The Heme Scavenger Hemopexin Reverts Heme-Driven Pro-Inflammatory Phenotypic Switching of Macrophages in Sickle Cell Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2205-2205
Author(s):  
Francesca Vinchi ◽  
Milene Costa da Silva ◽  
Giada Ingoglia ◽  
Sara Petrillo ◽  
Nathan Brinkman ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Inflammatory Markers ◽  
Heme Iron ◽  
Phenotypic Switching ◽  
Phenotypic Change ◽  
Cell Disease ◽  
Expression Levels ◽  
Arginase 1 ◽  
Inflammatory Phenotype

Abstract Hemolytic diseases, such as sickle cell anemia and thalassemia, are characterized by enhanced release of hemoglobin and heme into the circulation, heme-iron loading of reticulo-endothelial system macrophages as well as chronic inflammation. Here we demonstrate that in addition to activating the vascular endothelium, hemoglobin and heme alter the macrophage phenotype in sickle cell disease. We show that exposure of cultured macrophages to hemolytic aged red blood cells, heme or iron causes their functional phenotypic change towards a pro-inflammatory phenotype, with increased expression levels of inflammatory markers such as IL-6 (P<0.001), TNFα (P<0.0001), IL-1β (P<0.001) MHCII (P<0.001), CD86 (P<0.05) and CD14 (P<0.0001) and decreased expression levels of anti-inflammatory markers such as IL-10 (P<0.0001), CD206 (P<0.0001), Arginase-1 and Ym1. Interestingly, hemolysis and macrophage heme/iron accumulation in a mouse model of sickle cell disease triggers similar pro-inflammatory phenotypic alterations in hepatic macrophages, increasing the expression levels of IL-6 (P<0.0001), MHCII (P<0.05), CD86 (P<0.0001) and iNOS (P<0.01). On the mechanistic level, heme-induced pro-inflammatory phenotype switching of macrophages critically depends on ROS production and activation of the TLR4 signaling pathway. We further demonstrate that the heme scavenger hemopexin protects reticulo-endothelial macrophages from heme overload in heme-loaded Hx-null mice (P<0.05) and reduces production of cytokines (IL-6, TNFα: P<0.01) and reactive oxygen species (P<0.001). Importantly, in sickle mice the administration of human exogenous hemopexin attenuates the inflammatory phenotype of macrophages, by decreasing the expression of IL-6 (P<0.05), MHCII (P<0.01), CD86 (P<0.001) and iNOS (P<0.05). Taken together, our data suggest that therapeutical administration of hemopexin is beneficial to counteract heme-driven macrophage-mediated inflammation in sickle cell disease. Disclosures Brinkman: CSL Behring: Employment. Zuercher:CSL Behring: Employment.

Abstract P726: Cytochrome B5 Reductase 3 Modifies The Brain-Blood Axis Response To Ischemic Stroke In Mice With Sickle Cell Disease

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Katherine C Wood ◽  
Heidi M Schmidt ◽  
Scott Hahn ◽  
Mehdi Nouraie ◽  
Mara Carreno ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ischemic Stroke ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
African Ancestry ◽  
Cytochrome B5 ◽  
Heme Iron ◽  
Wild Type ◽  
Cell Disease ◽  
Cytochrome B5 Reductase

