Case Presentation: A 74 year old female with history of atrial flutter on warfarin presented to the emergency department with altered mental status and bilateral leg pain. She was found to have a leukocytosis (WBC 14.7), pre-renal azotemia and an elevated INR of 8.2. Exam was notable for bilateral lower extremity ulcers. She was treated with ceftriaxone for presumed cellulitis, and admitted to the hospital. Her azotemia resolved with IV fluids. The patient was unable to provide much history, but her family was contacted and reported that she had first developed blisters on both legs about three weeks before, and these wounds had become progressively worse. The wound care team was consulted, who reported a wound exam notable for mild bilateral peripheral edema with scattered necrotic skin lesions over the bilateral pretibial legs and calves. These were noted to be exquisitely tender to palpation. A biopsy was obtained, with initial pathology showing superficial epidermal and dermal necrosis with hemorrhage and scattered fibrin thrombi. This was felt to be suggestive of a primary thrombotic vasculopathy, and in the setting of the patient’s elevated INR on presentation, this was presumed to be a presentation of warfarin skin necrosis and her warfarin was discontinued. The ceftriaxone was also discontinued as there was no evidence of infection. The wounds failed to resolve and so plastic surgery was consulted and the patient underwent a second, deeper biopsy which showed the presence of calcification within the small vessels, consistent with a diagnosis of calciphylaxis. This diagnosis was ultimately made approximately 3 weeks after initial presentation and her warfarin use was felt to be the most likely risk factor for its occurrence.
Discussion: Calcemic uremic arteriolopathy (CUA), or calciphylaxis, is a rare but serious disorder characterized by arteriolar calcification and thrombosis leading to skin ischemia and necrosis1. It is most commonly seen in patients with end-stage renal disease, affecting approximately 1-4% of dialysis patients annually2. It is also increasingly recognized in patients without renal failure3,4. Its pathogenesis has been attributed to a dysregulation of the molecular and cytochemical factors involved in mineral deposition and resorption of bone5. The disease has been reported in patients with bone and mineral disorders such as hyperparathyroidism, hyperphosphatemia, hypoalbuminemia, and obesity. Warfarin has also been identified as an independent risk factor for CUA development, thought to be an important cofactor involved in vascular calcification through the receptor-activator of nuclear factor-κB (RANK) pathway1,6.
Conclusions: The patient’s lack of chronic renal disease as well as the rarity of CUA led to a delay in diagnosis of several weeks. Although her elevated INR on presentation prompted the consideration of warfarin as a factor in her lower extremity wounds, these were instead misattributed to warfarin skin necrosis until a second biopsy confirmed the diagnosis. The presentation of necrotic skin ulcers and recent warfarin use should elicit consideration of calciphylaxis as a diagnosis and prompt wound consultation and biopsy should ensue.
