bims-sicedi Biomed News
on Sickle cell disease
Issue of 2024–11–24
eleven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo



  1. Br J Haematol. 2024 Nov 20.
      This commentary discusses the therapeutic potential of drug repurposing in sickle cell disease, highlighting the efficacy of hydroxyurea in enhancing fetal haemoglobin and the work of Raz et al. discussing the potential of using memantine for improving cognitive function, while emphasizing the need for further research. Commentary on: Raz et al. Memantine treatment in sickle cell disease: A 1-year study of its effects on cognitive functions and neural processing. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19866.
    Keywords:  hydroxyurea; repurposed drugs; sickle cell disease
    DOI:  https://doi.org/10.1111/bjh.19912
  2. Br J Haematol. 2024 Nov 17.
      Hydroxycarbamide (HC) is the most widely used therapeutic for individuals with sickle cell disease (SCD, including sickle cell anemia and other forms of the disease). HC's clinical benefits are primarily associated with its ability to induce foetal haemoglobin (HbF); this limited view of HC's therapeutic potential may lead to its discontinuation when a modest amount of HbF is induced. A better understanding of the HbF-independent effects of HC on genes and pathways relevant to SCD pathophysiology is therefore needed. In this study, we performed bulk RNA-Seq on whole blood samples collected from a cohort of 25 paediatric patients with SCD to identify genes and pathways that are affected by treatment with HC. At the maximum tolerated dose (MTD) of HC, patients showed altered expression levels of several genes and biological pathways. Pathways related to haeme metabolism, interferon-alpha response, and interferon-gamma response were significantly downregulated at HC MTD relative to the matched pre-HC samples. Pathways linked with IL2-STAT5 signalling and TNFα signalling via NF-Kβ were observed to be up-regulated at HC MTD. These results illustrate the range of effects exerted by HC during therapy for SCD and pave the way for an improved understanding of the HbF induction-independent benefits of HC.
    Keywords:  RNA sequencing; faetal haemoglobin; hydroxycarbamide; hydroxyurea; sickle cell disease
    DOI:  https://doi.org/10.1111/bjh.19839
  3. Exp Hematol. 2024 Nov 14. pii: S0301-472X(24)00538-1. [Epub ahead of print] 104673
      Anemia in patients with sickle cell disease (SCD) increases 2,3-diphosphoglycerate (2,3-DPG), decreasing hemoglobin-oxygen (Hb-O2) affinity to improve oxygen offloading and promote hemoglobin polymerization (sickling) of red blood cells (RBCs). We report the discovery of FT-4202, an investigational, selective pyruvate kinase type-R (PKR) activator with a multimodal mechanism of action and potential to increase ATP and decrease 2,3-DPG, resulting in increased Hb-O2 affinity, decreased Hb polymerization, and improved RBC health. FT-4202 was identified via structure-enabled lead optimization medicinal chemistry using X-ray crystallography, molecular modeling, and thermal shift assays. FT-4202, an allosteric PKR activator, stabilizes the tetrameric enzyme and increases PKR activity in human and mouse RBCs in vitro. Seven-day oral administration of FT-4202 in Berkeley SCD mice reduced 2,3-DPG, increased Hb-O2 affinity, and reduced RBC sickling versus control. There were no adverse in vitro safety findings. FT-4202 offers a therapeutic opportunity to modify the course of SCD.
    Keywords:  R-type pyruvate kinase; Sickle cell disease
    DOI:  https://doi.org/10.1016/j.exphem.2024.104673
  4. Haematologica. 2024 Nov 21.
      Continuous vaso-occlusive and inflammatory processes cause extensive end-organ damage in adults with sickle cell disease (SCD), and there is little evidence that longterm hydroxyurea therapy prevents this. In initial trials, P-selectin blockade with crizanlizumab reduced SCD vaso-occlusive crisis frequency, and interleukin (IL)-1β inhibition in SCD patients, using canakinumab, lowered inflammatory markers. We used murine SCD models to examine the effects of acute and chronic blockade of Pselectin and of IL-1β on vaso-occlusive events, their inflammatory profile and organ health. Both approaches improved impaired cutaneous microvascular perfusion in SCD mice by reducing TNF-α-induced vaso-occlusion. Acute P-selectin blockade markedly reduced TNF-α-induced neutrophil-platelet aggregate formation in SCD mice, and decreased leukocyte-rolling movements in the microvasculature, while acute IL-1β inhibition attenuated microvascular leukocyte adhesion. Six weeks of IL-1β-blocking immunotherapy improved the inflammatory profile of SCD mice, considerably reduced hepatic fibrosis and provided some relief from lung injury. In contrast, although Pselectin blockade reduced glomerular congestion, no significant benefit to overall organ pathology was observed. Unexpectedly, while combining the two immunotherapies reduced microvascular occlusion, their prolonged use caused acute liver injury. Notably, inhibition of IL-1β, but not of P-selectin, remarkably decreased hemosiderosis, in association with reduced tissue macrophage infiltration and the correction of biomarkers of dysregulated iron turnover. Our findings suggest that the attenuation of inflammation, as well as of vaso-occlusive processes, may be crucial for mitigating organ damage in SCD. Future trials should explore the ability of cytokine blockade to prevent multiorgan damage in patients with SCD, beyond evaluating vaso-occlusive crisis frequency.
