Citrullinated Histone 3 as a Marker of NETosis at Opposite Ends of Hemostasis: Evidence From Thrombosis-Prone MPN and Bleeding-Prone Hemophilia

BackgroundNeutrophil extracellular trap (NET) formation has emerged as a key driver of thrombosis in myeloproliferative neoplasms (MPNs). Its role in congenital bleeding disorders, however, remains unexplored.ObjectivesTo investigate circulating citrullinated histone H3 (cit-H3), a marker of NETosis, in thrombosis-prone MPNs and bleeding-prone severe hemophilia A.MethodsIn a cross-sectional study, plasma cit-H3 was quantified by ELISA in patients with JAK2-mutated polycythemia vera or essential thrombocythemia, patients with severe hemophilia A, and matched healthy controls. Clinical and laboratory data were analyzed for associations with cit-H3 levels.ResultsEighty-nine participants were included: 26 with myeloproliferative neoplasms (MPNs), 31 with severe hemophilia A, and 32 healthy controls. Demographic characteristics were comparable across groups, though comorbidities were more frequent in MPNs. Laboratory analyses confirmed expected disease-specific differences, including elevated leukocyte, neutrophil, and platelet counts in MPNs and prolonged activated partial thromboplastin time in hemophilia A. Circulating citrullinated histone H3 (cit-H3) levels differed significantly among groups (p < 0.001), being lowest in controls, intermediate in MPNs, and highest in hemophilia A. Within disease groups, cit-H3 levels were unaffected by clinical variables such as MPN subtype, aspirin use, phlebotomy history, or factor replacement regimen.ConclusionsElevated circulating cit-H3 levels, suggestive of increased NETosis activity, were observed in both thrombosis-prone MPNs and bleeding-prone hemophilia A. These exploratory findings suggest a possible association between NET formation and thromboinflammatory processes across distinct hemostatic disorders.