Materiały źródłowe

• #1 Pathophysiology of Sickle Cell Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7053558/

  Since the discovery of sickle cell disease (SCD) in 1910, enormous strides have been made in the elucidation of the pathogenesis of its protean complications, which has inspired recent advances in targeted molecular therapies. In SCD, a single amino acid substitution in the -globin chain leads to polymerization of mutant hemoglobin S, impairing erythrocyte rheology and survival. Clinically, erythrocyte abnormalities in SCD manifest in hemolytic anemia and cycles of microvascular vaso-occlusion leading to end-organ ischemia-reperfusion injury and infarction. Vaso-occlusive events and intravascular hemolysis promote inflammation and redox instability that lead to progressive small- and large-vessel vasculopathy. Based on current evidence, the pathobiology of SCD is considered to be a vicious cycle of four major processes, all the subject of active study and novel therapeutic targeting: (a) hemoglobin S polymerization, (b) impaired biorheology and increased adhesion-mediated vaso-occlusion, (c) hemolysis-mediated endothelial dysfunction, and (d) concerted activation of sterile inflammation (Toll-like receptor 4 and inflammasome-dependent innate immune pathways). These molecular, cellular, and biophysical processes synergize to promote acute and chronic pain and end-organ injury and failure in SCD.

• #2 Sickle Cell Disease—Genetics, Pathophysiology, Clinical Presentation and Treatment

  https://www.mdpi.com/2409-515X/5/2/20

  Sickle cell disease (SCD) is a monogenetic disorder due to a single base-pair point mutation in the β-globin gene resulting in the substitution of the amino acid valine for glutamic acid in the β-globin chain. […] Understanding the pathogenesis and pathophysiology of the disorder is central to the choice of therapeutic development and intervention. […] The schematic representation in Figure 1 highlights the pathophysiology of SCD. Red blood cells (RBCs) that contain HbS or HbS in combination with other abnormal β alleles, when exposed to deoxygenated environment undergo polymerisation and become rigid. The rigid RBC’s are liable to haemolysis, and due to increased density may affect blood flow and endothelial vessel wall integrity. The dense rigid RBC’s lead to vaso-occlusion, tissue ischaemia, infarction as well as haemolysis.

• #3 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Sickle-Cell-Disease-Pathophysiology.aspx

  Sickle cell disease is an inherited genetic condition that involves defects in the shape and function of hemoglobin in the blood. This increases the likelihood of blockages in the blood vessels and disrupted blood flow, which can result in serious complications. […] Sickle hemoglobin differs in physical shape from normal hemoglobin, with a curved sickle-shape rather than flat-disc-shaped cells. The shape alters the properties of the cells, causing them to become more rigid and less flexible. As a result, the cells are more likely to hemolyze and cause blockages in the blood vessels that disrupt the flow of blood. […] The specific genetic mutation that results in sickle hemoglobin involves a substitution of thymine for adenine (from GAG to GTG) on the sixth codon of the genetic sequence. This leads to the coding of valine rather than glutamate on the sixth position of the hemoglobin beta chain.

• #4 Pathophysiology of Sickle Cell Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7053558/

  Intraerythrocytic HbS deoxygenation in tissues with high oxygen demand promotes the exposure of hydrophobic motifs on individual deoxygenated (T-state) HbS tetramers. As a result, S-globin chains on different deoxygenated HbS tetramers bind to each other to hide the hydrophobic motifs, thus initiating the nucleation of an HbS polymer. These HbS polymers grow rapidly to form long fibers that increase cellular rigidity and distort the erythrocyte membrane, leading to erythrocyte sickling, cellular energetic failure and stress, dehydration, impaired rheology and premature hemolysis. The rate of polymerization is proportional to the intraerythrocytic concentration of HbS and inversely proportional to the concentration of fetal Hb (HbF), which both replaces HbS and interferes with HbS polymerization.

• #5 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Sickle-Cell-Disease-Pathophysiology.aspx

  This genetic alteration changes the physical properties of the hemoglobin in cells, changing their shape to the characteristic sickle shape, as well as their physical properties, such as solubility and stability. It is these properties that account for changes in function and the common complications of the disease. […] When there is insufficient oxygen in the vascular system, sickle hemoglobin becomes considerably more insoluble, increasing the polymer formation in the blood and its overall viscosity. This leads to the formation of tactoids, which are a gel-like form of hemoglobin, that exists in equilibrium with its ordinary soluble state. […] Over time, the membrane of the cells becomes permanently damaged, leading cells to permanently stay in the bi-concave sickle shape, even when the blood is exposed to sufficient levels of oxygen once again.

