Cerebral Blood Flow-Velocity Is Associated with Increased Leukocyte Count and Systolic Blood Pressure in HbSS but Not HbSC

BACKGROUND

Sickle Cell Disease (SCD) is the most frequent severe genetic disease worldwide. Its frequency is rising in European countries, including Italy and Ireland. In Europe Sickle SC (HbSC) is the second most common form of SCD after sickle cell anaemia (HbSS/HbSB°) and accounts for 25-30% of cases. Neurological events are among the most frequent and disabling complications in children with SCD with an important impact on quality of life, health and educational system costs (DeBaun et al., 2012). Overt and silent stroke are reported in in HbSC disease, although to a lesser extent. Studies suggest that the life-time risk of stroke in HbSC is 2-3% (Deane et al., 2008). Stroke Prevention is limited to only for HbSS/HbSB° but not HbSC. CBF-V as measured by TCD ranges of velocities in the Middle Cerebral Artery (MCA) and in the distal Internal Carotid Artery (dICA) used to stratify patients with HbSS/HbSB° in risk categories might be inappropriate for HbSC patients. Unlike North America, in Europe HbSC phenotype is more common; we therefore set out in this three country European study (SCATES) to describe the pattern of CBF-velocity and also compare the findings with HbSS patients attending the same facilities:.

Hypothesis: Aims is to determine mean reference values of TCD velocities in MCA and dICA in a European prospective cohort of children with HbSC in comparison with a cohort of HbSS.

Main objectives

1. To assess the pattern of cerebral flow velocity distribution in HbSC and compare with HbSS in three European countries

2. To test if the impact of clinical and hematological factors on Cerebral blood flow velocity in HbSC and HbSS in order to make recommendation for screening HbSC.

METHODS

Following a formal evaluation and validation of the competency of the screening centres to perform TCD in sickle cell disease; consecutive patients were recruited into the prospective observational study. TCD was performed with imaging TCD (Philps, other makes) by certified TCD operators. The data were entered on-line (Study Trax) and downloaded for statistical analysis using STATA 10.0 (Stata-Corp LP, College Station, Texas). Before regression analyses were performed, all variables that did not have a normal distribution (BP diastolic, albumin creatinine ratio (ACR), lactate dehydrogenase (LDH) and bilirubin) were transformed to achieve a normal distribution. All variables were standardised to allow for clear interpretation. Univariable regression analyses were performed to examine the influence of laboratory and haematological parameters on maximum TCD velocity from the MCA or TICA, in each SCD type subgroup. As TCD velocity had a non-parametric distribution the 95% confidence intervals of TCD velocity for HbSC subgroup was determined using the bootstrap method (resampling with replacement from our data set), with 5,000 replications(Singh & Xie, 2010)

RESULTS

At recruitment, the participants' age ranged from 2 to 16 years with a mean age of 8.11 (sd ±4.07). Overall, 224 (76.12%) children had HbSS phenotype, and 61 (18.21%) children had HbSC phenotype. Mean values for haematological parameters for HbSS and HbSC subgroups: Mean Hb g/dl (std) was 8.32(1.16) for HbSS and 10.93(0.91) for HbSC; Albumin: creatinine ratio as 12.39 (3.92) and 8.32 (2.68) for HbSS and HbSC respectively. HbSS as expected show inverse relationship between CBF-V and hemoglobin (n = 224; beta = -7.90; 95%CI = -11.9 to -3.89; p = 0.00014); positive correlation with systolic blood pressure increase (beta=11.03; 95% 3.10 to 18.995 and P=0.008); and total leukocyte count (n-120; beta 1.50; 95% CI 0.38-2.63; P=0.009). However, there was no correlation between TCD and any parameter in the HbSC group.

Discussion and Conclusion

From this pan-European patient cohort with a substantial proportion of patients we show that the CBF-V in HbSC does not follow a normal distribution pattern and appears entirely unrelated to clinical or hemolytic markers as observed with HbSS. Higher systolic blood pressure has been reported as risk factor for the development of silent cerebral infarct in HbSS (DeBaun et al., 2014). To the best of our knowledge this is the first time systolic and increased leukocyte as a marker of thrombosis (Marchetti & Falanga, 2007) is a risk factor in SCD. CBF-V. The fact there is relationship with these markers in HbSC suggests the lack of benefit for this measurement.