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Bruna Gigante, Jerrold H Levy, Eric van Gorp, Alessandro Bartoloni, Marie-Luce Bochaton-Piallat, Magnus Bäck, Hugo ten Cate, Christina Christersson, José Luis Ferreiro, Tobias Geisler, Esther Lutgens, Sam Schulman, Robert F Storey, Jecko Thachil, Gemma Vilahur, Patricia C Liaw, Bianca Rocca, Management of patients on antithrombotic therapy with severe infections: a joint clinical consensus statement of the ESC Working Group on Thrombosis, the ESC Working Group on Atherosclerosis and Vascular Biology, and the International Society on Thrombosis and Haemostasis, European Heart Journal, Volume 44, Issue 32, 21 August 2023, Pages 3040–3058, https://doi.org/10.1093/eurheartj/ehad388
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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.
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
. | Points . | ||
---|---|---|---|
. | 0 . | 1 . | 2 . |
Prothrombin time (PT-INR) | >1.2 | 1.2–1.4 | >1.4 |
Platelet count (×109/L) | >150 | 100–149 | <100 |
Total SOFAb (respiratory, cardiovascular, hepatic, and renal) | 0 | 1 | ≥ 2 |
. | Points . | ||
---|---|---|---|
. | 0 . | 1 . | 2 . |
Prothrombin time (PT-INR) | >1.2 | 1.2–1.4 | >1.4 |
Platelet count (×109/L) | >150 | 100–149 | <100 |
Total SOFAb (respiratory, cardiovascular, hepatic, and renal) | 0 | 1 | ≥ 2 |
. | Points . | ||
---|---|---|---|
. | 0 . | 1 . | 2 . |
Prothrombin time (PT-INR) | >1.2 | 1.2–1.4 | >1.4 |
Platelet count (×109/L) | >150 | 100–149 | <100 |
Total SOFAb (respiratory, cardiovascular, hepatic, and renal) | 0 | 1 | ≥ 2 |
. | Points . | ||
---|---|---|---|
. | 0 . | 1 . | 2 . |
Prothrombin time (PT-INR) | >1.2 | 1.2–1.4 | >1.4 |
Platelet count (×109/L) | >150 | 100–149 | <100 |
Total SOFAb (respiratory, cardiovascular, hepatic, and renal) | 0 | 1 | ≥ 2 |
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.

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 2–4).
Management of antithrombotic therapy in patients with multiple cardiovascular risk factors and enhancers and no history of symptomatic ASCVD
. | Severe infections where only preventive antithrombotic treatment is indicated . | Severe infections and platelet count ≥20 × 109/L . | Severe infections and platelet count <20 × 109/L . | Severe infections and platelet count <20 × 109/L in the presence of multiorgan failure . |
---|---|---|---|---|
During | No routine antiplatelet therapy, SAPT as pre-existing indication | No routine antiplatelet therapy, SAPT as pre-existing indication | No antiplatelet therapy | No antithrombotic treatment |
Prophylactic anticoagulationa | Prophylactic anticoagulation | Prophylactic anticoagulation in patients at high thromboembolic risk | ||
After | SAPT as pre-existing indication | SAPT as pre-existing indication | SAPT as pre-existing indication | SAPT as pre-existing indication |
No routine prophylactic anticoagulationb | No routine prophylactic anticoagulationb | No routine prophylactic anticoagulationb | No routine prophylactic anticoagulationb |
. | Severe infections where only preventive antithrombotic treatment is indicated . | Severe infections and platelet count ≥20 × 109/L . | Severe infections and platelet count <20 × 109/L . | Severe infections and platelet count <20 × 109/L in the presence of multiorgan failure . |
---|---|---|---|---|
During | No routine antiplatelet therapy, SAPT as pre-existing indication | No routine antiplatelet therapy, SAPT as pre-existing indication | No antiplatelet therapy | No antithrombotic treatment |
Prophylactic anticoagulationa | Prophylactic anticoagulation | Prophylactic anticoagulation in patients at high thromboembolic risk | ||
After | SAPT as pre-existing indication | SAPT as pre-existing indication | SAPT as pre-existing indication | SAPT as pre-existing indication |
No routine prophylactic anticoagulationb | No routine prophylactic anticoagulationb | No routine prophylactic anticoagulationb | No 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.
