Redefining Calciphylaxis as a Uniquely Bone Forming Subcutaneous C5b-9-Mediated Microvascular Injury Syndrome Associated With Localized Subcutaneous and Systemic Complement Pathway Activation.

Background: Microvascular thrombosis is key to the pathogenesis of calciphylaxis. C5b-9-mediated microvascular injury reflective of complement pathway activation could be a key pathophysiologic event.

Methods: We conducted a retrospective multicenter study of 24 patients who have had biopsy-supported calciphylaxis from the 2010-2022 data base from Emory where C5b-9 immunohistochemistry (IHC) had not been conducted and the 2019-2023 data base from Cornell where C5b-9 IHC was done as part of the routine calciphylaxis work up. IHC for C5b-9 on lesional biopsy specimens was assessed and correlated with routine light microscopic findings and clinical features.

Results: Most of the patients in our study had uremic calciphylaxis associated with obesity, diabetes, dialysis, hypertension, hyperparathyroidism and elevated serum phosphorus. Most patients did not have defined procoagulant and/or hyperviscosity states. The vascular pathology was predominantly limited to the subcutaneous fat and ranged from a calcific intimal arteriopathy to microvascular thrombosis with endothelial injury with or without endothelial calcification. In most cases (ie, in excess of 80%), there was prominent deposition of C5b-9 within the vasculature including the microvasculature and arteries of the fat at least localized to injured vessels suggesting a causal association. In about 40% of cases, there was evidence of systemic complement pathway activation revealed by concurrent dermal microvascular C5b-9 deposition.

Conclusions: Calciphylaxis is characterized by subcuticular vascular changes that reflect an interplay between complement triggered endothelial cell injury, resultant vascular thrombosis, and subsequent abluminal calcification. Complement inhibition therapy defines a potential intervention that should be explored.