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Endothelial dysfunction and immunothrombosis in sepsis

Eleni Maneta, Evmorfia Aivalioti, Simon Tual-Chalot and 4 more

Frontiers in Immunology · 2023 · Review · CC BY

doi:10.3389/fimmu.2023.1144229

Abstract

Sepsis is a life-threatening clinical syndrome characterized by multiorgan dysfunction caused by a dysregulated or over-reactive host response to infection. During sepsis, the coagulation cascade is triggered by activated cells of the innate immune system, such as neutrophils and monocytes, resulting in clot formation mainly in the microcirculation, a process known as immunothrombosis. Although this process aims to protect the host through inhibition of the pathogen’s dissemination and survival, endothelial dysfunction and microthrombotic complications can rapidly lead to multiple organ dysfunction. The development of treatments targeting endothelial innate immune responses and immunothrombosis could be of great significance for reducing morbidity and mortality in patients with sepsis. Medications modifying cell-specific immune responses or inhibiting platelet–endothelial interaction or platelet activation have been proposed. Herein, we discuss the underlying mechanisms of organ-specific endothelial dysfunction and immunothrombosis in sepsis and its complications, while highlighting the recent advances in the development of new therapeutic approaches aiming at improving the short- or long-term prognosis in sepsis.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 23, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

The latest definition by the Third International Consensus Definition Task Force defines sepsis as a life-threatening organ dysfunction resulting from a dysregulated host response to infection. Despite a better understanding of the underlying pathophysiological mechanisms and improvements to existing therapeutic algorithms, morbidity and mortality in patients with sepsis still remain high. It is estimated that 2.8 million deaths per year are attributed to sepsis, with one in three hospital deaths related to it. Sepsis can originate from any infecting organism, but the most frequently identified ones are Staphylococcus aureus (S. aureus), Pseudomonas species, and Escherichia coli (E. coli). Among different sites susceptible to infection, the main ones leading to sepsis are the lungs (64%), the abdomen (20%), the bloodstream (15%), and the renal and genitourinary tract (14%).

Activated components of innate immunity act as the first line of host immune defense against invading pathogens. Apart from their direct role in clearing the microorganism, neutrophils, monocytes, and the complement can interact with platelets, and the coagulation cascade leading to the local formation of thrombi in microvessels. This process, known as “immunothrombosis,” contributes to the recognition and restriction of a pathogen’s spread, tissue invasion, and survival, thus consisting an essential component of intravascular immunity. Although this distinct innate immune mechanism seems initially beneficial for the host, uncontrolled activation of this process in sepsis can trigger aberrant thrombosis in the microcirculation. During immunothrombosis, immune cells interact also with endothelial cells, which acquire a proadhesive and prothrombotic phenotype. Indeed, coagulation abnormalities are common in patients with sepsis, with severity ranging from subclinical coagulation activation to devastating thrombotic and hemorrhagic complications. In sepsis, both the activation of the coagulation cascade and the dysregulation of the endogenous anticoagulant and fibrinolytic mechanisms lead to microvascular thrombosis and tissue ischemia, which in turn contribute to tissue injury and multiorgan failure. Specifically, high thrombin and d-dimer plasma levels, both markers of coagulation activation, are considered indicative of severe sepsis. Accordingly, decreased plasma levels of natural anticoagulants, such as protein C, protein S, and antithrombin (AT), have been found in sepsis and are associated with worse disease prognosis. Disseminated intravascular coagulation (DIC) is estimated to occur in up to 30%–50% of patients with severe sepsis, and it is associated with a twofold higher mortality risk. DIC is characterized by endothelial dysfunction and dysregulation of procoagulant, anticoagulant, and fibrinolytic factors. In sepsis-associated DIC, immunothrombosis is the underlying pathophysiological mechanism that triggers the initiation of DIC. Most of our knowledge regarding immunothrombosis suggests that it is a process mainly taking place in the microvasculature, affecting both arterioles and venules.

Despite the high prevalence of coagulation abnormalities and their potential deleterious effect on the outcome of sepsis patients, the current treatment approach is generally focused on antibiotics, fluid resuscitation, vasopressors, as well as oxygen and ventilatory support. Apart from heparin’s use for venous thromboembolism (VTE) prophylaxis in patients with sepsis, effective treatments specifically targeting the process of immunothrombosis, aiming to abrogate the devastating complications while maintaining its beneficial effects for the host, do not yet exist. A better understanding of the underlying mechanisms and cellular interactions in sepsis-related immunothrombosis is crucial to identifying new therapeutic targets that would open the field for the development of new treatments in sepsis. Our study summarizes the current literature regarding the role of endothelial cells and innate immune cells in immunothrombosis in sepsis and discusses clinical and preclinical evidence on drugs targeting immunothrombosis in sepsis.

Overview of hemostasis and thrombosis

The process of thrombus formation inside a blood vessel, which can lead to partial or total vessel occlusion, requires platelets’ accumulation and activation as well as activation of the coagulation cascade. The binding of platelet glycoprotein Ib (GP Ib) receptor to von Willebrand factor (vWF) and the interaction of platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor with fibrinogen are essential steps for platelet adhesion and aggregation, respectively. The coagulation cascade involves the activation of a series of clotting factors and is classically divided into three pathways: the extrinsic, the intrinsic, and the common pathway. The extrinsic pathway is initiated when tissue factor (TF) from the damaged vessel wall interacts with activated clotting factor VII (aFVII), while the intrinsic pathway begins when factor XII (FXII) interacts with the exposed collagen and becomes activated (aFXII). Both pathways end up in factor X (FX) activation, which in turn, along with activated factor V (aFV), cleaves prothrombin into thrombin. Afterward, thrombin activates fibrinogen into fibrin and also cleaves factor XIII (FXIII) into activated factor XIII (aFXIII), resulting in clot stabilization (common pathway). In normal hemostasis, along with the coagulation cascade activation, endogenous anticoagulant mechanisms are being recruited in order to prevent uncontrolled clot expansion and thrombosis. Tissue factor pathway inhibitor (TFPI), AT, activated protein C (APC), and protein S, as well as thrombomodulin (TM), which along with endothelial protein C receptor (EPCR) catalyzes the thrombin-mediated protein C activation, are some of the main physiologic anticoagulant mechanisms. Finally, under normal conditions, plasminogen is activated by tissue plasminogen activator (tPA) into plasmin, which catalyzes clot dissolution and fibrinolysis, while plasminogen activator inhibitor (PAI) serves as a tPA inhibitor.

Signals leading to endothelial activation

Many of the clinical manifestations related to sepsis can be attributed to endothelial dysfunction which constitutes one of the most prominent underlying pathophysiological mechanisms of sepsis and sepsis-related complications. Although a variety of inflammatory diseases are characterized by endothelial dysfunction, sepsis is linked to a distinctive procoagulant, proadhesive and apoptotic profile of endothelial cells. Normal endothelium contributes to vascular health through the expression of antithrombotic and anti-inflammatory molecules. In sepsis, the endothelium is activated directly by pathogen-associated molecular patterns (PAMPs) of bacteria, viruses, and fungi or indirectly via neutrophil extracellular traps (NETs) and proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 (IL-1) ( Figure 1A ). NETs are extracellular structures that are composed of cell-free DNA (cfDNA), histones, and antimicrobial proteins and are primarily released through a cell death process called NETosis or alternatively, through a process that does not require cell death, named non-lytic NETosis. PAMPs activate endothelial cells via pattern recognition receptors (PRRs), among which toll-like receptors (TLRs) exert the most profound inflammatory response in sepsis. Interestingly, endothelial activation during sepsis, as indicated by high circulating levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, P-selectin, and vWF, is correlated with disease severity and mortality.

Endothelial barrier dysfunction

One of the first signs of endothelial dysfunction in sepsis is endothelial glycocalyx (eGC) deconstruction ( Figure 1B ). The endothelial glycocalyx is a carbohydrate-rich layer that covers the luminal surface of endothelial cells and serves numerous protective roles for the vascular system. Specifically, eGC regulates vascular permeability and endothelial response to shear stress and inhibits leucocyte and platelet adhesion as well as coagulation cascade activation and hence microthrombus formation. During sepsis, distinctive mechanisms have been identified that promote eGC damage, which subsequently enhances endothelial dysfunction and sepsis complications. In vivo sepsis models suggest that sepsis-induced reduction in eGC thickness leads to increased albumin extravasation and circulating glycocalyx products such as hyaluronic acid and CD44. The underlying mechanism can be explained by a cascade of reactions where disintegrin and metalloproteinase 15 (ADAM15) cleave CD44 of eGC, leading to an increase in plasma levels of soluble CD44 and hyaluronic acid. This is followed by a decrease in endothelial barrier integrity and a disruption of vascular endothelial (VE)-cadherin and β-catenin, which are essential components of adherens cell junctions. Similarly, endothelial tight and gap junctions were found to be disrupted in sepsis. A variety of eGC products are emerging as biomarkers in sepsis as they add important prognostic value. For example, increased syndecan-1 (SYN-1) plasma levels during sepsis are correlated with the requirement for renal replacement therapy, respiratory failure, multiple organ dysfunction syndrome (MODS), and predict coagulation failure and mortality. Sphingosine-1-phosphate (S1P) is another eGC component that predicts sepsis coagulation failure and mortality, while increased plasma endocan levels, another marker of eGC destruction, are also associated with the need for mechanical ventilation and with higher mortality in sepsis patients. Angiopoietin-2 (Ang-2) is a growth factor produced by the endothelium under inflammatory conditions. It has been linked to increased vascular permeability in sepsis through enhancing endothelial heparanase secretion, which in turn cleaves heparan sulfate, the main component of eGC. Increased heparanase production by Ang-2 was shown to be mediated by the inhibition of endothelium-stabilizing receptor Tie2 signaling. Additionally, Tie2 tyrosine kinase inhibition by Ang2 in sepsis resulted in a procoagulant phenotype of endothelial cells. Interestingly, increased Ang-2 has been associated with higher mortality, respiratory, liver, and kidney failure, and predicted DIC severity in patients with sepsis.

Dysregulation of nitric oxide pathway

Nitric oxide (NO) is a soluble gas produced by endothelial cells and studied in depth for its protective role on the vascular endothelium. NO promotes vasodilation and is capable of inhibiting platelet activation and adherence to the endothelium. NO has another crucial role in impeding leucocyte adhesion on the vascular wall. This is possibly mediated through the downregulation of P-selectin, chemokine, E-selectin, ICAM-1, and VCAM-1 expression in endothelial cells. In preclinical sepsis models, an imbalance between endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) activity has been demonstrated. Specifically, eNOS activity was found to be decreased compared to the upregulated iNOS activity. Overproduced NO by iNOS reacts with superoxide anion resulting in reactive nitrogen species (RNS) production, which contributes to endothelial dysfunction ( Figure 1C ). Experimental and clinical studies are inconclusive regarding NO levels and their effects on the endothelium during sepsis. Some studies suggest that NO production increases during sepsis and this is associated with poor prognosis, while others support that NO levels are lower in sepsis patients compared to healthy controls. New evidence suggests that increased NO bioavailability in sepsis may be beneficial for the host without deteriorating vasodilation and subsequent hypotension, as has been proposed in previous studies. Overall, the dysregulation of the NO pathway during sepsis merits further investigation.

Proadhesive endothelial cell phenotype

Expression of proadhesive molecules in activated endothelial cells poses a hallmark process for the progression of sepsis-induced endothelial dysfunction ( Figure 1D ). Activated endothelium interacts both with leukocytes and platelets, while platelet–leucocyte aggregates deposit on endothelium and further enhance local inflammation. The infection triggers immune and endothelial cells to produce reactive oxygen species (ROS) and inflammatory and anti-inflammatory cytokines. Reversely, cytokines stimulate endothelial cells to express adhesion molecules such as selectins, integrins, ICAMs, and VCAM-1. These molecules interact with leukocytes, which roll, bind to the endothelium, and transmigrate through it. Furthermore, ROS released by immune cells during sepsis destroy the endothelium and result in increased permeability.

Prothrombotic endothelial cell phenotype

Accumulating evidence suggests that endothelial cells can interact with immune cells, triggering thrombus formation, a process implicated in the pathogenesis of numerous diseases, such as antiphospholipid syndrome, coronary artery disease, and sepsis. Both experimental and clinical studies, presented in Table 1, explain how endothelial cells can lose their anticoagulant properties and lead to thrombosis when stimulated directly or indirectly by pathogens ( Figure 1E ). A large body of evidence suggests that upon sepsis-induced endothelium activation, there is increased TF expression and secretion accompanied by enhanced TF activity. Complement, especially C5a, and the inactive terminal C complex (iTCC) formed by mixing C5b6, C7, C8, and C9, were also found to stimulate endothelial cells to produce active TF ( Table 2 ). Beyond TF, other important mechanisms contributing to immunothrombosis are the dysfunctional fibrinolytic and anticoagulant properties of the endothelium. Accumulating experimental data confirm that pathogen invasion is associated with increased endothelial expression of PAI-1 and decreased expression of EPCR, TM, and TFPI, as well as decreased protein C activation. Complement C3 activation stimulated by Shiga toxin was also shown to result in endothelial TM reduction and enhanced thrombus formation ( Table 2 ). Despite decreased endothelial TM expression during sepsis, soluble TM is increased in patients with sepsis and predicts acute kidney injury, multiple organ failure, and mortality. A possible illustrative mechanism is that apoptotic endothelial cells release their intracellular proteins into circulation. Similarly, elevated TFPI plasma levels are associated with overt DIC in patients with sepsis, in contrast to the reduced TFPI expression by endothelium. Accordingly, increased plasma levels of PAI-1 have been correlated with DIC in patients with sepsis and predicted mortality. Circulating levels of proteins C and S have also been evaluated, and clinical data support their deficiency in sepsis. Importantly, in patients with severe sepsis, decreased plasma levels of protein C and increased syndecan-1, which characterize endothelial damage, were associated with whole blood hypocoaguability in the context of DIC, as measured by thromboelastography.