Introduction: Stroke and silent infarcts are serious complications of sickle cell disease (SCD), occurring frequently in children. Decreased nitric oxide bioavailability and responsiveness contribute to neurovascular disease. Cytochrome b5 reductase 3 (Cyb5R3) is a heme iron reductase that reduces oxidized soluble guanylate cyclase heme iron (Fe 3+ --> Fe 2+ ) to preserve nitric oxide signaling. A loss-of-function Cyb5R3 missense variant (T117S) occurs with high frequency (0.23 minor allele) in persons of African ancestry. Hypothesis: We hypothesized that impaired reductase function of T117S Cyb5R3 exacerbates brain damage after ischemic stroke in SCD. Methods: Bone marrow transplant was used to create male SCD mice with wild type (SS/WT) or T117S (SS/T117S) Cyb5R3. Blood was sampled before and after middle cerebral artery occlusion (55 minutes occlusion, 48 hours reperfusion). Infarct volume (IV) was determined by 2,3,5-triphenyltetrazolium chloride. Intravascular hemolysis and correlation (Pearson’s R) of hematology changes with IV were determined. Baseline Walk-PHaSST (NCT00492531) data were analyzed for stroke occurrence. Results: Brain IV (63 vs 27 cm 3 , P=0.003) and mortality (3/6 vs 0/8) were greater in SS/T117S vs SS/WT. Red blood cells, hemoglobin and hematocrit declined as IV increased. Plasma oxyhemoglobin increased in parallel with IV (r = 0.74, P=0.09). There were different signatures to hematologic changes that occurred with IV in SCD. Relative to wild type, T117S contracted the erythroid compartment (red blood cell: -13% vs 13%, P=0.003; hematocrit: -20% vs 1%, P=0.008; hemoglobin: -18% vs 2%, P=0.007). Mean platelet volume correlated with IV in SS/T117S (r = 0.87, P=0.06), while the inverse occurred in SS/WT (r = -0.63, P=0.09) Monocytes increased in parallel with IV in SS/T117S (r = 0.73, P=0.16), but followed the opposite trajectory in SS/WT (r = -0.77, P=0.04). WalkPHaSST participants with T117S Cyb5R3 self-reported more ischemic stroke (7.4% vs 5.1%) relative to wild type. Conclusion: Cyb5R3 is an important modifier of the evolution and outcome of ischemic brain injury in SCD and its hematologic consequences. Our findings indicate a bidirectional relationship between stroke and anemia in SCD that may axially turn on Cyb5R3 activity.

Vitamin Deficiency, CD40L and VEGF in a Young Population with Sickle Cell Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4768-4768
Author(s):  
E. Leila Jerome Clay ◽  
Julia Brittain ◽  
Rupa Redding-Lallinger
Keyword(s):  
Vitamin D ◽  
Platelet Count ◽  
Sickle Cell Disease ◽  
Vitamin D Deficiency ◽  
Sickle Cell ◽  
Inflammatory Markers ◽  
Young Population ◽  
Cell Disease ◽  
Vitamin D Levels ◽  
25 Oh Vitamin D

Abstract Abstract 4768 Introduction: Vitamin D deficiency is known to be common in patients with sickle cell disease (SCD). Vitamin D is important in multiple aspects of health, including the cardiovascular, immune and skeletal systems and its effects are mediated through the vitamin D receptor. The systems affected by vitamin D are also perturbed by SCD. Vitamin D deficiency is common in SCD, but its contribution to disease manifestations is being investigated. Vitamin D modulates the immune response and may have an effect on the levels of increased inflammation seen in individuals with SCD. In children and young adults with SCD at UNC Hospitals, we sought to determine the prevalence of vitamin D deficiency and its association with inflammatory markers