:
706
720
. https://doi.org/10.1002/jcph.2020

96

Patrono
 
C
,
Rocca
 
B
.
Aspirin and other COX-1 inhibitors
.
Handb Exp Pharmacol
 
2012
:
210
:
137
164
. https://doi.org/10.1007/978-3-642-29423-5_6

97

Rocca
 
B
,
Petrucci
 
G
.
Personalized medicine, pharmacogenetics, and clopidogrel: unraveling variability of response
.
Mol Interv
 
2010
;
10
:
12
19
. https://doi.org/10.1124/mi.10.1.4

98

Varma
 
MVS
,
Bi
 
YA
,
Lazzaro
 
S
,
West
 
M
.
Clopidogrel as a perpetrator of drug-drug interactions: a challenge for quantitative predictions?
 
Clin Pharmacol Ther
 
2019
;
105
:
1295
1299
. https://doi.org/10.1002/cpt.1398

99

Hallas
 
J
,
Dall
 
M
,
Andries
 
A
,
Andersen
 
BS
,
Aalykke
 
C
,
Hansen
 
JM
, et al.  
Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study
.
BMJ
 
2006
;
333
:
726
. https://doi.org/10.1136/bmj.38947.697558.AE

100

Han
 
Y
,
Liao
 
Z
,
Li
 
Y
,
Zhao
 
X
,
Ma
 
S
,
Bao
 
D
, et al.  
Magnetically controlled capsule endoscopy for assessment of antiplatelet therapy-induced gastrointestinal injury
.
J Am Coll Cardiol
 
2022
;
79
:
116
128
. https://doi.org/10.1016/j.jacc.2021.10.028

101

Moayyedi
 
P
,
Eikelboom
 
JW
,
Bosch
 
J
,
Connolly
 
SJ
,
Dyal
 
L
,
Shestakovska
 
O
, et al.  
Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin
.
Gastroenterology
 
2019
;
157
:
682
691
.e2
. https://doi.org/10.1053/j.gastro.2019.05.056

102

MacLaren
 
R
,
Kassel
 
LE
,
Kiser
 
TH
,
Fish
 
DN
.
Proton pump inhibitors and histamine-2 receptor antagonists in the intensive care setting: focus on therapeutic and adverse events
.
Expert Opin Drug Saf
 
2015
;
14
:
269
280
. https://doi.org/10.1517/14740338.2015.986456

103

Ye
 
Z
,
Reintam Blaser
 
A
,
Lytvyn
 
L
,
Wang
 
Y
,
Guyatt
 
GH
,
Mikita
 
JS
, et al.  
Gastrointestinal bleeding prophylaxis for critically ill patients: a clinical practice guideline
.
BMJ
 
2020
;
368
:
l6722
. https://doi.org/10.1136/bmj.l6722

104

Frelinger
 
AL
 III,
Lee
 
RD
,
Mulford
 
DJ
,
Wu
 
J
,
Nudurupati
 
S
,
Nigam
 
A
, et al.  
A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers
.
J Am Coll Cardiol
 
2012
;
59
:
1304
1311
. https://doi.org/10.1016/j.jacc.2011.12.024

105

Ferreiro
 
JL
,
Ueno
 
M
,
Tomasello
 
SD
,
Capodanno
 
D
,
Desai
 
B
,
Dharmashankar
 
K
, et al.  
Pharmacodynamic evaluation of pantoprazole therapy on clopidogrel effects: results of a prospective, randomized, crossover study
.
Circ Cardiovasc Interv
 
2011
;
4
:
273
279
. https://doi.org/10.1161/circinterventions.110.960997

106

Ferreiro
 
JL
,
Ueno
 
M
,
Capodanno
 
D
,
Desai
 
B
,
Dharmashankar
 
K
,
Darlington
 
A
, et al.  
Pharmacodynamic effects of concomitant versus staggered clopidogrel and omeprazole intake: results of a prospective randomized crossover study
.
Circ Cardiovasc Interv
 