• #6 Biophysical chemistry behind sickle cell anemia and the mechanism of voxelotor action | Scientific Reports

  https://www.nature.com/articles/s41598-024-52476-8

  The polymerization of a biomolecule involves two steps. The first is the conformational change of the native monomer; the second is the binding of the open, flipped, monomer to the growing interdigitating polymer. […] The steric and electrostatic effects of the residue hosted through the mutation have also been found as a reason for the low oxygen affinity of a mutant hemoglobin. […] This electrostatic equilibrium perturbation is of functional significance for the overall structural stability of Hb. […] The presence and strength of the salt bridge make the Hb molecule stable which was proved when a different form of HbS was observed after the substitution of Lys132 with Asn132. […] The same thing was also supported by the earlier study of molecular dynamics simulation confirming the inter-facial electrostatic collaborations accountable for HbS polymerization.

• #7 Sickle Cell Disease—Genetics, Pathophysiology, Clinical Presentation and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7510211/

  The consequence of haemolysis is a complex cascade of events including nitric oxide consumption; haemolysis linked nitric oxide dysregulation and endothelial dysfunction which underlie complications such as leg ulceration, stroke, pulmonary hypertension and priapism. […] Unlike normal RBCs with half-life of approximately 120 days, sickle RBCs (sRBC) may survive just 10-20 days due to increased haemolysis. […] During deoxygenation; healthy haemoglobin rearranges itself into a different conformation, enabling binding with carbon dioxide molecules which reverts to normal when released. In contrast, HbS tends to polymerise into rigid insoluble strands and tactoids, which are gel-like substances containing Hb crystals. […] The increase in the concentration of Ca2+ leads to dysfunction in the calcium pump.

• #8 Sickle Cell Disease (SCD): Practice Essentials, Background, Genetics

  https://emedicine.medscape.com/article/205926-overview

  Oxygen tension is a factor in that polymer formation occurs only in the deoxy state. If oxygen is present, the liquid state prevails. Concentration of Hb S is a factor in that gelation of HbS occurs at concentrations greater than 20.8 g/dL (the normal cellular Hb concentration is 30 g/dL). The presence of other hemoglobins is a factor in that normal adult hemoglobin (HbA) and fetal hemoglobin (HbF) have an inhibitory effect on gelation. […] These and other Hb interactions affect the severity of clinical syndromes. HbSS produces a more severe disease than sickle cell HbC (HbSC), HbSD, HbSO Arab, and Hb with one normal and one sickle allele (HbSA). […] When red blood cells (RBCs) containing homozygous HbS are exposed to deoxy conditions, the sickling process begins. A slow and gradual polymer formation ensues. Electron microscopy reveals a parallel array of filaments. Repeated and prolonged sickling involves the membrane; the RBC assumes the characteristic sickled shape.

• #9 Sickle Cell Disease (SCD): Practice Essentials, Background, Genetics

  https://emedicine.medscape.com/article/205926-overview

  After recurrent episodes of sickling, membrane damage occurs and the cells are no longer capable of resuming the biconcave shape upon reoxygenation. Thus, they become irreversibly sickled cells (ISCs). From 5-50% of RBCs permanently remain in the sickled shape. […] When RBCs sickle, they gain Na+ and lose K+. Membrane permeability to Ca++ increases, possibly due, in part, to impairment in the Ca++ pump that depends on adenosine triphosphatase (ATPase). The intracellular Ca++ concentration rises to 4 times the reference level. The membrane becomes more rigid, possibly due to changes in cytoskeletal protein interactions; however, these changes are not found consistently. In addition, whether calcium is responsible for membrane rigidity is not clear. […] Membrane vesicle formation occurs, and the lipid bilayer is perturbed. The outer leaflet has increased amounts of phosphatidyl ethanolamine and contains phosphatidylserine. The latter may play a role as a contributor to thrombosis, acting as a catalyst for plasma clotting factors. Membrane rigidity can be reversed in vitro by replacing HbS with HbA, suggesting that HbS interacts with the cell membrane.

