Heparin-Functionalized Adsorbents Eliminate Central Effectors of Immunothrombosis, including Platelet Factor 4, High-Mobility Group Box 1 Protein and Histones

Ebeyer-Masotta, Marie; Eichhorn, Tanja; Weiss, René; Semak, Vladislav; Lauková, Lucia; Fischer, Michael B.; Weber, Viktoria

doi:10.3390/ijms23031823

Cited by 23 publications

(17 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Seraph-100) can remove these substances effectively. Ebeyer-Masotta et al [ 68 ] demonstrated that heparin-functionalised adsorbents efficiently depleted activated platelets, platelet-derived extracellular vesicles, PF4, HMGB1, and histones/nucleosomes. Similarly, Hogwood et al [ 69 ] demonstrated that heparin attenuates histones and NETs-induced inflammatory responses in whole blood.…”

Section: Pathogenesis Of Sepsismentioning

confidence: 99%

Rationale for sequential extracorporeal therapy (SET) in sepsis

et al. 2023

View full text Add to dashboard Cite

Sepsis and septic shock remain drivers for morbidity and mortality in critical illness. The clinical picture of patients presenting with these syndromes evolves rapidly and may be characterised by: (a) microbial host invasion, (b) establishment of an infection focus, (c) opsonisation of bacterial products (e.g. lipopolysaccharide), (d) recognition of pathogens resulting in an immune response, (e) cellular and humoral effects of circulating pathogen and pathogen products, (f) immunodysregulation and endocrine effects of cytokines, (g) endothelial and organ damage, and (h) organ crosstalk and multiple organ dysfunction. Each step may be a potential target for a specific therapeutic approach. At various stages, extracorporeal therapies may target circulating molecules for removal. In sequence, we could consider: (a) pathogen removal from the circulation with affinity binders and cartridges (specific), (b) circulating endotoxin removal by haemoperfusion with polymyxin B adsorbers (specific), (c) cytokine removal by haemoperfusion with sorbent cartridges or adsorbing membranes (non-specific), (d) extracorporeal organ support with different techniques for respiratory and cardiac support (CO2 removal or extracorporeal membrane oxygenation), and renal support (haemofiltration, haemodialysis, or ultrafiltration). The sequence of events and the use of different techniques at different points for specific targets will likely require trials with endpoints other than mortality. Instead, the primary objectives should be to achieve the desired action by using extracorporeal therapy at a specific point. Graphical Abstract

show abstract

Section: Pathogenesis Of Sepsismentioning

confidence: 99%

Rationale for sequential extracorporeal therapy (SET) in sepsis

et al. 2023

View full text Add to dashboard Cite

show abstract

“…None of the currently available anti-histone or anti-HMGB1 agents have been approved for immunomodulation in the management of critical illnesses by any clinical guideline due to the lack of evidence. Most recently, EBP using multiple hemofilters, such as Cytosorb [ 33 ], AN69ST membrane [ 34 ] and heparin-functionalized Seraph-100 blood filter [ 35 ], was found to adsorb circulating HMGB1 and histones in vitro and in vivo. It is noteworthy that the use of such EBP devices in patients with critical illness has great potential to mitigate HMGB1/histone-mediated inflammation, immune thrombosis and organ injury without the administration of traditional anti-histone or anti-HMGB1 agents.…”

Section: Introductionmentioning

confidence: 99%

Targeting circulating high mobility group box-1 and histones by extracorporeal blood purification as an immunomodulation strategy against critical illnesses

Chen

Yang

et al. 2023

Crit Care

View full text Add to dashboard Cite

Both high mobility group box-1 (HMGB1) and histones are major damage-associated molecular patterns (DAPMs) that mediate lethal systemic inflammation, activation of the complement and coagulation system, endothelial injury and multiple organ dysfunction syndrome in critical illnesses. Although accumulating evidence collectively shows that targeting HMGB1 or histones by their specific antibodies or inhibitors could significantly mitigate aberrant immune responses in multiple critically ill animal models, routine clinical use of such agents is still not recommended by any guideline. In contrast, extracorporeal blood purification, which has been widely used to replace dysfunctional organs and remove exogenous or endogenous toxins in intensive care units, may also exert an immunomodulatory effect by eliminating inflammatory mediators such as cytokines, endotoxin, HMGB1 and histones in patients with critical illnesses. In this review, we summarize the multiple immunopathological roles of HMGB1 and histones in mediating inflammation, immune thrombosis and organ dysfunction and discuss the rationale for the removal of these DAMPs using various hemofilters. The latest preclinical and clinical evidence for the use of extracorporeal blood purification to improve the clinical outcome of critically ill patients by targeting circulating HMGB1 and histones is also gathered.

show abstract

“…While this extracorporeal approach is currently mainly explored regarding pathogen depletion, we have provided evidence that heparin-immobilized adsorbents may exert beneficial effects by binding and depleting mediators of immunothrombosis, including activated platelets and PF4 + pEVs, as well as HMGB1 and histones/nucleosomes ( Ebeyer-Masotta et al, 2022 ), as suggested in Figure 2 , and we are currently assessing the ability of heparin-functionalized adsorbents to deplete NETs.…”

Section: Therapeutic Potential Of Platelet-derived Ev Depletion Durin...mentioning

confidence: 99%

Activated Platelets and Platelet-Derived Extracellular Vesicles Mediate COVID-19-Associated Immunothrombosis

Ebeyer-Masotta

Eichhorn

Weiss

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Activated platelets and platelet-derived extracellular vesicles (EVs) have emerged as central players in thromboembolic complications associated with severe coronavirus disease 2019 (COVID-19). Platelets bridge hemostatic, inflammatory, and immune responses by their ability to sense pathogens via various pattern recognition receptors, and they respond to infection through a diverse repertoire of mechanisms. Dysregulated platelet activation, however, can lead to immunothrombosis, a simultaneous overactivation of blood coagulation and the innate immune response. Mediators released by activated platelets in response to infection, such as antimicrobial peptides, high mobility group box 1 protein, platelet factor 4 (PF4), and PF4+ extracellular vesicles promote neutrophil activation, resulting in the release of neutrophil extracellular traps and histones. Many of the factors released during platelet and neutrophil activation are positively charged and interact with endogenous heparan sulfate or exogenously administered heparin via electrostatic interactions or via specific binding sites. Here, we review the current state of knowledge regarding the involvement of platelets and platelet-derived EVs in the pathogenesis of immunothrombosis, and we discuss the potential of extracorporeal therapies using adsorbents functionalized with heparin to deplete platelet-derived and neutrophil-derived mediators of immunothrombosis.

show abstract

Heparin-Functionalized Adsorbents Eliminate Central Effectors of Immunothrombosis, including Platelet Factor 4, High-Mobility Group Box 1 Protein and Histones

Cited by 23 publications

References 70 publications

Rationale for sequential extracorporeal therapy (SET) in sepsis

Rationale for sequential extracorporeal therapy (SET) in sepsis

Targeting circulating high mobility group box-1 and histones by extracorporeal blood purification as an immunomodulation strategy against critical illnesses

Activated Platelets and Platelet-Derived Extracellular Vesicles Mediate COVID-19-Associated Immunothrombosis

Contact Info

Product

Resources

About