Management of antithrombotic therapy in patients with multiple cardiovascular risk factors and enhancers and no history of symptomatic ASCVD
. | Severe infections where only preventive antithrombotic treatment is indicated . | Severe infections and platelet count ≥20 × 109/L . | Severe infections and platelet count <20 × 109/L . | Severe infections and platelet count <20 × 109/L in the presence of multiorgan failure . |
---|---|---|---|---|
During | No routine antiplatelet therapy, SAPT as pre-existing indication | No routine antiplatelet therapy, SAPT as pre-existing indication | No antiplatelet therapy | No antithrombotic treatment |
Prophylactic anticoagulationa | Prophylactic anticoagulation | Prophylactic anticoagulation in patients at high thromboembolic risk | ||
After | SAPT as pre-existing indication | SAPT as pre-existing indication | SAPT as pre-existing indication | SAPT as pre-existing indication |
No routine prophylactic anticoagulationb | No routine prophylactic anticoagulationb | No routine prophylactic anticoagulationb | No routine prophylactic anticoagulationb |
. | Severe infections where only preventive antithrombotic treatment is indicated . | Severe infections and platelet count ≥20 × 109/L . | Severe infections and platelet count <20 × 109/L . | Severe infections and platelet count <20 × 109/L in the presence of multiorgan failure . |
---|---|---|---|---|
During | No routine antiplatelet therapy, SAPT as pre-existing indication | No routine antiplatelet therapy, SAPT as pre-existing indication | No antiplatelet therapy | No antithrombotic treatment |
Prophylactic anticoagulationa | Prophylactic anticoagulation | Prophylactic anticoagulation in patients at high thromboembolic risk | ||
After | SAPT as pre-existing indication | SAPT as pre-existing indication | SAPT as pre-existing indication | SAPT as pre-existing indication |
No routine prophylactic anticoagulationb | No routine prophylactic anticoagulationb | No routine prophylactic anticoagulationb | No 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.
. | Patients on SAPT . | Patients on DAPT . | Patients on long-term OAC . | Patients 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 change | No change | |
SIC score = 3 | |||||
Plateleat count 100–149 × 109/L and PT ratio 1.2–1.4 | Platelet count ≥20 × 109/L: no change | <3 m after PCI or ACS: no change or consider P2Y12 inhibitor or ASA | Platelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change | Platelet 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 SAPT | Consider 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 >1.4 | Platelet 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 SAPT . | Patients on DAPT . | Patients on long-term OAC . | Patients 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 change | No change | |
SIC score = 3 | |||||
Plateleat count 100–149 × 109/L and PT ratio 1.2–1.4 | Platelet count ≥20 × 109/L: no change | <3 m after PCI or ACS: no change or consider P2Y12 inhibitor or ASA | Platelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change | Platelet 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 SAPT | Consider 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 >1.4 | Platelet 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.
. | Patients on SAPT . | Patients on DAPT . | Patients on long-term OAC . | Patients 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 change | No change | |
SIC score = 3 | |||||
Plateleat count 100–149 × 109/L and PT ratio 1.2–1.4 | Platelet count ≥20 × 109/L: no change | <3 m after PCI or ACS: no change or consider P2Y12 inhibitor or ASA | Platelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change | Platelet 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 SAPT | Consider 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 >1.4 | Platelet 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 SAPT . | Patients on DAPT . | Patients on long-term OAC . | Patients 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 change | No change | |
SIC score = 3 | |||||
Plateleat count 100–149 × 109/L and PT ratio 1.2–1.4 | Platelet count ≥20 × 109/L: no change | <3 m after PCI or ACS: no change or consider P2Y12 inhibitor or ASA | Platelet count 100–149 × 109/L and PT ratio 1.2–1.4: no change | Platelet 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 SAPT | Consider 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 >1.4 | Platelet 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.
