Sickle cell anemia is a qualitative genetic hemoglobinopathy caused by a single amino acid substitution in the beta globin chain of hemoglobin leading to expression of HbS [14]. It is one of the most common genetic diseases worldwide, with the East Mediterranean areas and the Middle East considered to be among the most heavily affected region with sickle cell disease burden [15]. In Egypt, it is highly common in the Oasis where the carrier rate ranges from 9 to 22% [16].
Stroke is one of the most severe complications of sickle cell disease (SCD), affecting children as well as adults, as reported by the Collaborative Study of Sickle Cell Disease (CSSCD) [17]. Silent cerebral infarcts are common among patients with sickle cell anemia. Around one quarter of the patients are expected to experience their first infarct before the age of six and 39% before the age [18].
This prospective cross-sectional study was conducted on 69 patients with sickle cell anemia regularly attending the at the pediatric hematology clinic and fulfilling the inclusion criteria aiming to assess the TCD velocities (TAmax and PSV) among patients with sickle cell disease who were classified into three variable blood transfusion groups (regular, occasional and never) and were taking hydroxyurea therapy with correlation to different clinical parameters.
The highest mean (TAmax) velocity recorded among our patients was 99.35 ± 22.39 cm/s and was noted in the right MCA. This is in accordance with the literature where the highest velocities are recorded in the right MCA [19.20,21] This velocity is comparable with that of healthy Egyptian children with recorded velocities of 92.15 ± 9.62 cm/s [22]. On the other hand, the least mean velocity was 81.86 ± 30.08 cm/s and was noted in the left PCA in comparison with DICA in two studies [19, 21].It is worth noting that the highest maximum (TAmax) velocity was 224 ± 42.09 cm/s and was recorded in the left ACA, this is in accordance with the study of [23], where the authors report stroke in two children with sickle cell disease and high blood flow velocity limited to the anterior cerebral artery and suggested that elevated velocity in this vessel may be associated with an increased risk of stroke.
According to (stop) classification for detection of stroke risk, TAmax measured in the arteries of the circle of Willis has been proven to detect SCD patients at high risk of developing ischemic stroke. Its significance in the prevention of stroke has also been widely acknowledged [24, 25]. Based on the STOP trial criteria the TAmax is used to classify patients into three risk groups: (1) no risk, when the TAmax is below 170 cm/s. (2) Conditional risk, when the velocity is between 170 and 199 cm/s carrying 7% risk of stroke. (3) High risk is seen when the TAmax is 200 m/s or over, conferring 40% risk of stroke to sufferers. The importance of this observation is that first stroke can be avoided in children at high risk by chronic transfusion, or hydroxyurea therapy. The prior studies reported up to 90% of first stroke might be prevented by prophylactic blood transfusion, and their study provided evidence for the efficacy of this approach in primary stroke prevention in children at risk [24,25,26,27].
Only 3 (4.3%) of our patients had abnormal velocities denoting high risk for stroke and 3 patients (4%) had a conditional risk for stroke, This finding is similar to that conducted by an Iranian study which detected that 3% of studied patients showed conditional and high risk stroke, respectively [28]. It is also similar to that reported by another study conducted on African population showing 3% with abnormal velocities > 200 cm/s [21]. However this contradicts several studies conducted on the American population that revealed 9.4% with high risk and 17.3% with conditional risk [29] and another French study that concluded 20.7% with high risk and 26.7% with conditional risk [30]. This could suggest regional or ethnic variations in the cerebral velocities. The reason for this low prevalence of high TCD velocities in African children with SCA is not clear and is interesting especially since we have a higher prevalence of stroke in Africa than in America [31], also contradicts the study of Lagunju et al. [32], in which no regular transfusion, The study had stated a prevalence of 8.4% for abnormal velocities (≥ 200 cm/s) and 21.9% for conditional velocities, this could suggest the important role of the transfusion regularity or combined with hydroxyurea treatment [1, 33, 34].
Patients with sickle cell anemia and conditional risk velocities must be closely monitored with frequent TCD scans to enable for early diagnosis of aberrant velocities and the implementation of primary stroke prevention strategies [35].
According to the frequency of blood transfusion, the right MCA (PSV), left DICA (PSV) & both DICA (TAmax) had a significant correlation with the frequency of blood transfusion, and this finding is in accordance with prior research. Abd-Allah et al. [36] which showed that the annual frequency of blood transfusion and HU dose was associated with a decreased frequency of abnormal TCD findings, but is opposite to Bowman et al.[37]; Gujjar et al. [38] that had reported that The differences in Doppler velocities noted were not significantly different between patients who had been transfused within 3 months of examination, and those who had not received transfusions.
According to frequency of blood transfusion the sensitivity and the specificity of the arterial velocities showed, The right MCA (PSV), the left DICA (PSV), and both DICA (TAmax) are the highest sensitive and specific velocities according to frequency of transfusion and this in accordance with Proust et al. [39] & Lagunju et al. [17] that had reported that sensitivity and specificity were higher than those for TCD for MCA (100% and 93%, respectively) and ICA (100% and 96.6%, respectively) in addition to Jones [40]; Naffaa [41] that showed PSV is at least as good as TAmax and can be used to select children with SCD for treatment or increased surveillance to prevent first stroke and the most frequent location of highest velocity measurement was noted to be in the middle cerebral artery regardless of whether it was measured by PSV or TAmax.
Among our patients, 65 patients had normal (not excised) spleen, while 4 patients underwent splenectomy (who were in low risk of stroke group). And there was insignificant difference between splenectomy status and Doppler velocities according to the risk of stroke, which is similar with the study done by Gutiérrez et al. [42]; Kanavaki et al. [43] had reported that there was no statistically significant difference in the TAmax values for all examined cerebral arteries between the non-splenectomized and splenectomized patient groups.
Regarding the hematological workup, the mean hemoglobin at our study was 8.23 ± 1.4 gm/dL and platelets was 333 ± 124.82 × 103. This is similar to that reported by Adekile et al. [20], where mean total hemoglobin was 8.5 ± 3.5 gm/dl among studied patients in Arabian Peninsula and platelets were on the upper limit with a value of 315.9 ± 140.6. Another study carried out in Nigeria deduced that the patients were anemic with platelets on the upper normal border. Chronic hemolysis, autosplenectomy, and chronic inflammation provide the unifying pathophysiological bases for the aforementioned hematological findings in SCD [44,45,46]. Several clinical studies have also linked severe anemia and thrombocytosis to adverse clinical events in SCD including acute chest syndrome, vaso-occlusive crisis, hospitalizations, silent cerebral infarcts, overt stroke, and death [47, 48].
In the current study, total bilirubin positively correlated with TCD velocities of all vessels apart from left PCA. This is similar finding to one study that correlated hemolytic markers with TCD velocities [19]. On the other hand, the same study concluded hemoglobin and hematocrit showed a negative correlation with TCD velocities, which is in line with our study. This can be explained by the compensatory mechanism of the cerebral perfusion under chronic anemia status [21]. Low baseline Hb were suggested to be associated with an increased risk of developing a conditional TCD or abnormal TCD later in childhood [49]. It is worth noting that direct bilirubin positively correlated with velocities in all vessels.
Our study revealed a positive correlation between age and TCD velocities. This is in line with a Sudanese study which detected the same correlation. Ismail et al. [21], but is opposite to that concluded by one Nigerian study Lagunju et al. [32] and another French study conducted by Bernaudi et al.[30], which showed a progressive decline in velocities after the age of 5 years. There is no clear explanation for this discrepancy.