2010
;
3
:
436
441
. https://doi.org/10.1161/circinterventions.110.957829

109

Du
 
F
,
Jiang
 
P
,
He
 
S
,
Song
 
D
,
Xu
 
F
.
Antiplatelet therapy for critically ill patients: a pairwise and Bayesian network meta-analysis
.
Shock
 
2018
;
49
:
616
624
. https://doi.org/10.1097/SHK.0000000000001057

110

Santoro
 
F
,
Nunez-Gil
 
IJ
,
Vitale
 
E
,
Viana-Llamas
 
MC
,
Reche-Martinez
 
B
,
Romero-Pareja
 
R
, et al.  
Antiplatelet therapy and outcome in COVID-19: the health outcome predictive evaluation registry
.
Heart
 
2022
;
108
:
130
136
. https://doi.org/10.1136/heartjnl-2021-319552

111

Blasco-Colmenares
 
E
,
Perl
 
TM
,
Guallar
 
E
,
Baumgartner
 
WA
,
Conte
 
JV
,
Alejo
 
D
, et al.  
Aspirin plus clopidogrel and risk of infection after coronary artery bypass surgery
.
Arch Intern Med
 
2009
;
169
:
788
796
. https://doi.org/10.1001/archinternmed.2009.42

112

Lupu
 
L
,
Shepshelovich
 
D
,
Banai
 
S
,
Hershkoviz
 
R
,
Isakov
 
O
.
Effect of ticagrelor on reducing the risk of gram-positive infections in patients with acute coronary syndrome
.
Am J Cardiol
 
2020
;
130
:
56
63
. https://doi.org/10.1016/j.amjcard.2020.06.016

113

Storey
 
RF
,
James
 
SK
,
Siegbahn
 
A
,
Varenhorst
 
C
,
Held
 
C
,
Ycas
 
J
, et al.  
Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study
.
Platelets
 
2014
;
25
:
517
525
. https://doi.org/10.3109/09537104.2013.842965

114

Varenhorst
 
C
,
Alström
 
U
,
Braun
 
O
,
Storey
 
RF
,
Mahaffey
 
KW
,
Bertilsson
 
M
, et al.  
Causes of mortality with ticagrelor compared with clopidogrel in acute coronary syndromes
.
Heart
 
2014
;
100
:
1762
1769
. https://doi.org/10.1136/heartjnl-2014-305619

115

Varenhorst
 
C
,
Alstrom
 
U
,
Scirica
 
BM
,
Hogue
 
CW
,
Åsenblad
 
N
,
Storey
 
RF
, et al.  
Factors contributing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery
.
J Am Coll Cardiol
 
2012
;
60
:
1623
1630
. https://doi.org/10.1016/j.jacc.2012.07.021

116

Nelson
 
TA
,
Parker
 
WAE
,
Ghukasyan Lakic
 
T
,
Westerbergh
 
J
,
James
 
SK
,
Siegbahn
 
A
, et al.  
Differential effect of clopidogrel and ticagrelor on leukocyte count in relation to patient characteristics, biomarkers and genotype: a PLATO substudy
.
Platelets
 
2022
;
33
:
425
431
. https://doi.org/10.1080/09537104.2021.1934667

117

CAPRIE Steering Committee
.
A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)
.
Lancet
 
1996
;
348
:
1329
1339
. https://doi.org/10.1016/s0140-6736(96)09457-3

118

Kiers
 
D
,
van der Heijden
 
WA
,
van Ede
 
L
,
Gerretsen
 
J
,
de Mast
 
Q
,
van der Ven
 
AJ
, et al.  
A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia
.
Thromb Haemost
 
2017
;
117
:
1798
1807
. https://doi.org/10.1160/TH16-10-0799

119

Rabouel
 
Y
,
Magnenat
 
S
,
Delabranche
 
X
,
Gachet
 
C
,
Hechler
 
B
.
Platelet P2Y 12 receptor deletion or pharmacological inhibition does not protect mice from sepsis or septic shock
.
TH Open
 
