The High Output State of Sickle Cell Patients: Associations with Anemia-Related Organ Damage
Authors: Biemond Bart J. , de Back Tim R. , Van Tuijn Charlotte F.J. , Nur Erfan , Bouma Berto J. 
Published: October 2019

Abstract
Introduction:
As longevity of sickle cell disease (SCD) patients increases, chronic organ damage becomes more prevalent. Tricuspid regurgitation velocity (TRV) ≥2.5 m/sec) has long been considered a reliable indicator of pulmonary hypertension (PH). However, studies using right heart catherization confirmed PH in only 25% of patients with TRV elevation, despite the independent association of an elevated TRV with mortality. Since TRV elevation is also associated with anemia and cardiac remodeling on trans-thoracic echocardiography (TTE), we hypothesized that an elevated TRV may also identify SCD patients with a hyperdynamic circulation due to severe anemia, putting them at higher risk for anemia-related organ damage and early mortality.
We aimed to determine the associations between TRV elevation and other high output parameters on TTE with anemia-related organ damage and to assess what echocardiographic parameters predict anemia-related organ damage and mortality.
Methods:
In this retrospective, longitudinal study, SCD patients were followed from the oldest TTE onwards. At baseline and after follow-up, TTE parameters of cardiac function (including TRV and signs of volume and pressure overload), anemia-related organ damage (microalbuminuria, renal failure, stroke, leg ulcers, priapism, diastolic dysfunction) and mortality were assessed. Logistic and cox regression analyses were applied to analyze associations between baseline echocardiographic findings and laboratory results with development of anemia-related organ damage during follow-up to identify predictors of organ damage.
Results:
In total 254 patients were included in the study cohort. The mean follow-up was 6.0 years (4.0-8.0 yr). Elevated TRV was found at baseline in 58/254 (22.8%) patients versus 196/254 (77.2%) patients with a normal TRV. Patients with an elevated TRV had an increased cardiac output (59 dL/min vs. 52 dL/min; P <0.01), E-wave velocity (104 cm/sec vs. 94 cm/sec; P=.03), septal E/e'-ratio (9.2 vs. 7.9; P=.02), left ventricular (LV) mass index (111 g/m2 vs. 94 g/m2; P <0.01) and left atrial (LA) volume index (50 g/m2 vs. 39 g/m2; P <0.01) compared to patients with a normal TRV, which remained unchanged during follow-up. At baseline and upon follow up microalbuminuria (28% vs. 15%; P 0.03) and renal failure (7% vs. 0%; P <0.01) were more prevalent in patients with TRV elevation as compared to patients without TRV elevation. The composite incidence of new forms of anemia-related organ damage after follow-up was higher in patients with an elevated TRV (45% vs. 27%; P 0.02). An elevated LV mass index (representing pressure overload) and septal E/e'-ratio (representing volume overload) were associated with TRV and a higher prevalence of anemia-related organ damage at baseline, but not with new organ damage upon follow-up or mortality. Predictors of organ damage after follow-up were hemoglobin level (OR 0.7 [0.5 - 0.9]; P <0.01) and age (OR 3.1 [1.7 - 5.5]; P <0.01) and new organ damage was predicted by lactate dehydrogenase (LDH) (OR 1.5 [1.1-2.0]; P=.02) and age (OR 2.0 [1.3 - 3.0]; P <0.01).
Conclusion:
A high output state in SCD patients is associated with an elevated TRV and anemia-related organ damage, in particular nephropathy, mainly as a consequence of severe anemia and increasing age. These associations may better explain early mortality in these patients despite the fact that only a limited part of these patients do have pulmonary hypertension. Patients with an elevated TRV or other signs of a high output state are at risk of anemia-related organ damage (in particular nephropathy) and should be monitored closely. Early administration of available treatment modalities should be considered.

Disclosures
No relevant conflicts of interest to declare.