Abstract Body: Calciphylaxis is an orphan disease characterized by dermal microvessel thrombosis, inflicting painful cutaneous necrosis. It occurs predominantly in patients with end-stage kidney disease and has high mortality, elusive pathogenesis, and no approved therapies. We demonstrate that the calciphylaxis sera induce de novo synthesis of IL-6 and soluble IL-6 receptor and stimulate JAK2-STAT3 phosphorylation in the primary human dermal microvascular endothelial cells (ECs) in a feedforward manner. Spatial transcriptomics and space-constrained probability analyses of calciphylaxis biopsies demonstrate a profoundly altered skin microenvironment with a gain of proximal and distal IL-6 ligand-receptor interactions. Microvessels are the predominant senders and recipients of IL-6 signaling, which, along with upregulated ADAM17 in dermal vasculature and interstitial IL-6R, support trans-IL-6 signaling in calciphylaxis lesions. The calciphylaxis sera upregulate Thymidine phosphorylase (TYMP) in ECs. TYMP is a potent upregulator of IL-6, which, in turn, activates tissue factor (TF), a primary trigger of the extrinsic coagulation cascade. The IL-6-TF axis in ECs is partially triggered by elevated IL-6 and kynurenine levels in calciphylaxis sera and inhibited by anti-IL-6 treatment. The TF-inducing ability of calciphylaxis sera correlates with disease activity and response to IL-6 inhibitors. This study uncovers calciphylaxis as a combination of systemic alteration (serum-inducing IL-6-TF axis in ECs) and a heterogenous permissive local dermal microenvironment characterized by microvessels initiating IL-6 signaling and complex multi-way crosstalk with adipocytes and glands perpetuating the sinister thrombotic milieu. It supports further exploration of the IL-6-TF-inducing ability of calciphylaxis serum as a potential biomarker and IL-6 as a target for uremic calciphylaxis.