Redefining Calciphylaxis as a Uniquely Bone Forming Subcutaneous C5b-9-Mediated Microvascular Injury Syndrome...

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.

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.

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.

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.