Ticagrelor does not impact patient-reported pain in young adults with sickle cell disease: a multicentre, randomised phase IIb study.

28-Year-Old Man With Joint Pain

A Randomized Controlled Trial of Patient Controlled Analgesia Versus Continuous Infusion of Morphine during Vaso-Occlusive Crisis in Sickle Cell Disease.

Stability and evolution of individual-level biomarker patterns across repeated vaso-occlusive crises in sickle cell disease

BackgroundEntrapment of sickled red blood cells in the microvasculature leads to sudden painful vaso-occlusive crises (VOCs) in sickle cell disease (SCD). This is potentially triggered by autonomic nervous system–mediated vasoconstriction in the microvasculature. Indeed, vasoconstriction biomarkers derived from a single night of laboratory-based fingertip photoplethysmography (PPG) recording were predictive of a higher frequency of future VOC in SCD. Noninvasive, remote, and longitudinal monitoring of autonomic vasoreactivity will facilitate the development of predictive biomarkers of imminent VOC.ObjectiveThis study aimed to assess the feasibility and performance of a wearable wristband device to longitudinally monitor nocturnal peripheral autonomic vasoreactivity and to cross-validate the vasoconstriction parameters across the “gold-standard” finger sensor.MethodsA total of 12 patients with SCD and 6 healthy controls were recruited to wear a wristband device (Biostrap) with a PPG sensor on a nightly basis. For cross-validation studies, 50% (3/6) controls wore both the wristband and a sleep monitoring device (AliceNightOne) with a finger PPG sensor. We quantified autonomic vasoreactivity by processing PPG signals and deriving vasoconstriction parameters—magnitude of vasoconstriction (Mvasoc) and photoplethysmography amplitude coefficient of variation (PPGampCV). We performed a correlation analysis of the vasoconstriction parameters within each device to investigate whether Mvasoc and PPGampCV can be used as surrogate markers of vasoconstriction, and then cross-validated the PPGampCV across the wristband and finger PPG devices.ResultsA total of 131 nocturnal PPG recordings were made with a wristband device (1‐19 nights per participant; patients with SCD: n=79, 60%; controls: n=52, 40%). A total of 9 nocturnal recordings (3 nights per participant) were made with both wristband and finger sensor devices. Longitudinal continuous PPG recordings were feasible with the wearable device, with significant within-night and night-to-night variability in vasoconstriction parameters, suggesting dynamic changes in autonomic vasoreactivity. Mvasoc and PPGampCV significantly correlated within devices—the maximum overnight correlation was 0.82 (P<.001) for the finger sensor and 0.69 (P<.001) for the wristband sensor, suggesting that PPGampCV can serve as a surrogate for Mvasoc. Cross-validation analysis of PPGampCV across wristband and fingertip sensors showed statistically significant correlations on all 9 nights (overnight correlation coefficient ranging from 0.24‐0.7), with some nightly segments of PPGampCV showing very strong correlation across devices.ConclusionsWearable wristband devices are feasible tools for the collection of continuous PPG measurements and vasoconstriction parameters, which serve as objective markers of autonomic vasoreactivity in users with and without SCD. We have optimized the methods of quantifying vasoconstriction from wearable device PPG signals, and cross-validated them with standardized sensors. These findings enable large-scale, real-time monitoring of autonomic vasoreactivity along with pain outcomes for the development of vasoconstriction parameters as biomarkers imminent VOC in patients with SCD. This biomarker also has the potential to impact other diseases involving autonomic vascular dysregulation.

Isoxsuprine is a tocolytic agent which improves erythrocyte deformability. It was accidentally found to be effective in the management of sickle cell disease (SCD) painful crises. The experience with the drug in the treatment of sickle cell disease is limited. This double-blind randomized comparative study was undertaken to test its efficacy and safety in the treatment of SCD painful crises. Forty-three SCD patients (33 males and 10 females) with 44 episodes of pain were included in the study (i.e., one patient was included twice). Only those with painful crises requiring hospital admission were included. Patients were randomized to receive either isoxsuprine 5-10 mg, or meperidine 50100 mg intramuscularly, according to body weight, every four hours. A random selection of 23 patients received isoxsuprine, and 21 received meperidine. Pain score, duration of crisis, hospital stay, and side effects were monitored. No significant difference was found in any parameter except for pain score at 30 and 60 minutes. We conclude that isoxsuprine appears to be effective in the treatment of sickle cell painful crises. Confirmation of its efficacy in studies involving a larger number of patients is warranted.

Effect of high-flow oxygen therapy on regional oxygen saturation during vaso-occlusive pain crisis: An observational study.