• #10 Pathophysiology of Sickle Cell Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7053558/

  Endothelial dysfunction and sterile inflammation, which are hallmarks of SCD, may contribute to upregulation of selectins (P- and E-), vascular-cell-adhesion-molecule-1 (VCAM-1), ICAM-1, and major leukocyte chemoattractants such as KC (in mice) or interleukin-8 (IL-8) (in humans) on endothelial cells. The inflammatory milieu in SCD may also promote activation of neutrophils, monocytes, and platelets, leading to their increased adhesion to each other and to activated endothelium. […] As patients with SCD live longer in high-income countries, the chronic impact of sustained hemolytic anemia and episodic vaso-occlusive events results in the progressive development of end-organ complications. HbS-containing erythrocytes with intra-cellular Hb polymer are less deformable and become entrapped within the microcirculation, resulting in episodic and sustained vaso-occlusion. Additionally, the polymer-containing erythrocytes are subject to intravascular and extravascular hemolysis, causing chronic anemia with Hb levels ranging from 611 g/dl. The process of intravascular hemolysis directly damages blood vessels, and the resulting anemia exerts additional stress on the cardiovascular system by chronically increasing cardiac output, ventricular chamber dilation, and ventricular wall stress.

• #11 Red Cell Physiology & Pathophysiology of Sickle Cell Disease | PPT

  https://www.slideshare.net/slideshow/red-cell-physiology-pathophysiology-of-sickle-cell-disease/243225812

  Polymerization – helical fiber formation Polymerization is the root cause for pathogenesis Fibers group together stiffen the red cell repeated and prolonged sickling involves the membrane give rise to the characteristic shape – Sickle. […] Factors affecting polymerization Oxygen saturation Intracellular Hb composition Intracellular Hb concentration. […] Repeated sickling – Membrane damage – activation of ion channels – Dysregulation of cation homeostasis K-Cl co-transport system Ca-dependent K-channel (Gardos channel) Loss of intracellular K+ – cellular dehydration Increase in intracellular Hb concentration – increase chances of sickling. […] Basic pathogenesis – Erythrocytic membrane changes Methemoglobin formation Fe 2+ – Fe3+ Denaturing of Hb – hemichromes Oxidative stress – membrane alterations The normal asymmetry of membrane phospholipids is disrupted (reversal) Promote coagulation Proteins of the cytoskeleton express outside Sp. protein band 3 (Band 3 anion transport protein) Anti-band 3 IgGs accumulate on the protein band 3 aggregates, inducing erythrophagocytosis by macrophages Membrane changes cause microparticle formation – cell membrane loss Leads to stiffening and increased fragility of the SS- RBCs.

• #12 Pathophysiology of Sickle Cell Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7053558/

  Vaso-occlusion, or blood vessel occlusion, leading to ischemia is the predominant pathophysiology responsible for acute systemic painful vaso-occlusive crisis (VOC) and the requirement for emergency medical care by SCD patients. Intravital imaging studies done in transgenic humanized SCD mice and in vitro flow chamber studies done with SCD human blood over the past decade have contributed to the current understanding of vaso-occlusion as the interplay among impaired blood rheology, increased adhesiveness of erythrocytes with inflammatory cells and vascular endothelium, and hemostatic activation. The blood rheology is dictated by the hematocrit, plasma viscosity, and erythrocyte deformability. The increased plasma viscosity, which occurs as a result of chronic hemolysis and reduced sickle erythrocyte deformability due to Hb polymerization and dehydration, contributes to impaired flow of blood through capillaries and postcapillary venules of tissues with high oxygen demand. Poorly deformable sickle erythrocytes may become mechanically sequestered in the microcirculation to promote transient vaso-occlusion.

• #13 Sickle Cell Disease (SCD): Practice Essentials, Background, Genetics

  https://emedicine.medscape.com/article/205926-overview

  Complex multifactorial mechanisms involving endothelial dysfunction underlie the acute and chronic manifestations of SCD. […] A current model proposes that vaso-occlusive crises in SCD result from adhesive interactions of sickle cell RBCs and leukocytes with the endothelium. […] In this model, the endothelium becomes activated by sickle cell RBCs, either directly, through adhesion molecules on the RBC surface, or indirectly through plasma proteins (eg, thrombospondin, von Willebrand factor) that act as a soluble bridge molecule. This leads, sequentially, to recruitment of adherent leukocytes, activation of recruited neutrophils and of other leukocytes (eg, monocytes or natural killer T cells), interactions of RBCs with adherent neutrophils, and clogging of the vessel by cell aggregates composed of RBCs, adherent leukocytes, and possibly platelets.

