In the United States, sickle cell disease (SCD) is a rare inherited hemoglobinopathy affecting about 100,000 individuals, mostly with African ancestry. SCD causes damage to multiple organ systems and SCD nephropathy (SCDN) is a common complication associated with early mortality. We previously performed a genome-wide association study (GWAS) for SCDN and identified a modest number of genome-wide significant loci. Here, we leveraged the ancestral composition of participants from two well-characterized adult SCD cohorts to boost statistical power and perform a local ancestry-aware GWAS for estimated glomerular filtration rate (eGFR), resulting in the identification of novel genome-wide significant loci within the African (AFR) and European (EUR) ancestral components of participants. Meta-analysis identified 12 significant genomic regions in the AFR tract, including PPIL6, ARHGAP24, RAB11A, and STEAP3, and 38 regions in the EUR tract, including UBLCP1, ADAMTS6, JAZF1, MYO7B, MYO1C, PDGFA, GPC5, LRP1B, KANK1, and TRPV5. The identified regions encompass genes affecting inflammation, extracellular matrix (ECM) integrity, iron metabolism, magnesium ion homeostasis, B cell apoptosis, tumor necrosis factor (TNF) production, and estrogen signaling. Many of these genes and pathways are important not only for renal function, but also for SCD biology, providing additional support for the hypothesis that SCDN pathophysiology is unique from other forms of kidney disease. This study represents the largest local ancestry-aware analysis of SCDN to date, furthers our understanding of the genetic risk factors underlying SCDN, and proposes new targets that could be useful for the early identification and treatment of kidney dysfunction in SCD patients.

Elevated erythropoietin (EPO) concentration associates with thrombotic risk in hypoxic conditions, hereditary erythrocytosis and treatment of anaemia with recombinant EPO. We evaluated sickle cell disease (SCD) patients from the University of Illinois at Chicago (UIC) and the Treatment of Pulmonary Hypertension and SCD with Sildenafil Therapy (Walk-PHaSST) study and found that higher serum EPO concentration associated with increased thromboembolic risk (combined odds ratio [OR] = 1.9, p = 0.0029, N = 557). Percent haemoglobin F and haemoglobin concentration strongly correlated with EPO concentration in SCD, and the haemoglobin F locus BCL11A affected EPO concentration through percent haemoglobin F. In peripheral blood mononuclear cells from 159 UIC patients, we identified an expression quantitative trait locus for EPOR encoding EPO receptor, in which the G allele of rs322139 associated with higher EPOR expression (β = 0.055, p = 2.0 × 10-5). This G allele associated with lower EPO concentration in Walk-PHaSST (β = -0.23, p = 6.4 × 10-5, N = 327) and UIC (β = -0.18, p = 0.017, N = 179), but not in normal populations. The G allele of rs322139 also associated with a trend to decreased thromboembolism (combined OR = 0.64, p = 0.054, N = 665). In summary, our study indicates that higher serum EPO concentration associates with thromboembolic risk in SCD and reveals a novel role of EPOR expression variation in modulating EPO concentration and, possibly, thromboembolic risk in this condition.

Sickle cell disease attenuates nitric oxide signaling, limiting soluble guanylyl cyclase (sGC) stimulation needed for hemo-vascular function. Cytochrome b5 reductase 3 (CYB5R3) regulates sGC activity and expression. We show CYB5R3 T117S associates with reduced efficacy of the sGC stimulator riociguat. (NCT02633397).

