Advances in understanding the pathogenesis of cerebrovascular vasculopathy in sickle cell anaemia

Abstract

SummaryCerebral vasculopathy is the most severe complication to affect children with sickle cell anaemia and its pathophysiology is complex. Traditionally, small-vessel occlusion by intravascular sickling and sludging was considered to underlie the strokes but, in the last 20 years, progressive major cerebral vessel involvement has become recognized as the principal responsible factor. Macrovasculopathy is well detected by abnormally high velocities on transcranial Doppler and with magnetic resonance angiography (MRA), and is responsible for the majority of overt strokes. Silent infarcts are ischaemic lesions detected by magnetic resonance imaging (MRI) in patients without history of stroke. They are associated with compromised cognitive functioning. The present review discusses the pathophysiologal mechanisms that could be involved in the development of cerebral vasculopathy, such as inflammation and hypoxia, anaemia, haemolysis and the resulting decreased nitric oxide bioavailability, genetic factors, impaired blood rheology and particular local haemodynamic profiles.

Chronic and acute anemia and extracranial internal carotid stenosis are risk factors for silent cerebral infarcts in sickle cell anemia

“…[19][20][21][22][23][24] We recently reported in 2 large cohorts of stroke-free SCA children that eICA velocities of 160 cm/s or higher were highly predictive of eICA stenosis. 24,25 We hypothesized that in addition to low baseline hemoglobin level, the rate of AAE and the presence of eICA stenosis could be additional risk factors for SCI. Thus, to determine the association between eICA stenosis and SCI, we chose to study this issue in a longitudinal cohort, the Créteil Newborn Cohort, as patients are systematically assessed by MRI/MRA.…”

Omega 3 (n−3) fatty acids down-regulate nuclear factor-kappa B (NF-κB) gene and blood cell adhesion molecule expression in patients with homozygous sickle cell disease

“…Chronic inflammation, intravascular haemolysis, imbalanced vascular nitric oxide (NO), oxidative stress are known factors that underlie vasculapathy-related complications in SCD [61,62]. Among these complications, pulmonary hypertension (PHT) and stroke stand out as the most prevalent and devastating.…”

Deoxygenation Reduces Sickle Cell Blood Flow at Arterial Oxygen Tension

“…In the absence of local oxygen-dependent effects, reduced arterial blood flow in sickle cell patients has been attributed to chronic cycles of polymerization and depolymerization that damage the RBC cytoskeleton and cause an oxygen-independent reduction in sickle RBC deformability, along with oxygen-independent adhesive and inflammatory responses (8,14). However, the degree of reduction in oxygen-independent RBC deformability is much more mild, and as has been previously suggested (21,22), only the dramatic decrease in deformability associated with deoxygenation-induced sickle hemoglobin (HbS) polymerization seems sufficient to explain the severity of sickle cell disease complications found in the cerebral vasculature of sickle cell patients (10). To understand the biophysical basis for these complications, we require a clearer picture of the rheologic behavior of blood under arterial oxygen conditions.…”

“…The major cause of morbidity and mortality in SCD is impaired blood flow culminating in vaso-occlusion, with occlusive events occurring throughout the vascular tree, from the relatively low-shear and low-oxygen tension postcapillary venules (8,9) to the relatively high-shear and highoxygen tension large cerebral arteries (10,11). The major causes of reduced blood flow are 1) altered sickle cell blood rheology, 2) increased inflammation, and 3) cellular adhesion, with pathologic inflammation and adhesion likely arising at least in part as a result of the underlying altered sickle cell blood rheology (12)(13)(14).…”