Reticulocytosis and Anemia in Early Infancy Is Associated with Abnormal and Conditional Transcranial Doppler Velocities in Pediatric Sickle Cell Anemia Patients
Authors: Meier Emily R. , Fasano Ross M. , Estrada Monica , He Jianping , Mccarter Robert , Luban Naomi L.C. 
Published: October 2019

Abstract
All sickle cell anemia patients (HbSS, SCA) have the same genetic mutation, but the clinical phenotype is highly variable and difficult to predict prior to the onset of complications. Transcranial Doppler (TCD) is the only validated predictive indicator of severe SCA currently available, identifying SCA patients age 2 years or older with the greatest stroke risk. Preliminary studies have identified that elevated absolute reticulocyte count (ARC) between 2 and 6 months of age is associated with an increased risk of hospitalization for SCA complications, stroke and death.1,2
To determine if early reticulocyte levels in SCA patients are useful in classifying children at highest risk of developing an abnormal (abTCD) or conditional (cdTCD) TCD, 121 consecutive patients with SCA who had TCD screening were identified after IRB review granted a waiver of consent. Retrospective chart review was then performed to collect the steady state ARC between 2 and 6 months of age; patients were excluded if this value was not available in the medical record. Steady state was defined as a sample collected at least 30 days from an acute illness and at least 60 days since the patient received a blood transfusion. ARC and hematologic data were analyzed using Cox regression analysis to determine the relationship between ARC levels and time to cdTCD/abTCD. TCDs were considered normal (nlTCD) if the Time Average Mean Maximum Velocity (TAMMV) in the middle cerebral artery or distal internal carotid artery was <170 cm/sec, cdTCD if TAMMV was 170-199 cm/sec and abTCD if TAMMV was 200 cm/sec or greater. To evaluate the utility of ARC or hemoglobin in risk stratification, patients were divided into groups: ARC less than 200K/uL (ARC<200) and ARC greater than or equal to 200K/uL (ARC≥200), or hemoglobin less than 8.5 g/dL (Hb<8.5) and hemoglobin greater than or equal to 8.5 g/dL (Hb≥8.5).
Twenty of the 121 (16.5%) patients had abTCD, while 36/121 (29.8%) had cdTCD; the remaining 65/121 (53.7%) had nlTCDs. Mean ARC between 2 and 6 months of age was highest in those children with abTCDs (264±149 K/uL) and cdTCDs (175±76 K/uL) while those who had nlTCDs had the lowest values (mean ARC 140±100K/uL, p<0.001 across groups). Mean hemoglobin was lower in the abTCD (8.1±1.2 g/dL) and cdTCD groups (8.9±1.1 g/dL) compared to the nlTCD group (9.5±1.5 g/dL, p<0.001). The three groups did not differ in age at time of ARC measurement [mean age in months: 3.6±1.2 (nlTCD) vs. 3.8±1.3 (cdTCD) vs. 3.4±1.0 (abTCD), p=0.86].
Kaplan Meier analysis revealed that those children with higher ARC had an increased rate of cdTCD/abTCD (p<0.001 by the log-rank test). Lower hemoglobin was also associated with an increased rate of cdTCD/abTCD (p=0.002). Cox regression analysis revealed that those subjects with an ARC≥200 between the ages of 2 and 6 months had 2.9 times the risk of having an abTCD or cdTCD than the group with an ARC<200 (HR 2.92, 95% CI 1.68-5.08, p=0.0004). In separate analyses, patients with a hemoglobin less than 8.5 g/dL had 2.4 [95%CI 1.38-4.06 (p=0.002)] times the risk of having an abTCD/cdTCD than patients with a hemoglobin level of 8.5 g/dL or greater.
These data suggest that both elevated ARC and low baseline hemoglobin during early infancy are associated with an increased risk of developing a cdTCD or abTCD later in childhood. ARC and hemoglobin at this early age should be prospectively studied as standard screening tests to assist with treatment decisions in young children with SCA. Meier ER, Byrnes C, Lee YT, et al. Increased reticulocytosis during infancy is associated with increased hospitalizations in sickle cell anemia patients during the first three years of life. PLoS One 2013; 8(8):e70794. doi: 10.1371/journal.pone.0070794.Meier ER, Wright EC, Miller JL. Reticulocytosis and anemia are associated with an increased risk of death and stroke in the newborn cohort of the Cooperative Study of Sickle Cell Disease. Am J Hematol 2014 May 31; doi: 10.1002/ajh.23777. [Epub ahead of print]

Disclosures
No relevant conflicts of interest to declare.