Hemophagocytic lymphohistiocytosis is characterized by tissue factor–driven coagulopathy, endothelial injury, and immunothrombosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome marked by defective cytotoxic lymphocyte function. While its immunologic features are recognized, the contribution of immunothrombosis is less defined. We analyzed plasma from 12 HLH patients with viral, lymphomatous, and autoimmune etiologies. Hallmark features included hyperferritinemia, cytopenias, hypertriglyceridemia, elevated sIL-2Rα, and acute-phase reactants. Cytokine profiling showed high IL-6, IL-8, IL-10, TNF-α, CRP, and IL-18, with variable IFN-γ. Coagulation studies revealed compensated DIC, elevated FVIIa/antithrombin complexes, and microparticle-bound tissue factor, implying in extrinsic pathway activation. Thrombomodulin shedding and reduced Protein S indicated impaired protein C anticoagulant function. The fibrinolytic system is impaired based on high levels of PAI-1/tPA, and complement activation with consumption of C3. Endothelial dysfunction was evidenced by elevated sVCAM-1, sICAM-1, angiopoietin-2, and decreased ADAMTS13. Elevated plasma SVEP-1 and immunohistochemical evidence of pS6 supported mTORC1 activation in histiocytes. In conclusion, HLH is more accurately described as a "cytokine storm" with pronounced immunothrombosis. The interplay between these 2 processes through multiple, redundant, and reciprocal mechanisms may represent a unifying pathway in HLH pathogenesis and reveal novel therapeutic targets.