On a quest for fingerprints of crystalglobulinemia on platelets and endothelium Open Access

• Crystalglobulinemia is associated with a procoagulant platelet phenotype and high shear stress-like endothelial alterations.

• Markers of platelet and endothelial function reflect M-protein burden.

Crystalglobulinemia is a rare plasma cell dyscrasia characterized by the crystallization of monoclonal proteins within the systemic vasculature and tissues, leading to occlusive vasculopathy, nephropathy, and tissue ischemia. We investigated platelet and endothelial activation status in a patient with crystalglobulinemia presenting with thrombotic events and acute kidney injury before and after anti-clonal therapy. Platelet function assessment revealed the presence of procoagulant platelets, characterized by phosphatidylserine exposure and increased P-selectin expression in the absence of external stimuli. This phenotype was reversed by ex-vivo calcium chelation. Furthermore, evidence support FcγRIIA-mediated platelet activation by crystal complexes. Platelet proteomic analysis demonstrated upregulation of complement-related proteins, apolipoproteins and proteins involved in platelet activation pathways. Additionally, crystal proteomic analysis identified immunoglobulin heavy constant gamma-1 (IGHG1) and albumin in a 1:2 ratio. Endothelial gene expression was evaluated using real-time PCR after co-culturing the patient’s serum, isolated platelets, and citrated platelet-poor plasma with a serum-starved EA.hy926 endothelial monolayer. The patient’s serum increased endothelial gene expression of ICAM-1 and ADAMTS-13, while VCAM-1 and E-selectin were significantly reduced compared to controls— a phenotype typically observed under high shear stress conditions. Platelet and endothelial dysfunction correlated with disease activity and showed partial reversal following treatment, highlighting potential implications for disease monitoring and therapeutic targeting.