BACKGROUND:Age-associated decline in mitochondrial oxidative capacity is associated with increased risk of disease, frailty, and disability. Oral nitrite and nitrate supplementation have been demonstrated to improve mitochondrial energetics and physical function in younger adults, but effects in older adults (age ≥70 years) remain unclear. METHODS:We conducted a randomized, placebo-controlled, double-blind, two-arm trial with a parallel group design to examine the effect of 20 mg sodium nitrite supplements administered three times a day for 12 weeks versus placebo in older (age ≥70 years) sedentary adults. Change in muscle mitochondrial respiration (complex I and II supported maximal oxidative phosphorylation [CI&II MaxOXPHOS]) was the primary outcome. Platelet bioenergetics, cardiorespiratory fitness, and other physical function measures were also assessed. RESULTS:Sixty-four adults (75.7 ± 5.7 years) completed the trial. Nitrite supplementation was not associated with improvements in skeletal muscle mitochondrial respiration, nor improvements in exercise capacity and physical function. However, platelet mitochondrial respiration changed significantly following an acute dose of oral nitrite. Notably, while nitrite levels increased 16- to 30-fold in plasma following an acute dose, levels increased only 1.6-fold in skeletal muscle. CONCLUSIONS:The divergent response of skeletal muscle versus platelet mitochondrial respiration in response to nitrite supplementation suggests tissue-specific pharmacokinetics and pharmacodynamics that likely impact the efficacy of nitrite supplementation. Results also suggest there may be age-related changes in drug delivery, metabolism, and mitochondrial responsiveness compared to the effects of nitrite/nitrate previously demonstrated in younger adults. Clinical Trial Registration Number: ClinicalTrials.gov NCT04405180.

ABSTRACT:Renin-angiotensin-aldosterone system inhibitors (RAASi) are suggested for treating albuminuria in patients with sickle cell disease (SCD). RAASi may exacerbate anemia in the general population and those with diabetes through unclear mechanisms. The impact of RAASi on anemia in chronic hemolytic disorders, such as SCD, is unknown. In a cross-sectional analysis of 658 Walk-PHaSST participants, RAASi use was independently associated with lower hemoglobin concentrations, adjusting for age, sex, SCD genotype, estimated glomerular filtration rate, and erythroid-stimulating agent and hydroxyurea use (β, -0.46 ± 0.21; P = .032). In 2 longitudinal cohorts (University of Illinois Chicago, n = 24; multicenter losartan clinical trial, n = 32), RAASi therapy led to a reduction in hemoglobin concentrations compared with pretreatment values by -0.44 ± 0.14 g/dL (P = .006) and -0.53 ± 0.17 g/dL (P = .005), respectively. SCD mice treated with losartan demonstrated lower hemoglobin concentrations after 6 and 14 weeks (P< .001) and lower absolute reticulocyte counts by 14 weeks (P = .03) vs control mice without changes in circulating erythropoietin, interleukin-12p70 (IL-12p70), IL-3, or insulin-like growth factor 1 levels. Bone marrow cells from losartan-treated SCD mice had lower colony-forming units (P ≤ .09) with rescue of erythroid colony formation after exogenous erythropoietin supplementation (P = .02). Bone marrow histopathology demonstrated reduced erythroid relative to myeloid ratios in losartan-treated vs untreated SCD mice. Hemoglobin levels should be closely monitored when using RAASi in this high-risk population.

