PracticalDermatology

Nonuremic calciphylaxis is a complex diagnosis. The condition presents as vessel calcification and thrombosis in the presence of normal kidney function. Here, the authors present a case of warfarin-induced nonuremic calciphylaxis of the lower extremities, with superimposed cellulitis. They also provide a comprehensive overview of its diagnosis and management based on updated data from the literature. Nonuremic calciphylaxis is a potentially fatal and complex condition. Further research is warranted to improve patient outcomes.

CASE REPORT

A 50-year-old woman with a history of atrial fibrillation, hypertension, myocardial infarction, heart failure, and diabetes mellitus presented for evaluation of a skin rash on her bilateral lower extremities. The rash reportedly began as dark spots that appeared on both legs about 2 weeks prior, following her discharge from the hospital where she had been treated for heart failure exacerbation. During that hospitalization, the patient had been restarted on her home warfarin, which she had been taking inconsistently for over 14 months. She had also been treated for suspected cellulitis of her right lower leg.

On physical examination, the patient’s right lower anterior leg had a large, dark, purple-black retiform plaque, and several hemorrhagic bullae were noted within this plaque (Figure 1). The nearby skin was severely tender but without crepitation. The left lower leg was leathery with an appearance like that of a dried raisin, and the posterior calf had a patch of partially denuded skin.

Figure 1. The patient’s right lower leg showed a large, dark purple-black retiform plaque. Within this plaque were several hemorrhagic-appearing bullae. The nearby skin was severely tender to palpation but without crepitation.

Her laboratory results were notable for a mild microcytic anemia (hemoglobin was 10.9 g/dL [reference range, 12.1–15.1 g/dL]), but protein C and protein S levels, factor 5 Leiden, and serum calcium and phosphate levels were normal.

A computed tomography scan with contrast of her bilateral lower extremities revealed soft tissue edema but was negative for gas in the tissues, edema extending along the fascial planes, and/or fascial enhancement, which can be observed in the setting of necrotizing fasciitis.

Two punch biopsy specimens were taken from the erythematous border of the retiform plaque on the patient’s right lower leg. The first specimen showed evidence of calcification of the subcutaneous microvascular fat and septal areas (Figure 2) and ischemic epidermal necrosis with subepidermal bulla formation and a fibrin occlusive vasculopathy (Figure 3) in the second specimen.

Figure 2. Von Kossa stain highlighted subcutaneous septal elastic fibers with mineral deposition.

Figure 3. A second biopsy showed fibrin occlusive vasculopathy with overlying epidermal ischemic necrosis and subepidermal bullae formation.

In the setting of the patient’s normal kidney function and the biopsies demonstrating calciphylaxis, she was diagnosed with nonuremic calciphylaxis secondary to warfarin therapy. The warfarin was discontinued and replaced with intravenous heparin, with low–molecular weight heparin recommended for long-term therapy. Wound care was consulted to assist with gentle management of the patient’s wounds. It was recommended to avoid trauma and debridement during the active ischemic phase of the disease. Treatment with sodium thiosulfate was considered but not started before the patient was discharged. Long-term follow-up in the dermatology clinic is planned, and consideration will be given to starting sodium thiosulfate, bisphosphonates (adjunctive first line in nonuremic calciphylaxis), and/or pentoxifylline (400 mg daily to three times daily).

DISCUSSION

The term nonuremic calciphylaxis refers to the findings of vessel calcification and thrombosis in the presence of normal kidney function (ie, patients not on dialysis or in the early stages of chronic kidney disease).¹ It is now understood as a separate entity from classic uremic calciphylaxis, but its presentation is far rarer. For example, in a recent review by Altman et al of 81 cases of calciphylaxis, only 16 (20%) were incited by nonuremic causes.² There is thus a relative paucity of information reported in the literature. Our case highlights a presentation incited by warfarin, but there are several other causes of nonuremic calciphylaxis and similarly presenting coagulopathies. Given the rarity of the condition and similarity in presentation to other coagulopathies, nonuremic calciphylaxis is a clinically challenging condition to diagnose and manage.³

The pathogenesis of warfarin-associated nonuremic calciphylaxis is poorly understood, but it may be related to the drug’s impact on proteins involved in clotting. Warfarin is a commonly used oral anticoagulant that acts on vitamin K epoxide reductase and prevents activation of vitamin K–dependent clotting factors (II, VII, IX, and X). The drug also inhibits anticoagulant proteins C and S. Before warfarin exerts its intended anticoagulant effect, there is a period of several days in which coagulation is favored owing to the shorter half-lives of proteins C and S.^4,5 There are several theories on how warfarin’s mechanism of action may lead to nonuremic calciphylaxis. One involves the inhibition of a vitamin K–dependent gamma-carboxylation of matrix Gla protein, a protein that normally prevents vascular mineralization.³ Warfarin may also paradoxically increase thrombosis by inhibiting protein S activity in vascular endothelial cells.³

Warfarin-associated nonuremic calciphylaxis usually presents with retiform purpura, typically on the lower extremities, followed by necrosis. The lesions are extremely painful with concomitant blistering and a history of poor healing. Limited case reports suggest this condition disproportionately affects women and is often associated with diabetes. Additional risk factors include a history of malignancy, corticosteroid use, and calcium abnormalities due to parathyroid hormone imbalance.¹ A thorough history of medications and comorbidities can assist with discerning potential causes of the condition.