• #14 Sickle Cell Disease (SCD): Practice Essentials, Background, Genetics

  https://emedicine.medscape.com/article/205926-overview

  Sickle cells express very late antigen4 (VLA-4) on the surface. VLA-4 interacts with the endothelial cell adhesive molecule, vascular cell adhesive molecule1 (VCAM-1). VCAM-1 is upregulated by hypoxia and inhibited by nitric oxide. […] Hypoxia also decreases nitric oxide production, thereby adding to the adhesion of sickle cells to the vascular endothelium. Nitric oxide is a vasodilator. Free Hb is an avid scavenger of nitric oxide. Because of the continuing active hemolysis, there is free Hb in the plasma, and it scavenges nitric oxide, thus contributing to vasoconstriction. […] In addition to leukocyte recruitment, inflammatory activation of endothelium may have an indispensable role in enhanced sickle RBC-endothelium interactions. Sickle RBC adhesion in postcapillary venules can cause increased microvascular transit times and initiate vaso-occlusion.

• #15 Sickle Cell Disease (SCD): Practice Essentials, Background, Genetics

  https://emedicine.medscape.com/article/205926-overview

  Several studies have shown involvement of an array of adhesion molecules expressed on sickle RBCs, including CD36, a-4–1 integrin, intercellular cell adhesion molecule4 (ICAM-4), and basal cell adhesion molecule (B-CAM). […] Adhesion molecules (ie, P-selectin, VCAM-1, a-V–3 integrin) are also expressed on activated endothelium. Finally, plasma factors and adhesive proteins (ie, thrombospondin [TSP], von Willebrand factor [vWf], laminin) play an important role in this interaction. […] For example, the induction of VCAM-1 and P-selectin on activated endothelium is known to enhance sickle RBC interactions. In addition, a-V–3 integrin is upregulated in activated endothelium in patients with sickle cell disease. a-V–3 integrin binds to several adhesive proteins (TSP, vWf, red-cell ICAM-4, and, possibly, soluble laminin) involved in sickle RBC adhesion, and antibodies to this integrin dramatically inhibit sickle RBC adhesion.

• #16

  https://www.jci.org/articles/view/89741

  Hemolysis is a fundamental feature of sickle cell anemia that contributes to its pathophysiology and phenotypic variability. […] Intravascular hemolysis can impair NO bioavailability and cause oxidative stress, altering redox balance and amplifying physiological processes that govern blood flow, hemostasis, inflammation, and angiogenesis. […] A cardinal feature of SCD pathogenesis involves inflammation, accompanied by heterocellular leukocyte-platelet-erythrocyte-endothelial adhesive events that trigger vaso-occlusive episodes, acute organ ischemia, and reperfusion injury. […] The crux of the hypothesis was a general appreciation that products of intravascular hemolysis damage the vascular system. […] NO is also depleted during intravascular hemolysis when arginase is liberated from erythrocytes, destroying arginine, the substrate for NOS.

• #17 Sickle Cell Disease—Genetics, Pathophysiology, Clinical Presentation and Treatment

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7510211/

  Furthermore, hypoxia also inhibits the production of nitric oxide, thereby causing the adhesion of sickle cells to the vascular endothelium. […] The lysis of erythrocytes leads to increase in extracellular haemoglobin, thus increasing affinity and binding to available nitric oxide or precursors of nitric oxide; thereby reducing its levels and further contributing to vasoconstriction.

• #18 Pathophysiology of Sickle Cell Disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7053558/

  Vaso-occlusion contributes to ischemia-reperfusion injury, which, along with release of eDAMPs, promotes the progression of sterile inflammation in SCD. Heme and its oxidized form, hemin, released following oxidation of Hb, are potent TLR4 agonists that contribute to a proinflammatory and procoagulant state in SCD, characterized by activated leukocytes, platelets, endothelial cells, tissue factor, cytokine storm, NO depletion, and generation of ROS. […] The interplay among genetics, HbS polymerization-dependent hemolysis and sickling, vaso-occlusion-dependent ischemia-reperfusion injury, endothelial dysfunction-dependent vasculopathy, and sterile inflammation contributes to the pathophysiology of SCD, which promotes acute and chronic complications of the CNS, heart, lung, kidney, liver, and other organs.