Background Despite wide utilization of automated red blood cell exchange (RBCX) transfusion in adult patients with sickle cell disease (SCD), no consensus or quality efficacy data exist on its use. The Sickle Cell Disease and CardiovAscular Risk- Red cell Exchange (SCD-CARRE) trial tests the hypothesis that an automated chronic RBCX transfusion strategy reduces acute health care encounters and death while improving quality of life and end-organ function (cardiac, pulmonary and renal) in participants with SCD that are at high risk of death. Methods Adult patients with SCD with elevated tricuspid regurgitant jet velocity (TRV) and/or chronic kidney disease were considered to be at high risk of death and were randomly assigned to RBCX plus standard of care vs standard of care alone. Participants assigned to RBCX received 12 months of exchange transfusions to maintain target pretransfusion hemoglobin S% < 30%, post-transfusion hemoglobin S% < 20%, and post-transfusion hemoglobin concentration ≥10 g/dL. All study participants were managed according to NHLBI/ASH/ATS Expert Panel guidelines. The primary endpoint was the number of SCD acute health care encounters or death over 13 months. Secondary endpoints included measures of cardiovascular and renal function, exercise capacity, patient reported outcomes (all collected at baseline, and months 4, 8, and 12), and transfusion-related adverse events (collected monthly). Results Between 2020 and 2025, the SCD-CARRE trial randomized 173 participants at 23 sites across 3 countries. Enrolled participants had mean (SD) age of 45.8 (11.8) years and 54% were female. At baseline, participants had average TRV of 2.8 (0.5) m/s such that 45.9% had a TRV between 2.5 to 2.9 m/sec and 28.1% had a TRV ≥ 3.0 m/sec. The median (Q1, Q3) eGFR in this cohort was 60 (36, 110) mL/min/1.73 m2. The median (Q1, Q3) 6-minute walk test distance was 375 meters (309, 439), the median daily steps were 3,728 (2,187, 5,821), and participants experienced a median (Q1, Q3) of 2 (1, 5) pain episodes in the year prior to randomization. The trial results are pending. Conclusions The SCD-CARRE trial successfully enrolled a cohort of n = 173 adults with SCD. This study highlights a rationale to evaluate the effect of automated chronic RBCX transfusion strategy plus standard of care as compared to standard of care alone in SCD patients at high risk of death with a focus on patient centered outcomes, preservation of cardiovascular function, end-organ complications and death. Trial registration ClinicalTrials.gov, Identifier: NCT04084080, https://clinicaltrials.gov/study/NCT04084080.

Nitric oxide (NO) is formed via the oxidation of L-arginine in a reaction catalyzed by the NO synthase enzymes or via reduction of inorganic nitrite (NO2–) by deoxygenated hemoproteins and molybdopterin enzymes. We have recently demonstrated that NO can form a stable, labile ferrous heme-nitrosyl complex (NO-ferroheme) that protects NO from scavenging reactions in blood and has potent vasodilatory and platelet signaling activity. To enable future in vivo and in vitro studies establishing physiological NO-ferroheme formation, transport, and signaling, accurate and sensitive detection methods specifically for NO-ferroheme in biological milieu must be developed and validated. NO-heme complexes can be oxidized to release NO into the gas-phase for ozone-based chemiluminescence detection, which has been used for detection of iron-nitrosylated hemoglobin. In the current studies, we extend classical assays such as acidic potassium triiodide – with and without acidified sulfanilamide (AS) pre-treatment to eliminate NO2– and mercury(II) chloride (HgCl2) pretreatment to eliminate S-nitrosothiols – to detect and quantify NO-ferroheme, S-nitrosothiols, and nitrite. We also developed a new potassium ferricyanide/cyanide-based assay for sensitive and specific NO-ferroheme detection. All assays are sensitive and specific for NO-ferroheme to concentrations as low as 5 nM, with validated detection in buffer, plasma, whole blood and in vivo studies in mice. Additionally, we detect and quantify in vivo plasma NO-ferroheme formation and levels in mice after treatment with lipopolysaccharide (LPS), modeling pathological sepsis. These studies validate highly sensitive and specific assays for NO-ferroheme quantification and for the first time demonstrate plasma NO-ferroheme formation in vivo in a sepsis model.

