Elevated Tricuspid Regurgitant Jet Velocity In Lebanese Patients With Sickle Cell Disease Is Associated With Severe Disease and Is Clustered In Families
Authors: Abdennour Rouba , Arabi Mariam , Nietert Paul , Keyrouz Sarah , Khoury Ruby , Saab Raya , Muwakkit Samar A. , El Abiad Jad , El Majzoub Nadim , Dabbous Ibrahim A. , Bitar Fadi , Abboud Miguel R. 
Published: October 2019

Introduction
Pulmonary hypertension (PHT) is a known complication of sickle cell disease (SCD), and it is indirectly assessed by measurement of the tricuspid regurgitant jet velocity (TRV). Despite the fact that PHT was found to be associated with early mortality in adults SCD patients, the association between elevated TRV and SCD severity and mortality is still controversial particularly in children and adolescents. The objective of this study was to investigate the relationship between elevated TRV and parameters of disease severity in children, adolescents and young adults with SCD.

Methods
The study is a retrospective review of medical records of patients with SCD followed at the comprehensive sickle cell clinic at the American University of Beirut Medical Center between April 2002 and January 2012. These include 115 patients with homozygous hemoglobin S disease, 8 with sickle β0-thalassemia, and 24 with sickle β+-thalassemia who have had at least one echocardiogram done as part of their routine medical care. All echocardiograms were done at steady state, at least four weeks after the last vasoocclusive crisis (VOC) or acute chest syndrome (ACS). Elevated TRV was defined as peak TRV of 2.5 meters per second or higher. Disease severity was assessed by comparing hemolysis biomarkers, rate of transfusions, VOCs and ACS and other SCD complications. In patients with sequential echocardiograms, changes in hydroxyurea (HU) doses were examined against TRV variation.

Results
147 patients were studied over a mean number of 3.77 ± 1.96 years. The mean age was 15.07 ± 8.62 years, ranging from 18 to 43.4 years, with 66% being below 18 years of age. Elevated TRV was found in 57 patients (38.8%). T-tests and chi-square tests did not show any statistically significant differences between the patients with normal and elevated TRV with respect to age, gender, SCD subtype, time of follow-up, presence of stroke, AVN, ulcers and splenectomy. In addition, hemoglobin (mean=9.43±1.46 in normal TRV group versus 9.20±1.19 in high TRV, p=0.309) mean corpuscular volume (MCV, mean=93.04±16.96 vs. 96.56±15.03, p=0.203), reticulocyte count (mean= 9.51 ± 4.81 vs 9.97±5.55, p=0.596), bilirubin (indirect bilirubin mean=1.40±1.28 vs. 1.44±1.04, p=0.883) and lactate dehydrogenase (LDH, mean=423.20±192.00 vs. 451.40±399.40, p=0.398) did not show any significant differences between the two groups.
Among patients with elevated TRV, 71.9% were on HU at a mean dose of 16.27 mg/kg/day compared to 70% of patients with low TRV who were on a mean HU dose of 15.13 mg/kg/day.
HU was started in both groups for indications including pain crises, ACS and low hemoglobin but not TRV alone. Initially markers of hemolysis including MCV, reticulocyte count, bilirubin and LDH were significantly higher and hemoglobin lower in patients with elevated TRV, but these differences between the two groups were no longer evident after the dose of HU was optimized. In the 99 patients with 2 or more echocardiograms, no trend in TRV variation was observed after HU dose adjustment and sequential TRV readings.
The mean transfusion rate per patient did not differ between the two groups. However, RBC alloimmunization was found in 6.2% of patients with normal TRV compared to 15% of patients with elevated TRV.
Results of the Poisson models demonstrated that the VOC rate was 1.4 times higher among subjects with TRV ≥ 2.5 compared to subjects with TRV < 2.5 (rate ratio = 1.4; 95% CI = 1.04 to 2.02; p=0.029). Additionally, ACS rate was almost 3 times higher among subjects with high TRV (rate ratio = 2.8; 95% CI = 1.3 to 6.2; p=0.01). No deaths were reported in either study groups.
Fisher's exact test and the generalized linear mixed model (GLMM) both indicated the presence of familial clustering of elevated TRV (Fisher's p-value: 0.009; GLMM p-value: 0.026).

Conclusion
The overall prevalence of elevated TRV in our study population was 38.8%. Despite improvement in hemolyis after introducing and optimizing hydroxyurea doses, patients with elevated TRV still had more severe disease as defined by higher rates of VOC, ACS and alloimmunization. Familial clustering of elevated TRV was observed in our highly consanguineous population. These findings suggest that elevated TRV is a marker that defines patients with more severe SCD even among children and young adults.

Disclosures:
No relevant conflicts of interest to declare.