Abstract
Hemoglobin E (HbE) is the most common hemoglobin mutation world-wide. EE individuals exhibit a mild anemia as do those with β-thalassemia trait. A paradox arises with the combination of two relatively benign genes in HbE/β-thalassemia (HbE/β-thal) giving rise to highly morbid symptoms, anemia, growth retardation, developmental retardation, thalassemic bone type development, chronic leg ulcers (for a review, S Fucharoen and DJ Weatherall 2012) and often early mortality arising from cardiac failure (N Olivieri, Z Pakbaz et al. 2011). One approach to understanding the characteristics of HbE and this paradox was to generate a transgenic mouse model, expressing solely human HbE. This HbE mouse model exhibits a mild oxidative stress that parallels that observed in human EE individuals (QY Chen, EE Bouhassira et al. 2004, QY Chen, ME Fabry et al. 2012). These transgenic mice also exhibit mild cardiac dysfunction with depressed left ventricular contraction. We present here the first evidence of a significant increase in cerebral blood flow in the full knockout HbE (HbEKO) transgenic mouse model expressing solely human HbE compared to both the HbE+HbF (γ, gamma)-globin transgenic mouse, and the normal background C57 mouse. Cerebral blood flow is assessed non-invasively by MRI imaging. All protocols were approved by the Albert Einstein Institutional Animal Care and Use Committee.
Comparing the HbEKO mouse (without human γ globin) to the C57 normal background mouse, a significant increase of over 20% in thalamus cerebral blood flow at baseline is observed (p=0.008). There is also an approximate 18% reduction in thalamus cerebral blood flow comparing HbE low γ mice to the full HbEKO (no γ) (p=0.011). Concomitant with these observations, no significant difference is observed comparing these low gamma HbE mice to the normal C57 background mouse (p=0.384). The goodness of the data is also seen in the relatively small variation in cerebral blood flow amongst the individual mice in each subset. These findings are of particular relevance to reports of neurologic symptoms, intracerebral hemorrhage, and brain infarct in HbE/β-thal patients (V Wong, YL Yu et al. 1990, S Das, S Dubey et al. 2019).
In conclusion, these results suggest a direct role of HbE RBC initiating altered cerebral blood flow that when further complexed with β-thal could lead to intracerebral hemorrhage and other cerebral pathophysiology. The finding that the HbEKO mice with high HbF are not significantly different in cerebral blood flow from C57 mice may lend further support to therapeutic approaches enhancing the production of HbF in severe hemoglobinopathies, such as in sickle cell anemia, HbE/β-thal, and β-thal individuals.
Disclosures
No relevant conflicts of interest to declare.
Persistent Metabolic Disturbance in the Perihemorrhagic Zone Despite a Normalized Cerebral Blood Flow Following Surgery for Intracerebral Hemorrhage