2021
;
5
:
e343
e352
. https://doi.org/10.1055/s-0041-1733857

120

Thomas
 
MR
,
Outteridge
 
SN
,
Ajjan
 
RA
,
Phoenix
 
F
,
Sangha
 
GK
,
Faulkner
 
RE
, et al.  
Platelet P2Y12 inhibitors reduce systemic inflammation and its prothrombotic effects in an experimental human model
.
Arterioscler Thromb Vasc Biol
 
2015
;
35
:
2562
2570
. https://doi.org/10.1161/ATVBAHA.115.306528

121

Totani
 
L
,
Dell'Elba
 
G
,
Martelli
 
N
,
Di Santo
 
A
,
Piccoli
 
A
,
Amore
 
C
, et al.  
Prasugrel inhibits platelet-leukocyte interaction and reduces inflammatory markers in a model of endotoxic shock in the mouse
.
Thromb Haemost
 
2012
;
107
:
1130
1140
. https://doi.org/10.1160/TH11-12-0867

122

Berger
 
JS
,
Kornblith
 
LZ
,
Gong
 
MN
,
Reynolds
 
HR
,
Cushman
 
M
,
Cheng
 
Y
, et al.  
Effect of P2Y12 inhibitors on survival free of organ support among non-critically ill hospitalized patients with COVID-19: a randomized clinical trial
.
JAMA
 
2022
;
327
:
227
236
. https://doi.org/10.1001/jama.2021.23605

123

Piccolo
 
R
,
Feres
 
F
,
Abizaid
 
A
,
Gilard
 
M
,
Morice
 
M-C
,
Hong
 
M-K
, et al.  
Risk of early adverse events after clopidogrel discontinuation in patients undergoing short-term dual antiplatelet therapy: an individual participant data analysis
.
JACC Cardiovasc Interv
 
2017
;
10
:
1621
1630
. https://doi.org/10.1016/j.jcin.2017.06.001

124

Khan
 
SU
,
Singh
 
M
,
Valavoor
 
S
,
Khan
 
MU
,
Lone
 
AN
,
Khan
 
MZ
, et al.  
Dual antiplatelet therapy after percutaneous coronary intervention and drug-eluting stents: a systematic review and network meta-analysis
.
Circulation
 
2020
;
142
:
1425
1436
. https://doi.org/10.1161/circulationaha.120.046308

125

Smeeth
 
L
,
Thomas
 
SL
,
Hall
 
AJ
,
Hubbard
 
R
,
Farrington
 
P
,
Vallance
 
P
, et al.  
Risk of myocardial infarction and stroke after acute infection or vaccination
.
N Engl J Med
 
2004
;
351
:
2611
2618
. https://doi.org/10.1056/NEJMoa041747

126

Capodanno
 
D
,
Baber
 
U
,
Bhatt
 
DL
,
Collet
 
J-P
,
Dangas
 
G
,
Franchi
 
F
, et al.  
P2y(12) inhibitor monotherapy in patients undergoing percutaneous coronary intervention
.
Nat Rev Cardiol
 
2022
;
19
:
829
844
. https://doi.org/10.1038/s41569-022-00725-6

127

Lopes
 
RD
,
Heizer
 
G
,
Aronson
 
R
,
Vora
 
AN
,
Massaro
 
T
,
Mehran
 
R
, et al.  
Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation
.
N Engl J Med
 
2019
;
380
:
1509
1524
. https://doi.org/10.1056/NEJMoa1817083

128

Schilling
 
U
,
Dingemanse
 
J
,
Ufer
 
M
.
Pharmacokinetics and pharmacodynamics of approved and investigational P2Y12 receptor antagonists
.
Clin Pharmacokinet
 
