Materiały źródłowe

• #1 Pathophysiology of Sickle Cell Disease

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

  Sickle cell anemia is caused by homozygosity of the beta-S (S) allele (located on chromosome 11p15.5), which differs from the wild-type -allele by a single nucleotide polymorphism dbSNP Rs334(T;T) in which GTG is substituted for GAG in the sixth codon of the -globin gene. This leads to replacement of a hydrophilic glutamic acid residue (Glu) with a hydrophobic valine residue (Val) at the sixth position in the -globin chain, resulting in a mutated hemoglobin tetramer HbS (2s2) in the erythrocytes of individuals with sickle cell anemia. Homozygous inheritance of the S mutation (HbSS) or coinheritance of S with other mutations such as C (HbSC), D (HbSD), O (HbSO/Arab), E (HbSE), or a -thalassemia allele (HbS/-thal0 or HbS/-thal+) leads to other forms of SCD via multiple interlinked molecular and cellular mechanisms, which are described in the following sections.

• #2 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.

• #3 Sickle Cell Anemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482164/

  Sickle cell anemia is characterized by two major components: Hemolysis and vaso-occlusive crises (VOC). The defect in the beta-globin gene makes the sickle hemoglobin (HbS) molecule susceptible to converting into rigid, elongated polymers in a deoxygenated state. The sickling process is cyclical initially, where sickle erythrocytes oscillate between the normal biconcave shape and the abnormal crescent shape (acquired under low oxygen pressure). However, there comes a time when the change becomes irreversible, and the sickle erythrocytes develop a permanent sickle shape, increasing the risk for hemolysis and VOC. All variants of SCD share the same pathophysiology leading to polymerization of the HbS component. […] Multiple factors inherent to sickle erythrocytes, like the low affinity of HbS for oxygen, physiologically high 2,3-diphosphoglycerate, and increased sphingokinase-1 activity, lead to deoxygenation, which promotes the polymerization of HbS. In addition to this, a high concentration of HbS, abnormal activity of the Gados channel leading to dehydration, and repeated damage to the red blood cell (RBC) membrane also increase the risk of polymerization of HbS.

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

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

  Sickle cell anemia disease has been a great challenge to the world in the present situation. It occurs only due to the polymerization of sickle hemoglobin (HbS) having ProValGlu typed mutation, while the polymerization does not occur in normal hemoglobin (HbA) having ProGluGlu peptides. […] The low oxygen affinity of a mutant hemoglobin is a characteristic of SCAD. It has already been confirmed that one of the glutamic acid residues of ProGluGlu (PGG) present in normal hemoglobin (HbA) is replaced by valine residue i.e. ProValGlu (PVG) in sickle cells, also called E6V mutation. […] The deoxygenated form of HbS (dHbS) takes part in the polymerization reaction rapidly while its oxygenated form (OHbS) does not. […] 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.

• #6 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.

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

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

  HbS arises from a mutation substituting thymine for adenine in the sixth codon of the beta-chain gene, GAG to GTG. This causes coding of valine instead of glutamate in position 6 of the Hb beta chain. The resulting Hb has the physical property of forming polymers under deoxy conditions. It also exhibits changes in solubility and molecular stability. These properties are responsible for the profound clinical expressions of the sickling syndromes. […] Under deoxy conditions, HbS undergoes marked decrease in solubility, increased viscosity, and polymer formation at concentrations exceeding 30 g/dL. It forms a gel-like substance containing Hb crystals called tactoids. The gel-like form of Hb is in equilibrium with its liquid-soluble form. A number of factors influence this equilibrium, including oxygen tension, concentration of Hb S, and the presence of other hemoglobins.

• #8 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.

• #9 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.