Transcription factor activation

Endothelial cell activation, following pathogen invasion, is mediated by intracellular signaling, which includes transcription factor activation such as nuclear factor kappa B (NFκB), activator protein-1 (AP-1), interferon regulatory transcription factor-3 (IRF3), and signal transducer and activator of transcription 3 (STAT3) ( Figure 1A ). Specifically, activation of endothelial NFκB by pathogens has been found to mediate increased expression of procoagulant molecules such as PAI-1 and TF, while fibrinolytic and anticoagulant factors such as TM, APC, and EPCR diminished in a way that was also dependent on NFκB. Indeed, NFκB has been associated with increased circulating d-dimers and tissue fibrin deposition in an endotoxemia mouse model.

Role of Weibel–Palade bodies

Weibel–Palade bodies (WPBs) are organelles inside endothelial cells containing procoagulant proteins such as vWF, P-selectin, and factor VIII (FVIII), which can rapidly undergo exocytosis under specific circumstances. Lipopolysaccharide (LPS) has been shown to induce WPBs’ content secretion both in vitro and in vivo ( Figure 1E ). Ultra-long vWF strings can be produced in vitro after endothelial cell activation by Shiga toxin. Furthermore, the Shiga toxin prevented cleavage of these vWF strings by inactivating ADAMTS13. It has been found that in preclinical sepsis models, increased markers of endothelial activation are associated with abnormal coagulation markers, while some studies have additionally demonstrated the subsequent thrombus formation in the microcirculation. Dysregulated coagulation was indicated by markers such as high levels of circulating d-dimers, fibrin, fibrin degradation products (FDPs), thrombin-antithrombin (TAT) complexes prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT), and/or decreased levels of plasma fibrinogen and platelets.

Neutrophils in immunothrombosis

Apart from endothelial dysfunction, which facilitates immunothrombosis in sepsis, activated cells of the innate immune system, in particular neutrophils and monocytes, also play a significant role ( Figure 2 ). Neutrophils are an essential part of the host’s innate immune response and are typically the first responders to acute inflammation. In sepsis, PAMPs and damage-associated molecular patterns (DAMPs) can activate neutrophils by binding to PRRs. Activated neutrophils exert their antimicrobial activity mainly through three processes: phagocytosis, degranulation, and the release of NETs.

Induction of NETosis in sepsis

A variety of different pathogens, bacterial toxins, and cytokines can induce NETosis. NETosis can also be enhanced by activated platelets. More specifically, in a sepsis mouse model, it was found that LPS binding to platelet TLR4 stimulated platelets to interact with neutrophils and induce NET production in the liver sinusoids and capillaries. The binding of platelet P-selectin to P-selectin glycoprotein ligand 1 (PGSL1) on neutrophils was found to be a key mechanism for NETosis induction in mice. However, this finding was not reproduced in studies with human neutrophils, and different agonists, where an antibody against P-selectin did not affect platelet-mediated NETosis. The interaction of platelet-derived high mobility group protein B1 (HMGB1) with the receptor for advanced glycation end products (RAGE) on neutrophils was also found to be a potential mechanism for NETosis stimulation by platelets, possibly through induction of autophagy in neutrophils. Moreover, it was shown that LPS and Pam3CSK4, a synthetic lipopeptide, through binding to platelet TLR4 and TLR2, respectively, activated platelets to interact with neutrophils and induce NETosis through platelet GP1b-neutrophil β2-integrin (CD18) interaction. Platelet-derived vWF, platelet factor 4 (PF4), and thromboxane A2 (TXA2) were essential mediators of this process. Furthermore, experimental studies have shown that platelet-derived CXCL4/CCL5 heterodimers and β-defensin 1 enhanced NET production. Besides platelet–neutrophil interaction and subsequent NETosis induction, it was found that also complement cleavage products, in particular, C3a and C5a anaphylatoxins could stimulate NETosis in sepsis animal models or in neutrophils stimulated by LPS or platelet-rich plasma from COVID-19 patients ( Table 2 ). Moreover, complement may play a role in the inhibition of NET degradation.

Role of NETs in endothelial dysfunction

It has been shown that NETs, apart from their beneficial role in clearing the invading microorganism, are implicated in the pathogenesis of many diseases in which endothelial dysfunction is present, such as sepsis and cardiovascular diseases. Therefore, there has been a growing interest in studying the role of NETs in endothelial dysfunction in sepsis. In vitro studies suggest that NETs can promote endothelial dysfunction, as indicated by increased endothelial expression of ICAM-1, VCAM-1, E-selectin, TF, and vWF. Cathepsin G is a component of NETs, capable of processing pro-IL-1α into IL-1α, which has been found to enhance VCAM-1 and ICAM-1 expression on the endothelial surface. Moreover, NET-induced ICAM-1 and E-selectin expression on endothelial cells was found to be dependent on the triggering receptor expressed on myeloid cell-1 (TREM-1). TREM-1 is an orphan immune receptor expressed on various types of cells, such as immune cells, platelets, and endothelial cells. Apart from mediating the NET-induced proadhesive phenotype of endothelial cells, TREM-1 potentiated NETosis triggered by LPS. NETs have also been associated with increased platelet adhesion on endothelial cells through enhancement of vWF expression on the endothelium. Both NETs and histones have been found to increase TF mRNA and TF activity in human aortic endothelial cells (HAECs) and human saphenous vein endothelial cells (HSVECs), resulting in plasma clotting acceleration. Specifically for histones, their effect on TF was mediated by TLR2 or TLR4, which in turn activated AP-1 and NFκB transcription factors. As one of the major components of NETs, histones have been further studied for their impact on endothelium, with results suggesting cytotoxicity in a concentration-dependent manner. Citrullinated histone H3 (CitH3) was found to increase endothelium permeability in vitro. Furthermore, images using intravital microscopy showed that CitH3 resulted in microvascular endothelial barrier dysfunction, by disrupting the adherens junctions and reorganizing the actin cytoskeleton without causing cell death. Accordingly, NETs have been found to decrease endothelial expression of VE-cadherin and Zonula occludens (ZO)-1 proteins, which are major components of adherens and tight junctions, respectively.

Prothrombotic role of NETs

NETs not only contribute to endothelial dysfunction but have also been found to exert procoagulant and prothrombotic activity through various mechanisms, as shown in Table 3. NETs could serve as a scaffold and inducer of platelet adhesion, activation, and aggregation, and this effect was largely mediated by specific NET components like histones H3 and H4. Nets not only served as a scaffold for platelet adhesion but also for red blood cells (RBCs), promoting the generation of red (RBC-rich) thrombus. Plasma proteins, implicated in thrombosis, such as vWF, fibronectin, and fibrinogen could also bind to NETs, while NETs contributed to thrombin-mediated fibrin generation. Histones, in particular H3 and H4, could activate platelets to promote plasma thrombin generation, through binding to platelet TLR2 and TLR4. Notably, this effect was enhanced when histones were in complex with DNA. In contrast, another study showed that the addition of deoxyribonuclease (DNase), which destroys the DNA network of NETs, enhanced histone-mediated, platelet-dependent thrombin generation, presumably due to increased exposure to histones. Besides NETs-induced platelet-dependent mechanisms of thrombin formation, NETs were capable of stimulating thrombin generation also in platelet-poor plasma via activation of the intrinsic coagulation pathway. This effect was largely attenuated with DNase administration, suggesting the crucial role of cell-free DNA (cfDNA) in that process. Accordingly, DNA–histone complexes measured in platelet poor plasma from sepsis patients were increased compared to plasma from healthy subjects, and cfDNA was positively correlated with thrombin generation. NETs, possibly due to their negatively charged extracellular DNA surface, could bind and promote activation of factor XII, thus triggering the contact pathway of coagulation. Interaction of NETs with membrane-derived microparticles released by activated neutrophils enhanced NET-mediated intrinsic coagulation pathway activation and subsequent thrombin formation. In support, it was demonstrated that NETs were capable of promoting pulmonary clot formation in mice with septicemia caused by LPS and heat-killed E. coli. However, despite robust evidence on the effect of NET components on thrombosis, the role of intact NETs may merit further investigation. Specifically, an in vitro study showed that although cfDNA and histones, separately, were capable of coagulation activation, intact NETs could not. One possible explanation for this is that the complex interactions between DNA and histones within the NET structure abrogate the thrombogenic negative charge of DNA and cover the histones’ binding sites. Moreover, the absence of other blood cells, endothelium, and blood flow in an in vitro model compared to an in vivo one may have contributed to the absence of the procoagulant effect of intact NETs.

Disruption of endogenous anticoagulant and fibrinolytic mechanisms by NETs

NETs were also shown to interfere with the endogenous anticoagulant mechanisms. More specifically, extracellular nucleosomes within NETs facilitated TFPI degradation by neutrophil elastase on the surface of activated neutrophils, thus abrogating TFPI-mediated inhibition of of the extrinsic coagulation pathway. Neutrophil elastase bound to DNA complexes was also shown to cleave plasminogen into fragments, resulting in decreased plasmin production and impaired fibrinolysis. Apart from decreased plasmin generation, cfDNA was capable of binding to plasmin and fibrin at the same time, and the formed complex was shown to be responsible for decreased plasmin-mediated fibrin clot dissolution. Besides cfDNA, histones, specifically H3 and H4, could also interact with TM and protein C, leading to the inhibition of APC generation.

Prognostic utility of NETs in sepsis

Therefore, experimental data support the crucial role of NETs in triggering thrombus formation. From a clinical point of view, it was shown that increased NET-forming capacity was significantly associated with thrombocytopenia, increased PT, aPTT, d-dimers, and low fibrinogen in patients with sepsis at intensive care unit (ICU) admission, while it could also predict DIC development and mortality after ICU admission. Noteworthy, specific components of NETs, such as circulating levels of cfDNA, neutrophil elastase, and the myeloperoxidase–DNA complex in patients with sepsis, are positively correlated with the risk of VTE. Increased MPO-DNA levels on days 3 and 7 during sepsis hospitalization were associated with decreased mean arterial pressure, a lower PaO2/FIO2 ratio, an increased sepsis-related organ failure assessment (SOFA) score, and 28-day mortality.

TF production and release by neutrophils

Regarding the production and release of TF by neutrophils, there is conflicting evidence. It was reported that neutrophils in the setting of appropriate interaction with injured endothelial cells or after stimulation with P-selectin or the peptide formyl-MetLeuPhe (Fmlp) were able to produce functional TF, initiating the extrinsic coagulation pathway. Moreover, C3a and C5a anaphylatoxins were found to stimulate neutrophils to produce and release active TF ( Table 2 ). However, these findings have been questioned in other studies, and it was proposed that granulocytes may acquire TF produced by monocytes. With respect to the presence of TF in NETs, it was found that neutrophils from patients with sepsis could release large amounts of functional TF-bearing NETs, and autophagy was implicated in that process.

Role of neutrophil-derived α-defensins in immunothrombosis

Another potential mechanism through which neutrophils may contribute to immunothrombosis is by secreting antimicrobial peptides. Specifically, α-defensins, which are secreted by neutrophils as part of the host innate immune response, have been found elevated in the plasma of septic patients. Recently, an in vivo study showed that α-defensins accelerate and stabilize fibrin clot formation, while also disrupting fibrinolysis. Consistently, circulating α-defensins have been correlated with the acceleration of clot formation and d-dimers plasma levels in COVID-19 patients.

Monocytes in immunothrombosis

Monocytes and macrophages have been found to play a vital role in sepsis-induced immunothrombosis ( Figure 2 ). TF expression by monocytes seems to be the most potent pathway leading to coagulation cascade activation in sepsis. While both hematopoietic and non-hematopoietic cells produce TF and enhance coagulation in an endotoxemia mouse model, monocytes are the main source of circulating TF. Additionally, other blood cells have been found to acquire TF released by monocytes through microparticles. Numerous studies depicted in Table 4 suggest that pathogens induce monocyte-derived TF expression and release in the circulation, which in turn activates the extrinsic coagulation pathway. The binding of LPS to transmembrane receptors such as TLR4 in monocytes induces TF mRNA expression via NF-κB activation. Moreover, the interaction of pathogen components either with TLRs or directly with intracellular pathways in monocytes can result in inflammasome activation and subsequent TF release via pyroptosis. Pyroptosis is a type of proinflammatory cell death induced by caspase-1 (canonical inflammasome) or caspase-11 (noncanonical inflammasome) and is characterized by gasdermin D-dependent pore formation in the cell membrane, subsequent osmotic cell lysis, and finally the release of cytosolic content. Indeed, LPS or type III secretion system (T3SS) rod proteins have been found to trigger in vivo caspase-11 and caspase-1 activation, respectively, leading to TF release. Gasdermin D-mediated pore formation induced by caspase-11 has also been proposed to activate TF on macrophages. Specifically, pore formation on the cell membrane can induce calcium influx, which triggers phosphatidylserine exposure on the membrane, followed by TF activation. Furthermore, sphingomyelin, another membrane lipid, is involved in the activation of TF to its procoagulant form. This process occurs on the macrophage cell membrane and is dependent on sphingomyelin hydrolysis by acid sphingomyelinase (ASMase).

Tissue factor production is additionally triggered by HMGB1, which is a DAMP released by myeloid cells, platelets, and hepatocytes. HMGB1 binds LPS, enhances endocytosis of the LPS-HMGB1 complex in monocytes, and is associated with increased TF release via caspase-11-induced pyroptosis. Furthermore, TF expression and activity are also induced by the interaction of monocytes or their microparticles with activated platelets. Monocyte activation by pathogens is followed by increased PSGL-1 expression and the release of TF- and PSGL-1-bearing microparticles. These microparticles can fuse in vitro with platelets, leading to increased TF activity. Additionally, a prospective clinical study confirms that LPS endotoxemia enhances platelet–monocyte aggregation, TF expression, and platelet activation. On the other hand, thrombin generated by coagulation cascade activation binds to monocytes via protease-activated receptor-1 (PAR-1), leading to increased TF expression. Accordingly, inhibition of PAR-1 by vorapaxar (a PAR-1 antagonist) has been found to attenuate sepsis-induced coagulation, as indicated by decreased plasma prothrombin fragments and TAT complexes.