    DOI:  https://doi.org/10.3324/haematol.2024.286418
  5. Am J Hematol. 2024 Nov 20.
      Sickle cell disease (SCD) is complicated by silent cerebral infarcts (SCIs), for which anemia is an important risk factor. Despite normal oxygen delivery (OD), cerebral vascular reserve (CVR), and cerebral metabolic rate of oxygen (CMRO2) are diminished in SCD, possibly causing the formation of SCIs. Voxelotor inhibits polymerization by increasing the hemoglobin oxygen binding, ameliorating hemolytic anemia. Furthermore, anemia is related to cardiac complications. Our aims were to assess the effect of voxelotor on markers of cerebral perfusion, cerebral oxygen metabolism, and markers of cardiac stress in SCD patients. Cerebral hemodynamics and oxygen metabolism were measured with MRI before and after 3 months of voxelotor treatment (1500 mg/day) in 18 adults with SCD (HbSS/HbSβ0-thalassemia). Hemoglobin levels significantly increased (p = .001) and markers of hemolysis decreased (p < .05). OD increased from 6.5 (IQR, 6.0-7.1) mL O2/100 g/min to 8.1 (IQR, 7.2-8.7) mL O2/100 g/min (p = .001). CBF and CVR did not change. CMRO2 decreased from 2.0 (IQR, 1.9-2.1) mL O2/100 g/min to 1.9 (IQR, 1.6-2.1) mL O2/100 g/min (p = .03). N-terminal pro-B type natriuretic peptide (NT-proBNP) levels decreased (p = .048) and maximum tricuspid regurgitation flow velocity (TRVmax) normalized in all but one patient with increased TRVmax. Voxelotor treatment in patients with severe SCD did not decrease CBF despite increased Hb levels. Cerebral oxygen metabolism slightly decreased, despite raised OD, most likely due to drug-induced increase in oxygen binding. Nonetheless, voxelotor improved clinically validated markers of cardiac stress.
    DOI:  https://doi.org/10.1002/ajh.27522
  6. Obstet Med. 2024 Jul 25. 1753495X241263135
       Background: Transthoracic echocardiography, a validated tool for risk assessment in non-pregnant population with sickle cell disease (SCD), uses tricuspid regurgitant velocity (TRV) over 2.5 m/s is an independent mortality risk factor. Its applicability in obstetrics lacks sufficient evidence.
    Methods: In this multicenter retrospective cohort study across five tertiary centers, we aimed to validate TRV as a determinant of increased maternal and fetal risk. Data was collected on 93 women and included 21 patients with TRV of at least 2.5 m/s. The maternal primary composite outcome included occurrence of vaso-occlusive crisis, acute chest syndrome, gestational hypertension, preeclampsia, and mortality. The fetal primary composite outcome comprised perinatal mortality, premature delivery, reduced birth weight, and fetal distress.
    Results: Adverse maternal and fetal events arose in both groups with no statistical difference.
    Conclusion: This study cannot support TRV of 2.5 m/s or more as an independent predictor of adverse obstetric outcomes among women with SCD.
