NADPH oxidase-mediated platelet isoprostane over-production in cirrhotic patients: implication for platelet activation

Background: In patients with cirrhosis conflicting findings, inherent to platelet function and its clinical implication, are still matters of discussion. Cirrhosis is characterized by enhanced production of isoprostanes, index of oxidative stress in vivo, that is known to stem from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2)-generating oxidative stress and elicit platelet activation. Aim: To analyse the relationship between oxidative stress and platelet activation in cirrhosis. Methods: A cross-sectional study including 51 cirrhotic patients and sex-and age-matched control patients has been designed. Soluble NOX2-derived peptide (sNOX2-dp), a direct marker of NADPH oxidase activation, isoprostanes urinary excretion, platelet isoprostanes and two markers of in vivo platelet activation, i.e. soluble CD40 Ligand (sCD40L) and soluble P-selectin (sPs), were measured. Results: Compared with controls, cirrhotic patients had higher levels of sPs (P = 0.034), sCD40L (P < 0.0001), sNOX2-dp (P = 0.0016), urinary excretion of isoprostanes (P < 0.0001) and arachidonic acid-induced platelet isoprostane formation (P < 0.0001). A significant correlation between sNOX2-dp and platelet (R(s) = 0.39, P = 0.0051) and urinary (R(s) = 0.67, P < 0.0001) isoprostanes was detected; also, sNOX2-dp and isoprostanes significantly correlated with sPs and sCD40L. A stepwise regression analysis revealed that sNOX2-dp was independently related to sCD40L plasma levels. Conclusions: This study provides evidence that in cirrhosis, platelet isoprostanes are over-produced and could be implicated in platelet activation.