A Case of Thrombotic Vasculopathy in the Setting of High-Dose Hydroxyurea Use

Skin ulceration and necrosis can be result of multiple conditions and disease processes. Underlying manifestations of skin necrosis can include organ disease, use of medications resulting in skin necrosis, and skin injuries related to unrelieved pressure. Skin manifestations resulting from medication use include warfarin-induced necrosis that can occur 3 days to 5 days after initiation of the medication, hemorrhagic blisters, and ulcers as well as drug-induced vasculitis involving myriad medications from multiple drug classes, presenting as palpable pruritic lesions or a maculopapular rash, with an unknown mechanism and resolving after withdrawal of the medication.¹ Vasculopathies may also present with dermatologic effects and can include livedoid vasculopathy, pigmented purpuric dermatosis, and calciphylaxis.² The challenge lies in determining the cause of wound development and managing the affected skin impairment to aid wound healing and prevent further skin damage. Herein, the patient presented with thrombotic vasculopathy and painful ulcerating wounds, and challenges included determining the etiology of wound development and managing the wounds to promote healing and prevent infection. It was evident in this case that management required input from multiple medical specialties. The goal of this case study is to illustrate the unusual presentation of this patient’s wounds and describe his journey from wound development to wound healing.

A 76-year-old-male with a past medical history of atrial fibrillation, essential hypertension, coronary artery disease status post cardiac stent placement, heart failure (ejection fraction, 40%–45%), hyperlipidemia, thyroid cancer (with thyroid resection resulting in hypothyroidism), prostate cancer status post brachytherapy (in remission), and a history of JAK2-positive myeloproliferative disease that was being managed with high-dose hydroxyurea (500 mg 4 times a day) presented to the emergency department (ED) in November 2019 with chest and back pain. The workup showed the patient to be in atrial fibrillation with a rapid ventricular response, with elevation of his troponin level to 2.45 ng/dL. The hemoglobin level during that time was 7.2 g/dL. The patient was evaluated by the hematology service with plans to hold hydroxyurea therapy and initiate blood transfusion. The patient was transferred to another hospital for treatment with his established cardiologist, where he underwent a cardiac catheterization. Attempted cardioversion was unsuccessful. Between both facilities, the patient received a total of 3 units of blood during the 2 hospital admissions. He was discharged on hydroxyurea 500 mg 4 times a day, with the addition of amiodarone 200 mg daily, apixaban 5 mg twice a day, digoxin 125 µg per day, and metoprolol 25 mg daily.

The patient followed up with cardiology shortly thereafter with reports of pain and bruising involving his groin, pelvis, chest wall, back, and neck (Figure 1). This was the initial presentation of his wounds. He was advised by his cardiologist at that office appointment to stop the apixaban. Three days later, due to increasing pain at the sites of the purple areas of hyperpigmentation, the patient presented to the ED for further evaluation. At that visit, the patient’s blood pressure was 87/64 mm Hg. After he received a 1-L bolus of normal saline, his blood pressure improved to 106/68 mm Hg. The patient was also tachycardic (108 beats per minute) and tachypneic (23 breaths per minute). The white blood cell count was 11.7 × 10⁹/L, hemoglobin level was 7.5 g/dL, and platelet count was 62 × 10⁹/L. The patient was found to have macrocytic anemia, which was thought to be caused by hydroxyurea therapy for myeloproliferative disease. A basic metabolic panel was unremarkable except for an elevated creatinine level of 1.71 mg/dL; the baseline creatinine level was 1.0 mg/dL to 1.2 mg/dL. A hepatic function panel showed a total bilirubin level of 2.5 mg/dL and direct bilirubin level of 0.7 mg/dL. Liver enzymes were normal. Brain natriuretic peptide level was 838 pg/mL, D-dimer level was 541 ng/mL of D-dimer units, and lactate level was 2.1 mmol/L. The international normalized ratio was 1.7, fibrinogen level was 529 mg/dL, and lactate dehydrogenase level was 567 U/L. A chest radiograph was unremarkable. Contrast-enhanced computed tomography (CT) of the abdomen and pelvis showed no acute findings, and chest CT angiography showed bilateral pleural effusions and no pulmonary embolism. Atrial fibrillation was noted on electrocardiogram, with a right bundle-branch block as well as ST segment depression in V2 to V5.

Two units of packed red blood cells were administered in the ED, and the patient was admitted with consults ordered for infectious diseases, oncology, rheumatology, and wound care. Additional laboratory workup included a test for antineutrophil cytoplasmic antibodies, tests for 2-glycoprotein and cardiolipin antibodies, and cryoglobulin levels, all of which were negative. Apixaban, hydroxyurea, and amiodarone were stopped due to concerns for drug reaction. For anticoagulation, a change was made to rivaroxaban. Methylprednisolone 20 mg intravenously every 8 hours and cefepime 2000 mg intravenously every 12 hours were initiated on admission. During the patient’s hospital stay, the steroids were tapered and discontinued prior to discharge and the cefepime was continued for an additional 5 days after discharge by the infectious disease team. A punch biopsy at the site of hyperpigmentation was positive for thrombotic vasculopathy. The patient was discharged to an extended care facility with plans for follow-up with outpatient hematology and oncology care. The wounds were managed with petrolatum-based fine mesh gauze containing 3% bismuth tribromophenate with plans to await evolution and demarcation (Figure 2 and Figure 3).