Platelet activation in sepsis

Accumulating evidence suggests a complex interaction between platelets and different immune cells. Increased platelet activation and platelet–leukocyte aggregates have been found in a variety of thrombotic conditions, such as unstable angina, myocardial infarction, stroke, and sepsis. Multiple roles of platelets have been demonstrated in experimental and clinical studies. Platelets were suggested to contribute to tissue regeneration and myocardial recovery following acute coronary syndrome (ACS). On the contrary, increased platelet activation and reactivity have been linked with a poor prognosis in several diseases, including ACS, dementia, diabetes, and sepsis. Specifically, in sepsis, thrombocytopenia is associated with increased disease severity and an ominous prognosis. Decreased platelet count is attributed to excessive peripheral consumption of platelets resulting from many causes, among which are the interaction of platelets with immune cells, the microcirculation thrombosis, and the direct binding of pathogens to platelets. Beyond innate immune cells, which play a crucial role in immunothrombosis, pathogens can directly activate platelets, which in turn promote thrombosis ( Figure 2 ). Recently, it has been found that during sepsis there is accelerated megakaryocyte maturation, triggered by PAMPs, DAMPs, TNF-α, or other cytokines. This subpopulation of megakaryocytes presents a stronger immunological profile and produces fewer platelets compared to megakaryocytes undergoing normal maturation induced by thrombopoietin. A variety of receptors on platelets interact with PAMPs, or pathogens coated by antibodies. Numerous pathogens have been proven to activate platelets and increase their aggregation, as presented in Table 5. Pathogens coated by immunoglobulins or pentraxins bind to low-affinity receptors for the constant fragment (Fc) of immunoglobulin (Ig) G (FcγRIIa) on platelets, leading to dense and α-granules secretion. FcγRIIa triggers an intracellular pathway for platelet activation by phosphorylating the tyrosine kinases Src, Syk, and phospholipase c gamma 2 (PLCγ2). Glycoproteins IIb/IIIa (GP IIb/IIIa) and Iba (GPIba), expressed on the surface of activated platelets, constitute another receptor category that promotes platelet degranulation and aggregation after binding pathogen components. Bacteria have also been found to activate platelets through TLR-2 and TLR-4. Specifically, intracellular signaling of TLR-2 is mediated by PI3 kinase, which activates the Rap1 guanine nucleotide. TLR-4 activation in platelets is followed by a complicated intracellular signaling pathway that implicates NFκB. The majority of NFκB signaling proteins are present in platelets, presenting nongenomic effects and resulting in degranulation. Moreover, LPS-induced platelet aggregation in vitro is dependent on both TLR-4 and TLR-2 platelet receptors as well as on myeloid differentiation factor 88 (MyD88) and cGMP-dependent protein kinase intracellular pathways. Accordingly, LPS accelerated in vivo thrombus formation and occlusion in FeCl3-injured carotid artery of mice, and this effect was dependent on the MyD88 signaling pathway.

Platelet aggregation and thrombus formation in sepsis

All the aforementioned platelet receptors induce immunothrombosis through different pathways after being triggered by PAMPs. The surface of activated platelets promotes thrombin generation and, subsequently, fibrin and clot formation. Both dense and α-granules are secreted by pathogen-activated platelets and enhance their aggregation. Specific proteins secreted by platelets are involved in the process of immunothrombosis, such as P-selectin, PF4, vWF from α-granules, and ADP/ATP from dense granules. Activated platelets have also been found to release polyphosphate (PolyP), an inorganic polymer that exerts procoagulant activity. In vitro, PolyP initiates the contact pathway by FXII activation, resulting in enhanced thrombin generation and clot formation. The procoagulant activity of PolyP has also been confirmed in a sepsis mouse model where LPS-induced Polyp is released by platelets, resulting in increased intravascular thrombin activity. Protein disulfide isomerase (PDI) is found in the platelet endoplasmic reticulum and is released into circulation by endothelial cells or platelets. The pathophysiological mechanism explaining PDI thrombotic effect in vivo is not fully elucidated. Activated platelets increase the secretion of PDI, which binds to the GPIIb/IIIa integrin and results in enhanced GPIIb/IIIa-binding affinity. An in vivo study suggests that TNF-α activated endothelium induces PDI secretion leading to platelet-neutrophil aggregation through GPIIb/IIIa and αΜβ2 receptors. Another possible mechanism has been proposed by an in vitro study finding that PDI enhances TF-mediated thrombin generation in peripheral blood mononuclear cells (PBMCs) triggered by LPS. Platelet-derived TF levels and activity have also been found to increase in vitro after activation by LPS, E. coli, or S. aureus α-toxin. TLR-4 is one of the platelet receptors mediating TF production by splicing of TF pre-mRNA. Indeed, a clinical study confirms that platelets from septic patients present increased TF activity in contrast to healthy ones. Furthermore, increased expression of P-selectin and GPIIb/IIIa has been found in a sepsis mouse model and is associated with neutrophil-platelet aggregates and thrombus formation. Similarly, a prospective clinical trial found that COVID-19 infection amplifies platelet activation, as indicated by P-selectin, and promotes platelet aggregation.

Clinical evidence on drugs targeting immunothrombosis in sepsis

The efficacy of FDA-approved drugs commonly used in clinical practice, such as heparin, P2Y12, and GPIIb/IIIa inhibitors, has been tested in patients with sepsis. AT, another FDA-approved drug indicated for the prevention of peri-operative and peripartum thromboembolic events in patients with hereditary AT deficiency, has been also assessed ( Table 6; Figure 3 ). In addition to FDA-approved drugs, a variety of currently non-FDA-approved agents, including recombinant TM, APC, and TFPI, have been evaluated in sepsis ( Table 7; Figure 3 ). According to the international guidelines for sepsis and septic shock, neither anticoagulant nor antiplatelet medications are recommended for sepsis or DIC treatment, except for low molecular weight heparin (LMWH) or unfractionated heparin (UFH) for VTE prevention. On the contrary, AT replacement therapy and recombinant TM are recommended for sepsis-associated DIC in Japan. The efficacy of AT in sepsis is controversial, as derived from studies depicted in Table 6 and meta-analyses. Decreased AT plasma levels and DIC presence have been correlated with higher efficacy of AT treatment. Furthermore, bleeding risk in patients receiving AT is increased, especially in co-administration with heparin. Studies assessing the efficacy of TM have shown more promising results, as TM administration resulted in decreased mortality and was not associated with increased bleeding events in sepsis-induced coagulopathy. APC (or drotrecogin alfa activated), despite its antithrombotic effects, is not used in clinical practice as it has not improved survival and has been associated with increased bleeding risk in sepsis. Similarly, heparin is not recommended in sepsis management, although some studies have found a beneficial effect on 28-day mortality. Bleeding events following heparin treatment in sepsis are an important disadvantage of its use. Antiplatelet agents, beyond aspirin, have been tested to a lesser extent than anticoagulants, resulting in scarce data regarding their effects on the survival of sepsis patients. As for aspirin, a recent study showed no effect on mortality in septic patients. However, there are multiple underlying mechanisms through which aspirin could affect sepsis, specifically through its known anti-inflammatory properties. As a result, aspirin’s effects on sepsis should not be attributed exclusively to its antithrombotic properties. Therefore, drugs targeting immunothrombosis are not approved for clinical use in sepsis due to both inconclusive results for their efficacy and an increased risk for side effects.

Preclinical evidence on potential molecules targeting immunothrombosis in sepsis

The general failure of clinical trials to identify pharmaceutical agents with an acceptable risk-to-benefit ratio poses the need for discovering new molecules that could mitigate the deleterious effects of immunothrombosis in sepsis. A variety of such molecules have been examined in sepsis animal models, showing promising results, as depicted in Table 8 and Figure 4. Administration of histidine-rich glycoprotein (HRG), a plasma protein found to be significantly depleted in septic conditions, attenuated immunothrombi formation in the lungs of septic mice. Reduced neutrophil adherence to endothelium due to shape changes and decreased NET generation, as well as reduced endothelial cell activation, all mediated by HRG, were suggested to be among the potential mechanisms responsible for this effect. Another study investigated the beneficial role of Annexin A1, an anti-inflammatory protein found in low levels in patients with sepsis, on LPS-induced thrombosis. Interestingly, Annexin A1 mimetic peptide attenuated platelet aggregation and resulted in delayed and reduced microthrombi formation in the cerebral microcirculation.

A variety of inhibitory molecules targeting pathways involved in TF expression in immune or endothelial cells or in TF procoagulant activity have also been proposed. Disrupting TLR4-mediated LPS signaling through cluster of differentiation 14 (CD14) inhibition in immune cells was one potential pathway to target. Specifically, CD14 is a protein responsible for LPS transfer to its cell surface receptor complex, TLR4/myeloid differentiation factor 2 (MD-2) (a co-receptor of TLR4). Inhibitory monoclonal antibody (mAb) against CD14 led to decreased activation of the extrinsic coagulation pathway through suppression of TF expression in leukocytes while also enhancing fibrinolysis through decreasing plasma PAI-1. Apart from anti-CD14 mAb, lidocaine could also inhibit LPS-induced TF expression in monocytes through upregulation of suppressor of cytokine signaling 3 (SOCS3), which in turn downregulated the TLR4-TF pathway. Another potential pathway that could serve as a therapeutic target for mitigating immunothrombosis was shown to be type 1 interferon (IFN-1)-induced upregulation of TF procoagulant activity. Type 1 IFNs are cytokines that increase in response to bacterial infection and are characterized by antimicrobial properties. Inhibition of the expression of IFN-1 receptors or downstream effectors (e.g., HMGB1) in macrophages reduced gram-negative bacteria-induced DIC. TF procoagulant activity was also found to be decreased by acid sphingomyelinase inhibitors. In response to LPS, acid sphingomyelinase translocates to the cell membrane and hydrolyzes sphingomyelin, which, in resting conditions, maintains TF in an encrypted form with minimal procoagulant activity. Therefore, inhibition of acid sphingomyelinase inhibitors could maintain sphingomyelin levels on cell membranes despite LPS stimulation, resulting in decreased TF activity and reduced TAT levels in a sepsis mouse model. Linagliptin, a dipeptidyl peptidase-4 inhibitor used for diabetes treatment, was also found to ameliorate LPS-induced pulmonary thrombosis in mice via decreased endothelial TF expression. This effect was shown to be mediated through linagliptin-induced activation of the Akt/eNOS pathway and subsequent NO production. Noteworthy, linagliptin or the glucagon-like peptide-1 (GLP-1) analog, liraglutide, were shown to have further inhibitory effects on platelet thrombin generation and platelet aggregation via the cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway. Among other clinically approved drugs, amitriptyline, a tricyclic antidepressant, was also capable of reducing thrombosis through TNF-α level reduction.

The NLRP3 inflammasome, a complex responsible for IL-1β and IL-18 release and a crucial mediator of pyroptosis, became activated in platelets in a sepsis rat model and correlated with lung and renal injury. Blockage of NLRP3, using a selective inhibitor, led to decreased platelet activation and offered protection from organ dysfunction in rats with sepsis. Another potential therapeutic target was shown to be SQSTM1, a stress response protein that was released from monocytes and macrophages upon LPS stimulation. Interestingly, an inhibitory antibody against SQSTM1 attenuated DIC in bacteria-induced sepsis.

Promising results have also been demonstrated in preclinical studies examining the effect of NET inhibition on sepsis-induced thrombosis. DNase is an enzyme capable of digesting DNA. Two types of DNases have been found: DNase 1, which degrades free DNA, and DNase 1-like 3 (DNase1L3), which degrades DNA bound to proteins, such as histones. Patients with sepsis were shown to have decreased levels of DNase 1 compared to healthy controls. Moreover, mice with a combined deficiency of DNase1 and DNase1L3 demonstrated increased thrombosis in pulmonary vessels compared to mice capable of producing at least one of these two enzymes when both were infected either with LPS or heat-killed E. coli. Exogenous DNase administration promoted NET degradation and resulted in reduced intravascular thrombin activity as well as decreased microthrombus formation in liver sinusoids. The timing of the DNase infusion seems to affect its beneficial effect, with delayed infusion resulting in a significant decrease in TAT complexes compared to the insignificant effect observed with early infusion. Importantly, DNase administration, aiming to decrease LPS-induced NETosis, prior to S. aureus infection, did not negatively affect pathogen capture and clearance. However, the impact of DNase infusion after bacterial infection was not examined in that study. In contrast, mice treated with DNase at seven consecutive time points, beginning 1 h after cecal ligation and puncture (CLP), showed increased bacterial dissemination and higher serum IL-6 levels 6 h after CLP and higher mortality at 24 h. However, it should be noted that pathogens’ spread and levels of systemic inflammation 24 h after CLP, as well as overall survival, did not increase in DNase-treated mice compared to controls. Besides the evaluation of DNase treatment in preclinical sepsis models, a clinical trial (NCT05453695) is going to assess intravenous DNase safety and tolerability as well as its effect on organ dysfunction, duration of ICU hospitalization, mortality, and blood coagulation in patients with sepsis. Regarding inhibition of NET formation, reparixin, an inhibitor of interleukin-8 CXC chemokine receptor type 1/2 (CXCR1/2), resulted in decreased NET formation and subsequently reduced fibrin deposition in the lungs of septic mice. Similarly, infusion of platelets pretreated with stachydrine, an herbal product, attenuated NET formation, platelet–neutrophil interaction, and subsequent thrombosis.

Complement activation, despite being an essential component of the innate immune response, is associated with increased mortality in sepsis, while it also contributes to immunothrombosis. Blockade of C3a or C5a led to decreased DIC in E. coli or (CLP)-induced sepsis animal models. Noteworthy, combined inhibition of C5 activation and CD14 attenuated more robustly hypercoagulability in sepsis.

