Sickle Cell Disease
Home
Sickle cell disease (SCD) is a hemoglobinopathy resulting in hemoglobin-S production, hemolytic anemia, and elevated stroke risk. Patients with SCD are at high risk for new and recurrent strokes, and this risk can be reduced through the use of conservative or emerging curative treatments: oral hydroxyurea vs. more aggressive monthly blood transfusions vs. curative genetic or hematopoietic stem cell transplantation (HSCT) . The overarching goal of this line of work is to develop comprehensive risk assessment strategies, based on new neuroimaging and blood tests, that can be used to triage patients for these different treatments based on personalized indicators of stroke risk.
Our manuscripts relevant to this work in sickle cell disease:
-
Cerebral Hemodynamic Responses to Disease-Modifying and Curative Sickle Cell Disease Therapies
-
Advances in neuroimaging to improve care in sickle cell disease
-
Non-invasive imaging of oxygen extraction fraction in adults with sickle cell anaemia
More specifically, while cerebral oxygen delivery depends on the cerebral blood flow (CBF; ml blood/100g tissue/minute) and blood oxygen content, it is becoming increasingly recognized that blood capillary transit time itself can also influence tissue oxygen extraction, even in the presence of normal or elevated CBF. In individuals with anemia where accelerated capillary flow velocities may be present as a result of hyperemia and cerebral autoregulation, reduced capillary transit time can lead to reduced times for tissue oxygen offloading. Compelling evidence has been provided for heterogeneous capillary flow underlying abnormal oxygen delivery in multiple conditions including expansion of infarcts in acute ischemic stroke, traumatic brain injury, and Alzheimer's disease. In sickle cell anemia (SCA), we have observed that rapid capillary transit, visible on arterial spin labeling (ASL) CBF-weighted MRI, is present in more than 50% of adults and children. We have shown in published work and preliminary data from 154 adults and children with SCA that hyperintense ASL signal within cerebral dural venous sinuses is directly associated with elevated arterial velocities, elevated CBF, and reduced oxygen extraction fraction (OEF; ratio of oxygen consumed to oxygen delivered), and that this effect may reduce following transfusion therapies that improve oxygen delivery to tissue. These findings indicate that venous hyperintense signal on ASL images may represent a marker of capillary-level disturbances in oxygen exchange efficiency. One of the most impactful findings of our preliminary work is that we have observed that rapid capillary-level arterio-venous transit is associated with reduced oxygen metabolism, suggesting that these transit times may provide a biomarker of cerebral ischemia in individuals with SCA who have greater than a 50% risk of cerebral infarcts by age 30 years, yet often lack conventional stroke risk factors. Here, we propose to refine neuroimaging methods for evaluating arterio-venous transit to allow for robust, quantitative measures of capillary transit time non-invasively in vivo, and subsequently to test fundamental hypotheses regarding cerebral oxygen utilization in anemic individuals with vs. without infarcts. To apply innovative ASL MRI methods and time regression analyses over major intracranial arteries and dural sinuses in healthy control and SCA participants. To quantify cerebral capillary transit time in SCA participants before and after treatment with blood transfusion to understand how increases in hemoglobin parallel an improvement in brain oxygen extraction. To test the hypothesis that arterio-venous transit times are reduced in individuals with SCA with versus without infarcts. The short-term goal is to utilize non-invasive imaging approaches to understand mechanisms of oxygen utilization and neurovascular dysfunction in anemia. The long-term goal is to use this information to triage individuals with anemia for personalized stroke prevention therapies, as well as to objectively quantify the impact of these therapies on brain health.