Heparin, warfarin, or calciphylaxis?
Authors: Rory Crotty, Rosalynn M. Nazarian, Philip I. Song, Elizabeth M. Van Cott
Journal: American Journal of Hematology (2014)

A 68-year-old male with chronic kidney disease presented with painful recent-onset lower extremity skin lesions (Image 1). These lesions had been slowly developing over the previous 3 months, following a recent admission for treatment of acute membranous glomerulonephritis and deep vein thrombosis for which warfarin was initiated. His past medical history is significant for coronary artery disease and Type 2 diabetes mellitus, well controlled on insulin. Phosphorus (5.5 mg/dL) and parathyroid hormone (113 pg/mL) were elevated and calcium (8.6 mg/dL) was normal. The initial differential diagnoses were warfarin-induced skin necrosis, calciphylaxis, and ischemic necrosis with secondary cellulitis. Surgical debridement revealed full-thickness necrosis of the skin. Biopsies of the lesions revealed subcutaneous arteriolar calcifications typical of calciphylaxis (Image 2). Warfarin skin necrosis or heparin-induced thrombocytopenia (HIT) may present with cutaneous lesions similar to calciphylaxis 1. Histologically, warfarin necrosis and HIT typically show widespread thrombosis without arteriolar calcification. The lesions of warfarin necrosis typically appear within 3–10 days of commencing warfarin therapy and tend to occur in a similar distribution to those of calciphylaxis. HIT skin lesions mostly occur at the site of injection approximately 1 week after heparin initiation. In contrast to typical HIT, which has a characteristic decline in platelet count, the platelet count is often normal when skin lesions are the presenting sign of HIT 2. In the present case, HIT testing was not performed, because biopsy results were already available when he was admitted to our hospital. Calciphylaxis is the disastrous consequence of prolonged calcium-phosphate balance dysregulation, affecting up to 5% of hemodialysis patients 3. The pathogenesis is incompletely understood. It is believed that a combination of factors, such as an increased concentration of reactive oxygen species, inhibition of anti-calcification factors, and a prolonged hyperphosphatemic state lead to the transformation of vascular smooth muscle cells into osteoblast-like calcifying vascular cells (CVCs). CVCs then lay down a hydroxyapatite-like substance in the media of small arterioles, leading to ischemia and thrombosis of the overlying tissues. The typical histological picture is a triad of vascular calcification, intimal fibrosis, and panniculitis. Dermal or subcutaneous thrombosis can also be present 4. Calciphylaxis characteristically presents with retiform purpura, in which there are violaceous skin lesions with jagged, geometric borders adjacent to fairly normal-appearing skin, which steadily enlarge, ulcerate, and become necrotic over a period of weeks. These lesions are painful and typically occur in areas with significant subcutaneous adipose tissue; including buttocks, lower extremities, and breasts. Vital organs are almost invariably involved at presentation. Calciphylaxis occurs almost exclusively in patients with chronic kidney disease. Hyperparathyroidism, obesity, and diabetes are important risk factors. Warfarin increases the risk of calciphylaxis, due to its potent inhibition of matrix-G1 protein, an anti-calcification agent 5. Calciphylaxis carries an 80% mortality rate, with over half of all deaths attributable to sepsis 6.