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

• Published in: International journal of molecular sciences Vol. 23; no. 3; p. 1823
• Main Authors: Ebeyer-Masotta, Marie, Eichhorn, Tanja, Weiss, René, Semak, Vladislav, Lauková, Lucia, Fischer, Michael B, Weber, Viktoria
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 05-02-2022; MDPI
• Subjects: Adsorbents; adsorption; Anticoagulants; Binding sites; Blood Coagulation - physiology; Blood platelets; Blood Platelets - metabolism; Blood Proteins - isolation & purification; Blood Proteins - metabolism; Coronaviruses; COVID-19; COVID-19 - metabolism; COVID-19 vaccines; Deregulation; Drug dosages; Effectors; Extracellular Traps - immunology; Extracellular Traps - metabolism; Extracellular vesicles; Heparan sulfate; Heparin; Heparin - metabolism; Heparin - pharmacology; Histones; Histones - isolation & purification; Histones - metabolism; HMGB Proteins - isolation & purification; HMGB Proteins - metabolism; HMGB1 protein; HMGB1 Protein - isolation & purification; HMGB1 Protein - metabolism; Humans; immunothrombosis; Inflammation; Ischemia; Leukocytes (neutrophilic); Microscopy; Mobility; neutrophil extracellular traps; Neutrophils; Neutrophils - metabolism; Nucleosomes; Pathogens; Platelet Activation - immunology; Platelet factor 4; Platelet Factor 4 - isolation & purification; Platelet Factor 4 - metabolism; Proteins; SARS-CoV-2 - pathogenicity; Sepsis; Sepsis - blood; Sepsis - metabolism; Thrombocytopenia; Thromboinflammation - drug therapy; Thromboplastin - metabolism; Thrombosis; Thrombosis - drug therapy; Tissue factor; COVID-19; heparin; adsorption; extracellular vesicles; neutrophil extracellular traps; platelet factor 4; immunothrombosis; platelets; sepsis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23031823

Inflammation and thrombosis are closely intertwined in numerous disorders, including ischemic events and sepsis, as well as coronavirus disease 2019 (COVID-19). Thrombotic complications are markers of disease severity in both sepsis and COVID-19 and are associated with multiorgan failure and increased mortality. Immunothrombosis is driven by the complement/tissue factor/neutrophil axis, as well as by activated platelets, which can trigger the release of neutrophil extracellular traps (NETs) and release further effectors of immunothrombosis, including platelet factor 4 (PF4/CXCL4) and high-mobility box 1 protein (HMGB1). Many of the central effectors of deregulated immunothrombosis, including activated platelets and platelet-derived extracellular vesicles (pEVs) expressing PF4, soluble PF4, HMGB1, histones, as well as histone-decorated NETs, are positively charged and thus bind to heparin. Here, we provide evidence that adsorbents functionalized with endpoint-attached heparin efficiently deplete activated platelets, pEVs, PF4, HMGB1 and histones/nucleosomes. We propose that this elimination of central effectors of immunothrombosis, rather than direct binding of pathogens, could be of clinical relevance for mitigating thrombotic complications in sepsis or COVID-19 using heparin-functionalized adsorbents.