Elevated Tricuspid Regurgitation Jet Velocity in Patients with Sickling and Non-Sickling Hemolytic Anemias: Prevalence and Correlates

Abstract

Background: Patients with sickle cell disease (SCD) have an increased risk of developing elevated tricuspid regurgitation jet velocity (TRV), which is associated with some markers of hemolysis and increased morbidity and mortality among affected adults. Elevated TRV also occurs in children with SCD, but with unclear clinical consequences. To date, most studies have not investigated elevated TRV by genotypes or the effects of disease-modifying therapies (e.g., hydroxyurea or chronic transfusions). Furthermore, there is paucity of data in non-sickling hemolytic anemias (HAs), which represents another group with anemia, chronic hemolysis and potential risk for elevated TRV. To better understand the prevalence of TRV elevation and its correlates, we prospectively studied a large cohort of individuals with sickling and non-sickling HAs.Methods: We enrolled children 5 to 18 years with SCD and other forms of HA in the Long Term Effects of Erythrocyte Lysis trial (ELYSIS, NCT 00842621). Adult parents or grandparents of children with non-sickling HA with the same diagnosis were also eligible. Prospective measurement of TRV by 2-D echocardiogram with left ventricular function (M-mode) and color flow Doppler was performed. Biomarkers and markers of hemolysis were obtained concurrently. All assessments were obtained ≥ 4 weeks from illness, transfusion, or hospitalization. All echocardiograms were reviewed by a single cardiologist. Our goals were three-fold: 1) to validate the association between TRV and lactate dehydrogenase (LDH) in sickling and non-sickling HAs, 2) to investigate the effect of disease-modifying therapies on TRV elevation in sickling HAs, and 3) to investigate the role of other biomarkers of hemolysis and vasculopathy on TRV elevation in sickling and non-sickling HAs.Results: 355 children and adults with sickling or non-sickling HAs were enrolled (Table). The proportion of TRV ≥2.5 m/sec as well as median LDH, N-terminal pro-brain natriuretic peptide (NTproBNP), and argninine/ornithine (arg/orn) ratio are shown for each cohort studied. Children with severe SCD receiving chronic transfusions (CTXFN) had considerably higher TRV values than all other cohorts. LDH was significantly associated with TRV in children with severe untreated SCD regardless of cut-off value (2.5, 2.8, or 3 m/sec), but not in any of the other cohorts. No significant association was noted between TRV and NTproBNP, whether evaluated as a continuous variable or dichotomous variable (using 160 pg/mL as the threshold) or between TRV and arg/orn ratio. LDH and Hb were associated with elevated TRV in children with severe untreated SCD, but only hemoglobin (Hb) remained significant in multivariate analysis including other markers for hemolysis (total bilirubin, aspartate aminotransferase, and absolute reticulocyte count), NTproBNP, and arg/orn ratio. TableCohortNAge (years)TRV ≥ 2.5 m/s (%)LDH (U/L)NTproBNP (pg/mL)Arg/Orn ratioSevere SCD, untreated(HbSS/HbSβ0-thal)1178.1(5-18.5)29.6582 (214-1315)86 (8-804)1.1 (0.4-7.5)Severe SCD, CTXFN2912.9 (5.7-18.3)57.1*491 (211-1150)50 (6-260)1 (0.6-1.8)Severe SCD, Hydroxyurea7613.2 (5.1-18)34.2450 (214-1354)65 (9-316)0.9 (0.2-1.8)Non-severe SCD(HbSC, HbSβ+-thal)7210.4 (5.2-17.8)21.7304 (157-811)36 (6-266)1.2 (0.1-1.8)Pediatric non-sickling HAs(hereditary spherocytosis, pyruvate kinase deficiency, unstable Hb variants)4010.5 (5.1-17.5)18259 (154-2622)75 (6-293)1.2 (0.3-2.7)Adult non-sickling HAs(hereditary spherocytosis, unstable Hb variants)2139 (27.9-59.8)27.8185 (136-263)42 (8-183)1.3 (0.9-2.2)Note: * Significantly higher than reference group (severe SCD untreated)Conclusions: Prevalence of elevated TRV in children with untreated SCD in our study is similar to previous literature, but our other cohorts varied by diagnosis and/or treatment received. The highest prevalence was found in children with severe SCD on CTXFN, possibly reflecting severity of disease. Our study validates the association between TRV and LDH in severe untreated SCD; however this association was not present in non-severe sickle genotypes or non-sickling HAs. The lack of association between TRV and NTproBNP suggests that this is not a useful marker to predict elevated TRV in these patients. The degree of anemia was an important determinant of TRV elevation, but contrary to prior literature, LDH was not. DisclosuresNo relevant conflicts of interest to declare.