• #10 Sickle Cell Anemia – WikiLectures

  https://www.wikilectures.eu/w/Sickle_Cell_Anemia

  The sickling of red blood cells depends on many changing factors: The amount of hemoglobin present in red cells excluding HbS. As mentioned above, in heterozygotes half of their hemoglobin is HbS. Therefore, the remaining HbA can influence the rate of polymerization and sickling occurs little or not at all. […] The amount of HbS in red cells influences the tendency of HbS to form polymers. For example, dehydration of red cells increases the concentration of HbS and promotes sickling. […] The time that red cells are exposed to low concentrations of oxygen. Red blood cells passing through microvascular beds where blood flow is diminished, are exposed to lower oxygen tension and sickling is easier to happen. This usually happens in bone marrow and spleen. In addition, inflamed tissues have also a decreased blood flow so sickling is more likely to happen.

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

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

  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.

• #13 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.

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

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

  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 RBC’s with half-life of approximately 120 days, sickle RBC’s (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.

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

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

  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 RBC’s with half-life of approximately 120 days, sickle RBC’s (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.

• #16 Sickle cell disease – Wikipedia

  https://en.wikipedia.org/wiki/Sickle_cell_disease

  The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells, because of their shape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction. Healthy red blood cells typically function for 90-120 days, but sickled cells only last 10-20 days. […] The rapid breakdown of RBC’s in SCD results in the release of free heme into the bloodstream exceeding the capacity of the body’s protective mechanisms. Although heme is an essential component of hemoglobin, it is also a potent oxidative molecule. Free heme is also an alarmin – a signal of tissue damage or infection, which triggers defensive responses in the body and increases the risk of inflammation and vaso-occlusive events.

• #17 Mechanisms and Clinical Complications of Hemolysis in Sickle Cell Disease and Thalassemia (Chapter 11) – Disorders of Hemoglobin

  https://www.cambridge.org/core/books/disorders-of-hemoglobin/mechanisms-and-clinical-complications-of-hemolysis-in-sickle-cell-disease-and-thalassemia/F28A5F766B9752DEA43CCF7B87A5BE45

  Anemia is the most basic clinical characteristic of sickle cell disease and thalassemia. In sickle cell disease, the polymerization of sickle hemoglobin (HbS) causes profound changes in the integrity and viability of the erythrocyte, leading to both extravascular and intravascular hemolysis. The lifespan of the erythrocyte in sickle cell disease is often shortened to less than one-tenth of normal. […] This chapter examines the mechanisms that give rise to the accelerated hemolysis characteristic of these hemoglobinopathies and considers emerging data suggesting that chronic intravascular hemolysis produces endothelial dysfunction and a progressive vasculopathy. […] The mechanisms and consequences of hemolysis differ by two main anatomical compartments: extravascular hemolysis, which primarily involves phagocytosis by macrophages in the reticuloendothelial system, and intravascular hemolysis, which occurs within the blood vessel lumen. […] Approximately two-thirds of hemolysis in sickle cell disease is extravascular and one-third intravascular.

• #18 Sickle Cell Anemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482164/

  Oxidative stress contributes to hemolysis by auto-oxidation of HbS, leading to erythrocyte cell membrane damage. The increased expression of xanthine dehydrogenase, xanthine oxidase, and decreased expression of NADPH oxidase increase the oxidative stress within sickle RBC. A hemolyzed cell releases free hemoglobin (scavenges nitrous oxide) and arginase 1 (competes for L-arginine) that prevent the action and formation of nitrous oxide and contribute to oxidative stress and vascular remodeling (arginase-1 converts arginine to ornithine). […] Besides the polymerization of the HbS and intravascular hemolysis, several other factors also contribute to vaso-occlusion. For example, the sickle RBC (expresses several adhesion molecules on the surface), free heme and Hb, reactive oxygen species, and endothelium interact with each other and with neutrophils and platelets to promote vaso-occlusion and thrombosis.

