Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia

Abstract

Blood transfusions are the mainstay of stroke prevention in pediatric sickle cell anemia (SCA), but the physiology conferring this benefit is unclear. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) are elevated in SCA, likely compensating for reduced arterial oxygen content (CaO). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO, thereby relieving cerebral oxygen metabolic stress. Twenty-one children with SCA receiving chronic transfusion therapy (CTT) underwent magnetic resonance imaging before and after exchange transfusions. Arterial spin labeling and asymmetric spin echo sequences measured CBF and OEF, respectively, which were compared pre- and posttransfusion. Volumes of tissue with OEF above successive thresholds (36%, 38%, and 40%), as a metric of regional metabolic stress, were compared pre- and posttransfusion. Transfusions increased hemoglobin (Hb; from 9.1 to 10.3 g/dL; < .001) and decreased Hb S (from 39.7% to 24.3%; < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; = .004) and OEF (from 34.4% to 31.2%; < .001). At all thresholds, transfusions reduced the volume of peak OEF found in the deep white matter, a location at high infarct risk in SCA ( < .001). Reduction of elevated CBF and OEF, both globally and regionally, suggests that CTT mitigates infarct risk in pediatric SCA by relieving cerebral metabolic stress at patient- and tissue-specific levels.

A mathematical model of cerebral blood flow control in anaemia and hypoxia

“…Kuwabara et al (2002) also found that OEF changed little with decreasing [Hb] in a study of anaemic adults. This lack of a significant OEF increase in response to anemia in normocapnia contrasts to that observed in sickle cell children Guilliams et al 2018) and infants (Morris et al 2018) where OEF increases in concert with CBF in response to anemia, and may be the result of an increased CMRO 2 (Bush et al 2014), which is predicted by the model but not shown. Further, in regions of the brain such as the white matter where perfusion is poor (Mandell et al 2008), D O 2 is decreased Chai et al 2019).…”

Haploidentical bone marrow transplantation improves cerebral hemodynamics in adults with sickle cell disease

“…There was no cutoff across different quantiles that predicted OS or EFS. Since the median VAF in our population (43%) was very similar to the previous cutoff reported by others to predict survival (44%), 4 we used a cutoff of 43% to correlate NPM1 VAF with outcomes. For the entire population, OS and EFS were not different between patients with VAF <43% and ≥43% ( Figure 1A,B).…”

“…Regional OEF methods have been applied in this population as well. 4 Our study highlights the importance of central neuroradiology adjudication of MRI and MRA of the brain 10 NPM1 mutant variant allele frequency correlates with leukemia burden but does not provide prognostic information in NPM1-mutated acute myeloid leukemia…”

“…These hemodynamic profiles have been associated with prior stroke and clinical impairment. 2 As a proof of principle that BMT improves cerebral hemodynamics via a decline or normalization in CBF and OEF, (Supporting Information Figure 1A) as is seen after blood transfusion with increased hematocrit (Hct), 3,4 For OEF quantification, T2 values from TRUST-MRI were converted to venous oxygen saturation (Yv) using previously characterized calibration curves. 2 Yv and arterial oxygenation saturation (Ya) were used to calculate OEF as the fractional difference of blood oxygenation in the arteries and veins, OEF = (Ya − Yv)/Ya.…”

“…3 One single-center retrospective study suggested that higher variant allelic frequency (VAF) of mutant NPM1 was associated with worse overall survival (OS) and event-free survival (EFS) in newly diagnosed AML, particularly in patients with a DNMT3A mutation or who underwent hematopoietic stem cell transplantation (HSCT) in first remission. 4 In light of these data, we sought to determine the impact of mutant NPM1 VAF on outcomes in patients with newly diagnosed AML treated at our institution with idarubicin and cytarabine (IA)-based regimens.…”