PULMONARY HYPERTENSION IN SICKLE CELL DISEASE: Relevance to Children

Abstract

Pulmonary arterial hypertension (PAH), once considered a rare complication of sickle cell disease (SCD) and thalassemia, appears to be more common in adults with hemoglobinopathy than previously appreciated. On prospective screening of adults with SCD, approximately one-third of adults are found on echocardiography to have a tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, many of whom are asymptomatic. Dyspnea on exertion is the most common presenting symptom. This TRV abnormality is a marker for approximately 40% 3-year mortality in adults, and it is associated with laboratory values suggestive of more severe intravascular hemolysis. Release of hemoglobin and arginase from lysed red cells causes scavenging of nitric oxide (NO) and catabolism of L-arginine, the obligate substrate for NO synthase. The resulting impairment in NO bioavailability is associated with pulmonary vasoconstriction, endothelial dysfunction, thrombosis, and eventual development of plexogenic arterial lesions, the histological hallmark of all forms of PAH. Undoubtedly, additional pathophysiological mechanisms will also play a role in its multifactorial pathogenesis. Early data from children with SCD indicate a similar prevalence of elevated TRV, but the prognostic implications of this remain to be established. Individual patient diagnosis of PAH requires confirmation by right heart catheterization studies and individualized management. Hemolysis-associated PAH with impairments in NO bioavailability is being identified in thalassemia and other hemolytic disorders, and may be a general consequence of long-standing, severe intravascular hemolytic anemia.Keywords sickle cell; thalassemia; pulmonary hypertension; nitric oxide; arginase Pulmonary hypertension is a complication of sickle cell disease (SCD) and thalassemia gaining considerable attention in the past 4 years. Cor pulmonale, the clinical syndrome of right ventricular failure, has been considered for decades to be a rare, but well-known, terminal complication in adults with both hemoglobinopathies [1,2]. As the survival of patients with hemoglobinopathies has improved dramatically in the last forty years, the prevalence of such chronic complications has increased. Well-documented studies of pulmonary arterial hypertension (PAH) have drawn the attention of the hematology community to its frequent occurrence and poor prognosis [3][4][5][6][7]. This article will review the current understanding of hemoglobinopathy-associated pulmonary hypertension, with special attention to the most recently developing data in children. PREVALENCE AND PROGNOSISIn the last few years, echocardiographic screening studies have suggested that the prevalence of hemoglobinopathy-associated PAH is much higher than previously known. In SCD, approximately one-third of adult patients have an elevated tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, a threshold that correlates in right heart catheterization studies to a pulmonary artery systolic pressure of at least 30 mm Hg [8][9]...

Cardiac involvement in sickle β-thalassemia

“…Similarly, in SCD, other conditions have been linked to PHT, including renal and liver involvement, arterial hypertension, and LV dysfunction, suggesting the presence of an underlying diffuse vascular injury, related to chronic hemolysis, which is probably the main factor affecting patients' survival [44]. In the present study, with the exception of LV function, no correlation between PHT and arterial hypertension or renal function, as assessed by serum creatinine and cystatin-C, was observed, confirming the results of a previous report on S-Thal patients [35].…”

Elevated tricuspid regurgitant jet velocity in children and adolescents with sickle cell disease: association with hemolysis and hemoglobin oxygen desaturation

“…This prevalence is lower than the prevalences in most of the previous studies of pediatric sickle cell disease patients. 6,11 The present study was prospective, included children as young as 3 years of age with mild to severe sickle phenotypes, and avoided effects of exercise or acute vaso-occlusive crisis, known to be confounding factors for the determination of steady state jet velocity in patients. 27 In particular, patients who were hospitalized in the preceding 3 weeks could not be enrolled and this …”

“…A recent review of published studies comprising over 600 children combined indicated that the prevalence of a jet velocity of 2.5 m/sec or more is about 30%. 6 Most studies were not prospective and some of the children were evaluated during a vaso-occlusive crisis or other exacerbation of sickle cell disease. These studies were, therefore, likely biased toward patients with more severe illness.…”

Mechanisms of Vasculopathy in Sickle Cell Disease and Thalassemia

“…As such, LDH represents a convenient biomarker of intravascular hemolysis and NO bioavailability associated with mortality that Kato and colleagues found helpful in identifying the clinical subphenotypes of hemolysis-associated vasculopathy ( Figure 5). 54 PH is the best characterized clinical complication of acute and chronic hemolysis 55 and occurs in about one third of adults 7,22,56 and children [57][58][59][60][61] with SCD. A Doppler echocardiogram measured tricuspid regurgitant jet velocity (TRV) of 2.5 m/sec or greater, suggesting PH is currently the strongest predictor for early death in SCD, with approximately 10-fold increased risk of early mortality 7,62,63 and a 40% mortality risk within 3 years of diagnosis.…”