Conclusion

Immunothrombosis is a key pathophysiological mechanism of sepsis, arising from the complex interplay between innate immune and endothelial cells on one side and platelets and the coagulation cascade on the other. Although initially beneficial for the host, uncontrolled and systemic activation of this process in sepsis can lead to thrombotic and bleeding complications, ranging from subclinical abnormalities in coagulation tests to severe clinical manifestations, such as DIC. Endothelial dysfunction, characterized by glycocalyx degradation, increased vascular permeability, as well as proinflammatory and procoagulant properties of endothelial cells, further facilitates immunothrombosis progression. Despite the high burden of coagulation disorders that have a negative impact on sepsis patients’ prognosis, there is no effective treatment aiming to target the immunothrombotic process. Although a variety of anticoagulants and antiplatelet drugs have been evaluated in clinical trials, their beneficial effects are inconsistent, and they are also characterized by a high rate of bleeding complications. However, there is still ongoing research assessing the effect of new molecules on thrombosis in sepsis, with agents targeting intracellular inflammatory pathways, NET formation, and complement components demonstrating promising results. Future studies are called to unravel the pathophysiologic mechanisms involved in immunothrombosis in sepsis, to identify potential prognostic biomarkers, to develop risk scores to predict the outcomes of sepsis, and to test novel therapeutics against immunothrombosis in sepsis.

Author contributions

EM and EA researched data for the article, contributed to the interpretation of the published studies, and drafted all display items. KSte developed the concept, discussed the content, jointly conceived the display items of the article, and edited the article. ST-C, BEV, AG, and KSta provided conceptual advice, participated in the interpretation of the data, and edited the manuscript. All authors contributed to the article and approved the submitted version.

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    Key NS Vercellotti GM Winkelmann JC Moldow CF Goodman JL Esmon NL. Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression. Proc Natl Acad Sci U.S.A. (1990 ) 87(18):7095–9

    Not in our library10.1073/pnas.87.18.7095

  69. 69.

    van Hinsbergh VW Kooistra T van den Berg EA Princen HM Fiers W Emeis JJ. Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. Blood (1988 ) 72(5):1467–73

    Not in our library10.1182/blood.v72.5.1467.1467

  70. 70.

    Bevilacqua MP Pober JS Majeau GR Fiers W Cotran RS Gimbrone MA Jr. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: Characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci U.S.A. (1986 ) 83(12):4533–7

    Not in our library10.1073/pnas.83.12.4533

  71. 71.

    Lupu C Westmuckett AD Peer G Ivanciu L Zhu H Taylor FB Jr.. Tissue factor-dependent coagulation is preferentially up-regulated within arterial branching areas in a baboon model of escherichia coli sepsis. Am J Pathol (2005 ) 167(4):1161–72

    Not in our library10.1016/s0002-9440(10)61204-7

  72. 72.

    Song D Ye X Xu H Liu SF. Activation of endothelial intrinsic nf-{Kappa}B pathway impairs protein c anticoagulation mechanism and promotes coagulation in endotoxemic mice. Blood (2009 ) 114(12):2521–9

    Not in our library10.1182/blood-2009-02-205914

  73. 73.

    Ye X Ding J Zhou X Chen G Liu SF. Divergent roles of endothelial nf-kappab in multiple organ injury and bacterial clearance in mouse models of sepsis. J Exp Med (2008 ) 205(6):1303–15

    Not in our library10.1084/jem.20071393

  74. 74.

    Cone JB Ferrer TJ Wallace BH Wang J Hauer-Jensen M. Alterations in endothelial thrombomodulin expression in zymosan-induced lung injury. J Trauma (2003 ) 54(4):731–6

    Not in our library10.1097/01.ta.0000054652.38788.5a

  75. 75.

    Drake TA Cheng J Chang A Taylor FB Jr. Expression of tissue factor, thrombomodulin, and e-selectin in baboons with lethal escherichia coli sepsis. Am J Pathol (1993 ) 142(5):1458–70.

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  76. 76.

    Faust SN Levin M Harrison OB Goldin RD Lockhart MS Kondaveeti S. Dysfunction of endothelial protein c activation in severe meningococcal sepsis. N Engl J Med (2001 ) 345(6):408–16

    Not in our library10.1056/nejm200108093450603

  77. 77.

    Ikeda M Matsumoto H Ogura H Hirose T Shimizu K Yamamoto K. Circulating syndecan-1 predicts the development of disseminated intravascular coagulation in patients with sepsis. J Crit Care (2018 ) 43:48–53

    Not in our library10.1016/j.jcrc.2017.07.049

  78. 78.

    Tedesco F Pausa M Nardon E Introna M Mantovani A Dobrina A. The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity. J Exp Med (1997 ) 185(9):1619–27

    Not in our library10.1084/jem.185.9.1619

  79. 79.

    Chen Y Li X Lin X Liang H Liu X Zhang X. Complement C5a induces the generation of neutrophil extracellular traps by inhibiting mitochondrial Stat3 to promote the development of arterial thrombosis. Thromb J (2022 ) 20(1):24

    Not in our library10.1186/s12959-022-00384-0

  80. 80.

    Fattahi F Grailer JJ Jajou L Zetoune FS Andjelkovic AV Ward PA. Organ distribution of histones after intravenous infusion of fitc histones or after sepsis. Immunol Res (2015 ) 61(3):177–86

    Not in our library10.1007/s12026-015-8628-2

  81. 81.

    Huang YM Wang H Wang C Chen M Zhao MH. Promotion of hypercoagulability in antineutrophil cytoplasmic antibody-associated vasculitis by C5a-induced tissue factor-expressing microparticles and neutrophil extracellular traps. Arthritis Rheumatol (2015 ) 67(10):2780–90

    Not in our library10.1002/art.39239

  82. 82.

    Morigi M Galbusera M Gastoldi S Locatelli M Buelli S Pezzotta A. Alternative pathway activation of complement by shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis. J Immunol (2011 ) 187(1):172–80

    Not in our library10.4049/jimmunol.1100491

  83. 83.

    Ritis K Doumas M Mastellos D Micheli A Giaglis S Magotti P. A novel C5a receptor-tissue factor cross-talk in neutrophils links innate immunity to coagulation pathways. J Immunol (2006 ) 177(7):4794–802

    Not in our library10.4049/jimmunol.177.7.4794

  84. 84.

    Wojta J Kaun C Zorn G Ghannadan M Hauswirth AW Sperr WR. C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils. Blood (2002 ) 100(2):517–23

    Not in our library10.1182/blood.v100.2.517

  85. 85.

    Ikeda K Nagasawa K Horiuchi T Tsuru T Nishizaka H Niho Y. C5a induces tissue factor activity on endothelial cells. Thromb Haemost (1997 ) 77(2):394–8

    Not in our library10.1055/s-0038-1655974

  86. 86.

    Peerschke EI Reid KB Ghebrehiwet B. Platelet activation by C1q results in the induction of alpha Iib/Beta 3 integrins (Gpiib-iiia) and the expression of p-selectin and procoagulant activity. J Exp Med (1993 ) 178(2):579–87

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  87. 87.

    Ando B Wiedmer T Hamilton KK Sims PJ. Complement proteins C5b-9 initiate secretion of platelet storage granules without increased binding of fibrinogen or Von willebrand factor to newly expressed cell surface gpiib-iiia. J Biol Chem (1988 ) 263(24):11907–14

    Not in our library10.1016/s0021-9258(18)37872-4

  88. 88.

    Wiedmer T Esmon CT Sims PJ. Complement proteins C5b-9 stimulate procoagulant activity through platelet prothrombinase. Blood (1986 ) 68(4):875–80

    Not in our library10.1182/blood.v68.4.875.875

  89. 89.

    Polley MJ Nachman RL. Human platelet activation by C3a and C3a des-arg. J Exp Med (1983 ) 158(2):603–15

    Not in our library10.1084/jem.158.2.603

  90. 90.

    Muhlfelder TW Niemetz J Kreutzer D Beebe D Ward PA Rosenfeld SI. C5 chemotactic fragment induces leukocyte production of tissue factor activity: A link between complement and coagulation. J Clin Invest (1979 ) 63(1):147–50

    Not in our library10.1172/jci109269

  91. 91.

    Keshari RS Silasi R Popescu NI Patel MM Chaaban H Lupu C. Inhibition of complement C5 protects against organ failure and reduces mortality in a baboon model of escherichia coli sepsis. Proc Natl Acad Sci U.S.A. (2017 ) 114(31):E6390–e9

    Not in our library10.1073/pnas.1706818114

  92. 92.

    Mizuno T Yoshioka K Mizuno M Shimizu M Nagano F Okuda T. Complement component 5 promotes lethal thrombosis. Sci Rep (2017 ) 7:42714

    Not in our library10.1038/srep42714

  93. 93.

    Silasi-Mansat R Zhu H Popescu NI Peer G Sfyroera G Magotti P. Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of escherichia coli sepsis. Blood (2010 ) 116(6):1002–10

    Not in our library10.1182/blood-2010-02-269746

  94. 94.

    Laudes IJ Chu JC Sikranth S Huber-Lang M Guo RF Riedemann N. Anti-C5a ameliorates Coagulation/Fibrinolytic protein changes in a rat model of sepsis. Am J Pathol (2002 ) 160(5):1867–75

    Not in our library10.1016/s0002-9440(10)61133-9

  95. 95.

    Liebman HA Feinstein DI. Thrombosis in patients with paroxysmal noctural hemoglobinuria is associated with markedly elevated plasma levels of leukocyte-derived tissue factor. Thromb Res (2003 ) 111(4-5):235–8

    Not in our library10.1016/j.thromres.2003.09.018

  96. 96.

    Hou PC Filbin MR Wang H Ngo L Huang DT Aird WC. Endothelial permeability and hemostasis in septic shock: Results from the process trial. Chest (2017 ) 152(1):22–31

    Not in our library10.1016/j.chest.2017.01.010

  97. 97.

    Johansen ME Johansson PI Ostrowski SR Bestle MH Hein L Jensen AL. Profound endothelial damage predicts impending organ failure and death in sepsis. Semin Thromb Hemost (2015 ) 41(1):16–25

    Not in our library10.1055/s-0034-1398377

  98. 98.

    Katayama S Nunomiya S Koyama K Wada M Koinuma T Goto Y. Markers of acute kidney injury in patients with sepsis: The role of soluble thrombomodulin. Crit Care (2017 ) 21(1):229

    Not in our library10.1186/s13054-017-1815-x

  99. 99.

    Zhang J Xue M Chen Y Liu C Kuang Z Mu S. Identification of soluble thrombomodulin and tissue plasminogen activator-inhibitor complex as biomarkers for prognosis and early evaluation of septic shock and sepsis-induced disseminated intravascular coagulation. Ann Palliat Med (2021 ) 10(10):10170–84

    Not in our library10.21037/apm-21-2222

  100. 100.

    Mosad E Elsayh KI Eltayeb AA. Tissue factor pathway inhibitor and p-selectin as markers of sepsis-induced non-overt disseminated intravascular coagulopathy. Clin Appl Thromb Hemost (2011 ) 17(1):80–7

    Not in our library10.1177/1076029609344981

  101. 101.

    Hoshino K Kitamura T Nakamura Y Irie Y Matsumoto N Kawano Y. Usefulness of plasminogen activator inhibitor-1 as a predictive marker of mortality in sepsis. J Intensive Care (2017 ) 5:42

    Not in our library10.1186/s40560-017-0238-8

  102. 102.
    Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569] · 2004
    No notice
  103. 103.

    Ostrowski SR Haase N Müller RB Møller MH Pott FC Perner A. Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: A prospective study. Crit Care (2015 ) 19(1):191

    Not in our library10.1186/s13054-015-0918-5

  104. 104.
    Activation of the JAK/STAT3 and PI3K/AKT pathways are crucial for IL-6 trans-signaling-mediated pro-inflammatory response in human vascular endothelial cells · 2018
    No notice
  105. 105.

    Nolasco LH Turner NA Bernardo A Tao Z Cleary TG Dong JF. Hemolytic uremic syndrome-associated shiga toxins promote endothelial-cell secretion and impair Adamts13 cleavage of unusually Large Von willebrand factor multimers. Blood (2005 ) 106(13):4199–209

    Not in our library10.1182/blood-2005-05-2111

  106. 106.

    Abrams ST Morton B Alhamdi Y Alsabani M Lane S Welters ID. A novel assay for neutrophil extracellular trap formation independently predicts disseminated intravascular coagulation and mortality in critically ill patients. Am J Respir Crit Care Med (2019 ) 200(7):869–80

    Not in our library10.1164/rccm.201811-2111oc

  107. 107.

    Clark SR Ma AC Tavener SA McDonald B Goodarzi Z Kelly MM. Platelet Tlr4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med (2007 ) 13(4):463–9

    Not in our library10.1038/nm1565

  108. 108.

    McDonald B Davis RP Kim SJ Tse M Esmon CT Kolaczkowska E. Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood (2017 ) 129(10):1357–67

    Not in our library10.1182/blood-2016-09-741298

  109. 109.

    Zhang H Zhou Y Qu M Yu Y Chen Z Zhu S. Tissue factor-enriched neutrophil extracellular traps promote immunothrombosis and disease progression in sepsis-induced lung injury. Front Cell Infect Microbiol (2021 ) 11:677902

    Not in our library10.3389/fcimb.2021.677902

  110. 110.

    Etulain J Martinod K Wong SL Cifuni SM Schattner M Wagner DD. P-selectin promotes neutrophil extracellular trap formation in mice. Blood (2015 ) 126(2):242–6

    Not in our library10.1182/blood-2015-01-624023

  111. 111.

    Carestia A Kaufman T Rivadeneyra L Landoni VI Pozner RG Negrotto S. Mediators and molecular pathways involved in the regulation of neutrophil extracellular trap formation mediated by activated platelets. J Leukoc Biol (2016 ) 99(1):153–62

    Not in our library10.1189/jlb.3a0415-161r

  112. 112.

    Maugeri N Campana L Gavina M Covino C De Metrio M Panciroli C. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J Thromb Haemost (2014 ) 12(12):2074–88

    Not in our library10.1111/jth.12710

  113. 113.
    Deep vein thrombosis in mice is regulated by platelet HMGB1 through release of neutrophil-extracellular traps and DNA · 2018
    No notice
  114. 114.

    Rossaint J Herter JM Van Aken H Napirei M Döring Y Weber C. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood (2014 ) 123(16):2573–84

    Not in our library10.1182/blood-2013-07-516484

  115. 115.