• #19 Sickle Cell Anemia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482164/

  Oxidative stress contributes to hemolysis by auto-oxidation of HbS, leading to erythrocyte cell membrane damage. The increased expression of xanthine dehydrogenase, xanthine oxidase, and decreased expression of NADPH oxidase increase the oxidative stress within sickle RBC. A hemolyzed cell releases free hemoglobin (scavenges nitrous oxide) and arginase 1 (competes for L-arginine) that prevent the action and formation of nitrous oxide and contribute to oxidative stress and vascular remodeling (arginase-1 converts arginine to ornithine). […] Besides the polymerization of the HbS and intravascular hemolysis, several other factors also contribute to vaso-occlusion. For example, the sickle RBC (expresses several adhesion molecules on the surface), free heme and Hb, reactive oxygen species, and endothelium interact with each other and with neutrophils and platelets to promote vaso-occlusion and thrombosis.

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

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

  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 RBC’s with half-life of approximately 120 days, sickle RBC’s (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.

• #21 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. […] Vaso-occlusion contributes to ischemia-reperfusion injury, which, along with release of eDAMPs, promotes the progression of sterile inflammation in SCD. Heme (ferrous protoporphyrin IX) and its oxidized form, hemin (ferric protoporphyrin IX), 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.

• #22 Sickle cell disease – Wikipedia

  https://en.wikipedia.org/wiki/Sickle_cell_disease

  The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells, because of their shape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction. Healthy red blood cells typically function for 90-120 days, but sickled cells only last 10-20 days. […] The rapid breakdown of RBC’s in SCD results in the release of free heme into the bloodstream exceeding the capacity of the body’s protective mechanisms. Although heme is an essential component of hemoglobin, it is also a potent oxidative molecule. Free heme is also an alarmin – a signal of tissue damage or infection, which triggers defensive responses in the body and increases the risk of inflammation and vaso-occlusive events.

• #23 Pathogenesis of Sickle Cell Anaemia | Encyclopedia MDPI

  https://encyclopedia.pub/entry/48960

  Free haemoglobin and heme released during haemolysis have been identified as key players in the activation of the innate and adaptive immune response with reports suggesting that patients with high haemolysis rates are at greater risk of early mortality. The continual breakdown and destruction of red blood cells result in sustained activation of innate immune cells resulting in a chronic inflammatory state. […] Endothelial cells are one of the first cell types to be activated in the presence of heme. Heme activates endothelial cells inducing the expression of adhesion molecules (E-selectin, intercellular P-selectin, vascular cell adhesion molecule 1) which initiates the activation and recruitment of other immune cells, including macrophages, neutrophils, mast cells, and platelets. […] Heme also has a direct link with the activation of neutrophils by acting as a prototypical pro-inflammatory molecule and recruiting neutrophils to the site of injury via the stimulation of protein kinase C and ROS generation.

• #24 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. Oxidative stress occurs due to an imbalance between the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the ability of antioxidant agents, including enzymes such as superoxide dismutases, catalase, and glutathione peroxidase, to neutralise them. […] 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.

• #25 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. Oxidative stress occurs due to an imbalance between the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the ability of antioxidant agents, including enzymes such as superoxide dismutases, catalase, and glutathione peroxidase, to neutralise them. […] 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.

• #26 Pathogenesis of Sickle Cell Anaemia | Encyclopedia MDPI

  https://encyclopedia.pub/entry/48960

  The oxidative damage to lipids known as lipid peroxidation happens when membrane phospholipids are exposed to a hydroxyl radical and hydroperoxyl, which have been reported as the two most prevalent ROS affecting lipids. […] Inflammation is the body’s natural response to toxic chemicals, infection, and injury. Although it is difficult to determine the exact events that trigger the chronic inflammatory state in sickle cell disease (SCD), some mechanisms have been reported. The sources of inflammation in SCD include red cell alterations, haemolysis, vaso-occlusive processes, ischemia–reperfusion injury, infections, release of histamine, oxidative stress, thrombin generation and activation of complement. Many reported complications such as acute chest syndrome, stroke, leg ulcers, nephropathy, and pulmonary hypertension have been linked to inflammatory processes.