Six days later, the patient was readmitted to the hospital for chest pain, hypotension, and concern for septic shock. Norepinephrine infusion was begun and continued for 2 days. The affected areas of the abdominal skinfold and right and left groin were evolving with eschar, tan drainage, and malodor (Figure 4 and Figure 5). Moist-to-moist dressing changes with quarter-strength sodium hypochlorite (0.125%) solution were initiated, after which the wound care plan was changed, adding collagenase to areas of dry eschar and covering all wounds with dressings moistened with quarter-strength sodium hypochlorite (0.125%) solution. The sodium hypochlorite solution was continued temporarily as a topical antiseptic to manage bacterial bioburden.³ Collagenase was used to keep the wound bed moist and promote enzymatic debridement until surgical debridement could be completed. With investigational use of both products prior to implementation, it was confirmed that collagenase and sodium hypochlorite could be safely used together.⁴

An infectious disease specialist was consulted, and vancomycin and cefepime were initiated. A vascular medicine specialist was asked to see the patient, and laboratory values including cryofibrinogen, dilute Russell viper venom time (DRVVT), inflammatory markers, and complement levels were assessed. Hydroxyurea was held once more, steroids were restarted, and a heparin drip was started. The DRVVT test was positive. Initially, there was some concern that this result was indicative of antiphospholipid syndrome. Rivaroxaban can cause a false-positive DRVVT result, however, and a DRVVT test conducted a few days later was negative; repeat checks remained negative. It was thereby determined that the patient did not have antiphospholipid syndrome. He was maintained on a heparin drip and was scheduled for surgical wound debridement in late January, with plans to transition to warfarin after wound debridement was completed. Wound care was continued, with application of collagenase to the areas of eschar followed by covering of all the wounds with gauze dressings moistened with quarter-strength sodium hypochlorite (0.125%) solution (Figure 6).

The patient returned to the hospital 4 days after the surgical wound debridement for treatment of bleeding from the groin wounds, which was quickly managed with adjustment of his anticoagulation therapy. Since the wound beds were cleaner post-debridement, wound care was transitioned to the use of foam dressings. Inpatient rehabilitation was begun, and the wound care plan was unchanged. The patient was discharged from inpatient rehabilitation to home with use of foam dressings to the affected areas (Figure 7). Follow-up care was administered in the outpatient wound care clinic, and continued wound healing was noted (Figure 8). Approximately 4 months after initial development of the wounds, successful wound healing was achieved (Figure 9).

The cause of this patient’s wounds was perplexing at the time of initial hospitalization. Wound care included treating the wound beds, managing infection, and promoting wound healing. Quarter-strength sodium hypochlorite (0.125%) solution was used to assist in cleaning the wound beds, and collagenase was used to soften the remaining eschar that was present in the wounds until surgical wound debridement could be completed. The use of these topical products as well as systemic antibiotics and eventual surgical debridement of the wounds resulted in cleaner wound beds and eventual wound healing. Infectious diseases specialists assisted in managing antibiotic therapy, and specialists in cardiology and vascular medicine worked to manage the patient’s anticoagulation therapy in an effort to prevent future embolic and microembolic events. Many different diagnoses were postulated while managing the patient’s overall condition.

Mixed cryoglobulinemia syndrome is a systemic vasculitis characterized by multiple organ involvement due to the vascular deposition of immune complexes. The syndrome is characterized clinically by a triad of painful purpuric lesions generally occurring in the lower and/or upper limbs, including distal necrosis of the hands and feet, weakness, and arthralgias, as well as by a series of pathologic conditions, including skin ulcers and diffuse vasculitis.⁵ This syndrome was considered in the differential diagnosis of the patient reported herein owing to his biopsy results. Also considered in that patient’s differential diagnosis was symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), a symmetrical rash that presents on the gluteal and intertriginous areas observed after exposure to systemic drugs including beta-lactam and non–beta-lactam antibiotics as well as other anti-infective agents.⁶ Additional medications that may contribute to SDRIFE include hydroxyurea, antihypertensive agents, and heparin,⁶ which, given this patient’s hospital course and history prompted inclusion of SDRIFE in the differential diagnosis. In addition, warfarin-induced necrosis was considered due to the patient’s history of warfarin use. Warfarin creates a procoagulant state that leads to fibrin clots in the microvasculature, causing interruption in the blood supply to the skin and leading to necrosis presenting as pain and erythema; petechial hemorrhages; red, purple, blue, or black discoloration; necrosis; and hemorrhagic blisters and/or bullae.⁷ The wound development in the present case was not consistent with warfarin skin necrosis, however.

