NETs-Induced Thrombosis Impacts on Cardiovascular and Chronic Kidney Disease

Abstract

Arterial and venous thrombosis constitute a major source of morbidity and mortality worldwide. Association between thrombotic complications and cardiovascular and other chronic inflammatory diseases are well described. Inflammation and subsequent initiation of thrombotic events, termed immunothrombosis, also receive growing attention but are still incompletely understood. Nevertheless, the clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is evident by an increased risk of thrombosis and cardiovascular events in patients with inflammatory or infectious diseases. Proinflammatory mediators released from platelets, complement activation, and the formation of NETs (neutrophil extracellular traps) initiate and foster immunothrombosis. In this review, we highlight and discuss prominent and emerging interrelationships and functions between NETs and other mediators in immunothrombosis in cardiovascular disease. Also, with patients with chronic kidney disease suffering from increased cardiovascular and thrombotic risk, we summarize current knowledge on neutrophil phenotype, function, and NET formation in chronic kidney disease. In addition, we elaborate on therapeutic targeting of NETs-induced immunothrombosis. A better understanding of the functional relevance of antithrombotic mediators which do not increase bleeding risk may provide opportunities for successful therapeutic interventions to reduce thrombotic risk beyond current treatment options.

Keywords: cardiovascular diseases; inflammation; kidney; neutrophils; thrombosis.

Figure 1.

NETs (neutrophil extracellular traps) components induce immunothrombosis. NETs components like negatively charged DNA scaffold, cathelicidin, MPO (myeloperoxidases), histones (H3 and H4), and NE (neutrophil elastase) act via different pathways including vWF (von Willebrand factor)-platelet string formation, platelet activation, aggregation, thrombin generation and TF (tissue factor) release to form immunothrombi. Elastases and cell-free DNA also promote thrombosis by reducing fibrinolysis. ADAMTS13 indicates A disintegrin and metalloprotease with a thrombospondin type 1 motif 13; EC, endothelial cell; GPVI, glycoprotein VI; and TLR, toll-like receptor. Made with biorender.com.

Figure 2.

NETs (neutrophil extracellular traps) targeting in thrombosis. Colchicine and other more general NETs inhibitors interfere with neutrophil activation, migration, and infiltration into sites of inflammation. IL (interleukin)-1β blockers will prevent an inflammatory loop between NETs and IL-1β. PAD4 (peptidyl arginase deiminase 4) and gasdermin D inhibitors will avert NETs formation more specifically while DNase (deoxyribonuclease) has been used safely to digest NETs. Interfering with toxic effects of histones and neutrophile elastase decorating the NET backbone also reduce thrombus formation and tissue damage. Abs indicates antibodies; AnxA1Ac2-26, annexin A1 mimetic peptide; BMS-P5, Bristol-Myers Squibb ((cis)-5-Amino-2-methylpiperidin-1-yl)(2-(1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-yl)methanone, hydrochloride); EC, endothelial cell; GSK, glycogen synthase kinase; RBC, red blood cell; RE31, 31-nt DNA aptamer; and TF, tissue factor. Made with biorender.com.