. | Patients on SAPT . | Patients on DAPT . | Patients on long-term OAC . | Patients on OAC due to recentb thromboembolic event . | |
---|---|---|---|---|---|
SIC score = 3 | |||||
Platelet count 100–149 × 109/LorPT ratio 1.2–1.4 | No 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 change | No 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 >1.4 | Platelet 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 heparin | Platelet count 30–50 × 109/L: prophylactic dose heparind; platelet count <30 × 109/L: stop heparin |
. | Patients on SAPT . | Patients on DAPT . | Patients on long-term OAC . | Patients on OAC due to recentb thromboembolic event . | |
---|---|---|---|---|---|
SIC score = 3 | |||||
Platelet count 100–149 × 109/LorPT ratio 1.2–1.4 | No 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 change | No 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 >1.4 | Platelet 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 heparin | Platelet 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.
. | Patients on SAPT . | Patients on DAPT . | Patients on long-term OAC . | Patients on OAC due to recentb thromboembolic event . | |
---|---|---|---|---|---|
SIC score = 3 | |||||
Platelet count 100–149 × 109/LorPT ratio 1.2–1.4 | No 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 change | No 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 >1.4 | Platelet 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 heparin | Platelet count 30–50 × 109/L: prophylactic dose heparind; platelet count <30 × 109/L: stop heparin |
. | Patients on SAPT . | Patients on DAPT . | Patients on long-term OAC . | Patients on OAC due to recentb thromboembolic event . | |
---|---|---|---|---|---|
SIC score = 3 | |||||
Platelet count 100–149 × 109/LorPT ratio 1.2–1.4 | No 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 change | No 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 >1.4 | Platelet 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 heparin | Platelet 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 statements . | Strength 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 2–4).19,71,72 | ![]() |
Additional parenteral anticoagulation at prophylactic or at higher doses depending on the individual bleeding risk may be appropriate in patients with high and very high cardiovascular risk as needed according to SIC severity (Tables 3 and 4).73–76 | ![]() |
Temporary switching to parental anticoagulation may be appropriate in some situations where combination is not justifiable (e.g. SIC with low platelet count and/or high bleeding risk). | ![]() |
Consensus statements . | Strength 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 2–4).19,71,72 | ![]() |
Additional parenteral anticoagulation at prophylactic or at higher doses depending on the individual bleeding risk may be appropriate in patients with high and very high cardiovascular risk as needed according to SIC severity (Tables 3 and 4).73–76 | ![]() |
Temporary switching to parental anticoagulation may be appropriate in some situations where combination is not justifiable (e.g. SIC with low platelet count and/or high bleeding risk). | ![]() |
Consensus statements . | Strength 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 2–4).19,71,72 | ![]() |
Additional parenteral anticoagulation at prophylactic or at higher doses depending on the individual bleeding risk may be appropriate in patients with high and very high cardiovascular risk as needed according to SIC severity (Tables 3 and 4).73–76 | ![]() |
Temporary switching to parental anticoagulation may be appropriate in some situations where combination is not justifiable (e.g. SIC with low platelet count and/or high bleeding risk). | ![]() |
Consensus statements . | Strength 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 2–4).19,71,72 | ![]() |
Additional parenteral anticoagulation at prophylactic or at higher doses depending on the individual bleeding risk may be appropriate in patients with high and very high cardiovascular risk as needed according to SIC severity (Tables 3 and 4).73–76 | ![]() |
Temporary switching to parental anticoagulation may be appropriate in some situations where combination is not justifiable (e.g. SIC with low platelet count and/or high bleeding risk). | ![]() |
Patients on single antiplatelet therapy
According to current guidelines, single antiplatelet therapy (SAPT), mainly with low-dose ASA, is used for prevalent stable symptomatic ASCVD or previous revascularization in the absence of history of MI.9,51 ASCVD patients have a high susceptibility to viral77 and bacterial infections78 and worse sepsis outcomes.79 Moreover, sepsis survivors appear at increased risk for future major vascular events.80
Observational studies on sepsis report that SAPT is associated with a better outcome (Table 5). Acetylsalicylic acid started before sepsis/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).