    Yipp BG Petri B Salina D Jenne CN Scott BN Zbytnuik LD. Infection-induced netosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med (2012 ) 18(9):1386–93

    Not in our library10.1038/nm.2847

  116. 116.
    Coagulation induced by C3aR-dependent NETosis drives protumorigenic neutrophils during small intestinal tumorigenesis · 2016
    No notice
  117. 117.

    Chen Z Zhang H Qu M Nan K Cao H Cata JP. Review: The emerging role of neutrophil extracellular traps in sepsis and sepsis-associated thrombosis. Front Cell Infect Microbiol (2021 ) 11:653228

    Not in our library10.3389/fcimb.2021.653228

  118. 118.

    Leffler J Martin M Gullstrand B Tydén H Lood C Truedsson L. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J Immunol (2012 ) 188(7):3522–31

    Not in our library10.4049/jimmunol.1102404

  119. 119.

    Yu S Liu J Yan N. Endothelial dysfunction induced by extracellular neutrophil traps plays important role in the occurrence and treatment of extracellular neutrophil traps-related disease. Int J Mol Sci (2022 ) 23(10)

    Not in our library10.3390/ijms23105626

  120. 120.

    Aldabbous L Abdul-Salam V McKinnon T Duluc L Pepke-Zaba J Southwood M. Neutrophil extracellular traps promote angiogenesis: Evidence from vascular pathology in pulmonary hypertension. Arterioscler Thromb Vasc Biol (2016 ) 36(10):2078–87

    Not in our library10.1161/atvbaha.116.307634

  121. 121.

    Boufenzer A Carrasco K Jolly L Brustolin B Di-Pillo E Derive M. Potentiation of nets release is novel characteristic of trem-1 activation and the pharmacological inhibition of trem-1 could prevent from the deleterious consequences of nets release in sepsis. Cell Mol Immunol (2021 ) 18(2):452–60

    Not in our library10.1038/s41423-020-00591-7

  122. 122.

    Jin J Qiao S Liu J Li W Wang F Gao X. Neutrophil extracellular traps promote thrombogenicity in cerebral venous sinus thrombosis. Cell Biosci (2022 ) 12(1):114

    Not in our library10.1186/s13578-022-00845-z

  123. 123.

    Yang X Li L Liu J Lv B Chen F. Extracellular histones induce tissue factor expression in vascular endothelial cells Via tlr and activation of nf-κb and ap-1. Thromb Res (2016 ) 137:211–8

    Not in our library10.1016/j.thromres.2015.10.012

  124. 124.
    Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones · 2012
    No notice
  125. 125.

    Liang Y Pan B Alam HB Deng Q Wang Y Chen E. Inhibition of peptidylarginine deiminase alleviates lps-induced pulmonary dysfunction and improves survival in a mouse model of lethal endotoxemia. Eur J Pharmacol (2018 ) 833:432–40

    Not in our library10.1016/j.ejphar.2018.07.005

  126. 126.

    Meegan JE Yang X Beard RS Jr. Jannaway M Chatterjee V Taylor-Clark TE. Citrullinated histone 3 causes endothelial barrier dysfunction. Biochem Biophys Res Commun (2018 ) 503(3):1498–502

    Not in our library10.1016/j.bbrc.2018.07.069

  127. 127.

    Bianchini EP Razanakolona M Helms J Zouiti F Couteau-Chardon A Marin-Esteban V. The proteolytic inactivation of protein z-dependent protease inhibitor by neutrophil elastase might promote the procoagulant activity of neutrophil extracellular traps in sepsis. Thromb Haemost (2022 ) 122(4):506–16

    Not in our library10.1055/a-1530-3980

  128. 128.

    Gould TJ Vu TT Swystun LL Dwivedi DJ Mai SH Weitz JI. Neutrophil extracellular traps promote thrombin generation through platelet-dependent and platelet-independent mechanisms. Arterioscler Thromb Vasc Biol (2014 ) 34(9):1977–84

    Not in our library10.1161/atvbaha.114.304114

  129. 129.

    Cruz DBD Helms J Aquino LR Stiel L Cougourdan L Broussard C. DNA-Bound elastase of neutrophil extracellular traps degrades plasminogen, reduces plasmin formation, and decreases fibrinolysis: Proof of concept in septic shock plasma. FASEB J (2019 ) 33(12):14270–80

    Not in our library10.1096/fj.201901363rrr

  130. 130.

    Yang S Qi H Kan K Chen J Xie H Guo X. Neutrophil extracellular traps promote hypercoagulability in patients with sepsis. Shock (2017 ) 47(2):132–9

    Not in our library10.1097/shk.0000000000000741

  131. 131.

    Semeraro F Ammollo CT Morrissey JH Dale GL Friese P Esmon NL. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: Involvement of platelet Tlr2 and Tlr4. Blood (2011 ) 118(7):1952–61

    Not in our library10.1182/blood-2011-03-343061

  132. 132.

    Ammollo CT Semeraro F Xu J Esmon NL Esmon CT. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein c activation. J Thromb Haemost (2011 ) 9(9):1795–803

    Not in our library10.1111/j.1538-7836.2011.04422.x

  133. 133.

    Gould TJ Vu TT Stafford AR Dwivedi DJ Kim PY Fox-Robichaud AE. Cell-free DNA modulates clot structure and impairs fibrinolysis in sepsis. Arterioscler Thromb Vasc Biol (2015 ) 35(12):2544–53

    Not in our library10.1161/atvbaha.115.306035

  134. 134.

    Fuchs TA Brill A Duerschmied D Schatzberg D Monestier M Myers DD Jr.. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U.S.A. (2010 ) 107(36):15880–5

    Not in our library10.1073/pnas.1005743107

  135. 135.

    Kambas K Markiewski MM Pneumatikos IA Rafail SS Theodorou V Konstantonis D. C5a and tnf-alpha up-regulate the expression of tissue factor in intra-alveolar neutrophils of patients with the acute respiratory distress syndrome. J Immunol (2008 ) 180(11):7368–75

    Not in our library10.4049/jimmunol.180.11.7368

  136. 136.

    Sun X Zhou M Pu J Wang T. Stachydrine exhibits a novel antiplatelet property and ameliorates platelet-mediated thrombo-inflammation. BioMed Pharmacother (2022 ) 152:113184

    Not in our library10.1016/j.biopha.2022.113184

  137. 137.

    Arroyo AB Fernández-Pérez MP Del Monte A Águila S Méndez R Hernández-Antolín R. Mir-146a is a pivotal regulator of neutrophil extracellular trap formation promoting thrombosis. Haematologica (2021 ) 106(6):1636–46

    Not in our library10.3324/haematol.2019.240226

  138. 138.

    Carestia A Davis RP Davis L Jenne CN. Inhibition of immunothrombosis does not affect pathogen capture and does not promote bacterial dissemination in a mouse model of sepsis. Platelets (2020 ) 31(7):925–31

    Not in our library10.1080/09537104.2019.1704711

  139. 139.

    Wang Y Luo L Braun O Westman J Madhi R Herwald H. Neutrophil extracellular trap-microparticle complexes enhance thrombin generation Via the intrinsic pathway of coagulation in mice. Sci Rep (2018 ) 8(1):4020

    Not in our library10.1038/s41598-018-22156-5

  140. 140.

    Jiménez-Alcázar M Rangaswamy C Panda R Bitterling J Simsek YJ Long AT. Host dnases prevent vascular occlusion by neutrophil extracellular traps. Science (2017 ) 358(6367):1202–6

    Not in our library10.1126/science.aam8897

  141. 141.

    Massberg S Grahl L von Bruehl ML Manukyan D Pfeiler S Goosmann C. Reciprocal coupling of coagulation and innate immunity Via neutrophil serine proteases. Nat Med (2010 ) 16(8):887–96

    Not in our library10.1038/nm.2184

  142. 142.

    Xu J Zhang X Pelayo R Monestier M Ammollo CT Semeraro F. Extracellular histones are major mediators of death in sepsis. Nat Med (2009 ) 15(11):1318–21

    Not in our library10.1038/nm.2053

  143. 143.

    Abdeen S Bdeir K Abu-Fanne R Maraga E Higazi M Khurram N. Alpha-defensins: Risk factor for thrombosis in covid-19 infection. Br J Haematol (2021 ) 194(1):44–52

    Not in our library10.1111/bjh.17503

  144. 144.

    Delabranche X Stiel L Severac F Galoisy AC Mauvieux L Zobairi F. Evidence of netosis in septic shock-induced disseminated intravascular coagulation. Shock (2017 ) 47(3):313–7

    Not in our library10.1097/shk.0000000000000719

  145. 145.

    Schoergenhofer C Schwameis M Hobl EL Ay C Key NS Derhaschnig U. Potent irreversible P2y12 inhibition does not reduce lps-induced coagulation activation in a randomized, double-blind, placebo-controlled trial. Clin Sci (Lond) (2016 ) 130(6):433–40

    Not in our library10.1042/cs20150591

  146. 146.

    von Brühl ML Stark K Steinhart A Chandraratne S Konrad I Lorenz M. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med (2012 ) 209(4):819–35

    Not in our library10.1084/jem.20112322

  147. 147.

    Noubouossie DF Whelihan MF Yu YB Sparkenbaugh E Pawlinski R Monroe DM. In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps. Blood (2017 ) 129(8):1021–9

    Not in our library10.1182/blood-2016-06-722298

  148. 148.

    Maruchi Y Tsuda M Mori H Takenaka N Gocho T Huq MA. Plasma myeloperoxidase-conjugated DNA level predicts outcomes and organ dysfunction in patients with septic shock. Crit Care (2018 ) 22(1):176

    Not in our library10.1186/s13054-018-2109-7

  149. 149.

    Darbousset R Thomas GM Mezouar S Frère C Bonier R Mackman N. Tissue factor-positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood (2012 ) 120(10):2133–43

    Not in our library10.1182/blood-2012-06-437772

  150. 150.

    Maugeri N Brambilla M Camera M Carbone A Tremoli E Donati MB. Human polymorphonuclear leukocytes produce and express functional tissue factor upon stimulation. J Thromb Haemost (2006 ) 4(6):1323–30

    Not in our library10.1111/j.1538-7836.2006.01968.x

  151. 151.

    Kambas K Mitroulis I Ritis K. The emerging role of neutrophils in thrombosis-the journey of tf through nets. Front Immunol (2012 ) 3:385

    Not in our library10.3389/fimmu.2012.00385

  152. 152.

    Osterud B Rao LV Olsen JO. Induction of tissue factor expression in whole blood: Lack of evidence for the presence of tissue factor expression in granulocytes. Thromb Haemost (2000 ) 83(6):861–7

    Not in our library10.1055/s-0037-1613934

  153. 153.

    Ho J Zhang L Liu X Wong SH Wang MHT Lau BWM. Pathological role and diagnostic value of endogenous host defense peptides in adult and neonatal sepsis: A systematic review. Shock (2017 ) 47(6):673–9

    Not in our library10.1097/shk.0000000000000815

  154. 154.

    Abu-Fanne R Stepanova V Litvinov RI Abdeen S Bdeir K Higazi M. Neutrophil α-defensins promote thrombosis in vivo by altering fibrin formation, structure, and stability. Blood (2019 ) 133(5):481–93

    Not in our library10.1182/blood-2018-07-861237

  155. 155.
    Autophagy Mediates the Delivery of Thrombogenic Tissue Factor to Neutrophil Extracellular Traps in Human Sepsis · 2012
    No notice
  156. 156.

    Bajaj MS Ghosh M Bajaj SP. Fibronectin-adherent monocytes express tissue factor and tissue factor pathway inhibitor whereas endotoxin-stimulated monocytes primarily express tissue factor: Physiologic and pathologic implications. J Thromb Haemost (2007 ) 5(7):1493–9

    Not in our library10.1111/j.1538-7836.2007.02604.x

  157. 157.

    Chen F Zhao Z Zhou J Lu Y Essex DW Wu Y. Protein disulfide isomerase enhances tissue factor-dependent thrombin generation. Biochem Biophys Res Commun (2018 ) 501(1):172–7

    Not in our library10.1016/j.bbrc.2018.04.207

  158. 158.

    Del Conde I Shrimpton CN Thiagarajan P López JA. Tissue-Factor-Bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood (2005 ) 106(5):1604–11

    Not in our library10.1182/blood-2004-03-1095

  159. 159.

    Rauch U Bonderman D Bohrmann B Badimon JJ Himber J Riederer MA. Transfer of tissue factor from leukocytes to platelets is mediated by Cd15 and tissue factor. Blood (2000 ) 96(1):170–5

    Not in our library10.1182/blood.v96.1.170

  160. 160.

    Zhou H Wolberg AS Roubey RA. Characterization of monocyte tissue factor activity induced by igg antiphospholipid antibodies and inhibition by dilazep. Blood (2004 ) 104(8):2353–8

    Not in our library10.1182/blood-2004-01-0145

  161. 161.

    Pawlinski R Wang JG Owens AP 3rd Williams J Antoniak S Tencati M. Hematopoietic and nonhematopoietic cell tissue factor activates the coagulation cascade in endotoxemic mice. Blood (2010 ) 116(5):806–14

    Not in our library10.1182/blood-2009-12-259267

  162. 162.

    Yang X Cheng X Tang Y Qiu X Wang Y Kang H. Bacterial endotoxin activates the coagulation cascade through gasdermin d-dependent phosphatidylserine exposure. Immunity (2019 ) 51(6):983–96.e6

    Not in our library10.1016/j.immuni.2019.11.005

  163. 163.

    Wu C Lu W Zhang Y Zhang G Shi X Hisada Y. Inflammasome activation triggers blood clotting and host death through pyroptosis. Immunity (2019 ) 50(6):1401–11.e4

    Not in our library10.1016/j.immuni.2019.04.003

  164. 164.

    Butenas S Bouchard BA Brummel-Ziedins KE Parhami-Seren B Mann KG. Tissue factor activity in whole blood. Blood (2005 ) 105(7):2764–70

    Not in our library10.1182/blood-2004-09-3567

  165. 165.