    Keywords:  Pregnancy complications; hematologic
    DOI:  https://doi.org/10.1177/1753495X241263135
  7. Haematologica. 2024 Nov 21.
      Sickle cell disease (SCD) is one of the commonest severe inherited disorders in the world. Infection accounts for a significant amount of the morbidity and mortality, particularly in sub- Saharan Africa, but is relatively poorly studied and characterized. Patients with SCD have significant immunodeficiency and are more likely to suffer severe and life-threatening complications of infection, and additionally infections can trigger complications of SCD itself. Those with more severe forms of SCD have functional asplenia from a very early age, which accounts for much of the morbidity in young children, particularly invasive infections from encapsulated bacteria including Streptococcus Pneumoniae, Haemophilus Influenzae, Salmonella Typhi and meningococcal disease. Additionally, there are other defects in immune function in SCD, associated with anemia, tissue infarction and impaired adaptive immunity. Complications of infections in SCD include acute chest syndrome (ACS), acute painful episodes, osteomyelitis, meningitis, urinary tract infections, overwhelming sepsis and death. Viral infections cause significant morbidity, particularly severe anemia associated with Parvovirus, and to a lesser extent other infections such as influenza and COVID19. The relationship between malaria and SCD is complicated and discussed in this review. Unlike many of the genetic risk factors for poor outcomes in SCD, it is theoretically possible to modify the risks associated with infections with established public health measures. These include the provision of vaccinations, prophylactic antibiotics and access to clean water and mosquito avoidance, although current financial restraints and political priorities have made this difficult.
    DOI:  https://doi.org/10.3324/haematol.2024.285066
  8. Physiol Rep. 2024 Nov;12(22): e70132
      This study investigates hemoglobin (Hb)-induced kidney injury and the protective role of the ApoHemoglobin-Haptoglobin (ApoHb-Hp) complex against heme and Hb damage. Hb facilitates oxygen (O2) delivery but poses challenges outside red blood cells (RBCs) due to toxic Hb and heme mechanisms. These are managed by binding to serum proteins like Haptoglobin (Hp) and Hemopexin (Hpx). During hemolysis, depletion of Hp and Hpx leaves tissues vulnerable to Hb and heme. To address this, we developed the ApoHb-Hp complex, based on Apohemoglobin, which is produced by removing heme from Hb, conjugated with Hp. This complex acts as a dual scavenger for Hb and heme, preventing tissue damage. Our findings demonstrate that ApoHb-Hp significantly protects MPC5 podocytes from Hb-induced damage. Fluorescent staining showed a higher percentage of nephrin-positive cells in the ApoHb-Hp group, and MTT assays revealed enhanced cell viability compared to Hb alone. Additionally, ApoHb-Hp reduced reactive oxygen species (ROS) production, with the Hb group exhibiting significantly elevated ROS levels. The ApoHb-Hp complex mitigated the depletion of protective mechanisms, as shown by significant increases in superoxide dismutase (SOD) and glutathione (GSH). Moreover, ApoHb-Hp treatment reduced the activation of the NLRP3 inflammasome signaling pathway and inflammatory cytokines IL-1β and IL-18. These findings underscore the therapeutic potential of ApoHb-Hp in mitigating Hb-induced renal damage by preserving podocyte viability and reducing oxidative stress. Overall, ApoHb-Hp maintained protective mechanisms depleted otherwise by Hb. These findings highlight ApoHb-Hp's potential as a therapeutic agent against Hb-induced renal damage, offering insights into its mechanisms and implications for treating conditions involving hemolysis.
    Keywords:  Hb scavenging; ROS; filtration barrier; heme scavenging; hemoglobin; hemoglobin toxicity; podocytes; renal damage
    DOI:  https://doi.org/10.14814/phy2.70132
  9. Br J Haematol. 2024 Nov 20.
    Sickle Cell Disease Implementation Consortium
      Depression, disrupted sleep and pain are common comorbidities in sickle cell disease. We tested (1) if these comorbidities are associated with attention/executive functioning, processing speed and instrumental activities of daily living (IADLs), which describe complex skills that support independence, and (2) if cognitive symptoms mediate the relationship between comorbidities and IADLs. Participants (n = 2417) completed patient-reported outcome measures through the Sickle Cell Disease Implementation Consortium. Mean age of participants was 28 years and HbSS/Sβ0 genotypes were prevalent (73%). Comorbidities of depression, pain frequency and disrupted sleep were associated with processing speed and attention/executive functioning (all p < 0.01) when controlling for stroke and demographics. IADLs were associated with depression, pain, sleep, attention/executive functioning, income (<$25 000) (all p < 0.001) and genotype (p = 0.0025) after controlling for covariates. The indirect effects of attention/executive functioning and processing speed were both significant (p < 0.001) in mediation models that examined pathways between comorbidities and IADLs. Attention/executive functioning accounted for 17.5% of the relationship between depression and IADLs and sleep and IADLs. Processing speed explained 10% of the relationship between sleep and IADLs and 8% of the relationship between depression and IADLs. Managing comorbidities should be prioritized to mitigate cognitive symptoms and improve complex daily living skills.
    Keywords:  cognitive; depression; instrumental activities of daily living; pain; sickle cell disease; sleep
    DOI:  https://doi.org/10.1111/bjh.19881