Studies in patients on single or dual antiplatelet therapy before hospitalization for severe infections or sepsis
Study (year) . | Design . | Population . | Comparison and type of antiplatelet agent(s) . | Effectiveness . | Safety . | Other remarks . |
---|---|---|---|---|---|---|
Erlich et al. (2011)81 | Multicentre observational, prospective study | 161 hospitalized patients at risk for acute lung injury, ∼30% due to sepsis or infection | Pre-hospitalization SAPT–ASA users: 79 | ASA 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)82 | Retrospective analysis of two cohorts | Cohort 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 use | Similar benefit also after correcting for SOFA score, age, gender, and C-reactive protein levels |
Valerio-Rojas et al. (2013)83 | Retrospective | 651 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)84 | Nationwide population-based cohort and nested case–control study | 683 421 patients hospitalized for sepsis | Use 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) | NA | Benefit 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)85 | Meta-analysis of 11 observational studies | n = 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 usage | Mortality: 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)86 | Meta-analysis of 10 studies | 689 897 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 studies | Mortality OR: 0.78 (95% CI: 0.77–0.80) SAPT–ASA: OR 0.60 (95% CI: 0.53–0.68) | NA | A subgroup on timing of APT showed benefit for APT administered also after hospitalization |
Chow et al. (2021)87 | Observational, 1:2 propensity score matched for demographics and comorbidities hospital mortality PE | 17 347 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) . | Design . | Population . | Comparison and type of antiplatelet agent(s) . | Effectiveness . | Safety . | Other remarks . |
---|---|---|---|---|---|---|
Erlich et al. (2011)81 | Multicentre observational, prospective study | 161 hospitalized patients at risk for acute lung injury, ∼30% due to sepsis or infection | Pre-hospitalization SAPT–ASA users: 79 | ASA 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)82 | Retrospective analysis of two cohorts | Cohort 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 use | Similar benefit also after correcting for SOFA score, age, gender, and C-reactive protein levels |
Valerio-Rojas et al. (2013)83 | Retrospective | 651 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)84 | Nationwide population-based cohort and nested case–control study | 683 421 patients hospitalized for sepsis | Use 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) | NA | Benefit 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)85 | Meta-analysis of 11 observational studies | n = 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 usage | Mortality: 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)86 | Meta-analysis of 10 studies | 689 897 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 studies | Mortality OR: 0.78 (95% CI: 0.77–0.80) SAPT–ASA: OR 0.60 (95% CI: 0.53–0.68) | NA | A subgroup on timing of APT showed benefit for APT administered also after hospitalization |
Chow et al. (2021)87 | Observational, 1:2 propensity score matched for demographics and comorbidities hospital mortality PE | 17 347 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.
Studies in patients on single or dual antiplatelet therapy before hospitalization for severe infections or sepsis
Study (year) . | Design . | Population . | Comparison and type of antiplatelet agent(s) . | Effectiveness . | Safety . | Other remarks . |
---|---|---|---|---|---|---|
Erlich et al. (2011)81 | Multicentre observational, prospective study | 161 hospitalized patients at risk for acute lung injury, ∼30% due to sepsis or infection | Pre-hospitalization SAPT–ASA users: 79 | ASA 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)82 | Retrospective analysis of two cohorts | Cohort 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 use | Similar benefit also after correcting for SOFA score, age, gender, and C-reactive protein levels |
Valerio-Rojas et al. (2013)83 | Retrospective | 651 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)84 | Nationwide population-based cohort and nested case–control study | 683 421 patients hospitalized for sepsis | Use 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) | NA | Benefit 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)85 | Meta-analysis of 11 observational studies | n = 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 usage | Mortality: 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)86 | Meta-analysis of 10 studies | 689 897 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 studies | Mortality OR: 0.78 (95% CI: 0.77–0.80) SAPT–ASA: OR 0.60 (95% CI: 0.53–0.68) | NA | A subgroup on timing of APT showed benefit for APT administered also after hospitalization |