• #19

  https://haematologica.org/article/view/9513

  Sickle cell disease (SCD), considered the most common monogenic disease worldwide, is a severe hemoglobin disorder. […] It has been increasingly suggested that innate immune cells, including monocytes, neutrophils, invariant natural killer T cells, platelets and mast cells, have a role in promoting inflammation, adhesion and pain in SCD. […] Here we review the evidence for a contribution of innate immune cells to the pathophysiology of SCD. […] Monocytes have long been considered important in SCD pathophysiology. […] The absolute monocyte count is lower in SCD children being treated with hydroxyurea than in those not receiving such treatment, which may reflect another positive effect of hydroxyurea in SCD. […] More importantly, monocytes from SCD patients display an activated profile, with increased expression of CD11b on their surface and increased production of interleukin (IL)-1 and tumor necrosis factor (TNF)- as compared with healthy control monocytes.

• #20

  https://haematologica.org/article/view/9513

  Another sign of SCD monocyte activation is increased numbers of circulating tissue factor-positive monocytes, which contribute to the coagulation abnormalities observed in SCD patients. […] In turn, as compared with normal monocytes, activated monocytes from SCD patients can activate endothelial cells via the nuclear factor (NF)-B pathway, resulting in enhanced expression of E-selectin, intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). […] Endothelial activation is mediated by IL-1 and TNF-, produced by SCD monocytes, as demonstrated by its abrogation with antibodies targeting these two pro-inflammatory cytokines. […] Recently, a prominent role for the monocyte-TNF-endothelial activation axis was reported in transgenic sickle mice, with more global benefits from the TNF- blockers etanercept and infliximab than from the IL-1 blocker anakinra.

• #21

  https://haematologica.org/article/view/9513

  New insights into the role of monocytes in SCD pathophysiology have recently been provided by the description of a patrolling monocyte subset expressing a very high level of heme oxygenase-1 (HO-1) in SCD patients. […] Patrolling monocytes can also take up endothelial-adherent sickle RBC, especially during VOC, and HO-1 upregulation increases the survival of the patrolling monocytes by counteracting the cytotoxic effects of RBC-engulfed material. […] The main findings on the involvement of monocytes in SCD pathophysiology are summarized in Figure 1. […] Neutrophils have long been suspected to be involved in the pathophysiology of SCD. […] An important step in understanding the role of neutrophils in SCD pathophysiology was the intravital microscopy demonstration in SCD mice of increased neutrophil adhesion to the endothelium but also to sickle RBC in postcapillary venules.

• #22 Pathogenesis of Sickle Cell Anaemia | Encyclopedia MDPI

  https://encyclopedia.pub/entry/48960

  Platelets, which are small anucleate cells and play a role in the immune response, have also been implicated in the pathogenesis of SCD. […] Although many studies have investigated the role of the innate immune system, the role of the adaptive immune response is still poorly understood. […] Oxidative stress is an important contributor to the pathogenesis of sickle cell anaemia (SCD) and associated complications such as sickling, vaso-occlusion, and ischemia–reperfusion injury. […] Patients with SCD are frequently exposed to oxidative stress, and studies have found higher levels of ROS in the RBCs of SCD patients compared to healthy controls. […] Oxidative stress in SCD is associated with worsening symptoms, including accelerated haemolysis, endothelial damage, decreased NO bioavailability, and hypercoagulability.

• #23 Role of free radicals in the pathogenesis of acute chest syndrome in sickle cell disease | Respiratory Research | Full Text

  https://respiratory-research.biomedcentral.com/articles/10.1186/rr70

  In addition, oxygen-related species can directly injure the endothelium by peroxidation of the lipid membrane and/or DNA fragmentation, potentially leading to cellular apoptosis. […] There is a growing body of literature that suggests that patients with SCD are subjected to increased oxidative stress, particularly during vaso-occlusive crises (VOCs) and ACS. […] These findings suggest, both in humans and in mouse models of SCD, that there is increased oxidative burden and that alterations in the redox state may play a role in the development of vaso-occlusion. […] The RBC is an important source of oxygen-related radicals in SCD. […] Hebbel et al demonstrated that sickle RBCs produce greater quantities of O2-, H2O2 and OH than do normal RBCs. […] Because hemoglobin S auto-oxidizes at 1.7 times the rate of hemoglobin A, SCD patients may have a higher propensity for oxidant production.