    Kälsch T Elmas E Nguyen XD Suvajac N Klüter H Borggrefe M. Endotoxin-induced effects on platelets and monocytes in an in vivo model of inflammation. Basic Res Cardiol (2007 ) 102(5):460–6

    Not in our library10.1007/s00395-007-0667-y

  166. 166.

    Ryan TAJ Preston RJS O'Neill LAJ. Immunothrombosis and the molecular control of tissue factor by pyroptosis: Prospects for new anticoagulants. Biochem J (2022 ) 479(6):731–50

    Not in our library10.1042/bcj20210522

  167. 167.

    Wang J Pendurthi UR Rao LVM. Acid sphingomyelinase plays a critical role in lps- and cytokine-induced tissue factor procoagulant activity. Blood (2019 ) 134(7):645–55

    Not in our library10.1182/blood.2019001400

  168. 168.

    Ryan TAJ O'Neill LAJ. Innate immune signaling and immunothrombosis: New insights and therapeutic opportunities. Eur J Immunol (2022 ) 52(7):1024–34

    Not in our library10.1002/eji.202149410

  169. 169.

    Schoergenhofer C Schwameis M Gelbenegger G Buchtele N Thaler B Mussbacher M. Inhibition of protease-activated receptor (Par1) reduces activation of the endothelium, coagulation, fibrinolysis and inflammation during human endotoxemia. Thromb Haemost (2018 ) 118(7):1176–84

    Not in our library10.1055/s-0038-1655767

  170. 170.

    Htun P Fateh-Moghadam S Tomandl B Handschu R Klinger K Stellos K. Course of platelet activation and platelet-leukocyte interaction in cerebrovascular ischemia. Stroke (2006 ) 37(9):2283–7

    Not in our library10.1161/01.str.0000236638.75591.61

  171. 171.

    Langer HF Daub K Braun G Schönberger T May AE Schaller M. Platelets recruit human dendritic cells Via mac-1/Jam-C interaction and modulate dendritic cell function in vitro. Arterioscler Thromb Vasc Biol (2007 ) 27(6):1463–70

    Not in our library10.1161/atvbaha.107.141515

  172. 172.

    Bakogiannis C Sachse M Stamatelopoulos K Stellos K. Platelet-derived chemokines in inflammation and atherosclerosis. Cytokine (2019 ) 122:154157

    Not in our library10.1016/j.cyto.2017.09.013

  173. 173.

    Vardon Bounes F Mémier V Marcaud M Jacquemin A Hamzeh-Cognasse H Garcia C. Platelet activation and prothrombotic properties in a mouse model of peritoneal sepsis. Sci Rep (2018 ) 8(1):13536

    Not in our library10.1038/s41598-018-31910-8

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    Tatsidou PT Chantzichristos VG Tsoumani ME Sidiropoulou S Ntalas IV Goudevenos JA. Circulating progenitor cells and their interaction with platelets in patients with an acute coronary syndrome. Platelets (2019 ) 30(3):314–21

    Not in our library10.1080/09537104.2018.1430355

  175. 175.

    Rath D Chatterjee M Borst O Müller K Stellos K Mack AF. Expression of stromal cell-derived factor-1 receptors Cxcr4 and Cxcr7 on circulating platelets of patients with acute coronary syndrome and association with left ventricular functional recovery. Eur Heart J (2014 ) 35(6):386–94

    Not in our library10.1093/eurheartj/eht448

  176. 176.

    Stellos K Bigalke B Borst O Pfaff F Elskamp A Sachsenmaier S. Circulating platelet-progenitor cell coaggregate formation is increased in patients with acute coronary syndromes and augments recruitment of Cd34+ cells in the ischaemic microcirculation. Eur Heart J (2013 ) 34(32):2548–56

    Not in our library10.1093/eurheartj/eht131

  177. 177.

    Geisler T Fekecs L Wurster T Chiribiri A Schuster A Nagel E. Association of platelet-Sdf-1 with hemodynamic function and infarct size using cardiac Mr in patients with Ami. Eur J Radiol (2012 ) 81(4):e486–90

    Not in our library10.1016/j.ejrad.2011.06.019

  178. 178.

    Stellos K Bigalke B Langer H Geisler T Schad A Kögel A. Expression of stromal-Cell-Derived factor-1 on circulating platelets is increased in patients with acute coronary syndrome and correlates with the number of Cd34+ progenitor cells. Eur Heart J (2009 ) 30(5):584–93

    Not in our library10.1093/eurheartj/ehn566

  179. 179.

    Stellos K Bigalke B Stakos D Henkelmann N Gawaz M. Platelet-bound p-selectin expression in patients with coronary artery disease: Impact on clinical presentation and myocardial necrosis, and effect of diabetes mellitus and anti-platelet medication. J Thromb Haemost (2010 ) 8(1):205–7

    Not in our library10.1111/j.1538-7836.2009.03659.x

  180. 180.

    Stellos K Panagiota V Kögel A Leyhe T Gawaz M Laske C. Predictive value of platelet activation for the rate of cognitive decline in alzheimer's disease patients. J Cereb Blood Flow Metab (2010 ) 30(11):1817–20

    Not in our library10.1038/jcbfm.2010.140

  181. 181.

    Geisler T Mueller K Aichele S Bigalke B Stellos K Htun P. Impact of inflammatory state and metabolic control on responsiveness to dual antiplatelet therapy in type 2 diabetics after pci: Prognostic relevance of residual platelet aggregability in diabetics undergoing coronary interventions. Clin Res Cardiol (2010 ) 99(11):743–52

    Not in our library10.1007/s00392-010-0179-x

  182. 182.

    Geisler T Anders N Paterok M Langer H Stellos K Lindemann S. Platelet response to clopidogrel is attenuated in diabetic patients undergoing coronary stent implantation. Diabetes Care (2007 ) 30(2):372–4

    Not in our library10.2337/dc06-1625

  183. 183.
    Biomarkers of Platelet Activation and Their Prognostic Value in Patients With Sepsis-Associated Disseminated Intravascular Coagulopathy · 2021
    Not checked
  184. 184.

    McDonald B Dunbar M. Platelets and intravascular immunity: Guardians of the vascular space during bloodstream infections and sepsis. Front Immunol (2019 ) 10:2400

    Not in our library10.3389/fimmu.2019.02400

  185. 185.

    Garcia C Compagnon B Poëtte M Gratacap MP Lapébie FX Voisin S. Platelet versus megakaryocyte: Who is the real bandleader of thromboinflammation in sepsis? Cells (2022 ) 11(9)

    Not in our library10.3390/cells11091507

  186. 186.

    Ghuman H Shepherd-Roberts A Watson S Zuidscherwoude M Watson SP Voelz K. Mucor circinelloides induces platelet aggregation through integrin αiibβ3 and fcγriia. Platelets (2019 ) 30(2):256–63

    Not in our library10.1080/09537104.2017.1420152

  187. 187.

    Matus V Valenzuela JG Hidalgo P Pozo LM Panes O Wozniak A. Human platelet interaction with e. coli O111 promotes tissue-Factor-Dependent procoagulant activity, involving toll like receptor 4. PloS One (2017 ) 12(9):e0185431

    Not in our library10.1371/journal.pone.0185431

  188. 188.

    Arman M Krauel K Tilley DO Weber C Cox D Greinacher A. Amplification of bacteria-induced platelet activation is triggered by fcγriia, integrin αiibβ3, and platelet factor 4. Blood (2014 ) 123(20):3166–74

    Not in our library10.1182/blood-2013-11-540526

  189. 189.

    Tilley DO Arman M Smolenski A Cox D O'Donnell JS Douglas CW. Glycoprotein ibα and fcγriia play key roles in platelet activation by the colonizing bacterium, streptococcus oralis. J Thromb Haemost (2013 ) 11(5):941–50

    Not in our library10.1111/jth.12175

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    Vanassche T Kauskot A Verhaegen J Peetermans WE van Ryn J Schneewind O. Fibrin formation by staphylothrombin facilitates staphylococcus aureus-induced platelet aggregation. Thromb Haemost (2012 ) 107(6):1107–21

    Not in our library10.1160/th11-12-0891

  191. 191.

    Rondina MT Schwertz H Harris ES Kraemer BF Campbell RA Mackman N. The septic milieu triggers expression of spliced tissue factor mrna in human platelets. J Thromb Haemost (2011 ) 9(4):748–58

    Not in our library10.1111/j.1538-7836.2011.04208.x

  192. 192.

    Keane C Tilley D Cunningham A Smolenski A Kadioglu A Cox D. Invasive streptococcus pneumoniae trigger platelet activation Via toll-like receptor 2. J Thromb Haemost (2010 ) 8(12):2757–65

    Not in our library10.1111/j.1538-7836.2010.04093.x

  193. 193.

    Miajlovic H Zapotoczna M Geoghegan JA Kerrigan SW Speziale P Foster TJ. Direct interaction of iron-regulated surface determinant isdb of staphylococcus aureus with the Gpiib/Iiia receptor on platelets. Microbiol (Reading) (2010 ) 156(Pt 3)

    Not in our library10.1099/mic.0.036673-0

  194. 194.

    Zhang G Han J Welch EJ Ye RD Voyno-Yasenetskaya TA Malik AB. Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation Via Tlr4/Myd88 and the cgmp-dependent protein kinase pathway. J Immunol (2009 ) 182(12):7997–8004

    Not in our library10.4049/jimmunol.0802884

  195. 195.

    Kerrigan SW Jakubovics NS Keane C Maguire P Wynne K Jenkinson HF. Role of streptococcus gordonii surface proteins Sspa/Sspb and hsa in platelet function. Infect Immun (2007 ) 75(12):5740–7

    Not in our library10.1128/iai.00909-07

  196. 196.

    O'Brien L Kerrigan SW Kaw G Hogan M Penadés J Litt D. Multiple mechanisms for the activation of human platelet aggregation by staphylococcus aureus: Roles for the clumping factors clfa and clfb, the serine-aspartate repeat protein sdre and protein a. Mol Microbiol (2002 ) 44(4):1033–44

    Not in our library10.1046/j.1365-2958.2002.02935.x

  197. 197.

    Kerrigan SW Douglas I Wray A Heath J Byrne MF Fitzgerald D. A role for glycoprotein ib in streptococcus sanguis-induced platelet aggregation. Blood (2002 ) 100(2):509–16

    Not in our library10.1182/blood.v100.2.509

  198. 198.

    Lourbakos A Yuan YP Jenkins AL Travis J Andrade-Gordon P Santulli R. Activation of protease-activated receptors by gingipains from porphyromonas gingivalis leads to platelet aggregation: A new trait in microbial pathogenicity. Blood (2001 ) 97(12):3790–7

    Not in our library10.1182/blood.v97.12.3790

  199. 199.

    Landoni VI Pittaluga JR Carestia A Castillo LA Nebel MC Martire-Greco D. Neutrophil extracellular traps induced by shiga toxin and lipopolysaccharide-treated platelets exacerbate endothelial cell damage. Front Cell Infect Microbiol (2022 ) 12:897019

    Not in our library10.3389/fcimb.2022.897019

  200. 200.

    Surewaard BGJ Thanabalasuriar A Zeng Z Tkaczyk C Cohen TS Bardoel BW. α-toxin induces platelet aggregation and liver injury during staphylococcus aureus sepsis. Cell Host Microbe (2018 ) 24(2):271–84.e3

    Not in our library10.1016/j.chom.2018.06.017

  201. 201.

    Manne BK Denorme F Middleton EA Portier I Rowley JW Stubben C. Platelet gene expression and function in patients with covid-19. Blood (2020 ) 136(11):1317–29

    Not in our library10.1182/blood.2020007214

  202. 202.

    Stellos K Sauter R Fahrleitner M Grimm J Stakos D Emschermann F. Binding of oxidized low-density lipoprotein on circulating platelets is increased in patients with acute coronary syndromes and induces platelet adhesion to vascular wall in vivo–brief report. Arterioscler Thromb Vasc Biol (2012 ) 32(8):2017–20

    Not in our library10.1161/atvbaha.111.244707

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    Galgano L Guidetti GF Torti M Canobbio I. The controversial role of lps in platelet activation in vitro. Int J Mol Sci (2022 ) 23(18)

    Not in our library10.3390/ijms231810900

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    Cell Type-Specific Roles of NF-κB Linking Inflammation and Thrombosis · 2019
    No notice
  205. 205.

    van Geffen JP Swieringa F Heemskerk JW. Platelets and coagulation in thrombus formation: Aberrations in the Scott syndrome. Thromb Res (2016 ) 141(Suppl 2):S12–6

    Not in our library10.1016/s0049-3848(16)30355-3

  206. 206.

    Müller F Mutch NJ Schenk WA Smith SA Esterl L Spronk HM. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell (2009 ) 139(6):1143–56

    Not in our library10.1016/j.cell.2009.11.001

  207. 207.

    Li J Kim K Jeong SY Chiu J Xiong B Petukhov PA. Platelet protein disulfide isomerase promotes glycoprotein ibα-mediated platelet-neutrophil interactions under thromboinflammatory conditions. Circulation (2019 ) 139(10):1300–19

    Not in our library10.1161/circulationaha.118.036323

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    Liu XL Wang XZ Liu XX Hao D Jaladat Y Lu F. Low-dose heparin as treatment for early disseminated intravascular coagulation during sepsis: A prospective clinical study. Exp Ther Med (2014 ) 7(3):604–8

    Not in our library10.3892/etm.2013.1466

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    Jaimes F de la Rosa G Morales C Fortich F Arango C Aguirre D. Unfractioned heparin for treatment of sepsis: A randomized clinical trial (the hetrase study). Crit Care Med (2009 ) 37(4):1185–96

    Not in our library10.1097/ccm.0b013e31819c06bc

  210. 210.

    Shorr AF Williams MD. Venous thromboembolism in critically ill patients. observations from a randomized trial in sepsis. Thromb Haemost (2009 ) 101(1):139–44.