2020
;
59
:
545
566
. https://doi.org/10.1007/s40262-020-00864-4

129

Storey
 
RF
,
Bliden
 
KP
,
Patil
 
SB
,
Karunakaran
 
A
,
Ecob
 
R
,
Butler
 
K
, et al.  
Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study
.
J Am Coll Cardiol
 
2010
;
56
:
185
193
. https://doi.org/10.1016/j.jacc.2010.01.062

130

Arora
 
S
,
Shemisa
 
K
,
Vaduganathan
 
M
,
Qamar
 
A
,
Gupta
 
A
,
Garg
 
SK
, et al.  
Premature ticagrelor discontinuation in secondary prevention of atherosclerotic CVD: JACC review topic of the week
.
J Am Coll Cardiol
 
2019
;
73
:
2454
2464
. https://doi.org/10.1016/j.jacc.2019.03.470

131

Sumaya
 
W
,
Parker
 
WAE
,
Fretwell
 
R
,
Hall
 
I
,
Barmby
 
D
,
Richardson
 
J
, et al.  
Pharmacodynamic effects of a 6-hour regimen of enoxaparin in patients undergoing primary percutaneous coronary intervention (PENNY PCI Study)
.
Thromb Haemost
 
2018
;
118
:
1250
1256
. https://doi.org/10.1055/s-0038-1657768

132

Shimizu
 
M
,
Natori
 
T
,
Tsuda
 
K
,
Yoshida
 
M
,
Kamada
 
A
,
Oi
 
K
, et al.  
Thrombin-induced platelet aggregation—effect of dabigatran using automated platelet aggregometry−
.
Platelets
 
2020
;
31
:
360
364
. https://doi.org/10.1080/09537104.2019.1624707

133

Lamontagne
 
F
,
Garant
 
MP
,
Carvalho
 
JC
,
Lanthier
 
L
,
Smieja
 
M
,
Pilon
 
D
, et al.  
Pneumococcal vaccination and risk of myocardial infarction
.
Cmaj
 
2008
;
179
:
773
777
. https://doi.org/10.1503/cmaj.070221

134

Eisen
 
DP
,
Reid
 
D
,
McBryde
 
ES
.
Acetyl salicylic acid usage and mortality in critically ill patients with the systemic inflammatory response syndrome and sepsis
.
Crit Care Med
 
2012
;
40
:
1761
1767
. https://doi.org/10.1097/CCM.0b013e318246b9df

135

Meizlish
 
ML
,
Goshua
 
G
,
Liu
 
Y
,
Fine
 
R
,
Amin
 
K
,
Chang
 
E
, et al.  
Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: a propensity score-matched analysis
.
Am J Hematol
 
2021
;
96
:
471
479
. https://doi.org/10.1002/ajh.26102

136

Otto
 
GP
,
Sossdorf
 
M
,
Boettel
 
J
,
Kabisch
 
B
,
Breuel
 
H
,
Winning
 
J
, et al.  
Effects of low-dose acetylsalicylic acid and atherosclerotic vascular diseases on the outcome in patients with severe sepsis or septic shock
.
Platelets
 
2013
;
24
:
480
485
. https://doi.org/10.3109/09537104.2012.724482

137

Umemura
 
Y
,
Yamakawa
 
K
,
Ogura
 
H
,
Yuhara
 
H
,
Fujimi
 
S
.
Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials
.
J Thromb Haemost
 
2016
;
14
:
518
530
. https://doi.org/10.1111/jth.13230

138

Wang
 
C
,
Chi
 
C
,
Guo
 
L
,
Wang
 
X
,
Guo
 
L
,
Sun
 
J
, et al.  
Heparin therapy reduces 28-day mortality in adult severe sepsis patients: a systematic review and meta-analysis
.
Crit Care
 
2014
;
18
:
563
. https://doi.org/10.1186/s13054-014-0563-4

139

Li
 
X
,
Liu
 
Z
,
Luo
 
M
,
Xi
 
Y
,
Li
 
C
,
Wang
 
S
, et al.  
Therapeutic effect of low-molecular-weight heparin on adult sepsis: a meta-analysis
.
Ann Palliat Med
 
