Abstract

Background: Sickle cell disease shares common complications such as vasculopathy and organ dysfunction involving the heart, the lungs, the liver and the kidneys with other hemolytic conditions. We hypothesized that a hemolytic vasculopathy may underlie some of these complications. Distinguishing whether a complication is due to hemolysis or to the degree of anemia has been a challenge.

Methods: A prospective, multicenter study of 310 children and adolescents with sickle cell disease in steady state was conducted. The associations of measures of hemolysis and of hemoglobin concentration with disease complications were assessed. Principle component analysis was used to develop a hemolytic index from the measurements of reticulocyte count, lactate dehydrogenase, aspartate aminotransfersae and total bilirubin. In order to determine the independent associations of hemolysis with the clinical manifestations of sickle cell disease, we computed correlation coefficient of the hemolytic index with these manifestations that controlled for hemoglobin concentration. P values were adjusted for multiple comparisons.

Results: Hemolysis and hemoglobin had no significant correlation with number of the severe pain episodes, acute chest syndrome and priapism. The hemolytic index correlated with history of stroke (r= 0.19, p=0.026), white blood cell count (r=0.22, p<0.001), tricuspid regurgitation velocity (r=0.25, p<0.001), left ventricular mass index (r=0.33, 0<0.001), left ventricular internal diastolic z score (r=0.30, p<0.001) and hemoglobin oxygen desaturation (r=−0.30, p<0.001) but not independently with platelet count and creatinine and six-minute-walk

Correlation of clinical outcomes with hemolytic index and hemoglobin concentration in sickle cell cases

 N Hemolytic index (r and P value) Hemoglobin (r and P value) Hemolytic index adjusted for hemoglobin (partial r and P value) 
1 Square roots 
2Natural Log 
3Adjusted for patient’s height 
p values are adjusted for 13 comparisons. 
Number of severe pain episodes in the last year 283 −0.05 (0.4) 0.06 (0.3) −0.02 (0.7) 
History of acute chest or pneumonia 278 0.11 (0.09) −0.63 (<0.0001) 0.06 (0.3) 
History of priapism History of stroke 137 0.13 (0.1) −0.63 (<0.0001) 0.06 (0.5) 
277 0.14 (0.3) 0.003 (1.0) 0.19 (0.026) 
Platelet count 1 283 0.32 (<0.0001) −0.35 (<0.0001) 0.11 (0.07) 
White blood cells 2 283 0.46 (<0.0001) −0.47 (<0.0001) 0.22 (<0.001) 
Creatinine 1 282 −0.34 (<0.0001) 0.45 (<0.0001) −0.07 (0.2) 
Systolic blood pressure 283 0.01 (0.8) 0.16 (0.07) 0.14 (0.2) 
Tricuspid regurgitant jet velocity 264 0.35 (<0.0001) −0.27 (<0.001) 0.25 (<0.001) 
Left ventricular internal diastolic diameter z score 282 0.53 (<0.0001) −0.50(<0.001) 0.30 (<0.001) 
Left ventricular mass index1 215 0.51 (<0.0001) −0.44 (<0.001) 0.33 (<0.001) 
O2 saturation 273 −0.49 (<0.0001) 0.42 (<0.001) −0.30 (<0.001) 
Six-minute-walk (m)3 228 −0.03 (0.6) 0.17 (0.1) 0.07 (0.3) 
 N Hemolytic index (r and P value) Hemoglobin (r and P value) Hemolytic index adjusted for hemoglobin (partial r and P value) 
1 Square roots 
2Natural Log 
3Adjusted for patient’s height 
p values are adjusted for 13 comparisons. 
Number of severe pain episodes in the last year 283 −0.05 (0.4) 0.06 (0.3) −0.02 (0.7) 
History of acute chest or pneumonia 278 0.11 (0.09) −0.63 (<0.0001) 0.06 (0.3) 
History of priapism History of stroke 137 0.13 (0.1) −0.63 (<0.0001) 0.06 (0.5) 
277 0.14 (0.3) 0.003 (1.0) 0.19 (0.026) 
Platelet count 1 283 0.32 (<0.0001) −0.35 (<0.0001) 0.11 (0.07) 
White blood cells 2 283 0.46 (<0.0001) −0.47 (<0.0001) 0.22 (<0.001) 
Creatinine 1 282 −0.34 (<0.0001) 0.45 (<0.0001) −0.07 (0.2) 
Systolic blood pressure 283 0.01 (0.8) 0.16 (0.07) 0.14 (0.2) 
Tricuspid regurgitant jet velocity 264 0.35 (<0.0001) −0.27 (<0.001) 0.25 (<0.001) 
Left ventricular internal diastolic diameter z score 282 0.53 (<0.0001) −0.50(<0.001) 0.30 (<0.001) 
Left ventricular mass index1 215 0.51 (<0.0001) −0.44 (<0.001) 0.33 (<0.001) 
O2 saturation 273 −0.49 (<0.0001) 0.42 (<0.001) −0.30 (<0.001) 
Six-minute-walk (m)3 228 −0.03 (0.6) 0.17 (0.1) 0.07 (0.3) 

Conclusion: These observations support the hypothesis that a hemolytic vasculopathy independent of the degree of anemia contributes to the pathogenesis of stroke and pulmonary hypertension and to the development of increased systemic vascular resistance. They also raise the possibility that leukocytosis may in part serve as a predictor of poor outcome by its association with hemolysis. Therapeutic interventions that reduce the rate of hemolysis need to be studied for their potential benefit in decreasing the risk and severity of vasculopathy and the resulting organ damage.

Disclosures: Gordeuk: Ikaria Pharmaceutical Company: Consultancy; Actelion pharmaceutical company: Research Funding; Biomarin pharmaceutical company: Research Funding.

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