A toe ulcer in a patient with essential thrombocythemia successfully treated with a combination of anagrelide and prednisolone

Dear Editor Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by sustained thrombocytosis derived from increased megakaryocyte production. The main cutaneous manifestation of ET is thrombosis, and thrombotic ulcers accompanied by microvascular occlusion can lead to gangrene. Although ET-related ulcers are treated with hydroxycarbamide and aspirin, some reports have shown hydroxycarbamide to produce the paradoxical reaction of leg ulcers. This adverse effect has never been reported for anagrelide alone, an alternative drug for ET. Moreover, to our knowledge, no reports have addressed the efficacy of anagrelide for ET-related ulcers. Here, we report the first case of ET-related toe ulcer successfully treated with anagrelide. A 59-year-old Japanese woman presented with a 1-month history of skin ulcer on her right fifth toe. She had no history of thrombosis. Physical examination revealed an irregular ulcer on the right fifth toe with painful non-palpable purpura (Figure 1A). The ankle brachial pressure index for the right foot was 1.20 (normal: 1.00– 1.29). Contrast-enhanced computed tomography showed splenomegaly but no arteriosclerosis obliterans. Blood tests revealed elevated platelets of 131.6 10/μl (normal: 15–40 10/μl). Antinuclear antibody, proteinase-3 and myeloperoxidase antineutrophil cytoplasmic antibodies were all negative. The histology of the purpura showed the occlusion of dilated small blood vessels in the upper dermis without cholesterol embolization (Figure 1B,C). A bone marrow biopsy showed hypercellular bone marrow with increased aberrant megakaryocytes, and a mutational analysis revealed a homozygous JAK2 V617F mutation but no BCR-ABL mutation. Based on these findings, ET-related ulcer was diagnosed. Hydroxycarbamide at 500 mg/day and aspirin at 100 mg/day were initiated, and prednisolone at 30 mg/day (0.5 mg/kg/day) was used concomitantly for its anti-inflammatory and analgesic effects. After the hydroxycarbamide dose was increased to 1000 mg, the platelet count tended to decrease but remained high and the skin lesion pain worsened. After 4 weeks of hydroxycarbamide administration, that drug was switched to anagrelide. Thereafter, the pain was relieved, the ulcer epithelialized completely in 2 months, and the platelet count decreased to 39.2 10/μl in 12 months (Figure 1D, E). The prednisolone dose was tapered gradually and then terminated at 12 months. There were no clinical recurrences or adverse effects at 12 months follow-up. This case raises two important clinical issues. First, ET causes microvascular obstruction, and ET can present initially as toe ulcers. Itin and Winkelmann reported that 10% of 268 patients with ET had cutaneous symptoms at the time of the diagnosis. Early diagnosis and treatment are essential to prevent peripheral gangrene and amputation or other thromboembolic complications. Second, anagrelide is an alternative to hydroxycarbamide for ET-related ulcers. Although anagrelide is widely used as an alternative to hydroxycarbamide, there are no reports on the treatment of ET-related ulcers. Previous reports have shown hydroxycarbamide with aspirin to be helpful for ET-related ulcers. However, hydroxycarbamide-induced leg ulcers are reported in approximately 5.0%–15.7% of patients with ET. The pathogenetic mechanism behind hydroxycarbamide-induced ulcers involves numerous factors: minor trauma, tissue hypoxia and cellular damage, which are consequences of hydroxycarbamide-induced megaloblastosis. It should be noted that hydroxycarbamide can decrease keratinocyte viability because of its direct cytotoxic effect on keratinocytes or on collagen bundles that comes from inhibiting DNA synthesis. In contrast, the detailed effects of anagrelide on wounds are unknown, but we considered the possibility that the lower platelet count reduced the severity of peripheral circulatory failure from microthrombosis and that anagrelide was less disruptive to keratinocytes than hydroxycarbamide was. In conclusion, this is the first report on ET-related ulcers to describe the usefulness of anagrelide. Anagrelide may be an alternative treatment to hydroxycarbamide. Further studies should investigate the efficacy of anagrelide for patients with ET-related ulcers.