Elevated Pulse Pressure Is Associated with Hemolysis, Proteinuria and Chronic Kidney Disease in Sickle Cell Disease

A seeming paradox of sickle cell disease is that patients do not suffer from a high prevalence of systemic hypertension in spite of endothelial dysfunction, chronic inflammation and vasculopathy. However, some patients do develop systolic hypertension and increased pulse pressure, an increasingly recognized major cardiovascular risk factor in other populations. Hence, we hypothesized that pulse pressure, unlike other blood pressure parameters, is independently associated with markers of hemolytic anemia and cardiovascular risk in sickle cell disease. We analyzed the correlates of pulse pressure in patients (n = 661, 53% female, 76% HbSS) enrolled in the walk-PHaSST multicenter, international sickle cell trial with data on clinical laboratory tests and echocardiographic measures. In univariate analyses, pulse pressure was consistently and positively correlated with all markers of hemolysis, including reticulocyte proportion, LDH, total bilirubin, AST and hemolytic component (a variable derived using principal component analysis from four markers of hemolysis - LDH, AST, total bilirubin, and reticulocyte percent) in HbSS patients. Pulse pressure was also positively correlated with creatinine, urine albumin-to-creatinine ratio and presence of proteinuria. Among SS patients, four risk factors were associated with pulse pressure independently of each other: reticulocyte count (beta = 2.37, p = 0.02), hemolytic index (beta = 1.53, p=0.002), serum creatinine (beta = 3.21, p = 0.02), and proteinuria (beta = 2.52, p = 0.04). By contrast, markers of hemolysis were not independently associated with systolic, diastolic and mean arterial pressure. These results from the largest sickle cell disease cohort to date since the Cooperative Study of Sickle Cell Disease show that pulse pressure is strongly and independently associated with hemolysis, proteinuria and chronic kidney disease. We propose that high pulse pressure may be associated with clinical complications of vascular dysfunction in sickle cell disease.