NT-Pro Brain Natriuretic Peptide Levels and the Risk of Stroke and Death in the Cooperative Study of Sickle Cell Disease.

Elevations in NT-proBNP levels are associated with hemolysis-associated pulmonary hypertension and mortality in adults with sickle cell disease. The association of this vasculopathy with the risk of stroke has not been explored. The Cooperative Study of Sickle Cell Disease (CSSCD) is the largest cohort of adult and pediatric patients with sickle cell disease with the longest median follow-up. Using stored plasma samples from patients enrolled in the CSSCD, we tested the hypothesis that adult patients with high levels of NT-proBNP would be at a high risk of death and stroke and that pediatric patients with a high BNP might be at a high risk of stroke.

A threshold NT-pro-BNP value previously identified to predict mortality in adults with sickle cell disease was used to determine the association between the risk of stroke and mortality in a cohort of 758 participants (pediatric cohort, n=428 and adult cohort, n=330) in the CSSCD.

The prevalence of an abnormal NT-proBNP level ≥ 160 pg/ml was 27.6 % in patients in the adult CSSCD cohort. The prevalence of a NT-proBNP level ≥ 160 pg/ml was 27.4 % in the pediatric cohort, which is at least in part explained by known higher normal NT-proBNP levels in children, especially during the first year of life. The incidence of the development of a high NT-proBNP level in subjects with a normal baseline level was 6 % over a mean follow-up time of 5.9 years (incidence rate per 100-person years of 1.03) in the pediatric cohort and 16.5 % over a mean follow-up time of 1.9 years in the adult cohort (incidence rate per 100-person years of 8.59). In subjects with normal baseline levels, multivariate logistic regression analysis of clinical and laboratory factors associated with the development of a high NT-proBNP level included increasing age (OR 3.43, 95% CI 1.6-7.2, P = 0.001), low hemoglobin (OR 0.47, 95% CI 0.3-0.7, P < 0.001), high white blood cell count (OR 1.69, 95% CI 1.05-2.7, P = 0.03), high creatinine (OR 2.22, 95% CI 1.1-4.3, P = 0.02), blood urea nitrogen (OR 1.64, 95% CI 1.2-2.3, P = 0.004), alanine aminotransferase (OR 1.26, 95% CI 1.01-1.6, P = 0.04) and uric acid levels (OR 2.32, 95% CI 1.4-3.8, P = 0.001), and history of leg ulcers (OR 7.46, 95% CI 2.0-28.5, P = 0.003). Elevated NT pro-BNP levels were associated with indices of hemolytic anemia (hemoglobin: OR 0.33, 95% CI 0.2-0.4, P < 0.001) and a history of stroke (OR 1.86, 95% CI 0.9-3.7, P = 0.02). An NT-pro-BNP level ≥160 pg/ml was a predictor of mortality (RR 6.24, 95% CI 2.9-13.3, P < 0.001) and stroke (RR 3.84, 95 % CI 1.0-14.3, P = 0.05) in this cohort.

A high NT-proBNP level is a major risk factor for death in patients with sickle cell disease. These findings provide further support for a mechanistic link between hemolytic anemia and the development of cardiovascular complications in this patient population. Finally, we have identified a novel widely available biomarker of the risk of death and stroke in sickle cell disease.

No relevant conflicts of interest to declare.