Myoglobin plays a key role in oxygen storage and delivery through oxygen binding and release from the ferrous (Fe+2) heme. However, when the heme is oxidized to its ferric (Fe+3) form it can no longer bind oxygen and further oxidation leads to lipid peroxidation which can lead to a variety of pathological consequences. Ferric heme can be reduced to the ferrous form by nitric oxide (NO•) through classical reductive nitrosylation but this reaction, where a second NO• molecule binds to the reduced heme to form iron nitrosyl myoglobin, is very slow and inefficient. We have recently demonstrated that glutathione (and other thiols) can catalyze reductive nitrosylation of free ferric heme (hemin) when solubilized in albumin or red blood cell ghosts and that the resultant NO-ferroheme has potent NO• signaling properties. In this work we show this catalysis is also viable in myoglobin and that ascorbate is a better catalyst than glutathione with reductive nitrosylation occurring 1000 times faster in the presence of ascorbate compared to its absence under some conditions. Our data support a mechanism involving ascorbate-mediated heme reduction forming an ascorbyl radical. Only one NO• molecule and 0.5 ascorbate molecules are needed to convert one ferric myoglobin to one nitrosyl myoglobin molecule. Addition of NO• and ascorbate are shown to be more protective against lipid peroxidation due to myoglobin oxidation by hydrogen peroxide than either ascorbate or NO• alone. This reaction has potential application in meat preservation and treatment of ischemic reperfusion injury, various myopathies, and rhabdomyolysis.

Carbon monoxide (CO) poisoning is responsible for around 50,000 emergency department visits per year in the U.S. alone. With the present standard of care, persistent neurological sequelae occur in ~30-40% of severe CO poisoning cases. Currently, there is no available targeted molecular antidote for CO poisoning. In previous work, we have developed an antidotal therapy for CO poisoning based on an engineered hemeprotein, human neuroglobin (Ngb-H64Q-CCC). Intravenous infusion of Ngb-H64Q-CCC removes CO from the circulating red blood cells and improves survival in a lethal CO-poisoning mouse model. However, the infusion of heme-containing proteins has inherent heme toxicity risks that may limit the dose that can be used safely without liver or kidney toxicity. In order to overcome these problems, we have investigated the development of immobilized Ngb in a solid matrix. This approach allows for the development of a CO removal system using an extracorporeal blood circulating system coupled with a stationary matrix with immobilized Ngb-H64Q-CCC. Such system avoids drug infusion and possible organ injury, allows for antidote recycling, and provides advantages for storage and handling of the antidote. By assessing the efficacy of Ngb-H64Q-CCC immobilized through different linkage strategies, we have identified N-hydroxysuccinimide agarose resin as a viable stationary phase. The immobilized protein shows preserved heme redox activity, can be chemically reduced/oxidized for activation/CO release purposes, and retains its CO removal capacity after successive regeneration cycles. We expect that this novel approach will advance the development of new scavenger-based therapies for CO poisoning.

Sickle cell disease (SCD) is the most common monogenic-hemolytic disorder affecting people of African ancestry. Adenosine diphosphate (ADP) released following intravascular hemolysis activates platelets by stimulating purinergic receptors to promote thrombosis. Despite brisk intravascular hemolysis, which releases high levels of ADP into plasma, and evidence of platelet and hemostatic activation, it remains elusive why only a subset of SCD patients develop lung thrombosis. Using real-time in vivo lung microscopy, we report a surprising finding that humanized SCD mice are protected from ADP-induced lung thrombosis, which is secondary to the degradation of ADP by CD39 present in circulating extracellular vesicles released by the lung endothelium. ADP-induced platelet aggregation is also impaired in the blood of SCD patients with elevated levels of CD39+ extracellular vesicles. CD39 polymorphism rs3176891A→G is associated with the incidence of lung thrombosis in SCD patients but not healthy humans of African ancestry. Remarkably, CD39+ extracellular vesicles are fewer and ADP-induced platelet aggregation is higher in the blood of SCD patients with rs3176891G allele. This study identifies a novel extracellular vesicle-dependent mechanism preventing lung thrombosis in SCD and reveals how CD39 polymorphisms may impair this protection to increase the risk for lung thrombosis in a subset of SCD patients. It remains unknown why only some sickle cell disease (SCD) patients develop lung thrombosis. Here, the authors show that an extracellular vesicle-dependent mechanism prevents lung thrombosis in SCD and how a CD39 polymorphism impairs this protection to promote lung thrombosis in subset of patients.