Chow et al. (2021)87 | Observational, 1:2 propensity score matched for demographics and comorbidities hospital mortality PE | 17 347 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) . | Design . | Population . | Comparison and type of antiplatelet agent(s) . | Effectiveness . | Safety . | Other remarks . |
---|---|---|---|---|---|---|
Erlich et al. (2011)81 | Multicentre observational, prospective study | 161 hospitalized patients at risk for acute lung injury, ∼30% due to sepsis or infection | Pre-hospitalization SAPT–ASA users: 79 | ASA 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)82 | Retrospective analysis of two cohorts | Cohort 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 use | Similar benefit also after correcting for SOFA score, age, gender, and C-reactive protein levels |
Valerio-Rojas et al. (2013)83 | Retrospective | 651 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)84 | Nationwide population-based cohort and nested case–control study | 683 421 patients hospitalized for sepsis | Use 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) | NA | Benefit 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)85 | Meta-analysis of 11 observational studies | n = 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 usage | Mortality: 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)86 | Meta-analysis of 10 studies | 689 897 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 studies | Mortality OR: 0.78 (95% CI: 0.77–0.80) SAPT–ASA: OR 0.60 (95% CI: 0.53–0.68) | NA | A subgroup on timing of APT showed benefit for APT administered also after hospitalization |
Chow et al. (2021)87 | Observational, 1:2 propensity score matched for demographics and comorbidities hospital mortality PE | 17 347 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 statements . | Strength 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.71,86,88 | ![]() |
We advise to check for clinically relevant drug interactions with antimicrobials when clopidogrel or ticagrelor is used and with PPIs when clopidogrel is used.107,108 | ![]() |
We advise to treat patients with high degree of SIC, including thrombocytopenia, with gastroprotective agents, preferably PPIs.19,93,99,102,103 | ![]() |
Consensus statements . | Strength 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.71,86,88 | ![]() |
We advise to check for clinically relevant drug interactions with antimicrobials when clopidogrel or ticagrelor is used and with PPIs when clopidogrel is used.107,108 | ![]() |
We advise to treat patients with high degree of SIC, including thrombocytopenia, with gastroprotective agents, preferably PPIs.19,93,99,102,103 | ![]() |
Consensus statements . | Strength 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.71,86,88 | ![]() |
We advise to check for clinically relevant drug interactions with antimicrobials when clopidogrel or ticagrelor is used and with PPIs when clopidogrel is used.107,108 | ![]() |
We advise to treat patients with high degree of SIC, including thrombocytopenia, with gastroprotective agents, preferably PPIs.19,93,99,102,103 | ![]() |
Consensus statements . | Strength 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.71,86,88 | ![]() |
We advise to check for clinically relevant drug interactions with antimicrobials when clopidogrel or ticagrelor is used and with PPIs when clopidogrel is used.107,108 | ![]() |
We advise to treat patients with high degree of SIC, including thrombocytopenia, with gastroprotective agents, preferably PPIs.19,93,99,102,103 | ![]() |
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 statements . | Strength 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.81–87 | ![]() |
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.69,81–87,133–136 | ![]() |
Continuing SAPT with ASA may be appropriate in patients with more severe thrombocytopenia and at higher risk of major vascular event recurrence, on a case-by-case basis.66,81–87 | ![]() |
Continue with one antiplatelet agent (ASA or a P2Y12 inhibitor, preferably clopidogrel) may be appropriate when patients receive therapeutic dose of anticoagulation or develop higher degree of SIC (>3) with PT >1.4. | ![]() |
We advise to check for relevant drug–drug interactions for ticagrelor and clopidogrel and ongoing antiviral or antibiotic agents.107,108 | ![]() |
We advise to treat patients with gastroprotective agents, preferably PPIs.19,93,99,102,103 | ![]() |
Consensus statements . | Strength 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.81–87 | ![]() |
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.69,81–87,133–136 | ![]() |