and the influence of VDR haplotype. We report here on vitamin D status and several markers of inflammation. Methods: We recruited pediatric and young adult SCD patients in their steady state attending routine periodic evaluations at the Pediatric and Adult Sickle Cell Clinics at the University of North Carolina Hospitals between February and June 2012. After consent, patients had their blood collected for inflammatory markers, 25-OH vitamin D and DNA. Patients with active pain crisis or recent illness were excluded. A chart review was done for the last 5 years to obtain SCD genotype, baseline white blood cell count, hemoglobin, platelets, calcium, phosphate and alkaline phosphatase. We measured inflammatory markers IL2, IL6, CD40L, TNFa, plasma VEGF and CD40L levels using ELISA (R&D Systems). At present only the VEGF and CD40L levels, along with baseline clinical laboratory data are available with the other inflammatory marker data expected shortly. Spearman's regression was used to examine potential correlations between continuous variables. A p value of < 0.05 was considered significant. P-values are considered nominal and are uncorrected for multiple analyses. Results: Vitamin D levels were measured in 78 patients, ages ranging from 2 to 26 years, with 55% males. The SCD genotypes were SS and Sb°Thal at 80%, SC and Sb+Thal at 20%. Thirty percent of patients were on hydroxyurea and ten percent of patients were on chronic exchange transfusions. Severe vitamin D deficiency (<10 ng/mL) was present in 18%, mild to moderate deficiency (10–24 ng/mL) in 54% and only 28% were sufficient (>25 ng/mL). VEGF mean was 110.1 pg/mL (SD 125.8). CD40L mean was 642.2 pg/mL (SD 378.2). For the group as a whole, there were no correlations between the inflammatory markers and 25-OH vitamin D levels. However, when the group who was vitamin D deficient (< 25 ng/mL) was examined (n=39), vitamin D levels were inversely correlated with platelet count (rho= −0.3596, p =0.0246). Platelet count was positively correlated with CD40L level (rho= 0.3176, p= 0.0488). VEGF and CD40L levels were positively correlated (rho= 0.4520, p= 0.0039). Vitamin D levels are negatively correlated with age (rho= −0.3794, p = 0.0172). Restricting the analyses by age and gender did not change the results, nor did removing the individuals on hydroxyurea or chronic transfusions. Discussion: As has been noted previously, vitamin D deficiency is very common in people with sickle cell disease, including this young population, with mean age of 14 years. Inflammation is common as well, as reflected by the markedly elevated CD40L levels as well as the high-normal distribution of white cell count and platelet count. VEGF levels in adults with SCD appear to be elevated although are quite variable; VEGF appears to be a marker of inflammation in this disease. Little is known about VEGF levels in children with SCD. No associations between vitamin D levels and CD40L or VEGF levels were seen, however an inverse correlation between vitamin D level and platelet count was found. As platelets are a marker of inflammation, this suggests that further investigation of the relationship between vitamin D deficiency and inflammation could be fruitful. We anticipate having data concerning vitamin D and IL2, IL6 and TNFa in this group in the near future, as well as the ability to stratify the individuals by VDR haplotype. Disclosures: Redding-Lallinger: Eli Lilly and Company: Research Funding.

