Sickle Cell Leg Ulcers Are Associated with Hyperuricemia, Hemolysis, Pulmonary Hypertension and Death.

Leg ulceration is a common, debilitating complication of sickle cell disease (SCD), affecting 8 to 50% of patients, and recently found to be associated with the hemolytic phenotype. We evaluated the relationship of leg ulceration history with estimated pulmonary artery systolic pressure, hemolytic rate and other clinical characteristics in a cohort of 396 adults with SCD.

All SCD patients were enrolled in a NHLBI-approved protocol and were screened for pulmonary hypertension with echocardiography at steady state. We collected a detailed past medical history, as well as a comprehensive set of laboratory tests. Comparisons between patients with and without a history of leg ulcers were made using Wilcoxon rank sum tests to compare medians of continuous variables. Associations between categorical variables and leg ulcer history in two groups were tested using the chi-square test of independence.

Eighteen % of all subjects had a history of leg ulceration. Patients affected were older, predominantly had homozygous SCD, and had markers of significantly more severe hemolysis, including low hemoglobin and high reticulocyte counts, LDH and AST. They also had a significantly higher prevalence of elevated tricuspid regurgitation velocities (TRV≥2.5 m/sec, 56% vs. 40%, p=0.02; TRV≥3 m/sec, 22% vs. 12%, p=0.006). High serum uric acid and lower serum albumin were significantly associated with a history of leg ulcers. A self-reported history of hepatitis also was associated with leg ulceration. None of the other parameters evaluated were significantly associated with leg ulceration, including history of pain, acute chest syndrome, stroke or priapism. Significantly, patients with a history of leg ulcers were more likely to have died by the time of data analysis (21% vs. 9%, P=0.02).

These data in SCD patients with a history of leg ulcers provide the first demonstration of an association with elevated serum uric acid and confirmation of published associations with elevated pulmonary pressures and markers of hemolytic severity. The uric acid association is more significant than that for serum creatinine or urea nitrogen, suggesting that uric acid is more than simply a marker of renal dysfunction. In patients without SCD, there is a growing literature implicating uric acid as a possible cause of hypertension and a marker of risk for cardiovascular disease, pulmonary hypertension, and early mortality. This is particularly interesting, in view of the epidemiological relationship between leg ulcers and pulmonary hypertension demonstrated here and previously by others. The results continue to support linkage of leg ulcers and pulmonary hypertension to a hyperhemolytic -vasculopathy subphenotype of SCD.

No relevant conflicts of interest to declare.