Continuing SAPT with ASA may be appropriate in patients with more severe thrombocytopenia and at higher risk of major vascular event recurrence, on a case-by-case basis.66,81–87 | ![]() |
Continue with one antiplatelet agent (ASA or a P2Y12 inhibitor, preferably clopidogrel) may be appropriate when patients receive therapeutic dose of anticoagulation or develop higher degree of SIC (>3) with PT >1.4. | ![]() |
We advise to check for relevant drug–drug interactions for ticagrelor and clopidogrel and ongoing antiviral or antibiotic agents.107,108 | ![]() |
We advise to treat patients with gastroprotective agents, preferably PPIs.19,93,99,102,103 | ![]() |
Consensus statements . | Strength 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.81–87 | ![]() |
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.69,81–87,133–136 | ![]() |
Continuing SAPT with ASA may be appropriate in patients with more severe thrombocytopenia and at higher risk of major vascular event recurrence, on a case-by-case basis.66,81–87 | ![]() |
Continue with one antiplatelet agent (ASA or a P2Y12 inhibitor, preferably clopidogrel) may be appropriate when patients receive therapeutic dose of anticoagulation or develop higher degree of SIC (>3) with PT >1.4. | ![]() |
We advise to check for relevant drug–drug interactions for ticagrelor and clopidogrel and ongoing antiviral or antibiotic agents.107,108 | ![]() |
We advise to treat patients with gastroprotective agents, preferably PPIs.19,93,99,102,103 | ![]() |
Consensus statements . | Strength 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.81–87 | ![]() |
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.69,81–87,133–136 | ![]() |
Continuing SAPT with ASA may be appropriate in patients with more severe thrombocytopenia and at higher risk of major vascular event recurrence, on a case-by-case basis.66,81–87 | ![]() |
Continue with one antiplatelet agent (ASA or a P2Y12 inhibitor, preferably clopidogrel) may be appropriate when patients receive therapeutic dose of anticoagulation or develop higher degree of SIC (>3) with PT >1.4. | ![]() |
We advise to check for relevant drug–drug interactions for ticagrelor and clopidogrel and ongoing antiviral or antibiotic agents.107,108 | ![]() |
We advise to treat patients with gastroprotective agents, preferably PPIs.19,93,99,102,103 | ![]() |
Patients on oral anticoagulants
Anticoagulants, including antithrombin and soluble thrombomodulin (see Supplementary data online, Figure S3), may improve outcomes in SIC by reducing organ dysfunction, especially with pre-existing 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
Studies in patients with anticoagulant therapy during severe infections or sepsis
Study (year) . | Study type . | Population . | Comparison or intervention . | Efficacy outcome . | Safety outcome . | Other remarks . |
---|---|---|---|---|---|---|
Umemura et al. (2016)137 | Meta-analysis of 24 RCTs | 14 767 patients with sepsis, treated with any anticoagulant, of those 3206 had DIC | Anticoagulants vs. control | Mortality 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)138 | Meta-analysis of nine controlled trials | Patients with sepsis (592) or severe sepsis (3011) | UFH or LMWH vs. control | 28-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)139 | Meta-analysis of 10 RCTs | 684 adult patients with sepsis | LMWH at mainly intermediate dose vs. control | 28-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)140 | Nationwide healthcare database. Inverse probability of treatment weighting | 3030 patients with AF on warfarin vs. 55 721 patients without AF and warfarin, all admitted for sepsis | Warfarin at the time of sepsis diagnosis vs. no warfarin. Warfarin effect will remain 3–5 days after stopping | 90-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 type . | Population . | Comparison or intervention . | Efficacy outcome . | Safety outcome . | Other remarks . |
---|---|---|---|---|---|---|
Umemura et al. (2016)137 | Meta-analysis of 24 RCTs | 14 767 patients with sepsis, treated with any anticoagulant, of those 3206 had DIC | Anticoagulants vs. control | Mortality 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)138 | Meta-analysis of nine controlled trials | Patients with sepsis (592) or severe sepsis (3011) | UFH or LMWH vs. control | 28-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)139 | Meta-analysis of 10 RCTs | 684 adult patients with sepsis | LMWH at mainly intermediate dose vs. control | 28-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)140 | Nationwide healthcare database. Inverse probability of treatment weighting | 3030 patients with AF on warfarin vs. 55 721 patients without AF and warfarin, all admitted for sepsis | Warfarin at the time of sepsis diagnosis vs. no warfarin. Warfarin effect will remain 3–5 days after stopping | 90-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.
