IMAGES IN HEMATOLOGY
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Heparin, warfarin, or calciphylaxis? Rory Crotty,1 Rosalynn M. Nazarian,2 Philip I. Song,3 and Elizabeth M. Van Cott2
Image 1. Cutaneous lesions on admission showed angulated ulceration with violaceous border, hemorrhagic crust and necrosis, and nearby retiform purpura involving the left calf (Image 1A) and right calf (Image 1B).
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 1
School of Medicine, University College Cork, Cork, Ireland; 2Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
3
Conflict of interest: No conflict of interest. *Correspondence to: Elizabeth M. Van Cott, MD; Director, Coagulation Laboratory, Massachusetts General Hospital, GRJ235, 55 Fruit Street, Boston, MA 02114. E-mail:
[email protected] Received for publication: 18 January 2014; Accepted: 23 January 2014 Am. J. Hematol. 89:785–786, 2014. Published online: 28 January 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23679 C 2014 Wiley Periodicals, Inc. V
doi:10.1002/ajh.23679
American Journal of Hematology, Vol. 89, No. 7, July 2014
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IMAGES IN HEMATOLOGY
Crotty et al.
Image 2. Biopsy of cutaneous lesions, H&E stains, showing the triad of calcification (red arrows), fibrointimal hyperplasia (single blue asterisk), and panniculitis (double black asterisk), affecting a medium size cutaneous vessel (Image 2A, 203 magnification) and a small vessel in the subcutaneous adipose tissue (Image 2B, 403 magnification).
invariably involved at presentation. Calciphylaxis occurs almost exclusively in patients with chronic kidney disease. Hyperparathyroidism, obesity, and diabetes are important risk factors. Warfarin increases
䊏 References 1. Latif S, Zaman F, Abreo F, et al. A young woman with indurated skin and subcutaneous lesions. Lab Med 2005;36:221–223. 2. Warkentin TE, Roberts RS, Hirsh J, Kelton JG. Heparin-induced skin lesions and other unusual sequelae of the heparin-induced thrombocytopenia syndrome: A nested cohort study. Chest 2005;127:1857–1861.
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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].
3. Rogers NM, Coates PT. Calcific uraemic arteriolopathy: An update. Curr Opin Nephrol Hypertens 2008;17:629–634. 4. Brandenburg VM, Cozzolino M, Ketteler M. Calciphylaxis: A still unmet challenge. Nephrol 2011; 24:142–148. 5. Palaniswamy C, Sekhri A, Aronow WS, Kalra A, Peterson SJ. Association of warfarin use with valvular and vascular calcification: A review. Clin Cardiol 2011;34:74–81.
6. Vedvyas C, Winterfield LS, Vleugels RA. Calciphylaxis: A systematic review of existing and emerging therapies. J Am Acad Dermatol 2012; 67(6):253–260.
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