2021
;
10
:
3115
3127
. https://doi.org/10.21037/apm-21-169

140

Søgaard
 
M
,
Skjøth
 
F
,
Kjældgaard
 
JN
,
Lip
 
GYH
,
Larsen
 
TB
.
Bleeding complications in anticoagulated patients with atrial fibrillation and sepsis: a propensity-weighted cohort study
.
J Am Heart Assoc
 
2017
;
6
:
e007453
. https://doi.org/10.1161/jaha.117.007453

141

Darwish
 
OS
,
Strube
 
S
,
Nguyen
 
HM
,
Tanios
 
MA
.
Challenges of anticoagulation for atrial fibrillation in patients with severe sepsis
.
Ann Pharmacother
 
2013
;
47
:
1266
1271
. https://doi.org/10.1177/1060028013500938

146

Ray
 
WA
,
Chung
 
CP
,
Murray
 
KT
,
Smalley
 
WE
,
Daugherty
 
JR
,
Dupont
 
WD
, et al.  
Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding
.
Gastroenterology
 
2016
;
151
:
1105
1112
.e10
. https://doi.org/10.1053/j.gastro.2016.08.054

147

Komen
 
J
,
Pottegård
 
A
,
Hjemdahl
 
P
,
Mantel-Teeuwisse
 
AK
,
Wettermark
 
B
,
Hellfritzsch
 
M
, et al.  
Non-vitamin K antagonist oral anticoagulants, proton pump inhibitors and gastrointestinal bleeds
.
Heart
 
2022
;
108
:
613
618
. https://doi.org/10.1136/heartjnl-2021-319332

148

Mar
 
PL
,
Gopinathannair
 
R
,
Gengler
 
BE
,
Chung
 
MK
,
Perez
 
A
,
Dukes
 
J
, et al.  
Drug interactions affecting oral anticoagulant use
.
Circ Arrhythm Electrophysiol
 
2022
;
15
:
e007956
. https://doi.org/10.1161/circep.121.007956

149

Vamos
 
EP
,
Pape
 
UJ
,
Curcin
 
V
,
Harris
 
MJ
,
Valabhji
 
J
,
Majeed
 
A
, et al.  
Effectiveness of the influenza vaccine in preventing admission to hospital and death in people with type 2 diabetes
.
CMAJ
 
2016
;
188
:
E342
E351
. https://doi.org/10.1503/cmaj.151059

150

Vardeny
 
O
,
Kim
 
K
,
Udell
 
JA
,
Joseph
 
J
,
Desai
 
AS
,
Farkouh
 
ME
, et al.  
Effect of high-dose trivalent vs standard-dose quadrivalent influenza vaccine on mortality or cardiopulmonary hospitalization in patients with high-risk cardiovascular disease: a randomized clinical trial
.
JAMA
 
2021
;
325
:
39
49
. https://doi.org/10.1001/jama.2020.23649

151

Modin
 
D
,
Claggett
 
B
,
Kober
 
L
,
Schou
 
M
,
Jensen
 
JUS
,
Solomon
 
SD
, et al.  
Influenza vaccination is associated with reduced cardiovascular mortality in adults with diabetes: a nationwide cohort study
.
Diabetes Care
 
2020
;
43
:
2226
2233
. https://doi.org/10.2337/dc20-0229

152

Modin
 
D
,
Claggett
 
B
,
Jorgensen
 
ME
,
Køber
 
L
,
Benfield
 
T
,
Schou
 
M
, et al.  
Flu vaccine and mortality in hypertension: a nationwide cohort study
.
J Am Heart Assoc
 
2022
;
11
:
e021715
. https://doi.org/10.1161/JAHA.121.021715

153

Hollingsworth
 
R
,
Palmu
 
A
,
Pepin
 
S
,
Dupuy
 
M
,
Shrestha
 
A
,
Jokinen
 
J
, et al.  
Effectiveness of the quadrivalent high-dose influenza vaccine for prevention of cardiovascular and respiratory events in people aged 65 years and above: rationale and design of a real-world pragmatic randomized clinical trial
.
Am Heart J
 