Studies in patients with anticoagulant therapy during severe infections or sepsis
Study (year) . | Study type . | Population . | Comparison or intervention . | Efficacy outcome . | Safety outcome . | Other remarks . |
---|---|---|---|---|---|---|
Umemura et al. (2016)137 | Meta-analysis of 24 RCTs | 14 767 patients with sepsis, treated with any anticoagulant, of those 3206 had DIC | Anticoagulants vs. control | Mortality 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)138 | Meta-analysis of nine controlled trials | Patients with sepsis (592) or severe sepsis (3011) | UFH or LMWH vs. control | 28-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)139 | Meta-analysis of 10 RCTs | 684 adult patients with sepsis | LMWH at mainly intermediate dose vs. control | 28-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)140 | Nationwide healthcare database. Inverse probability of treatment weighting | 3030 patients with AF on warfarin vs. 55 721 patients without AF and warfarin, all admitted for sepsis | Warfarin at the time of sepsis diagnosis vs. no warfarin. Warfarin effect will remain 3–5 days after stopping | 90-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 type . | Population . | Comparison or intervention . | Efficacy outcome . | Safety outcome . | Other remarks . |
---|---|---|---|---|---|---|
Umemura et al. (2016)137 | Meta-analysis of 24 RCTs | 14 767 patients with sepsis, treated with any anticoagulant, of those 3206 had DIC | Anticoagulants vs. control | Mortality 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)138 | Meta-analysis of nine controlled trials | Patients with sepsis (592) or severe sepsis (3011) | UFH or LMWH vs. control | 28-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)139 | Meta-analysis of 10 RCTs | 684 adult patients with sepsis | LMWH at mainly intermediate dose vs. control | 28-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)140 | Nationwide healthcare database. Inverse probability of treatment weighting | 3030 patients with AF on warfarin vs. 55 721 patients without AF and warfarin, all admitted for sepsis | Warfarin at the time of sepsis diagnosis vs. no warfarin. Warfarin effect will remain 3–5 days after stopping | 90-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 statements . | Strength of advice . |
---|---|
For patients on oral anticoagulation for stroke prophylaxis in AF in case of severe infection, we advise to switch to low- or intermediate-dose LMWH when platelets drop between 100 and 30 × 109/L (only if INR is <2.0 for those on a VKA).138,139 | ![]() |
We advise to interrupt anticoagulant treatment for platelet count <30 × 109/L. For patients with VTE, the dose of heparin should be based on the severity of the infection and whether the indication is a recent thromboembolic event.66 | ![]() |
For patients with VTE within 1 month, it may be appropriate to remain on full anticoagulation, preferably with LMWH, split into two daily doses. | ![]() |
We advise to check for clinically relevant drug–drug interactions in patients treated with OAC based on ongoing antimicrobial treatment and on the specific anticoagulant drug in use.148 | ![]() |
We advise to treat patients with high degree of SIC with gastroprotective agents, preferably PPIs.19,93,99,102,103 | ![]() |
In patients with a long-term VKA indication, we advise to intensify INR monitoring or switch to heparin during hospitalization.71,141 | ![]() |
Consensus statements . | Strength of advice . |
---|---|
For patients on oral anticoagulation for stroke prophylaxis in AF in case of severe infection, we advise to switch to low- or intermediate-dose LMWH when platelets drop between 100 and 30 × 109/L (only if INR is <2.0 for those on a VKA).138,139 | ![]() |
We advise to interrupt anticoagulant treatment for platelet count <30 × 109/L. For patients with VTE, the dose of heparin should be based on the severity of the infection and whether the indication is a recent thromboembolic event.66 | ![]() |
For patients with VTE within 1 month, it may be appropriate to remain on full anticoagulation, preferably with LMWH, split into two daily doses. | ![]() |
We advise to check for clinically relevant drug–drug interactions in patients treated with OAC based on ongoing antimicrobial treatment and on the specific anticoagulant drug in use.148 | ![]() |
We advise to treat patients with high degree of SIC with gastroprotective agents, preferably PPIs.19,93,99,102,103 | ![]() |
