Vascular Instability and Neurological Morbidity in Sickle Cell Disease: An Integrative Framework

Abstract

It is well-established that patients with sickle cell disease (SCD) are at substantial risk of neurological complications, including overt and silent stroke, microstructural injury, and cognitive difficulties. Yet the underlying mechanisms remain poorly understood, partly because findings have largely been considered in isolation. Here, we review mechanistic pathways for which there is accumulating evidence and propose an integrative systems-biology framework for understanding neurological risk. Drawing upon work from other vascular beds in SCD, as well as the wider stroke literature, we propose that macro-circulatory hyper-perfusion, regions of relative micro-circulatory hypo-perfusion, and an exhaustion of cerebral reserve mechanisms, together lead to a state of cerebral vascular instability. We suggest that in this state, tissue oxygen supply is fragile and easily perturbed by changes in clinical condition, with the potential for stroke and/or microstructural injury if metabolic demand exceeds tissue oxygenation. This framework brings together recent developments in the field, highlights outstanding questions, and offers a first step toward a linking pathophysiological explanation of neurological risk that may help inform future screening and treatment strategies.

Functional Connectivity Decreases with Metabolic Stress in Sickle Cell Disease

“…Our prior findings of elevated OEF in children with SCD 11,12 are in agreement with investigations using positron emission tomography (PET) 63 and T2 relaxation under spin tagging (TRUST) MR measurements of OEF, 64 whereas other investigations utilizing a TRUST sequence reported lower OEF in patients with SCD 65,66 . This discrepancy is postulated to be secondary to differences in MR sequence and postprocessing, combined with the possibility of regional shunting of blood flow in patients with SCD due to dysregulated cerebrovascular reserve and cerebral autoregulation 65,67 . Our cognitive evaluation was limited to the NIHTB‐CB and an estimated IQ with 2 WASI‐II subtests.…”

“…65,66 This discrepancy is postulated to be secondary to differences in MR sequence and postprocessing, combined with the possibility of regional shunting of blood flow in patients with SCD due to dysregulated cerebrovascular reserve and cerebral autoregulation. 65,67 Our cognitive evaluation was limited to the NIHTB-CB and an estimated IQ with 2 WASI-II subtests. Earlier cognitive testing showing differences between SCD and controls did not utilize the NIHTB-CB.…”

A cross‐sectional, case‐control study of intracranial arterial wall thickness and complete blood count measures in sickle cell disease

“…Vascular reactivity is well known to be largely mediated by autoregulation and relaxation of smooth muscle located within the middle tunica media layer of the arterial wall 37–40 . Reduced cerebrovascular reactivity potential and associated autoregulatory capacity is of high clinical significance in SCD owing to well‐known dependence of brain health on this compensatory property, 41–43 yet whether intracranial vessel wall thickening is present in SCD is not well‐established.…”

Neuroimaging in Sickle Cell Disease: A Review

“…HbS crystals deform the red blood cell (RBC) into a sickle shape, which are relatively rigid and adherent to vascular endothelium. Rigid RBCs are less able to flow through terminal arterioles and capillaries, causing congestion, intravascular sludging, and hemolysis 1 . Adherence of RBCs to endothelium and circulating extracellular hemoglobin causes a vasculopathy due to a cascade of endothelial activation, vasoconstriction, intimal hyperplasia, and smooth muscle proliferation.…”

“…Rigid RBCs are less able to flow through terminal arterioles and capillaries, causing congestion, intravascular sludging, and hemolysis. 1…”