Haemoglobin is a ferrous iron (Fe2+)-containing intracellular protein that is crucial for multiple homeostatic functions, including transport of oxygen and carbon dioxide, acid-base buffering and cellular signalling through nitric oxide oxidation and nitrite reduction. When erythrocyte membranes are disrupted, a process known as haemolysis that is caused by either disease or an exogenous stressor, haemoglobin is liberated into the plasma. This plasma free haemoglobin is highly pathogenic, disrupting a range of physiological processes and causing downstream organ damage through multiple mechanisms, including nitric oxide scavenging, vasoconstriction, generation of reactive oxygen species, activation of innate immune inflammation, disruption of cellular signalling, activation of the coagulation cascade and direct end-organ injury. Haemolysis and an elevated level of plasma free haemoglobin are associated with increased cardiovascular mortality, haemodynamic derangements, renal dysfunction and immune system dysregulation. These injurious pathways are exacerbated as the plasma free haemoglobin concentration and duration of exposure increase and are mitigated by endogenous scavenging pathways. In cardiovascular disease, proliferation of the use of mechanical circulatory support technologies, as well as an ageing population with chronic low levels of haemolysis, has increased exposure to plasma free haemoglobin and its detrimental effects. In this Review, we summarize the relationship between chronic haemolysis and cardiovascular disease and discuss current and future approaches towards the prevention and treatment of haemolytic injury.

The clinical benefit of blood transfusion is undeniable, and yet reliance on donated blood products has several shortcomings. These include risks of supply shortages due to reliance on volunteer donors, short storage life, and potential infectious disease transmission. Immune response complications to donated blood cannot be completely avoided, despite significant advances in testing. Many of these limitations are exacerbated in low-income countries. For decades, cell-free hemoglobin-based blood substitutes have been developed and tested as potential substitutes for red blood cell transfusions. Early studies found that purified, native hemoglobin exhibited significant safety risks, such as hypertension from excessive vasoconstriction and evidence of multiple organ toxicities. These effects are likely in part due to the reactive heme center, which will scavenge nitric oxide, generate reactive oxygen species, and may drive sterile inflammation. Numerous strategies have been explored to further modify hemoglobin in the hope of creating a safe and well-tolerated blood substitute. Despite some promising results in preliminary studies, large-scale clinical trials have continued to show elevated rates of adverse events and/or a failure to meet specified clinical endpoints. As a result, no hemoglobin-based oxygen carrier (HBOC) has obtained US Food and Drug Administration approval for clinical use. This review focuses on the history of HBOC development, the lessons that have been learned from prior failures of HBOC programs, and the status of ongoing artificial oxygen carrier development efforts.

Carbon monoxide (CO) poisoning causes 50,000 to 100,000 emergency department visits and ~1,500 deaths in the United States annually. Current treatments are limited to supplemental and/or hyperbaric oxygen to accelerate CO elimination. Even with oxygen therapy, nearly half of CO poisoning survivors suffer long-term cardiac and neurocognitive deficits related to slow CO clearance, highlighting a need for point of care antidotal therapies. Given the natural interaction between CO and ferrous heme, we hypothesized that the hemoprotein RcoM, a transcriptional regulator of microbial CO metabolism, would make an ideal platform for CO-selective scavenging from endogenous hemoproteins. We engineered an RcoM truncate (RcoM-HBD-CCC) that exhibits high CO affinity ( K a,CO = 2.8 × 10 10 M −1 ), remarkable selectivity for CO over oxygen ( K a,O2 = 1.4 × 10 5 M −1 ; K a,CO / K a,O2 = 1.9 × 10 5 ), thermal stability (T m = 72 °C), and slow autoxidation rate ( k ox = 1.1 h −1 ). In a murine model of acute CO poisoning, infused RcoM-HBD-CCC accelerated CO clearance from hemoglobin in red blood cells (RBCs) and was rapidly excreted in urine. Moreover, infused RcoM-HBD-CCC elicited minimal hypertension in mice compared to infused globins (hemoglobin, myoglobin, and neuroglobin), attributed to a comparatively limited reactivity toward nitric oxide (NO) via dioxygenation [ k NOD (RcoM) = 6 to 8 × 10 6 M −1 s −1 vs k NOD (Hb) = 6 to 8 × 10 7 M −1 s −1 ]. These data suggest that RcoM-HBD-CCC is a safe, selective, and efficacious CO scavenger. By limiting hypertension through minimal NO scavenging, RcoM-HBD-CCC improves end-organ adverse effects compared with other hemoprotein-based therapeutics.

