Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy

Idiopathic multicentric Castleman disease (iMCD) is an inflammatory disease associated with a "cytokine storm", activation of the PI3K/Akt/mTOR pathway, coagulopathy and increased risk of thrombosis. The mechanisms underlying these pathologic processes remain elusive. We have studied novel markers of mTOR activation and thrombosis in one patient with typical features of iMCD with TAFRO syndrome (iMCD-TAFRO). Plasma levels of SVEP1, a newly identified mTOR activator associated with cardiovascular diseases and dementia, was evaluated by ELISA. Arrays for cytokines, chemokines and the complement cascade and ELISA for numerous hemostatic factors were also employed. The patient`s plasma showed marked cytokinemia during a flare, with high levels of acute phase proteins, growth factors, immune mediators and monocytic chemoattractants. Notably, a 15-fold increase in SVEP1 compared to healthy controls was observed. High levels of FVIIa/AT and microparticles expressing functional TF (blocked by the inhibitor Ixolaris) were detected. The anticoagulants thrombomodulin and sEPCR were elevated, indicating shedding from endothelial cells with decreased protein C activation. Moreover, PAI-1 was increased, consistent with hypofibrinolysis, while high levels of C3b and C5a are in keeping with complement activation. Furthermore, markers of endothelial cell activation, including vWF, angiopoietin-2, cell adhesion molecules (E-selectin, sICAM-1, sICAM-3, sVCAM-1) and angiogenesis (endoglin, VEGF-A, Tie-2, bFGF, sFLT-1) were upregulated. High plasma levels of SVEP1 suggest a potential mechanism of mTOR activation in iMCD-TAFRO. Multiple pathways influence coagulopathy, including a "cytokine storm", TF, NETs, PAI-1, complement activation and endotheliopathy, implying a prothrombotic/antifibrinolytic state. Immunothrombosis emerges as a potential therapeutic target for iMCD, together with currently available immunomodulators.