• #24

  https://journals.lww.com/hemasphere/fulltext/2021/06000/research_in_sickle_cell_disease__from_bedside_to.13.aspx

  After building an electrophoresis machine, Pauling was able to separate normal adult hemoglobin (HbA) from abnormal sickle hemoglobin (HbS) and describe SCD at a molecular level for the first time. But, many questions remained unanswered, such as how HbS lead to the formation of these thin, elongated sickle-shaped red cells, the key phenotype in sickle pathophysiology, motivating an enormous amount of basic science studies on the Hb polymer structure, thermodynamics, and kinetics of HbS polymerization. […] Since polymerization of HbS can only occur when HbS is deoxygenated, increasing HbS oxygen affinity as a therapeutic approach has been discussed for many years, culminating in the development of oxygen affinity modifying drugs such as voxelotor. […] A key bedside observation that fetal Hb (HbF) had beneficial effects was first hypothesized by the pediatrician Watson in 1948, who noted that African American infants with SCD were less prone to have sickling events in the first few months of life during which HbF gradually disappears from the blood.

• #25

  https://journals.lww.com/hemasphere/fulltext/2021/06000/research_in_sickle_cell_disease__from_bedside_to.13.aspx

  As polymerization of deoxy-HbS is the key event that triggers the downstream consequences of SCD, several therapeutic approaches have focused on mitigation of this root cause, utilizing both genetic and pharmacological anti-sickling strategies. […] The best-established strategy is induction of HbF synthesis borne out not only by the plentiful clinical and epidemiological studies, but also by the kinetics and thermodynamics of the polymerization process itself. […] Advances in our understanding of the molecular mechanisms regulating the fetal to adult Hb switch have led to the generation of new agents that do not rely on causing stress erythropoiesis and they fall into 2 main groups: those that affect chromatin regulators and others that affect DNA-binding transcription factors. […] Identification of the key erythroid-specific enhancer elements was critical and important in the development of the clinical trials aimed at downregulating BCL11A using 2 different genetic approaches lentiviral short hairpin RNA (shRNA) and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated nuclease-9 (Cas-9) editing. […] Molecular dissection of these mechanisms led to new insights on the pathophysiology of SCD and new therapeutic targets on vaso-occlusion, HbS polymerization, and vascular adhesion that were approved by the FDA in the last 5 years.

• #26

  https://haematologica.org/article/view/9039

  In short, HbF interdicts the root-cause pathophysiology of SCD. […] The scientific foundation for efforts to chemically modify HbS is the two-state allosteric Monod-Wyman-Changeux structural model which characterizes the rapidly reversible equilibrium between the quarternary structure of hemoglobin with low oxygen affinity (fully deoxygenated hemoglobin, T quarternary structure) and the hemoglobin quarternary structure with high affinity for oxygen (oxygenated hemoglobin, R quarternary structure). […] The Monod-Wyman-Changeux model demonstrated incompatibility of the R conformation with polymerization, creating a foundation to propose molecules to favor the high oxygen affinity R conformation, as a method to delay HbS polymerization.

• #27

  https://link.springer.com/article/10.1007/s00277-025-06216-1

  Voxelotor (GBT440) is an oral, first-in-class, small-molecule inhibitor of HbS polymerization. It reversibly binds to and stabilizes oxyhemoglobin, preventing the polymerization of deoxygenated HbS and erythrocytic sickling and hemolysis. […] Activation of the complement pathway occurs in patients with SCD during baseline, acute pain crises, and delayed hemolytic transfusion reactions. Research indicates that complement dysregulation may contribute to SCD’s pathophysiology, impacting vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and organ damage. […] Chronic thromboembolic disease (CTED) and pulmonary hypertension (PH) are both common in sickle cell disease. The nitric oxide (NO) signaling pathway is disrupted in sickle cell disease, which leads to pulmonary artery endothelial dysfunction and smooth muscle proliferation.

• #28 Sickle Cell Disease (SCD): Types, Symptoms & Causes

  https://my.clevelandclinic.org/health/diseases/12100-sickle-cell-disease

  A genetic mutation in the HBB gene causes sickle cell disease. The HBB gene is responsible for making a part of the hemoglobin. People with SCD received two mutated HBB genes coded for abnormal hemoglobin one from each parent. […] People inherit SCD in an autosomal recessive manner. This means each parent of a child with SCD carries one copy of the mutated gene, but they typically dont show signs and symptoms of the condition. […] Sickle cell disease treatment includes medications, transfusions, blood and marrow transplant and gene therapy. […] Voxelotor can prevent red blood cells from sickling and binding together. It may reduce the destruction of some red blood cells, which improves blood flow to your organs and lowers your risk for anemia. […] Crizanlizumab: This medicine helps prevent sickled red blood cells from sticking to your blood vessel walls. This can improve blood flow and reduce inflammation and pain crises.

