Pulmonary hypertension in patients with sickle cell disease: a longitudinal study

Abstract

SummaryAlthough pulmonary hypertension (PHT) is a common complication in patients with sickle cell disease (SCD), the rate of development of PHT and the factors that affect disease progression are unknown. We observed 93 patients over a median follow-up period of 2AE6 years (range 0AE2-5AE1 years). Data were censored at the time of death or loss to follow-up. Pulmonary hypertension was associated with an increased risk of death (relative risk, 9AE24; 95% confidence interval: 1AE2-73AE3; P ¼ 0AE01). There was no difference in the risk of death when patients with different degrees of PHT were compared. Lactate dehydrogenase and blood urea nitrogen were significantly associated with PHT in a logistic regression model. Higher levels of fetal haemoglobin and treatment with hydroxycarbamide were observed more frequently in patients without PHT. Thirteen per cent of patients with no previous evidence of PHT developed PHT following 3 years of observation. In conclusion: (1) PHT, regardless of severity, is associated with an increased risk of death in SCD patients; (2) haemolysis is strongly associated with PHT in SCD; (3) high levels of fetal haemoglobin and hydroxycarbamide therapy may decrease the occurrence of PHT; (4) screening for PHT is indicated for SCD patients in their non-crisis, steady states.

Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease

“…In particular, some of the variability in Hb F expression is attributable to functional alleles in the fetal hemoglobin genes inherited on specific b S -globin haplotypes [48,[51][52][53]. Fetal hemoglobin expression may be relevant to pulmonary hypertension, as this and other studies have observed significantly lower levels of Hb F in SCD pulmonary hypertension cases (Table IV) [9,10]. However, the haplotype analysis would predict that the strongest loci underlying this effect would be present outside the b-globin locus.…”

“…Perhaps intravascular hemolysis represents a lower fraction of total hemolysis in Hb SC than is the case in homozygous SCD. However, anemia, renal insufficiency, elevated alkaline phosphatase, and excess iron remain consistent distinguishing characteristics across all SCD pulmonary hypertension patients (Table V) [5,10]. Prior studies have documented phenotypic associations between pulmonary hypertension, hemolysis, and priapism in patients who may have less frequent vasoocclusive manifestations [2,5,36].…”

“…Recent screening studies using Doppler echocardiography and N-terminal pro-BNP (NTproBNP) suggest that pulmonary hypertension occurs in approximately one third of adults with SCD. Furthermore, elevated pulmonary pressures are associated with an approximate ten-fold increased risk of early death, making this complication a leading predictor of mortality [5,[7][8][9][10]. Intravascular hemolysis, which inhibits nitric oxide (NO) bioavailability via the release of red cell hemoglobin and arginase into plasma, has been proposed as one of several etiologic mechanisms [5,11,12].…”

Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity

“…[1][2][3][4][5][6] Similarly, an increase in pulmonary artery systolic pressure, also as assessed by Doppler echocardiography, is associated with an increased risk of death in individuals older than 45 years without SCD. 7 In SCD, the risk of developing an elevated TRV increases with age, hemolysis (defined by indirect markers of hemolysis), renal insufficiency (defined as an elevated creatinine level), iron overload (defined as an elevated ferritin level), and systemic hypertension (defined as an elevated systolic systemic blood pressure).…”

“…7 In SCD, the risk of developing an elevated TRV increases with age, hemolysis (defined by indirect markers of hemolysis), renal insufficiency (defined as an elevated creatinine level), iron overload (defined as an elevated ferritin level), and systemic hypertension (defined as an elevated systolic systemic blood pressure). 2,5,6 Chronic intravascular hemolysis has been shown to cause endothelial dysfunction (defined as a resistance to nitric oxide-mediated vasodilation or impaired responses to L-NMMA or acetylcholine 8,9 ) secondary to the nitric oxidescavenging effects of plasma hemoglobin and catabolism of L-arginine by erythrocyte arginase 1. 10 These mechanisms suggest that therapeutic interventions enhancing the effects of nitric oxide could be beneficial.…”