    Not in our library

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    Levi M Levy M Williams MD Douglas I Artigas A Antonelli M. Prophylactic heparin in patients with severe sepsis treated with drotrecogin Alfa (Activated). Am J Respir Crit Care Med (2007 ) 176(5):483–90

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    Pernerstorfer T Hollenstein U Hansen J Knechtelsdorfer M Stohlawetz P Graninger W. Heparin blunts endotoxin-induced coagulation activation. Circulation (1999 ) 100(25):2485–90

    Not in our library10.1161/01.cir.100.25.2485

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    Hofmann M Rest A Hafner G Tanner B Brockerhoff P Weilemann LS. D-dimer, thrombin-antithrombin iii-complex (Tat) and prothrombin fragment 1+2 (Ptf). parameters for monitoring therapy with low molecular-weight heparin in coagulation disorders. Anaesthesist (1997 ) 46(8):689–96

    Not in our library10.1007/s001010050455

  214. 214.

    Manios SG Kanakoudi F Maniati E. Fulminant meningococcemia. heparin therapy and survival rate. Scand J Infect Dis (1971 ) 3(2):127–33

    Not in our library10.3109/inf.1971.3.issue-2.06

  215. 215.

    Thomas MR Outteridge SN Ajjan RA Phoenix F Sangha GK Faulkner RE. Platelet P2y12 inhibitors reduce systemic inflammation and its prothrombotic effects in an experimental human model. Arterioscler Thromb Vasc Biol (2015 ) 35(12):2562–70

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  216. 216.

    Berthelsen RE Ostrowski SR Bestle MH Johansson PI. Co-Administration of iloprost and eptifibatide in septic shock (Co-ilepss)-a randomised, controlled, double-blind investigator-initiated trial investigating safety and efficacy. Crit Care (2019 ) 23(1):301

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  217. 217.

    Derhaschnig U Pachinger C Schweeger-Exeli I Marsik C Jilma B. Blockade of Gpiib/Iiia by eptifibatide and tirofiban does not alter tissue factor induced thrombin generation in human endotoxemia. Thromb Haemost (2003 ) 90(6):1054–60

    Not in our library10.1160/th03-04-0233

  218. 218.

    Galstian GM Krechetova AV Troitskaia VV Makarova PM Shutova NA Gemdzhian ÉG. Therapy with high-doses of antithrombin iii in patients with septic shock and agranulocytosis. Anesteziol Reanimatol (2014 ) 59(4):39–45.

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    A randomized, controlled, multicenter trial of the effects of antithrombin on disseminated intravascular coagulation in patients with sepsis · 2013
    No notice
  220. 220.

    Hoffmann JN Wiedermann CJ Juers M Ostermann H Kienast J Briegel J. Benefit/Risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin. Thromb Haemost (2006 ) 95(5):850–6

    Not in our library10.1160/th05-07-0530

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    Kienast J Juers M Wiedermann CJ Hoffmann JN Ostermann H Strauss R. Treatment effects of high-dose antithrombin without concomitant heparin in patients with severe sepsis with or without disseminated intravascular coagulation. J Thromb Haemost (2006 ) 4(1):90–7

    Not in our library10.1111/j.1538-7836.2005.01697.x

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    Leitner JM Firbas C Mayr FB Reiter RA Steinlechner B Jilma B. Recombinant human antithrombin inhibits thrombin formation and interleukin 6 release in human endotoxemia. Clin Pharmacol Ther (2006 ) 79(1):23–34

    Not in our library10.1016/j.clpt.2005.10.003

  223. 223.

    Gonano C Sitzwohl C Meitner E Weinstabl C Kettner SC. Four-day antithrombin therapy does not seem to attenuate hypercoagulability in patients suffering from sepsis. Crit Care (2006 ) 10(6):R160

    Not in our library10.1186/cc5098

  224. 224.

    Hoffmann JN Mühlbayer D Jochum M Inthorn D. Effect of long-term and high-dose antithrombin supplementation on coagulation and fibrinolysis in patients with severe sepsis. Crit Care Med (2004 ) 32(9):1851–9

    Not in our library10.1097/01.ccm.0000139691.54108.1f

  225. 225.

    Warren BL Eid A Singer P Pillay SS Carl P Novak I. Caring for the critically ill patient. high-dose antithrombin iii in severe sepsis: A randomized controlled trial. Jama (2001 ) 286(15):1869–78

    Not in our library10.1001/jama.286.15.1869

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    Eisele B Lamy M Thijs LG Keinecke HO Schuster HP Matthias FR. Antithrombin iii in patients with severe sepsis. a randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin iii in severe sepsis. Intensive Care Med (1998 ) 24(7):663–72

    Not in our library10.1007/s001340050642

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    Inthorn D Hoffmann JN Hartl WH Mühlbayer D Jochum M. Effect of antithrombin iii supplementation on inflammatory response in patients with severe sepsis. Shock (1998 ) 10(2):90–6

    Not in our library10.1097/00024382-199808000-00002

  228. 228.

    Inthorn D Hoffmann JN Hartl WH Mühlbayer D Jochum M. Antithrombin iii supplementation in severe sepsis: Beneficial effects on organ dysfunction. Shock (1997 ) 8(5):328–34

    Not in our library10.1097/00024382-199711000-00003

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    Fourrier F Chopin C Huart JJ Runge I Caron C Goudemand J. Double-blind, placebo-controlled trial of antithrombin iii concentrates in septic shock with disseminated intravascular coagulation. Chest (1993 ) 104(3):882–8

    Not in our library10.1378/chest.104.3.882

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    Schoergenhofer C Buchtele N Gelbenegger G Derhaschnig U Firbas C Kovacevic KD. Defibrotide enhances fibrinolysis in human endotoxemia - a randomized, double blind, crossover trial in healthy volunteers. Sci Rep (2019 ) 9(1):11136

    Not in our library10.1038/s41598-019-47630-6

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    Murao A Kato T Yamane T Honda G Eguchi Y. Benefit profile of thrombomodulin Alfa combined with antithrombin concentrate in patients with sepsis-induced disseminated intravascular coagulation. Clin Appl Thromb Hemost (2022 ) 28:10760296221077096

    Not in our library10.1177/10760296221077096

  232. 232.

    Kuroda H Masuda Y. Comparison of protective effects of recombinant antithrombin gamma and plasma-derived antithrombin on sepsis-induced disseminated intravascular coagulation and multiple organ failure. Clin Appl Thromb Hemost (2020 ) 26

    Not in our library10.1177/1076029620981630

  233. 233.

    Kim YJ Ko BS Park SY Oh DK Hong SB Jang S. Effect of high-dose antithrombin supplementation in patients with septic shock and disseminated intravascular coagulation. Sci Rep (2019 ) 9(1):16626

    Not in our library10.1038/s41598-019-52968-y

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    Hayakawa M Yamakawa K Kudo D Ono K. Optimal antithrombin activity threshold for initiating antithrombin supplementation in patients with sepsis-induced disseminated intravascular coagulation: A multicenter retrospective observational study. Clin Appl Thromb Hemost (2018 ) 24(6):874–83

    Not in our library10.1177/1076029618757346

  235. 235.

    Tagami T Matsui H Fushimi K Yasunaga H. Supplemental dose of antithrombin use in disseminated intravascular coagulation patients after abdominal sepsis. Thromb Haemost (2015 ) 114(3):537–45

    Not in our library10.1160/th15-01-0053

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    Tagami T Matsui H Horiguchi H Fushimi K Yasunaga H. Antithrombin and mortality in severe pneumonia patients with sepsis-associated disseminated intravascular coagulation: An observational nationwide study. J Thromb Haemost (2014 ) 12(9):1470–9

    Not in our library10.1111/jth.12643

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    Eid A Wiedermann CJ Kinasewitz GT. Early administration of high-dose antithrombin in severe sepsis: Single center results from the kybersept-trial. Anesth Analg (2008 ) 107(5):1633–8

    Not in our library10.1213/ane.0b013e318184621d

  238. 238.

    Kreuz WD Schneider W Nowak-Göttl U. Treatment of consumption coagulopathy with antithrombin concentrate in children with acquired antithrombin deficiency–a feasibility pilot study. Eur J Pediatr (1999 ) 158(Suppl 3):S187–91

    Not in our library10.1007/pl00014353

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    Gtc Biotherapeutics, Inc. Antithrombin (Recombinant). Food and Drug Administration Website (2009 ). Available at: https://www.fda.gov/media/75529/download.

    Not in our library

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    Vincent JL Francois B Zabolotskikh I Daga MK Lascarrou JB Kirov MY. Effect of a recombinant human soluble thrombomodulin on mortality in patients with sepsis-associated coagulopathy: The scarlet randomized clinical trial. Jama (2019 ) 321(20):1993–2002

    Not in our library10.1001/jama.2019.5358

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    Hagiwara A Tanaka N Uemura T Matsuda W Kimura A. Can recombinant human thrombomodulin increase survival among patients with severe septic-induced disseminated intravascular coagulation: A single-centre, open-label, randomised controlled trial. BMJ Open (2016 ) 6(12):e012850

    Not in our library10.1136/bmjopen-2016-012850

  242. 242.

    Vincent JL Ramesh MK Ernest D LaRosa SP Pachl J Aikawa N. A randomized, double-blind, placebo-controlled, phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, art-123, in patients with sepsis and suspected disseminated intravascular coagulation. Crit Care Med (2013 ) 41(9):2069–79

    Not in our library10.1097/ccm.0b013e31828e9b03

  243. 243.

    Pappalardo F Crivellari M Di Prima AL Agracheva N Celinska-Spodar M Lembo R. Protein c zymogen in severe sepsis: A double-blinded, placebo-controlled, randomized study. Intensive Care Med (2016 ) 42(11):1706–14

    Not in our library10.1007/s00134-016-4405-5

  244. 244.

    Ranieri VM Thompson BT Barie PS Dhainaut JF Douglas IS Finfer S. Drotrecogin Alfa (Activated) in adults with septic shock. N Engl J Med (2012 ) 366(22):2055–64

    Not in our library10.1056/nejmoa1202290

  245. 245.

    Dhainaut JF Antonelli M Wright P Desachy A Reignier J Lavoue S. Extended drotrecogin Alfa (Activated) treatment in patients with prolonged septic shock. Intensive Care Med (2009 ) 35(7):1187–95

    Not in our library10.1007/s00134-009-1436-1

  246. 246.

    Nadel S Goldstein B Williams MD Dalton H Peters M Macias WL. Drotrecogin Alfa (Activated) in children with severe sepsis: A multicentre phase iii randomised controlled trial. Lancet (2007 ) 369(9564):836–43

    Not in our library10.1016/s0140-6736(07)60411-5

  247. 247.

    Abraham E Laterre PF Garg R Levy H Talwar D Trzaskoma BL. Drotrecogin Alfa (Activated) for adults with severe sepsis and a low risk of death. N Engl J Med (2005 ) 353(13):1332–41

    Not in our library10.1056/nejmoa050935

  248. 248.

    van der Poll T Levi M Nick JA Abraham E. Activated protein c inhibits local coagulation after intrapulmonary delivery of endotoxin in humans. Am J Respir Crit Care Med (2005 ) 171(10):1125–8

    Not in our library10.1164/rccm.200411-1483oc

  249. 249.

    Kalil AC Coyle SM Um JY LaRosa SP Turlo MA Calvano SE. Effects of drotrecogin Alfa (Activated) in human endotoxemia. Shock (2004 ) 21(3):222–9

    Not in our library10.1097/01.shk.0000116778.27924.79

  250. 250.

    Ely EW Angus DC Williams MD Bates B Qualy R Bernard GR. Drotrecogin Alfa (Activated) treatment of older patients with severe sepsis. Clin Infect Dis (2003 ) 37(2):187–95

    Not in our library10.1086/375775

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    Bernard GR Vincent JL Laterre PF LaRosa SP Dhainaut JF Lopez-Rodriguez A. Efficacy and safety of recombinant human activated protein c for severe sepsis. N Engl J Med (2001 ) 344(10):699–709

    Not in our library10.1056/nejm200103083441001

  252. 252.

    Abraham E Reinhart K Opal S Demeyer I Doig C Rodriguez AL. Efficacy and safety of tifacogin (Recombinant tissue factor pathway inhibitor) in severe sepsis: A randomized controlled trial. Jama (2003 ) 290(2):238–47

    Not in our library10.1001/jama.290.2.238

  253. 253.

    Abraham E Reinhart K Svoboda P Seibert A Olthoff D Dal Nogare A. Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: A multicenter, randomized, placebo-controlled, single-blind, dose escalation study. Crit Care Med (2001 ) 29(11):2081–9

    Not in our library10.1097/00003246-200111000-00007

  254. 254.

    de Jonge E Dekkers PE Creasey AA Hack CE Paulson SK Karim A. Tissue factor pathway inhibitor dose-dependently inhibits coagulation activation without influencing the fibrinolytic and cytokine response during human endotoxemia. Blood (2000 ) 95(4):1124–9

    Not in our library10.1182/blood.v95.4.1124.002k20_1124_1129

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    Mayr FB Firbas C Leitner JM Spiel AO Reiter RA Beyer D. Effects of the pan-selectin antagonist bimosiamose (Tbc1269) in experimental human endotoxemia. Shock (2008 ) 29(4):475–82

    Not in our library10.1097/shk.0b013e318142c4e8

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    Derhaschnig U Bergmair D Marsik C Schlifke I Wijdenes J Jilma B. Effect of interleukin-6 blockade on tissue factor-induced coagulation in human endotoxemia. Crit Care Med (2004 ) 32(5):1136–40

    Not in our library10.1097/01.ccm.0000126265.08175.be

  257. 257.