• #29 Mechanism of Action of Hydroxyurea

  https://www.hcplive.com/view/mechanism-of-action-of-hydroxyurea

  Hydroxyurea has multiple different benefits. The mechanism of actions include the inhibition of ribonucleotide reductase, which inhibits reticulocyte production. Its myelosuppressive, so you get a drop in the white blood cell count. We all know that sickle cell disease is an inflammatory disease, so decreasing the white blood cell count as an inflammatory marker is potentially another important strategy. […] We also know that hydroxyurea will decrease the red blood cell adhesion to the endothelial markers. Whats not talked about is that hydroxyurea decreases the overall number of red blood cells. So not only does it decrease the endothelial adhesion, but it decreases the overall number of red blood cells that are likely to cause the microvascular occlusion. […] Hydroxyurea also increases hemoglobin F by hypomethylation of the gamma genes. This is the most highlighted approach to why hydroxyurea should work, but I think the evidence is clear that there are children and adults with high hemoglobin F levels who still go on to have pain.

• #30 Mechanism of Action of Hydroxyurea

  https://www.hcplive.com/view/mechanism-of-action-of-hydroxyurea

  Last but not least, there are clearly other methods, but hydroxyurea acts as an NO [nitric oxide] donor with at least 3 documented pathways for NO donation by hydroxyurea. […] In summary, it has a range of benefits or mechanisms to support its use. […] The real game changer in this field was the study out of Johns Hopkins University with Samuel Charache, [MD,] that demonstrated that hydroxyurea dropped the rate of significant pain episodes by about 50% in adults. It significantly drops the rate of acute chest syndrome by about 50%, and also, importantly, drops the rate of blood transfusion therapy by about 50%. […] We also know that hydroxyurea increases the parameters of blood flow to the brain. Specifically, theres evidence that hydroxyurea will drop the transcranial doppler measurement, transcranial doppler is a marker for increased risk of strokes. That benefit occurs within 3 months of starting hydroxyurea.

• #31 Casgevy and Lyfgenia: Two Gene Therapies Approved for Sickle Cell Disease > News > Yale Medicine

  https://www.yalemedicine.org/news/gene-therapies-sickle-cell-disease

  Sickle cell disease is a red blood cell disorder that affects hemoglobin, the protein that carries oxygen throughout the body. […] With Casgevy, an edit (or cut) is made in a particular gene to reactivate the production of fetal hemoglobin, which dilutes the faulty red blood cells caused by sickle cell disease. […] The goal of genetic therapies for SCD is to treat or cure the disease by changing DNA or adding new DNA. […] With Casgevy, the patients blood stem cells are edited in a way that makes them produce high levels of fetal hemoglobin, which is produced during fetal development and binds to oxygen more strongly than adult hemoglobin. […] Casgevy targets the parts of the DNA involved in switching the fetal hemoglobin off and deletes it from the genome. The body then starts to produce fetal hemoglobin, which dilutes sickle hemoglobin.

• #32 Casgevy and Lyfgenia: Two Gene Therapies Approved for Sickle Cell Disease > News > Yale Medicine

  https://www.yalemedicine.org/news/gene-therapies-sickle-cell-disease

  Essentially, Casgevy works by reducing the number of sickle cells in the body to a negligible amount, which may permanently ease symptoms. […] Lyfgenia, meanwhile, works by taking a piece of a virus (a lentivirus, which belongs to the HIV family) and using it to deliver a functional version of a hemoglobin-producing gene. […] While Casgevy activates the native fetal hemoglobin, Lyfgenia uses an artificial gene. But both are trying to dilute the sickle hemoglobin that the body would otherwise continue to make.

• #33

  https://link.springer.com/article/10.1007/s00277-025-06216-1

  HbS polymerization also alters the cell membrane of erythrocytes and causes oxidative stress, causing chronic hemolytic anemia. […] Free heme further initiates the cascade of inflammation via increased innate immune response, inflammatory cytokines, and endothelial cell and platelet activation, worsening the hypercoagulable state and exacerbating the vicious cycle of thrombosis in patients with SCD. […] P-selectin is upregulated in endothelial cells and platelets and contributes to the pathogenesis of vaso-occlusion and sickle cell pain crises. Vaso-occlusion is caused by the adhesion of deformed erythrocytes and leukocytes to the endothelium, which results in vascular obstruction and tissue ischemia. […] Crizanlizumab inhibits P-selectin interaction with P-selectin glycoprotein ligand 1 (PSGL-1).