Antiphospholipid syndrome was also considered in the differential diagnosis. This syndrome is an autoimmune disease characterized by recurrent vascular thrombosis, causing venous or arterial thrombotic events; treatment includes use of anticoagulation therapy to help prevent future events. There are multiple manifestations of antiphospholipid syndrome affecting multiple organs and systems (including the skin), including livedo reticularis, ulcers, pseudovasculitic lesions, digital gangrene, and cutaneous necrosis.⁸ Although the initial lupus anticoagulant test was positive in the patient in this case study, this was thought to be a false-positive result from rivaroxaban use, and follow-up testing yielded negative results, thereby ruling out antiphospholipid syndrome as a cause for the wounds.

Cutaneous thrombolytic vasculopathy, another condition included in the differential diagnosis for this case, was reported by Cheely at al⁹ in a patient with poorly controlled ulcerative colitis with purpuric painful eruptions of the chest, arms, buttocks, back, shoulders, and thighs. In that instance, the condition was associated with hypercoagulable states and thromboembolism that occur in patients with inflammatory bowel disease. Cheeley et al⁹ explained the medical treatment, which included anticoagulation therapy, but they did not discuss wound care. The individual in the case study reported herein did not have ulcerative colitis.

Myeloproliferative disorders include polycythemia vera, essential thrombocytopenia, chronic myeloid leukemia, primary myelofibrosis, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. Findings associated with these disorders can include erythrocytosis, leukocytosis, thrombocytosis, bone marrow hypercellularity and/or fibrosis, and splenomegaly, with a genetic mutation in the JAK2, CALR, and MPL genes.¹⁰ Myelofibrosis is characterized by abnormalities in the bone marrow and blood cells and is associated with JAK mutations. Essential thrombocytopenia is characterized by thrombocytosis with bone marrow megakaryocytic hyperplasia and can promote both thrombotic and hemorrhagic complications.¹¹ Polycythemia vera is characterized by erythrocytosis/polycythemia and can put patients at risk for thrombotic complications. The patient in the case reported herein had a JAK2 myeloproliferative disorder (overlap of essential thrombocytosis and polycythemia vera) that was treated with high-dose hydroxyurea. Concern was voiced by the members of the patient’s health care team that this might have been the cause of the wound development. In reviewing the patient’s overall condition, the authors of this article think that the case was in fact consistent with thrombotic vasculopathy in the setting of high-dose hydroxyurea.

Hydroxyurea is reportedly associated with the development of leg ulcers and as discussed in the research of Sirieix et al¹² and Bader et al.¹³ In chronic use, it can cause skin reactions in 10% to 30% of patients.¹⁴ Use of hydroxyurea can contribute to decreased blood flow in the microcirculation and anoxia due to hydroxyurea-induced macrocytosis, resulting in platelet deregulation and microthrombus formation.¹⁵ The development of palmoplantar and submammary ulcerations as well as painful ulcers of the leg has been reported in patients undergoing treatment with hydroxyurea.¹⁴ In addition, multiple lesions of the skin have developed in patients patients on hydroxyurea and include multiple lesions of the skin, including hyperpigmentation, longitudinal melanonychia of multiple nails, diffuse cutaneous xerosis, right forearm ulcer, and ulceration on the right outer ear.¹⁵ Hyperpigmentation can be accentuated in pressure areas. It is hypothesized by the present authors that due to decreased mobility in bed or a chair in a frequent to almost continuous semi-Fowler, Fowler, or semirecumbent position, when the patient reported herein suffered a cardiac event, skin injuries developed injuries that progressed to open ulcerations to areas of the abdomen, groin, and neck folds. This may have been exacerbated by ongoing high-dose hydroxyurea use. The primary mechanism of wound formation with hydroxyurea is not well understood but is thought to be related to inhibition of the S phase of the cell cycle, leading to basal keratinocyte damage and, ultimately, to inhibition of collagen production.¹⁶ In this reported case, pressure injuries to the sacrococcygeal and ischial areas were avoided due to pressure injury prevention interventions such as use of a pressure redistribution mattress. With proper wound care and progression of activity, wound healing occurred and resolution of the wounds was ultimately achieved.

This is a single report of the present authors’ experience. Similar reported cases are needed to strengthen the conclusions herein.

Overall, this case stresses the complex nature of many wounds and the need for a multidisciplinary team to evaluate patients who present with these complex situations. This patient’s wounds were multifactorial but were thought to be related to high-dose hydroxyurea use. Pressure applied in skinfolds may have resulted in worsening of the wounds. As previously noted, this patient had multiple medical problems and required treatment by a skilled multidisciplinary team to heal this complicated and unusual presentation of wound development.

Authors: Jill Michalak, DNP, APRN, NP-C, CWOCN¹; Richard Simman, MD, FACS, FACCWS¹^,²; Drew Oostra, MD¹

Affiliations: ¹Jobst Vascular Institute/ProMedica Health System, Toledo, OH; ²University of Toledo, Department of Surgery, Division of Plastic Surgery.

Correspondence: Richard Simman, MD, Director of Wound Care, ProMedica Toledo Hospital, Jobst Vascular Institute, 2109 Hughes Drive Suite 400, Toledo, OH 43606; richard.simmanmd@promedica.org

Disclosure: The authors disclose no financial or other conflicts of interest.