    Verbon A Meijers JC Spek CA Hack CE Pribble JP Turner T. Effects of Ic14, an anti-Cd14 antibody, on coagulation and fibrinolysis during low-grade endotoxemia in humans. J Infect Dis (2003 ) 187(1):55–61

    Not in our library10.1086/346043

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    Jilma B Marsik C Mayr F Graninger MT Taylor FB Jr. Ribel MC. Pharmacodynamics of active site-inhibited factor viia in endotoxin-induced coagulation in humans. Clin Pharmacol Ther (2002 ) 72(4):403–10

    Not in our library10.1067/mcp.2002.127740

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    Pajkrt D van der Poll T Levi M Cutler DL Affrime MB van den Ende A. Interleukin-10 inhibits activation of coagulation and fibrinolysis during human endotoxemia. Blood (1997 ) 89(8):2701–5

    Not in our library10.1182/blood.v89.8.2701

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    Mitaka C Kawagoe I Satoh D Hayashida M. Effect of recombinant human soluble thrombomodulin on coagulation-related variables in patients with sepsis-induced disseminated intravascular coagulation: A retrospective observational study. Clin Appl Thromb Hemost (2021 ) 27

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    Levi M Vincent JL Tanaka K Radford AH Kayanoki T Fineberg DA. Effect of a recombinant human soluble thrombomodulin on baseline coagulation biomarker levels and mortality outcome in patients with sepsis-associated coagulopathy. Crit Care Med (2020 ) 48(8):1140–7

    Not in our library10.1097/ccm.0000000000004426

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    Ogura T Eguchi T Amano M Sano T Nishioka N Miyano A. Multicenter clinical experience with recombinant soluble thrombomodulin for disseminated intravascular coagulation associated with severe acute cholecystitis. Thromb Res (2019 ) 176:74–8

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    Yoshihiro S Sakuraya M Hayakawa M Ono K Hirata A Takaba A. Recombinant human-soluble thrombomodulin contributes to reduced mortality in sepsis patients with severe respiratory failure: A retrospective observational study using a multicenter dataset. Shock (2019 ) 51(2):174–9

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    Hayakawa M Yamakawa K Saito S Uchino S Kudo D Iizuka Y. Recombinant human soluble thrombomodulin and mortality in sepsis-induced disseminated intravascular coagulation. A multicentre retrospective study. Thromb Haemost (2016 ) 115(6):1157–66

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    Yasuda N Goto K Ohchi Y Abe T Koga H Kitano T. The efficacy and safety of antithrombin and recombinant human thrombomodulin combination therapy in patients with severe sepsis and disseminated intravascular coagulation. J Crit Care (2016 ) 36:29–34

    Not in our library10.1016/j.jcrc.2016.06.008

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    Yamakawa K Ogura H Fujimi S Morikawa M Ogawa Y Mohri T. Recombinant human soluble thrombomodulin in sepsis-induced disseminated intravascular coagulation: A multicenter propensity score analysis. Intensive Care Med (2013 ) 39(4):644–52

    Not in our library10.1007/s00134-013-2822-2

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    Yamakawa K Fujimi S Mohri T Matsuda H Nakamori Y Hirose T. Treatment effects of recombinant human soluble thrombomodulin in patients with severe sepsis: A historical control study. Crit Care (2011 ) 15(3):R123

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    Rimmer E Kumar A Doucette S Marshall J Dial S Gurka D. Activated protein c and septic shock: A propensity-matched cohort study*. Crit Care Med (2012 ) 40(11):2974–81

    Not in our library10.1097/ccm.0b013e31825fd6d9

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    Dalton HJ Carcillo JA Woodward DB Short MA Williams MD. Biomarker response to drotrecogin Alfa (Activated) in children with severe sepsis: Results from the resolve clinical trial*. Pediatr Crit Care Med (2012 ) 13(6):639–45

    Not in our library10.1097/pcc.0b013e318250ad48

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    Decembrino L D'Angelo A Manzato F Solinas A Tumminelli F De Silvestri A. Protein c concentrate as adjuvant treatment in neonates with sepsis-induced coagulopathy: A pilot study. Shock (2010 ) 34(4):341–5

    Not in our library10.1097/shk.0b013e3181e7623e

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    Crivellari M Della Valle P Landoni G Pappalardo F Gerli C Bignami E. Human protein c zymogen concentrate in patients with severe sepsis and multiple organ failure after adult cardiac surgery. Intensive Care Med (2009 ) 35(11):1959–63

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    Vincent JL Angus DC Artigas A Kalil A Basson BR Jamal HH. Effects of drotrecogin Alfa (Activated) on organ dysfunction in the prowess trial. Crit Care Med (2003 ) 31(3):834–40

    Not in our library10.1097/01.ccm.0000051515.56179.e1

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    Yamakawa K Umemura Y Hayakawa M Kudo D Sanui M Takahashi H. Benefit profile of anticoagulant therapy in sepsis: A nationwide multicentre registry in Japan. Crit Care (2016 ) 20(1):229

    Not in our library10.1186/s13054-016-1415-1

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    The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020) · 2021
    No notice
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    Wiedermann CJ. Antithrombin concentrate use in disseminated intravascular coagulation of sepsis: Meta-analyses revisited. J Thromb Haemost (2018 ) 16(3):455–7

    Not in our library10.1111/jth.13950

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    Valeriani E Squizzato A Gallo A Porreca E Vincent JL Iba T. Efficacy and safety of recombinant human soluble thrombomodulin in patients with sepsis-associated coagulopathy: A systematic review and meta-analysis. J Thromb Haemost (2020 ) 18(7):1618–25

    Not in our library10.1111/jth.14812

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    Yamakawa K Murao S Aihara M. Recombinant human soluble thrombomodulin in sepsis-induced coagulopathy: An updated systematic review and meta-analysis. Thromb Haemost (2019 ) 119(1):56–65

    Not in our library10.1055/s-0038-1676345

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    Martí-Carvajal AJ Solà I Lathyris D Cardona AF. Human recombinant activated protein c for severe sepsis. Cochrane Database Syst Rev (2012 ) 3:Cd004388

    Not in our library10.1002/14651858.cd004388.pub5

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    Fan Y Jiang M Gong D Zou C. Efficacy and safety of low-Molecular-Weight heparin in patients with sepsis: A meta-analysis of randomized controlled trials. Sci Rep (2016 ) 6:25984

    Not in our library10.1038/srep25984

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    Fu S Yu S Wang L Ma X Li X. Unfractionated heparin improves the clinical efficacy in adult sepsis patients: A systematic review and meta-analysis. BMC Anesthesiol (2022 ) 22(1):28

    Not in our library10.1186/s12871-021-01545-w

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    Li X Liu Z Luo M Xi Y Li C Wang S. Therapeutic effect of low-Molecular-Weight heparin on adult sepsis: A meta-analysis. Ann Palliat Med (2021 ) 10(3):3115–27

    Not in our library10.21037/apm-21-169

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    Eisen DP Leder K Woods RL Lockery JE McGuinness SL Wolfe R. Effect of aspirin on deaths associated with sepsis in healthy older people (Antisepsis): A randomised, double-blind, placebo-controlled primary prevention trial. Lancet Respir Med (2021 ) 9(2):186–95

    Not in our library10.1016/s2213-2600(20)30411-2

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    He W Xi Q Cui H Zhang P Huang R Wang T. Forsythiaside b ameliorates coagulopathies in a rat model of sepsis through inhibition of the formation of Pad4-dependent neutrophil extracellular traps. Front Pharmacol (2022 ) 13:1022985

    Not in our library10.3389/fphar.2022.1022985

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    Alsabani M Abrams ST Cheng Z Morton B Lane S Alosaimi S. Reduction of netosis by targeting Cxcr1/2 reduces thrombosis, lung injury, and mortality in experimental human and murine sepsis. Br J Anaesth (2022 ) 128(2):283–93

    Not in our library10.1016/j.bja.2021.10.039

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    Keshari RS Silasi R Popescu NI Regmi G Chaaban H Lambris JD. Cd14 inhibition improves survival and attenuates thrombo-inflammation and cardiopulmonary dysfunction in a baboon model of escherichia coli sepsis. J Thromb Haemost (2021 ) 19(2):429–43

    Not in our library10.1111/jth.15162

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    Zheng B Yang H Zhang J Wang X Sun H Hu F. Lidocaine alleviates sepsis-induced acute lung injury in mice by suppressing tissue factor and matrix metalloproteinase-2/9. Oxid Med Cell Longev (2021 ) 2021:3827501

    Not in our library10.1155/2021/3827501

  287. 287.

    Vital SA Senchenkova EY Ansari J Gavins FNE. Targeting Anxa1/Formyl peptide receptor 2 pathway affords protection against pathological thrombo-inflammation. Cells (2020 ) 9(11)

    Not in our library10.3390/cells9112473

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    Cornelius DC Travis OK Tramel RW Borges-Rodriguez M Baik CH Greer M. Nlrp3 inflammasome inhibition attenuates sepsis-induced platelet activation and prevents multi-organ injury in cecal-ligation puncture. PloS One (2020 ) 15(6):e0234039

    Not in our library10.1371/journal.pone.0234039

  289. 289.

    Yang X Cheng X Tang Y Qiu X Wang Z Fu G. The role of type 1 interferons in coagulation induced by gram-negative bacteria. Blood (2020 ) 135(14):1087–100

    Not in our library10.1182/blood.2019002282

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    Zhou B Liu J Zeng L Zhu S Wang H Billiar TR. Extracellular Sqstm1 mediates bacterial septic death in mice through insulin receptor signalling. Nat Microbiol (2020 ) 5(12):1576–87

    Not in our library10.1038/s41564-020-00795-7

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    Wang D Yang Y Wang Y Proulle V Andreasen PA Hong W. Embelin ameliorated sepsis-induced disseminated intravascular coagulation intensities by simultaneously suppressing inflammation and thrombosis. BioMed Pharmacother (2020 ) 130:110528

    Not in our library10.1016/j.biopha.2020.110528

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    Xia BT Beckmann N Winer LK Kim Y Goetzman HS Veile RE. Amitriptyline treatment mitigates sepsis-induced tumor necrosis factor expression and coagulopathy. Shock (2019 ) 51(3):356–63

    Not in our library10.1097/shk.0000000000001146

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    Steven S Jurk K Kopp M Kröller-Schön S Mikhed Y Schwierczek K. Glucagon-like peptide-1 receptor signalling reduces microvascular thrombosis, nitro-oxidative stress and platelet activation in endotoxaemic mice. Br J Pharmacol (2017 ) 174(12):1620–32

    Not in our library10.1111/bph.13549

  294. 294.

    Wake H Mori S Liu K Morioka Y Teshigawara K Sakaguchi M. Histidine-rich glycoprotein prevents septic lethality through regulation of immunothrombosis and inflammation. EBioMedicine (2016 ) 9:180–94

    Not in our library10.1016/j.ebiom.2016.06.003

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    Egge KH Thorgersen EB Pischke SE Lindstad JK Pharo A Bongoni AK. Organ inflammation in porcine escherichia coli sepsis is markedly attenuated by combined inhibition of C5 and Cd14. Immunobiology (2015 ) 220(8):999–1005

    Not in our library10.1016/j.imbio.2015.04.002

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    Mai SH Khan M Dwivedi DJ Ross CA Zhou J Gould TJ. Delayed but not early treatment with dnase reduces organ damage and improves outcome in a murine model of sepsis. Shock (2015 ) 44(2):166–72

    Not in our library10.1097/shk.0000000000000396

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    Barratt-Due A Thorgersen EB Egge K Pischke S Sokolov A Hellerud BC. Combined inhibition of complement C5 and Cd14 markedly attenuates inflammation, thrombogenicity, and hemodynamic changes in porcine sepsis. J Immunol (2013 ) 191(2):819–27

    Not in our library10.4049/jimmunol.1201909

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    Thorgersen EB Hellerud BC Nielsen EW Barratt-Due A Fure H Lindstad JK. Cd14 inhibition efficiently attenuates early inflammatory and hemostatic responses in escherichia coli sepsis in pigs. FASEB J (2010 ) 24(3):712–22

    Not in our library10.1096/fj.09-140798

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    Tsai WH Shih CH Yu YB Hsu HC. Plasma levels in sepsis patients of annexin A1, lipoxin A4, macrophage inflammatory protein-3a, and neutrophil gelatinase-associated lipocalin. J Chin Med Assoc (2013 ) 76(9):486–90

    Not in our library10.1016/j.jcma.2013.05.004

  300. 300.

    Cornelius DC Baik CH Travis OK White DL Young CM Austin Pierce W. Nlrp3 inflammasome activation in platelets in response to sepsis. Physiol Rep (2019 ) 7(9):e14073

    Not in our library10.14814/phy2.14073

  301. 301.

    Swanson KV Deng M Ting JP. The Nlrp3 inflammasome: Molecular activation and regulation to therapeutics. Nat Rev Immunol (2019 ) 19(8):477–89

    Not in our library10.1038/s41577-019-0165-0

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    Sohrabipour S Muniz VS Sharma N Dwivedi DJ Liaw PC. Mechanistic studies of dnase I activity: Impact of heparin variants and Pad4. Shock (2021 ) 56(6):975–87

    Not in our library10.1097/shk.0000000000001804

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    Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial sepsis in mice · 2012
    No notice
  304. 304.

    National Library of Medicine (U.S.). Intravenous dnase I for the treatment of sepsis (Idealsepsisi) (2022 ). Available at: https://clinicaltrials.gov/ct2/show/NCT?term=NCT&draw=2&rank=1.

    Not in our library

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    Hack CE Nuijens JH Felt-Bersma RJ Schreuder WO Eerenberg-Belmer AJ Paardekooper J. Elevated plasma levels of the anaphylatoxins C3a and C4a are associated with a fatal outcome in sepsis. Am J Med (1989 ) 86(1):20–6

    Not in our library10.1016/0002-9343(89)90224-6

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    Robin M Intrator L Rapin M. Letter: Complement activation in septic shock. N Engl J Med (1975 ) 293(24):1261–2

    Not in our library10.1056/nejm197512112932416

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    Keragala CB Draxler DF McQuilten ZK Medcalf RL. Haemostasis and innate immunity - a complementary relationship: A review of the intricate relationship between coagulation and complement pathways. Br J Haematol (2018 ) 180(6):782–98

    Not in our library10.1111/bjh.15062

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    Markiewski MM Nilsson B Ekdahl KN Mollnes TE Lambris JD. Complement and coagulation: Strangers or partners in crime? Trends Immunol (2007 ) 28(4):184–92

    Not in our library10.1016/j.it.2007.02.006

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