2021
;
237
:
54
61
. https://doi.org/10.1016/j.ahj.2021.03.007

154

Gurfinkel
 
EP
,
de la Fuente
 
RL
,
Mendiz
 
O
,
Mautner
 
B
.
Influenza vaccine pilot study in acute coronary syndromes and planned percutaneous coronary interventions: the FLU Vaccination Acute Coronary Syndromes (FLUVACS) study
.
Circulation
 
2002
;
105
:
2143
2147
. https://doi.org/10.1161/01.cir.0000016182.85461.f4

155

Frobert
 
O
,
Gotberg
 
M
,
Erlinge
 
D
,
Akhtar
 
Z
,
Christiansen
 
EH
,
MacIntyre
 
CR
, et al.  
Influenza vaccination after myocardial infarction: a randomized, double-blind, placebo-controlled, multicenter trial
.
Circulation
 
2021
;
144
:
1476
1484
. https://doi.org/10.1161/CIRCULATIONAHA.121.057042

156

Fonseca
 
HAR
,
Furtado
 
RHM
,
Zimerman
 
A
,
Lemos
 
PA
,
Franken
 
M
,
Monfardini
 
F
, et al.  
Influenza vaccination strategy in acute coronary syndromes: the VIP-ACS trial
.
Eur Heart J
 
2022
;
43
:
4378
4388
. https://doi.org/10.1093/eurheartj/ehac472

157

Phrommintikul
 
A
,
Kuanprasert
 
S
,
Wongcharoen
 
W
,
Kanjanavanit
 
R
,
Chaiwarith
 
R
,
Sukonthasarn
 
A
, et al.  
Influenza vaccination reduces cardiovascular events in patients with acute coronary syndrome
.
Eur Heart J
 
2011
;
32
:
1730
1735
. https://doi.org/10.1093/eurheartj/ehr004

158

Gurfinkel
 
EP
,
Leon de la Fuente
 
R
,
Mendiz
 
O
,
Mautner
 
B
.
Flu vaccination in acute coronary syndromes and planned percutaneous coronary interventions (FLUVACS) study
.
Eur Heart J
 
2004
;
25
:
25
31
. https://doi.org/10.1016/j.ehj.2003.10.018

159

Ciszewski
 
A
,
Bilinska
 
ZT
,
Brydak
 
LB
,
Brydak
 
LB
,
Kepka
 
C
,
Kruk
 
M
, et al.  
Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery disease: FLUCAD study
.
Eur Heart J
 
2008
;
29
:
1350
1358
. https://doi.org/10.1093/eurheartj/ehm581

160

Jaiswal
 
V
,
Ang
 
SP
,
Yaqoob
 
S
,
Yaqoob
 
S
,
Ishak
 
A
,
Chia
 
JE
, et al.  
Cardioprotective effects of influenza vaccination among patients with established cardiovascular disease or at high cardiovascular risk: a systematic review and meta-analysis
.
Eur J Prev Cardiol
 
2022
;
29
:
1881
1892
. https://doi.org/10.1093/eurjpc/zwac152

161

Hung
 
IF
,
Leung
 
AY
,
Chu
 
DW
,
Leung
 
D
,
Cheung
 
T
,
Chan
 
C-K
, et al.  
Prevention of acute myocardial infarction and stroke among elderly persons by dual pneumococcal and influenza vaccination: a prospective cohort study
.
Clin Infect Dis
 
2010
;
51
:
1007
1016
. https://doi.org/10.1086/656587

162

Ochoa-Gondar
 
O
,
Vila-Corcoles
 
A
,
Rodriguez-Blanco
 
T
,
de Diego-Cabanes
 
C
,
Hospital-Guardiola
 
I
,
Jariod-Pamies
 
M
, et al.  
Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: the CAPAMIS study, three-year follow-up
.
Vaccine
 