Introduction: Hemorrhagic shock remains a leading cause of preventable death in warfare or acute trauma. Thus, the ongoing research for a successful artificial oxygen carrier as an alternative to blood. Our protein, the Bacterial Regulator of Carbon Monoxide Metabolism (RcoM), helps bridge this gap through its easily sourced nature, reproducibility, and effectiveness in delivering oxygen to the tissues. RCom is an engineered variant that lacks a DNA binding domain and contains cysteine mutations for improved stability (RcoM HBD-CCC), this optimized it's ligand binding ability, autoxidation rate, thermostability and nitric reduction rate. Hypothesis: We hypothesize that resuscitation with RcoM would improve mean arterial pressure (MAP) in hemorrhagic shock more than crystalloid resuscitation. Methods: A murine model of traumatic hemorrhagic shock was anesthetized with 1.5% isofluorane and received a laparotomy with a 2 cm abdominal incision to induce soft-tissue trauma. Left femoral artery and vein were cannulated for blood pressure monitoring and intravenous infusion respectively. Hemorrhage was induced by a 30-minute controlled pressure bleeding (25 to 40 mmHg) then shock was maintained for 30 minutes followed by resuscitation infusion for 30 minutes by either 2 mM lactated Ringer (LR) solution, human hemoglobin (HHb), or RcoM with a volume equal to the shed blood volume. Baseline MAP, post-resuscitation MAP, and MAP change were compared across the three groups using a one-way ANOVA. Results: There was no difference in the ratio of shed blood volume to the total blood volume (26.8 ± 3.4% for LR, 26.0 ±2.6% for HHb and 27.6 ± 1.3% for Rcom, p = 0.7295). There was no difference for the baseline MAP between LR (83.5 ± 5.7 mmHg), HHb (87.4 ± 3.0 mmHg) and Rcom (82.3 ± 1.9 mmHg; p = 0.2931). Post-resuscitation MAP was significantly higher for RcoM (67.0 ± 6.3 mmHg) and HHb (60.4 ± 16.0 mmHg) compared to LR (25.9 ± 21.4 mmHg, p = 0.0029). There was no difference between Rcom and HHb in the post-resuscitation MAP (p = 0.8573). Similarly, the MAP change was significantly lower for Rcom (-15.3 ± 6.8 mmHg) and HHb (-27.0 ± 13.5 mmHg) compared to LR (-57.5 ± 18.7 mmHg, p = 0.0011) but no difference between the HHb and Rcom groups (p = 0.5462). Conclusion: This study demonstrates that resuscitation with RcoM supports the blood pressure in a murine traumatic hemorrhagic shock model, suggesting its potential application as a non-globin artificial oxygen carrier for hemorrhagic shock.