scholarly journals Leukocyte Telomere Length Correlates with Disease Severity and Inflammation in Sickle Cell Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2173-2173 ◽  
Author(s):  
Marina Pereira Colella ◽  
Barbara Santana ◽  
Rodrigo T. Calado ◽  
Sara T. Olalla Saad
Keyword(s):  
Sickle Cell Disease ◽  
Telomere Length ◽  
Disease Severity ◽  
Sickle Cell ◽  
Inflammatory Markers ◽  
Quantitative Polymerase Chain Reaction ◽  
Cell Disease ◽  
Inflammation Markers ◽  
Telomere Attrition ◽  
Tnf Α

Abstract Telomeres are specialized nucleoprotein structures that protect chromosome ends. The loss of telomeric structure permits DNA-damage and results in cellular senescence and apoptosis. Short telomeres may be due to either impaired telomere elongation due to telomerase defect as observed in dyskeratosis congenita, aplastic anemia, and pulmonary fibrosis or caused by "stress" hematopoiesis and increased cell proliferation due to chronic inflammation and oxidative stress. As bone marrow demand and inflammation are characteristics of sickle cell disease (SCD), we sought to evaluate telomere length in SCD patients. Mean telomere length was measured in peripheral blood leukocytes by quantitative polymerase chain reaction (qPCR), as we have previously described (Gutierrez-Rodrigues, PLoS ONE 2014; 9(11):e113747). The telomere length for each sample was determined using the telomere to single copy gene ratio (T/S ratio) with the calculation of the DCt [Ct(telomere)/Ct(single gene) ]. To validate the qPCR results, we performed terminal restriction fragment (TRF) analysis for 17 samples with long and short telomeres, according to the manufacturer's instructions (TeloTAGGG Telomere Length Assay - Roche Applied Science, Mannheim, Germany). Tumor necrosis factor-alpha (TNF-α) and interleukin 8 (IL-8) were assessed as pro-inflammatory markers, measured in serum samples, in duplicate, using ultra sensitive ELISA kits. Spearman's rank correlation coefficient was used to analyze bivariate associations between telomere lengths, hemolysis markers and inflammation markers. We compared telomere length according to the diagnosis, use of hydroxyurea and gender using Wilcoxon rank sum test. All p values ≤0.5 were considered significant. In all of the analysis we used age-ajusted T/S ratios. A total of 91 adult SCD patients were included in the study, 51 with HbSS, 38 with HbSC and 2 with HbSβ. Fifty-one were off hydroxyurea and 40 were taking the drug, with a median dose of 1g/day (range 500-1750mg/day). We compared age-adjusted T/S ratio of SCD patients to 261 healthy controls and found significantly shorter telomeres in SCD patients (p<0.0001). When we compared HbSS patients to HbSC and HbSβ patients HbSS patients had significantly shorter telomeres (p<0.0001). Telomere length also was shorter in patients on hydroxyurea when compared to those off the drug (p=0.02). We found no difference in T/S ratio according to gender or age in the SCD cohort. To evaluate whether inflammation or hemolysis were associated with telomere attrition in SCD patients, we analyzed the associations between T/S ratios and hemolysis (hemoglobin, hematocrit, lactate dehydrogenase, indirect bilirubin, reticulocyte counts) and inflammation markers (IL-8, TNF-α, total leucocyte, neutrophil, lymphocyte and monocyte counts). We found a significant positive correlation between hemoglobin level and T/S ratio (r=0.29; p=0.004), and a negative correlation between lymphocyte counts and telomere length (r=-0.29; p=0.005), and between IL-8 serum levels and telomere length (r=-0.4; P=0.02). SCD patients presented shorter telomeres in comparison to age-matched health controls. Telomere erosion in SCD appeared to correlate with disease severity and to treatment with hydroxyurea. Our results also indicate that telomere attrition correlated with the intensity of anemia and inflammatory markers. Disclosures No relevant conflicts of interest to declare.