• #34

  https://link.springer.com/article/10.1007/s00277-025-06216-1

  Riociguat potentiates guanylate cyclase enzyme, which produces cyclic guanosine monophosphate (cGMP) upon activation by NO. cGMP functions as a smooth muscle relaxant and thus causes vaso-dilation. This may reduce pulmonary arterial pressures and right heart strain and improve exercise tolerance. […] The breakdown of sickle cell red blood cells releases heme, which activates inflammatory proteins that result in vaso-occlusion.

• #35 Sickle Cell Disease: A 2025 Update

  https://frontlinegenomics.com/sickle-cell-disease-a-2024-update/

  Sickle cell disease is a genetic blood disorder, characterised by defective haemoglobin in red blood cells. Haemoglobin is responsible for the transport of oxygen throughout the body, and the mutation responsible for the disorder leads to abnormal haemoglobin that causes the red blood cells to form a ‘sickle’ shape. These defective cells are prone to clumping together and can obstruct blood flow. This can result in what is known as vaso-occlusive events or crises – episodes of severe pain, and in extreme cases, organ damage – as well as increasing the infection risk in patients. […] The disease is inherited in an autosomal recessive manner. It stems from an A•T point mutation in the haemoglobin-beta gene (HBB), and predominantly affects those of African descent. […] Different forms of gene editing have been trialled to correct the mutation over the years, and in 2021, base editing showed potential in mice. Gene editing pioneer David Liu was at the forefront of this research, which involved the use of an adenine base editor to switch the pathogenic thymine to a harmless cytosine.

• #36 Sickle Cell Disease: A 2025 Update

  https://frontlinegenomics.com/sickle-cell-disease-a-2024-update/

  Enter prime editing. Almost two years after the aforementioned work was published, in April 2023 Liu’s team showed that prime editing could restore the wild type HBB gene in cell models. […] Perhaps the biggest news in the genomics world in the last couple of years was the approval of the first CRISPR-based gene therapy, which was designed to treat sickle cell disease and beta-thalassemia. […] It does this by knocking out the regulatory elements that prevent the expression of foetal haemoglobin in mature cells, allowing for functional transport of oxygen around the body. […] Last summer, researchers reported the development of an oral therapy that could be used to trigger the expression of foetal haemoglobin, similar to the fundamental mechanism behind Casgevy. […] Ultimately, the disease’s relatively simple mechanism combined with the significant global health burden make it an effective target for researchers.

• #37 Sickle Cell Disease, a Review

  https://www.mdpi.com/2673-6357/3/2/24

  Sickle cell disease and its variants constitute the most common inherited blood disorders affecting millions of individuals worldwide. […] In recent years, detailed data regarding molecular genetics, pathophysiology, mechanisms for the development of symptoms and side effects of sickle cell disease have been published. […] The sickling process results in gradual development of a parallel array of filaments called polymer formation. […] The pathophysiology of the SCD is complex and multi-systemic. […] This, as noted previously, starts with polymerization of HbS under low oxygen tension, changing the shape, structure and function of the erythrocytes, and reducing their lifespan. […] The sickle red blood cells interact with the vascular endothelium and trigger activation of neutrophils, monocytes, and platelets.

• #38 Sickle Cell Disease, a Review

  https://www.mdpi.com/2673-6357/3/2/24

  Hemolysis and release of cell-free hemoglobin on a continuous basis, depletes hemopexin and haptoglobin, resulting in reduced bioavailability of nitric oxide (NO) and vascular endothelial dysfunction. […] Changes which result from hemoglobin S polymerization, alteration of blood flow due to the increased erythrocyte tendency for adhesion, which result in vaso-occlusion, endothelial dysfunction related to hemolysis, and iron-regulated gene expression associated with upregulation of inflammasome pathway gene expression, are major factors involved. […] The latter results in a 200-fold increase in Toll-like receptor 4 (TLR4) expression in the peripheral blood mononuclear cells. […] A combination of these events and other processes promotes vaso-occlusion resulting in pain, end organ injuries, and failure in sickle cell disease.

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