Physician-reported impact of vaso-occlusive crises in people with sickle cell disease: A multinational, real-world survey

Efficacy and Safety of a Single Dose of Exagamglogene Autotemcel for Severe Sickle Cell Disease

Free Iron in Sera of Patients with Sickle Cell Disease Contributes to the Release of Neutrophil Extracellular Traps

Vaso-Occlusive Crises and Costs of Sickle Cell Disease from a Commercial Payer's Perspective

Elevated Tricuspid Regurgitant Jet Velocity In Lebanese Patients With Sickle Cell Disease Is Associated With Severe Disease and Is Clustered In Families

Hemopexin Replacement Therapy Protects Sickle Cell Disease Mice from Acute Kidney Injury

Presentation Date: 6/8/2024 Presentation Start Time: 9:00:00 AM Background Vaso-occlusive crisis (VOC) is the primary reason for hospitalization among patients with sickle cell disease (SCD). Free heme from ongoing hemolysis contributes to VOC by activating endothelium and blood cells adhesiveness. The resulting blockage of blood circulation produces the characteristic pain of VOC. Hemopexin (Hx) is an endogenous plasma glycoprotein that binds extracellular heme. In people living with SCD, Hx is consumed during hemolysis, leading to its depletion. Administration of Hx relieves experimental vaso-occlusion induced by free heme, hemoglobin or hypoxia-reoxygenation in Townes SCD mice (Gentinetta et al. 2022). We are investigating the potential for plasma-derived human hemopexin (CSL889) to neutralize heme toxicity and normalize blood circulation. We report results of a phase 1, first-in-human study evaluating the safety, tolerability and pharmacokinetics (PK) of CSL889 in adults with SCD [NCT04285827]. Methods This 2-part, multicenter, open-label cohort study was conducted in the US, UK, and the Netherlands. The primary objective was to determine the safety and tolerability of single intravenous (IV) doses of CSL889 in adults with SCD of any genotype. Secondary and exploratory objectives included pharmacokinetics, immunogenicity, and biomarkers of target engagement and mechanism of action. In Part A, 6 ascending single dose levels (3, 10, 30, 60, 120, and 200 mg/kg) were tested in subjects not in VOC (n = 4 per cohort). In Part B, 4 subjects hospitalized for management of VOC with IV opioids received a single IV dose of 60 mg/kg CSL889 within 36 hours of admission. All subjects were followed for approximately 32 days post-infusion of CSL889. The serum assay of Hx measures total Hx and cannot distinguish CSL889 from endogenous Hx, nor heme-bound from free Hx. Noncompartmental analysis of PK was completed using total and pre-dose baseline-adjusted Hx values. Results All 28 subjects self-reported as Black or African American, 15/28 (54%) were female, and age ranged from 20 to 57 years. Most (86%) had HbSS genotype. Half of the subjects in Part A and all in Part B reported concomitant hydroxyurea use. In Part B, 3 subjects were receiving voxelotor and/or crizanlizumab. All Part B subjects had histories of ≥ 3 VOC within the prior 12 months, while most Part A subjects (18/24) had ≤ 2. Seventy treatment emergent adverse events (TEAEs) were reported in 22 subjects (51 mild, 18 moderate and 1 severe). Number or severity of TEAEs did not increase with dose or VOC status. The most common TEAEs were sickle cell anemia with crisis (29% of subjects, all ³1 week after CSL889) and headache (17%). Four TEAEs were considered related to CSL889, all nonserious, of mild severity and resolved: 2 TEAEs of transient dizziness in 2 subjects; and TEAEs of transient increase in fibrin D-dimer and decrease in blood fibrinogen level in 1 subject. Two serious adverse events (SAEs) of moderate severity were reported in 1 subject in Part A, neither related to CSL889 (simultaneous COVID-19 and VOC, both resolved). One SAE of acute chest syndrome occurred in Part B, in the setting of an intercurrent diarrheal illness &amp;gt; 8 days after CSL889; considered not related to CSL889 and all resolved. No ECG changes or other notable lab findings were observed. No subjects developed treatment-emergent anti-CSL889 antibody. Baseline levels of endogenous Hx were low but highly variable (range 7.2 to 499 µg/mL; normal value 2000 µg/mL). Total serum heme was also variable over time, within and across cohorts. CSL889 Tmax was ≤ 2.33 hours and T1/2 ranged from 0.375 to 3.52 days across the dose levels. Mean total Hx Cmax at 200 mg/kg was approximately 2-fold higher than the average healthy human level (Santiago et al 2018). Mean Cmax was comparable within variability based on standard deviation in the subjects with and without VOC that received the same dose (60 mg/kg). Biomarker analysis confirmed target engagement, but no trends in pharmacodynamic biomarker concentrations were observed. Conclusions CSL889 had an excellent safety and tolerability profile when administered as a single dose up to 200 mg/kg in subjects with stable SCD and at 60 mg/kg in subjects with VOC. The observed half-life may support dosing once daily or every other day. These results provide a strong foundation for future trials to evaluate potential efficacy.

Gout and sickle cell disease: not all pain is sickle cell pain.

Humanistic and economic burden among caregivers of adults and children with sickle cell disease and recurrent vaso-occlusive crises