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Treating A Rare Foot Ulcer Caused By Hydroxyurea
This author details the treatment of an infected ulceration and osteomyelitis in a man who had been on a longstanding hydroxyurea regimen to control his polycythemia vera.
An 84-year-old Caucasian male with polycythemia vera presented to the ER with an infected first metatarsophalangeal joint (MPJ) ulceration that had been present on the right foot for eight months. A dermatologist previously used topical wound care to treat the ulceration but there was no resolution or improvement. The ulceration eventually began probing to bone and became red, swollen and infected. The dermatologist advised the patient to go the ER for further workup and more aggressive treatment.
History revealed a longstanding polycythemia vera with no history of trauma or previous infections. The patient had been taking hydroxyurea 1,000 mg daily for 11 years for control of his polycythemia vera.
The physical examination revealed an ulcer at the medial right first MPJ that measured 2.9 cm x 2 cm x 0.2 cm. The ulcer also probed to bone centrally. The ulcer base was mixed granulation and fibrotic tissue with diffuse peri-ulcerative erythema and induration. There was no frank purulence and no odor. There was no crepitation or fluctuance of the surrounding tissue.
The vascular examination revealed palpable pedal pulses with normal capillary refill time. There was mild, non-pitting edema on both legs with no varicosities or hemosiderin deposits. An arterial Doppler showed biphasic flow in both lower extremities below the knees. The neurological examination revealed normal sensation to both feet with intact deep tendon reflexes. The musculoskeletal examination showed normal muscle strength and range of motion of the feet and legs. Toes two through five were contracted bilaterally.
Foot X-rays and magnetic resonance imaging (MRI) showed changes consistent with septic arthritis and osteomyelitis at the first MPJ.
The following are the lab results:
- White blood cell count: 52.6 (3.7-10.7)
- Hemoglobin: 10.1 (13.0-17.0)
- Hematocrit: 30.3 (39-51)
- Platelets: 797,000 (125-375)
- Sedimentation Rate: 10 (0-13)
A bone biopsy confirmed osteomyelitis of the first metatarsal and proximal phalanx. Surgical cultures were positive for Enterococcus faecalis. The ulcer biopsy showed no malignancy with necrosis and granulation tissue with extensive chronic and acute inflammation.
Due to the medical history and lack of arterial or neurological disease, I diagnosed him with hydroxyurea-induced cutaneous foot ulceration with secondary osteomyelitis and a septic joint.
The patient agreed to surgical resection of necrotic bone and tissue. I resected the base of the proximal phalanx and distal two-thirds of the first metatarsal, and completely excised the ulceration. I left the surgical site partially open for drainage. Postoperative treatment included negative pressure wound therapy, collagen-alginate wound dressings, offloading and antibiotics.
The patient’s hydroxyurea use could not stop as per his hematologist due to the severity of his polycythemia vera. The hematologist did, however, start the patient on anagrelide (Agrylin, Shire) to help with the patient’s thrombocythemia (overproduction of blood platelets). The ulceration and surgical site healed in three months without reulceration at the original site after a 10-month follow-up.
A Closer Look At The Research On Polycythemia Vera
Physicians often misdiagnose and mistreat ulcerations of the lower extremities caused by polycythemia vera with the use of the medication hydroxyurea. Without proper treatment, the ulcerations are unlikely to heal and can potentially lead to infections and amputations.
Polycythemia vera is one of the chronic myeloproliferative neoplasms. These disorders are characterized by clonal proliferation of myeloid cells. Polycythemia vera typically presents with the presence of an elevated red blood cell mass and hematocrit, a decreased erythropoietin level, and the presence of the janus kinase 2 (JAK2) mutation. It is the elevated red blood cell mass that distinguishes it from the other myeloproliferative disorders (chronic myelogenous leukemia, primary myelofibrosis, essential thrombocythemia and mast cell disease).1
Survival for patients with polycythemia vera is compromised due to the increased viscosity of the blood.2,3 The overall mortality is 1.6 to 1.7 times that of the normal matched population. If the disease goes untreated, median survival is only six to 18 months from the time of diagnosis. When treated, median survival is 10 years or possibly more. The causes of death associated with polycythemia vera include thrombosis (29 percent), hematologic malignancies (23 percent), non-hematologic malignancies (16 percent), hemorrhage (7 percent) and myelofibrosis/myeloid metaplasia (3 percent).4 Other problems associated with polycythemia vera include severe itching, hyperuricemia with acute gout, bleeding and erythromelalgia.5-7
Treatment for polycythemia vera consists of serial phlebotomy, aspirin and myelosuppressive agents. The myelosuppressive agents in most common use are alkylating agents, radioactive P32, interferon alpha and hydroxyurea.8
What You Should Know About Hydroxyurea
Hydroxyurea can treat many diseases including polycythemia vera, chronic myeloid leukemia, solid tumors, sickle cell anemia, cervical cancer, essential thrombocythemia, head and neck cancer, hypereosinophilic syndrome, meningioma and psoriasis. Dermatological side effects of hydroxyurea use are xerosis, hyperpigmentation, brown-nail discoloration, stomatitis, erythema, scaling of the skin and cutaneous ulcerations.9,10
Ulcers from hydroxyurea use are characterized as painful, fibrotic and persistent with trophic, periulcerative skin. Necrosis is present in 25 percent of cases.11-13 The most common sites for ulceration are at the malleoli or tibial crest. However, ulcers can also appear on the feet. Taking a biopsy of an ulcer caused by hydroxyurea will not help you diagnose it. The histopathological findings show no specific changes.14
When it comes to the medication hydroxyurea, it can cause direct cytologic damage by selectively killing off cells in the synthesis phase of the cell cycle. This process damages the basal keratinocytes and interrupts collagen synthesis.11,14,15 In addition, the medication causes red blood cell deformation. This causes the cell volume to increase by 39 percent with a 12 percent increase in cell diameter. These larger cells can impair blood flow in the microvasculature, which can lead to painful cutaneous anoxia and eventual ulceration, especially if there is minor trauma.16
The best treatment for ulcerations caused by hydroxyurea use is cessation of hydroxyurea. In a study of 41 cases of hydroxyurea-induced leg ulcerations, complete recovery from the ulcers occurred quickly after the withdrawal of treatment in 33 (80 percent) of the cases.17 If the drug therapy resumes after the ulcer has healed, the ulcers tend to reopen.11
In Conclusion
This case represents a rare foot ulcer induced by polycythemia vera and hydroxyurea use, and further complicated by secondary soft tissue infection, a septic joint and osteomyelitis. The traditional treatment protocol of cessation of hydroxyurea could not occur to the extent of the patient’s polycythemia vera. Therefore, more aggressive surgical treatment was warranted and ultimately led to complete healing.
One should suspect hydroxyurea-induced lower extremity ulcerations in patients who have had long-term hydroxyurea therapy, especially if one can find no other causes for ulceration through the patient’s history or physical exam. If cessation of hydroxyurea is not feasible, explore other medication modifications in coordination with the patient’s hematologist to help with healing.
Dr. Swain is a board certified wound specialist physician (CWSP) of the American Board of Wound Management. He is a Diplomate of the American Board of Multiple Specialties in Podiatry, and is board certified in podiatric surgery, primary care in podiatric medicine, and limb preservation and salvage. He is in private practice at the First Coast Cardiovascular Institute and is a co-founder of the First Coast Center for Amputation Prevention in Jacksonville, Fla.
References
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