Stroke in sickle cell anaemia is more than stenosis and thrombosis: the role of anaemia and hyperemia in ischaemia

Dowling, Michael M.; Kirkham, Fenella J.

doi:10.1111/bjh.14422

Cited by 6 publications

(7 citation statements)

References 19 publications

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“…However, while oxygen delivery to gray matter appears to be preserved, deep white matter structures are relatively hypoperfused and ischemic . In addition, elevated baseline cerebral blood flow consequently lowers cerebral vascular reserve, and leaves patients more susceptible to ischemic brain injury under metabolic stress . Lower cerebral vascular reserve predicts white matter hyperintensities cross‐sectionally and longitudinally, presumably through acute‐on‐chronic interruptions in oxygen delivery .…”

Section: Discussionmentioning

confidence: 99%

Anemia predicts lower white matter volume and cognitive performance in sickle and non‐sickle cell anemia syndrome

et al. 2019

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Severe chronic anemia is an independent predictor of overt stroke, white matter damage, and cognitive dysfunction in the elderly. Severe anemia also predisposes to white matter strokes in young children, independent of the anemia subtype. We previously demonstrated symmetrically decreased white matter (WM) volumes in patients with sickle cell disease (SCD). In the current study, we investigated whether patients with non-sickle anemia also have lower WM volumes and cognitive dysfunction. Magnetic Resonance Imaging was performed on 52 clinically asymptomatic SCD patients (age = 21.4 ± 7.7; F = 27, M = 25; hemoglobin = 9.6 ± 1.6 g/dL), 26 non-sickle anemic patients (age = 23.9 ± 7.9; F = 14, M = 12; hemoglobin = 10.8 ± 2.5 g/dL) and 40 control subjects (age = 27.7 ± 11.3; F = 28, M = 12; hemoglobin = 13.4 ± 1.3 g/dL). Voxel-wise changes in WM brain volumes were compared to hemoglobin levels to identify brain regions that are vulnerable to anemia. White matter volume was diffusely lower in deep, watershed areas proportionally to anemia severity. After controlling for age, sex, and hemoglobin level, brain volumes were independent of disease. WM volume loss was associated with lower Full Scale Intelligence Quotient (FSIQ; P = .0048; r 2 = .18) and an abnormal burden of silent cerebral infarctions (P = .029) in males, but not in females.Hemoglobin count and cognitive measures were similar between subjects with and without white-matter hyperintensities. The spatial distribution of volume loss suggests chronic hypoxic cerebrovascular injury, despite compensatory hyperemia. Neurocognitive consequences of WM volume changes and silent cerebral infarctionwere strongly sexually dimorphic. Understanding the possible neurological consequences of chronic anemia may help inform our current clinical practices.

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Section: Discussionmentioning

confidence: 99%

Anemia predicts lower white matter volume and cognitive performance in sickle and non‐sickle cell anemia syndrome

et al. 2019

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“…The distribution of SCI is similar, with up to 90% of SCI reportedly occurring in a relatively small deep watershed white matter region, encompassing only 5.6% of brain volume (31). SCI and overt ischemic stroke are often indistinguishable on MRI (32), and several authors have suggested that it may be differences in lesion size and location, rather than underlying physiological mechanism, that determines whether an ischemic insult is accompanied by focal symptoms (ischemic stroke) or goes undetected [SCI; (33)].…”

Section: Stroke and Cerebrovascular Diseasementioning

confidence: 99%

“…There is indirect evidence that cerebral embolic events occur in SCD patients, including reports of associations between overt ischemic stroke and thromboemboli (109, 110) as well as of fat-embolism syndrome from bone-marrow necrosis (111–114). Although comprehensive prevalence data are lacking, shunting at intra-pulmonary or intra-cardiac (e.g., through a PFO; patent foramen ovale) level and paradoxical embolism may also be more common in children (33, 115, 116) and adult (117) SCD patients and may be associated with cerebral infarction (118). Although there are few data in SCD, PFO is an established risk-factor for overt stroke in the general population (119–121).…”

Section: Hypercoagulability and Embolic Eventsmentioning

confidence: 99%

“…There is also evidence that watershed white matter regions are disproportionately at risk of steal in young healthy populations during hypercapnia (196), suggesting that these regions may be continuously compensating for low perfusion pressure. Exhausted CVR, alone or in combination with steal, may thus render the watershed white matter regions disproportionately vulnerable to ischemia in settings where there is increased metabolic demand (e.g., infection, pyrexia, seizures) or an acute drop in CaO 2 [e.g., acute chest syndrome with acute anemia and hypoxia; (33)], which are common in SCD.…”

Section: Hemodynamic Compromisementioning

confidence: 99%

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

et al. 2019

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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.

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“…However this dichotomy is likely false, as the two can be radiographically indistinguishable. 5 Strokes may have lifelong devastating consequences, including limited educational attainment and decreased quality of life in children. 6,7 Sickle cell anemia refers to the most severe SCD phenotypes, SS and Sβ 0 thalassemia, which have the highest stroke incidence.…”

Section: Introductionmentioning

confidence: 99%

Advances in Understanding Ischemic Stroke Physiology and the Impact of Vasculopathy in Children With Sickle Cell Disease

Guilliams

Fields

Dowling

2019

Stroke

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Stroke in sickle cell anaemia is more than stenosis and thrombosis: the role of anaemia and hyperemia in ischaemia

Cited by 6 publications

References 19 publications

Anemia predicts lower white matter volume and cognitive performance in sickle and non‐sickle cell anemia syndrome

Anemia predicts lower white matter volume and cognitive performance in sickle and non‐sickle cell anemia syndrome

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

Advances in Understanding Ischemic Stroke Physiology and the Impact of Vasculopathy in Children With Sickle Cell Disease

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