Controversies in the pathophysiology of leg ulcers in sickle cell disease

Summary Patients with sickle cell disease (SCD) often experience painful vaso‐occlusive crises and chronic haemolytic anaemia, as well as various acute and chronic complications, such as leg ulcers. Leg ulcers are characterized by their unpredictability, debilitating pain and prolonged healing process. The pathophysiology of SCD leg ulcers is not well defined. Known risk factors include male gender, poor social conditions, malnutrition and a lack of compression therapy when oedema occurs. Leg ulcers typically start with spontaneous pain, followed by induration, hyperpigmentation, blister formation and destruction of the epidermis. SCD is characterized by chronic haemolysis, increased oxidative stress and decreased nitric oxide bioavailability, which promote ischaemia and inflammation and consequently impair vascular function in the skin. This cutaneous vasculopathy, coupled with venostasis around the ankle, creates an ideal environment for local vaso‐occlusive crises, which can result in the development of leg ulcers that resemble arterial ulcers. Following the development of the ulcer, healing is hindered as a result of factors commonly observed in venous ulceration, including venous insufficiency, oedema and impaired angiogenesis. All of these factors are modulated by genetic factors. However, our current understanding of these genetic factors remains limited and does not yet enable us to accurately predict ulceration susceptibility.