Ps1522 Central Physiologic Mechanisms Which Augment Oxygen Release (Bohr Effect and 2,3‐dpg Binding) Are Preserved in the Presence of Voxelotor at the Therapeutic Target of 30% Hb Modification

Abstract

Background: Amongst patients with sickle cell disease (SCD) the leading cause of death is the acute chest syndrome (ACS). This pneumonia-like complication frequently occurs during or shortly after a vaso-occlusive crisis (VOC). In pediatric patients hospitalized for VOC, incentive spirometry has demonstrated to prevent the development of ACS. Aims: This study was designed to determine if a comparable effect of incentive spirometry can be demonstrated in adult patients with SCD. Furthermore, we aimed to validate the ability of the Bartolucci score to identify patients at risk of ACS and assessed the value of procalcitonin as a potential biomarker for ACS. In addition, clinical characteristics and laboratory results were determined to identify potential risk factors. Methods: In this multicenter prospective randomized trial, we included consecutive adult patients (≥18 yr) admitted for VOC presenting with chest or back pain above the diaphragm. Patients were randomly assigned to spirometry or control group. Patients presenting with ACS were excluded. A chest radiograph was performed 5 days after admission, or sooner when clinically indicated, in order to diagnose pulmonary abnormalities. ACS was defined as a new infiltrate/atelectasis combined with pulmonary symptoms. At presentation, procalcitonin plasma levels were assessed and the Bartolucci risk score was calculated to determine to the risk of developing ACS for each patient. In addition, clinical and laboratory parameters were compared between patients with and without ACS during admission. Results: In total 66 episodes of hospitalization for VOC in 48 patients were included. Median age was 26 years and 46 of the hospitalizations concerned patients with a severe genotype (HbSS/HbSβ 0 thalassemia) versus 20 hospitalization with a mild genotype (HbSC/HbSβ + thalassemia). The overall incidence of ACS in this study cohort was 19.7%. In the spirometry group, ACS was diagnosed in 5/34 (14.7%) hospitalizations compared to 8/32 (25%) hospitalizations in the control group ]; P = .293). Twelve of the 13 ACS episodes occurred in patients with a severe genotype. The Bartolucci risk score could be calculated for 50 hospitalizations. The scores area under the curve (AUC) was 0.747 (P = .013), with a negative predictive value (NPV) of 94% and a positive predictive value (PPV) of 31%. No difference in procalcitonin plasma levels were found between patients with and patients without ACS (0.52 ± 1.56 µg/ml versus 0.56 ± 1.44 µg/ml, respectively). At baseline, hemoglobin levels were significantly lower while LDH plasma levels, leukocyte and platelet counts were significantly higher in ACS hospitalizations as compared to non-ACS hospitalizations. Patients who developed ACS showed significantly more documented fever during admission (61.5% vs 17.0%) and a longer length of hospital stay (median 10.0 days vs 4.5 days). Summary/Conclusion: Incentive spirometry did not significantly reduce the development of ACS in this prospective study in adult patients with SCD admitted with VOC and...

Effects of an allosteric hemoglobin affinity modulator on arterial blood gases and cardiopulmonary responses during normoxic and hypoxic low-intensity exercise

“…To determine the physiological relevance of a small rise in EPO (with no change in Hb concentration) on the oxygen affinity of Hb, the effects of voxelotor on other important regulators of Hb affinity (e.g., 2,3-diphosphoglycerate concentration) should be explored in vivo. In vitro, however, voxelotor does not inhibit the Bohr effect or offloading effects of 2,3-DPG (32). Given the complex biochemical regulation of Hb and the numerous physiological determinants of oxygen transport -which are each both individually and collectively modulated by hypoxia -additional integrative physiology studies are warranted to determine the potential clinical and physiological utility of allosteric Hb modulators.…”

“…This effect is reversible and dose-dependent (29,33) as measured by the percent occupancy of Hb (22,27). Interestingly, in experimental models voxelotor-modified Hb retains the Bohr effect (i.e., releases more oxygen with increasing acidity) and responds to allosteric modulators such as 2,3-diphosphoglycerate, albeit with a mildly reduced rate of oxygen unloading (32). In animal studies under hypoxic conditions, ~30% drug occupancy of Hb has been shown to increase the overall affinity for oxygen in the blood, as evidenced by increased arterial oxygen saturation, with associated reduction in tissue hypoxia and improved survival (10).…”

Voxelotor: alteration of sickle cell disease pathophysiology by a first-in-class polymerization inhibitor

“…Additionally, voxelotor-modified hemoglobin was shown to still respond to the natural right-shifting substances (promoting oxygen offloading) concentrated in metabolically active tissue: H + and 2,3-DPG. 59 Some have expressed concern, though, that even slightly decreased oxygen offloading in the brain would, via normally functioning metabolic sensors in the brain, increase cerebral blood flow, which in the presence of chronic cerebrovascular disease could again result in stroke. Even in wild-type mouse models with presumed normal baseline p50 (i.e.…”

Influence of High Hemoglobin-Oxygen Affinity on Humans During Hypoxia

“…For example, voxelotor binds allosterically to some, but not all hemoglobin and increases Hb-O 2 affinity. Hemoglobin modified with voxelotor exhibits a reduced Bohr effect compared to unmodified hemoglobin (Pochron et al, 2019), which may limit O 2 offloading during instances where blood pH decreases such as rigorous exercise.…”

“…Recently, Stewart et al (2021) showed that pharmaceutical induction of high Hb-O 2 affinity (only ∼2 mmHg decrease in P 50 ) using voxelotor reduced normoxic maximal O 2 consumption ( VO 2max ) in humans. The decrement in normoxic VO 2max observed by Stewart et al (2021) could be due to both an increase in Hb-O 2 affinity and a reduced Bohr effect: the transient reduction of Hb-O 2 affinity with decreasing pH (Pochron et al, 2019). A reduced Bohr effect in exercising muscle would further compromise O 2 off-loading, particularly during periods of high metabolic demand (Mairbäurl, 2013).…”