In addition to the clinical presentation and history, histopathology is valuable in diagnosing nonuremic calciphylaxis. Histology may show calcification of the small and medium-sized arteries (highlighted with Von Kossa), and thrombi are often present within these vessels. Necrosis of surrounding adipose tissue is also seen.^1,3 Although histopathology can provide valuable information, the biopsy to obtain the specimen is invasive and painful and has poor sensitivity. Multiple biopsies are often necessary to diagnose the condition, and this can promote infection in a patient already at risk.^3,6 Image-guided core needle biopsies may address these concerns and have promising utility in the diagnosis of calciphylaxis by having a higher diagnostic yield and lower infection risk than standard biopsy techniques.⁷ Computed tomography is also capable of showing calciphylaxis (visualized as branching structures) and can be useful for ruling out other similarly presenting diagnoses.⁸

The differential diagnosis for warfarin-associated nonuremic calciphylaxis is complicated by its similarity to other conditions, but key clinical findings can help when histology is not available or diagnostic. Nonuremic calciphylaxis induced by warfarin occurs (on average) about 30 months after the initiation of the medication.³ This timing is central to distinguishing the condition from warfarin-induced skin necrosis. The latter also results in the formation of blistering and necrotic patches on the lower extremities, but most cases occur within 1 to 10 days of warfarin initiation.⁹ Necrotizing fasciitis can also present with bullous necrotic lesions similar to those seen in warfarin-induced nonuremic calciphylaxis. Other findings, however, such as an acutely ill and febrile patient with the presence of gas in the tissues are distinguishing features.¹⁰

No gold standard of treatment currently exists for warfarin-induced nonuremic calciphylaxis, but several therapies appear beneficial. The inciting factor, warfarin, should be discontinued as soon as possible and replaced by another anticoagulant, most commonly heparin.^3,11 Wound care should also be included in all cases owing to the high infection risk and known difficulties in healing with the condition. Techniques include removal of necrotic tissue if tolerated (but only after the ischemic phase has passed), application of an antiseptic, and appropriate dressings.¹ Proper wound care may be limited by intense pain, and analgesics should be supplemented as appropriate.¹² Sodium thiosulfate, either intravenous or intralesional, is the most common adjunct treatment cited in cases of nonuremic as well as classic calciphylaxis. The exact mechanism of action is unknown, but the compound is thought to be capable of chelating the calcium to increase clearance and promoting vasodilation.^13,14 Although intravenous sodium thiosulfate was specifically noted in nonuremic cases, intralesional sodium thiosulfate may offer additional healing benefits due to targeted delivery or in those with compromised vascular access for intravenous treatment. However, intralesional administration may be limited by pain while injecting directly into the lesions.^15,16 Yu et al reported a survival rate of 78% (7/9) for patients treated with sodium thiosulfate versus a rate of 48% (17/36) in a study by Nigwekar et al in which no patients were treated with sodium thiosulfate.^1,3

Other less commonly utilized treatments include bisphosphonates, hyperbaric oxygen, and vitamin K. Bisphosphonates, which decrease bone resorption, may provide a chelating benefit. Treatment with bisphosphonates was found to be successful in a few documented nonuremic cases with improvement in skin lesions. However, the research of bisphosphonate’s benefits toward calciphylaxis is heavily weighted towards classic calciphylaxis and requires further evaluation.^17,18 A minority of cases were treated with hyperbaric oxygen treatment, which can increase oxygen content even in necrotic regions and facilitate wound healing.¹¹ There are significant barriers, however, to this form of treatment, including cost and lack of general access. There may be a role for vitamin K in the treatment of calciphylaxis. Nigwekar et al conducted a study to evaluate the role of phytonadione, vitamin K1, in the treatment of calciphylaxis in 26 patients. The investigators found that patients treated with phytonadione showed greater improvement in both pain and lesion size compared to placebo. This may be due to the renewed ability to gamma-carboxylate, the previously mentioned G1a matrix protein that prevents vascular mineralization. Further studies are required to determine the efficacy and safety of this treatment.¹⁹ Overall, the evidence surrounding treatment is poor because of a lack of data, and ideal treatment duration has not been established.

Conclusion

Warfarin-induced nonuremic calciphylaxis is a potentially fatal condition that imposes diagnostic and treatment challenges. We presented a case of warfarin-associated nonuremic calciphylaxis of the lower extremities. Our patient was successfully treated with the substitution of heparin for warfarin and wound care, which have both been successful in other documented cases. Other potential treatments such as sodium thiosulfate, bisphosphonates, vitamin K, and hyperbaric oxygen were also reviewed. Additional case reports of conditions treated successfully are needed to increase the strength of research surrounding treatment modalities for this serious condition. Warfarin-associated nonuremic calciphylaxis remains a diagnostic and therapeutic challenge—one encountered by dermatologists because of the condition’s initial skin manifestation. It is essential providers be aware of treatment options for the condition because they may find themselves key actors in its recognition and management.

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2. Altman K, Shinohara M. Demographics, comorbid conditions, and outcomes of patients with nonuremic calciphylaxis. JAMA Dermatol. 2019;155(2):251-252. doi:10.1001/jamadermatol.2018.4937

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12. Erfurt-Berge C, Renner R. Management of patients with calciphylaxis: current perspectives. Chronic Wound Care Management and Research. 2019;6:109.

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16. Gabel CK, Nguyen ED, Dobry AS, et al. Assessment of outcomes of calciphylaxis lesions treated with intralesional sodium thiosulfate. J Am Acad Dermatol. 2021;85(3):770-773. doi:10.1016/j.jaad.2020.07.090

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