Plasma Biomarkers of Iron Regulation, Overload, and Inflammation in Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1380-1380
Author(s):  
Abhishek Mangaonkar ◽  
Niren Patel ◽  
Hongyan Xu ◽  
Kavita Natrajan ◽  
Betsy Clair ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Inflammatory Markers ◽  
Conflicts Of Interest ◽  
Plasma Concentrations ◽  
Transferrin Saturation ◽  
Iron Regulation ◽  
Cell Disease ◽  
Transfusion History

Abstract Transfusional iron overload has been increasingly recognized among patients with sickle cell disease (SCD) over the past two decades. We recently reported on the prevalence of iron overload among 635 adult SCD patients followed at our center and found that 80 patients (12%) had developed iron overload as a result of repeated blood transfusions. Fifty six (70%) of these subjects developed iron overload as a result of episodic, mostly unnecessary transfusions at outlying hospitals. There have been reports of association of increased morbidity and mortality among iron overloaded SCD patients; it has also been hypothesized that SCD patients tend to develop fewer complications of iron overload, compared to transfusion dependent beta thalassemia, primarily due to the chronic inflammatory state with resultant upregulation of hepcidin, and lower extra-hepatic iron loading. We studied biomarkers of iron metabolism, iron regulation, and inflammatory markers in 22 patients with SCD (SS) and iron overload (two consecutive ferritin levels of >1000 ng/ml and significant transfusion history) and compared these with 14 SCD patients without iron overload (ferritin <1000 ng/ml, and no significant transfusion history). Serum Fe, ferritin, %transferrin saturation (Tf) and total iron binding capacity, as well as high sensitivity C reactive protein (hsCRP) were performed by routine laboratory methods. Plasma concentrations of soluble transferrin receptor (sTfR), interleukin-6 (IL-6), Growth Differentiation Factor-15 (GDF-15) were measured using commercially available ELISA kits (R&D Systems, Minneapolis, USA). Plasma hepcidin was measured using a commercially available kit from DRG Diagnostics (Marburg, Germany). The results are summarized below: Abstract 1380. TableAgeyearsFerritin ng/ml% sathsCRPmg/dLHepcidinng/mlsTfRnmol/LGDF-15pg/mlIL-6pg/mlCases (n=22)33.42083.560.40.8829.872.21201.55.2Controls (n=14)29.0401.840.40.9512.477.11115.34.1p-value0.236.14E-050.020.80.0020.20.550.24 As expected, ferritin and % Tf saturation were significantly higher in the iron overloaded group. Hepcidin levels were also significantly higher in cases vs. controls, indicative of appropriate upregulation of hepcidin in Fe overload. sTfR and GDF-15 levels, as well as the inflammatory markers (hsCRP and IL-6) did not differ significantly between Fe overloaded and non-iron overloaded SCD patients. The two groups did not differ significantly in terms of the measures of disease severity (number of pain crises/year and number of hospitalizations/year). We further looked at the ratio of hepcidin/ferritin, sTfR/log ferritin, GDF-15/hepcidin, and tested the correlation between GDF-15 and hepcidin levels and ferritin and hepcidin levels; the ratio of hepcidin to ferritin was not different between cases and controls (0.019 and 0.021, respectively, p=0.73). sTfR to log ferritin ratio was significantly lower in cases compared to controls (22.3 vs 33.24, p=0.0004). GDF-15/hepcidin ratio was also found to be significantly lower in cases (262.1 vs 1896.7, p=0.01). Additionally, GDF-15 and hepcidin levels correlated significantly in controls but not iron overloaded SCD patients (p=0.04 vs p=0.7). Similarly, hepcidin and ferritin levels were significantly correlated in controls (p=0.03) but not in cases (p=0.8). Our results suggest that i) hepcidin levels are appropriately upregulated in iron overloaded SCD patients, ii) inflammatory markers (hsCRP and IL-6) were not significantly different between iron overloaded and non-iron overloaded patients, suggesting that systemic inflammation is not the driving factor behind hepcidin upregulation in iron overloaded SCD patients; however, a local/paracrine effect of IL-6 on hepatocytes secondary to Fe related inflammation in the liver cannot be excluded; and iii) GDF-15 and sTfR levels are not different between cases and controls, indicating that erythropoiesis does not differ between Fe overloaded and non-iron overloaded SCD patients. The observation that the correlation between GDF-15 and hepcidin levels is lost in iron overloaded SCD patients suggests that erythropoiesis does not contribute to hepcidin regulation in these subjects. This can further be clarified by studying the role of the newly described erythroid regulator of hepcidin, erythroferrone in SCD with and without iron overload. Disclosures No relevant conflicts of interest to declare.

scholarly journals Angiogenic and Inflammatory Markers of Cardiopulmonary Changes in Children and Adolescents with Sickle Cell Disease

PLoS ONE ◽  
2009 ◽  
Vol 4 (11) ◽  
pp. e7956 ◽  
Author(s):  
Xiaomei Niu ◽  
Mehdi Nouraie ◽  
Andrew Campbell ◽  
Sohail Rana ◽  
Caterina P. Minniti ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Children And Adolescents ◽  
Sickle Cell ◽  
Inflammatory Markers ◽  
Cell Disease

scholarly journals Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease

Blood ◽  
2016 ◽  
Vol 127 (4) ◽  
pp. 473-486 ◽  
Author(s):  
Francesca Vinchi ◽  
Milene Costa da Silva ◽  
Giada Ingoglia ◽  
Sara Petrillo ◽  
Nathan Brinkman ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Mouse Model ◽  
Sickle Cell ◽  
Phenotypic Switching ◽  
Cell Disease ◽  
Key Points ◽  
Free Heme

Key Points Heme and iron induce macrophage phenotypic switching toward an M1 proinflammatory phenotype. By scavenging free heme, hemopexin reverts heme-induced proinflammatory activation of macrophages in a mouse model of sickle cell disease.

scholarly journals The T117S Variant of Cytochrome b5 Reductase 3 Increases the Risk for Ischemic Stroke with Enhanced Anemia in Mice with Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
Katherine C Wood ◽  
Heidi M Schmidt ◽  
Scott Hahn ◽  
Subramaniam Sanker ◽  
Samit Ghosh ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Infarct Volume ◽  
Cytochrome B5 ◽  
Heme Iron ◽  
Cerebral Infarct ◽  
Cell Disease ◽  
Brain Infarct ◽  
Cytochrome B5 Reductase