2014
;
32
:
252
257
. https://doi.org/10.1016/j.vaccine.2013.11.017

163

Vila-Corcoles
 
A
,
Ochoa-Gondar
 
O
,
Rodriguez-Blanco
 
T
,
de Diego-Cabanes
 
C
,
Satue-Gracia
 
E
,
Vila-Rovira
 
A
, et al.  
Evaluating clinical effectiveness of pneumococcal vaccination in preventing stroke: the CAPAMIS study, 3-year follow-up
.
J Stroke Cerebrovasc Dis
 
2014
;
23
:
1577
1584
. https://doi.org/10.1016/j.jstrokecerebrovasdis.2013.12.047

164

Ren
 
S
,
Newby
 
D
,
Li
 
SC
,
Walkom
 
E
,
Miller
 
P
,
Hure
 
A
, et al.  
Effect of the adult pneumococcal polysaccharide vaccine on cardiovascular disease: a systematic review and meta-analysis
.
Open Heart
 
2015
;
2
:
e000247
. https://doi.org/10.1136/openhrt-2015-000247

165

Marchandot
 
B
,
Curtiaud
 
A
,
Trimaille
 
A
,
Sattler
 
L
,
Grunebaum
 
L
,
Morel
 
O
.
Vaccine-induced immune thrombotic thrombocytopenia: current evidence, potential mechanisms, clinical implications, and future directions
.
Eur Heart J Open
 
2021
;
1
:
oeab014
. https://doi.org/10.1093/ehjopen/oeab014

166

Pavord
 
S
,
Scully
 
M
,
Hunt
 
BJ
,
Lester
 
W
,
Bagot
 
C
,
Craven
 
B
, et al.  
Clinical features of vaccine-induced immune thrombocytopenia and thrombosis
.
N Engl J Med
 
2021
;
385
:
1680
1689
. https://doi.org/10.1056/NEJMoa2109908

167

Greinacher
 
A
,
Thiele
 
T
,
Warkentin
 
TE
,
Weisser
 
K
,
Kyrle
 
PA
,
Eichinger
 
S
, et al.  
Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination
.
N Engl J Med
 
2021
;
384
:
2092
2101
. https://doi.org/10.1056/NEJMoa2104840

168

Hwang
 
J
,
Park
 
SH
,
Lee
 
SW
,
Lee
 
SB
,
Lee
 
MH
,
Jeong
 
GH
, et al.  
Predictors of mortality in thrombotic thrombocytopenia after adenoviral COVID-19 vaccination: the FAPIC score
.
Eur Heart J
 
2021
;
42
:
4053
4063
. https://doi.org/10.1093/eurheartj/ehab592

169

See
 
I
,
Su
 
JR
,
Lale
 
A
,
Woo
 
EJ
,
Guh
 
AY
,
Shimabukuro
 
TT
, et al.  
US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021
.
JAMA
 
2021
;
325
:
2448
2456
. https://doi.org/10.1001/jama.2021.7517

170

Mandal
 
AKJ
,
Kho
 
J
,
Ioannou
 
A
,
Van den Abbeele
 
K
,
Missouris
 
CG
.
COVID-19 and in situ pulmonary artery thrombosis
.
Respir Med
 
2021
;
176
:
106176
. https://doi.org/10.1016/j.rmed.2020.106176

171

Udell
 
JA
,
Zawi
 
R
,
Bhatt
 
DL
,
Keshtkar-Jahromi
 
M
,
Gaughran
 
F
,
Phrommintikul
 
A
, et al.  
Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis
.
JAMA
 
2013
;
310
:
1711
1720
. https://doi.org/10.1001/jama.2013.279206

Author notes

P.C.L. and B.R. are last co-authors.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://dbpia.nl.go.kr/pages/standard-publication-reuse-rights)

Supplementary data