In patients with a long-term VKA indication, we advise to intensify INR monitoring or switch to heparin during hospitalization.71,141 | ![]() |
Consensus statements . | Strength of advice . |
---|---|
For patients on oral anticoagulation for stroke prophylaxis in AF in case of severe infection, we advise to switch to low- or intermediate-dose LMWH when platelets drop between 100 and 30 × 109/L (only if INR is <2.0 for those on a VKA).138,139 | ![]() |
We advise to interrupt anticoagulant treatment for platelet count <30 × 109/L. For patients with VTE, the dose of heparin should be based on the severity of the infection and whether the indication is a recent thromboembolic event.66 | ![]() |
For patients with VTE within 1 month, it may be appropriate to remain on full anticoagulation, preferably with LMWH, split into two daily doses. | ![]() |
We advise to check for clinically relevant drug–drug interactions in patients treated with OAC based on ongoing antimicrobial treatment and on the specific anticoagulant drug in use.148 | ![]() |
We advise to treat patients with high degree of SIC with gastroprotective agents, preferably PPIs.19,93,99,102,103 | ![]() |
In patients with a long-term VKA indication, we advise to intensify INR monitoring or switch to heparin during hospitalization.71,141 | ![]() |
Consensus statements . | Strength of advice . |
---|---|
For patients on oral anticoagulation for stroke prophylaxis in AF in case of severe infection, we advise to switch to low- or intermediate-dose LMWH when platelets drop between 100 and 30 × 109/L (only if INR is <2.0 for those on a VKA).138,139 | ![]() |
We advise to interrupt anticoagulant treatment for platelet count <30 × 109/L. For patients with VTE, the dose of heparin should be based on the severity of the infection and whether the indication is a recent thromboembolic event.66 | ![]() |
For patients with VTE within 1 month, it may be appropriate to remain on full anticoagulation, preferably with LMWH, split into two daily doses. | ![]() |
We advise to check for clinically relevant drug–drug interactions in patients treated with OAC based on ongoing antimicrobial treatment and on the specific anticoagulant drug in use.148 | ![]() |
We advise to treat patients with high degree of SIC with gastroprotective agents, preferably PPIs.19,93,99,102,103 | ![]() |
In patients with a long-term VKA indication, we advise to intensify INR monitoring or switch to heparin during hospitalization.71,141 | ![]() |
Vaccination in patients at high and very high cardiovascular risk
Vaccinations decrease the risk of ASCVD, though with different effectiveness. Influenza vaccine, regardless of formulation and 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 statements . | Strength of advice . |
---|---|
We advise to vaccinate against influenza patients at high and very high risk of ASCVD or with previous ASCVD.51,160,171 | ![]() |
It may be appropriate to reinforce the use of vaccinations for patients at high and very high risk of ASCVD or with previous ASCVD to reduce the risk of severe infections and the consequent possible associated SIC. | ![]() |
Consensus statements . | Strength of advice . |
---|---|
We advise to vaccinate against influenza patients at high and very high risk of ASCVD or with previous ASCVD.51,160,171 | ![]() |
It may be appropriate to reinforce the use of vaccinations for patients at high and very high risk of ASCVD or with previous ASCVD to reduce the risk of severe infections and the consequent possible associated SIC. | ![]() |
Consensus statements . | Strength of advice . |
---|---|
We advise to vaccinate against influenza patients at high and very high risk of ASCVD or with previous ASCVD.51,160,171 | ![]() |
It may be appropriate to reinforce the use of vaccinations for patients at high and very high risk of ASCVD or with previous ASCVD to reduce the risk of severe infections and the consequent possible associated SIC. | ![]() |
Consensus statements . | Strength of advice . |
---|---|
We advise to vaccinate against influenza patients at high and very high risk of ASCVD or with previous ASCVD.51,160,171 | ![]() |
It may be appropriate to reinforce the use of vaccinations for patients at high and very high risk of ASCVD or with previous ASCVD to reduce the risk of severe infections and the consequent possible associated SIC. | ![]() |
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
Author notes
P.C.L. and B.R. are last co-authors.