Introduction. Stroke and silent infarcts are serious complications of sickle cell disease (SCD), occurring frequently in children between 3 and 14 years old. A vast amount of clinical and experimental evidence has concluded that decreased nitric oxide (NO) bioavailability and/or NO responsiveness, as is seen in SCD, is a major contributing factor in the pathogenesis of neurovascular disease. NO responsiveness, which occurs via NO-induced activation of soluble guanylate cyclase (sGC), requires reduced heme iron (Fe2+) in the sGC active site. We recently identified cytochrome b5 reductase 3 (Cyb5R3) as an sGC heme iron reductase in vascular smooth muscle (VSM), where it reverses the oxidized heme iron of sGC (Fe3+ --&gt; Fe2+) to preserve NO sensing/signaling under conditions of oxidative stress. In a mouse model of SCD we have shown that knockdown of Cyb5R3 in VSM accelerates the development of pulmonary hypertension and cardiac remodeling. A missense variant of Cyb5R3 (T117S) that results in loss-of-function methemoglobin reductase activity occurs at a high frequency in persons of African ancestry (0.23 minor allele frequency). Unpublished baseline data from the Walk-PHaSSt trial (NCT00492531) reveals that persons with SCD who carry the T117S variant are at increased risk of ischemic stroke; these individuals self-reported almost 50% more (74 vs 51 cases per 1000 individuals) ischemic stroke than those with wild-type (WT) Cyb5R3. Hypothesis. We hypothesized that impaired reductase function of Cyb5R3 T117S leads to sustained sGC heme oxidation, which drives cerebral vascular dysfunction and exacerbates brain damage after ischemic stroke in SCD. Methods. Bone marrow transplant was used to create SCD mice with global expression of WT or T117S Cyb5R3, hereafter referred to as SS/WT or SS/T117S, respectively. All mice were male, C57Bl/6 background, and &gt;85% engrafted with SS Hb for 12 weeks. Ischemic stroke was induced using transient middle cerebral artery occlusion (MCAO: 55 min occlusion, 48 hr reperfusion), after which brains were stained with 2,3,5-triphenyltetrazolium chloride (TTC,1%) to determine infarct volume. Blood was sampled before and after MCAO to assess effects of brain infarct on hematological parameters. Student's t-test was used for analysis of 2 groups and Pearson's R used for correlation analyses of brain infarct volume with hematology changes [(post-pre/pre) * 100]. Results. Global expression of T117S Cyb5R3 in SCD caused increased cerebral infarct volume (62.9 vs 26.7 cm3, P=0.003) and mortality (3/6 vs 0/6) relative to WT Cyb5R3. WT and T117S Cyb5R3 mice with SCD were similar in that both showed declining red blood cells (RBC), hemoglobin (Hgb) and hematocrit (Hct) as infarct volumes increased. In the SS/T117S group, the anemia was more severe in keeping with larger infarct volumes. There were different signatures to the hematologic changes that occurred with cerebral infarct in SCD. When compared to WT Cyb5R3, T117S caused the erythroid compartment to contract (RBC: -12.97% vs 13.41%, P=0.01; Hct: -19.75% vs 0.31%, P=0.025; Hgb: -17.93% vs 2.78%, P=0.017). In SS/WT mice platelet numbers increased more relative to SS/T117S (17.5 vs 9.7 * 103 cells/uL); and MPV, a measure of platelet activation, inversely correlated with brain infarct volume (r = -0.94, P=0.006), the opposite of what was seen in SS/T117S (r = 0.87, P=0.056). Monocytes seem to play an important role in the volume of brain infarct in SS/T117S as their numbers increased in parallel with infarct volume (r = 0.73, P=0.16), but followed the opposite trajectory in SS/WT mice (r = -0.75, P=0.14). Conclusion. These results indicate that Cyb5R3 is an important modifying factor in the evolution and outcome of ischemic brain injury in SCD. Our findings also raise questions on just how cerebral infarct modifies the anemia of SCD, as well as the role played by Cyb5R3 in the dynamics of that relationship. To what extent is the sGC-cGMP-PKG pathway involved at the cerebrovascular and erythropoietic levels? Does Cyb5R3 contribute resilience to ischemic stroke in SCD? The development and application of targeted therapies for effectively preventing and treating cerebrovascular disease in SCD rely on finding the answers to these questions. Disclosures No relevant conflicts of interest to declare.

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