BACKGROUND:Despite favorable hemodynamic and neurohormonal effects, endothelin receptor antagonists have not improved outcomes in patients with heart failure (HF), possibly because they cause fluid retention. METHODS:In this randomized, double-blind, multicenter trial (SERENADE [Macitentan in Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease]), we evaluated the effects of an endothelin receptor antagonist, macitentan, in patients with HF, left ventricular ejection fraction ≥40%, and pulmonary vascular disease. After a 4-week placebo run-in (to ensure clinical stability), followed by a 5-week single-blind macitentan run-in, patients who did not exhibit fluid retention were randomized to macitentan or placebo. The primary end point was change in NT-proBNP (N-terminal pro-B-type natriuretic peptide; baseline to 24 weeks); secondary end points included change in KCCQ (Kansas City Cardiomyopathy Questionnaire) clinical summary score (baseline to 24 weeks) and time to worsening HF by 52 weeks. RESULTS:Of 230 patients enrolled, 28 were excluded during the placebo run-in, 60 excluded during the macitentan run-in, and 142 were randomized. Macitentan had no effect on change in NT-proBNP (geometric mean ratio [macitentan/placebo], 1.02 [90% CI, 0.88-1.19]; P=0.79) or on secondary end points (placebo-corrected change in KCCQ clinical summary score, -3.5 [90% CI, -8.2 to +1.2]; P=0.22). Worsening HF occurred in 20 (28%) patients assigned to macitentan and 13 (18%) assigned to placebo (hazard ratio, 1.48 [90% CI, 0.83-2.67]; P=0.24). More macitentan-treated patients developed fluid retention (16 [23%] versus 10 [14%]) and cardiac adverse events (33 [46%] versus 22 [31%]) versus placebo. CONCLUSIONS:Despite a novel enrichment trial design to target pulmonary vascular disease and exclude treatment-related fluid retention in patients with HF and preserved/mildly reduced left ventricular ejection fraction, macitentan neither lowered NT-proBNP nor improved HF outcomes. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03153111 and NCT03714815.

PURPOSE:Pulmonary hypertension (PH) is a chronic complication of sickle cell disease (SCD) with limited known biomarkers, beyond increases in plasma brain natriuretic peptide levels. EXPERIMENTAL DESIGN:We conducted a proof-of-concept study to identify serum protein biomarkers that were differentially expressed in SCD patients with elevated tricuspid regurgitation velocity (TRV-a noninvasive marker of PH). RESULTS:We found 41 out of 92 target proteins that were significantly different between the nonelevated (TRV ≤ 2.6 m/s; N = 35) and highly elevated TRV group (TRV ≥ 2.9 m/s; N = 35, p < 0.05). Six of them passed a Bonferroni correction (p value < 0.0005), including T-cell surface glycoprotein, lymphotactin, SLAM family member 7, galectin-9, TNF-related apoptosis-inducing ligand receptor 2, and tumor necrosis factor receptor superfamily member 11A. We observed up to a 1.2-fold increase in the high TRV group for these six proteins. These six proteins had a strong positive correlation with serum NT-proBNP levels (a positive control marker elevated in PH [r ≥ 0.44]). Additionally, these markers correlated with other clinical parameters of PH in SCD. CONCLUSION:Circulatory protein markers of the immune response are increased in SCD patients with elevated TRV as compared to those without elevated TRV. SUMMARY:This study demonstrates that the circulatory protein markers of the immune response are increased in SCD patients with elevated TRV compared to those without elevated TRV. These biomarkers may be important tools for risk-stratifying patients with SCD or targets for therapeutic intervention.

The impact of common hemoglobinopathies, such as sickle cell trait (SCT), on outcomes in adults requiring extracorporeal membrane oxygenation (ECMO) remains understudied. Extracorporeal Life Support Organization registry data was analyzed to assess outcomes of adults with SCT or sickle cell disease (SCD) who underwent venoarterial or venovenous ECMO. Among 215 patients identified, 49 had SCT and 166 had SCD. The prevalence of SCT appeared grossly underestimated. Age-adjusted survival rates for SCT patients were favorable compared with those with SCD for venoarterial (43.5% vs. 19.5%; p = 0.04) and venovenous (73.3% vs. 44.8%; p = 0.11) ECMO. Bleeding and thrombotic event rates and renal complications in SCT patients were comparable to those with SCD and similar to reported rates in general adult ECMO populations. While our findings suggest that ECMO may be safely used in patients with SCT, further investigation is essential to determine the clinical impact of sickle cell and other hemoglobinopathies on ECMO therapy.