Idiopathic Multicentric Castleman Disease Results in Endothelium Activation and Coagulation Dysregulation Via Tissue Factor and PAI-1

Idiopathic Multicentric Castleman disease (iMCD) is an inflammatory disease which may be associated with thrombosis. Diagnosis of this condition may be delayed with increase in morbidity and mortality. We investigated the cause of hypercoagulability in one patient with iMCD, who presented with shortness of breath, anasarca, abdominal distension and severe pulmonary hypertension with clinicopathologic findings consistent with iMCD with some features of TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis, organomegaly) variant. Lab results detected high levels of inflammatory markers IL-6, CRP and ferritin. During the patient's hospital course, our patient developed evidence of consumptive coagulopathy, based on prolonged PT, aPTT, thrombocytopenia, high D-dimers and reduced fibrinogen levels, with associated microvascular thrombosis, limb gangrene, and biopsy-proven vascular fibrin formation. We examined several markers of coagulation activation in this patient to characterize the pattern of hypercoagulability in mCD. Cytokine and chemokine arrays and ELISA for selected coagulation factors were employed. We found an elevation in FVIIa/AT suggestive of in vivo upregulation of Tissue Factor (TF) as well as an increase in microparticles expressing functional TF (inhibited by Ixolaris). Our patient also demonstrated a marked increase in C5a and C3b. With respect to anticoagulants associated with the endothelium, both thrombomodulin and sEPCR were augmented in our patient, indicating endothelial cell injury and decreased protein C activation (APC). High levels of PAI-1, the main fibrinolysis inhibitor was evident. In addition, an increase in the chemoattractants for monocytes MCP-1, MCP-4 was noted. Similarly, we noted an increase in angiopoietin-2 and other markers associated with endothelial cell activation including adhesion molecules E-selectin, sICAM-1, sICAM-3 and sVCAM-1. Molecules affecting angiogenesis such as endoglin, IL-8, VEGF-A were also increased. Most markers were at normal levels when the patient was in remission. Our findings suggest that multiple pathways influence hypercoagulability in iMCD, including direct activation of coagulation through TF and complement, increase in thromboinflammation via monocytes, and endotheliopathy. Mechanistically, it is likely that the cytokine storm in iMCD, characterized by endothelial activation, components of immunothrombosis and complement activation result in TF-mediated coagulation dysregulation, shifting hemostasis towards a prothrombotic and antifibrinolytic state. Components of immunothrombosis, including inhibitors of TF, emerge as a therapeutic target in iMCD.