• #27 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.

• #28 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.

• #29 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.

• #30 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. […] Vaso-occlusion contributes to ischemia-reperfusion injury, which, along with release of eDAMPs, promotes the progression of sterile inflammation in SCD. Heme (ferrous protoporphyrin IX) and its oxidized form, hemin (ferric protoporphyrin IX), 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.

• #31 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. […] Vaso-occlusion contributes to ischemia-reperfusion injury, which, along with release of eDAMPs, promotes the progression of sterile inflammation in SCD. Heme (ferrous protoporphyrin IX) and its oxidized form, hemin (ferric protoporphyrin IX), 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.

• #32 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. […] Vaso-occlusion contributes to ischemia-reperfusion injury, which, along with release of eDAMPs, promotes the progression of sterile inflammation in SCD. Heme (ferrous protoporphyrin IX) and its oxidized form, hemin (ferric protoporphyrin IX), 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.

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

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

  Mechanisms Participating In the Vaso-occlusive Event Retardation of the blood flow through the microcirculation Adhesion of young red cells on the endothelial wall Activation of the endothelial cells Activation of the passing-by leucocytes and platelets and adhesion on the endothelial wall Vasoconstriction. […] Proposed model of sickle cell VOC 1. endothelial activation by SS-RBCs and other inflammatory mediators 2. recruitment of adherent leukocytes 3. activation of recruited neutrophils and of other leukocytes (eg, monocytes or NK cells) 4. interactions of sickle erythrocytes with adherent neutrophils 5. vascular clogging by heterotypic cell-cell aggregates composed of SS-RBCs, adherent leukocytes and possibly platelets 6. increased transit time to greater than the delay time for deoxygenation-induced hemoglobin polymerization, propagating retrograde VOC 7. ischemia as a result of the obstruction that creates a feedback loop of worsening endothelial activation.

• #34 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.

• #35 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.

• #36 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.

• #37 Pathophysiology of Sickle Cell Disease

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

  Sickle cell anemia is caused by homozygosity of the beta-S (S) allele (located on chromosome 11p15.5), which differs from the wild-type -allele by a single nucleotide polymorphism dbSNP Rs334(T;T) in which GTG is substituted for GAG in the sixth codon of the -globin gene. This leads to replacement of a hydrophilic glutamic acid residue (Glu) with a hydrophobic valine residue (Val) at the sixth position in the -globin chain, resulting in a mutated hemoglobin tetramer HbS (2s2) in the erythrocytes of individuals with sickle cell anemia. Homozygous inheritance of the S mutation (HbSS) or coinheritance of S with other mutations such as C (HbSC), D (HbSD), O (HbSO/Arab), E (HbSE), or a -thalassemia allele (HbS/-thal0 or HbS/-thal+) leads to other forms of SCD via multiple interlinked molecular and cellular mechanisms, which are described in the following sections.

• #38 Pathophysiology of Sickle Cell Disease

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

  Sickle cell anemia is caused by homozygosity of the beta-S (S) allele (located on chromosome 11p15.5), which differs from the wild-type -allele by a single nucleotide polymorphism dbSNP Rs334(T;T) in which GTG is substituted for GAG in the sixth codon of the -globin gene. This leads to replacement of a hydrophilic glutamic acid residue (Glu) with a hydrophobic valine residue (Val) at the sixth position in the -globin chain, resulting in a mutated hemoglobin tetramer HbS (2s2) in the erythrocytes of individuals with sickle cell anemia. Homozygous inheritance of the S mutation (HbSS) or coinheritance of S with other mutations such as C (HbSC), D (HbSD), O (HbSO/Arab), E (HbSE), or a -thalassemia allele (HbS/-thal0 or HbS/-thal+) leads to other forms of SCD via multiple interlinked molecular and cellular mechanisms, which are described in the following sections.

• #39 Sickle cell disease – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/sickle-cell-disease/

  Hemolysis and the subsequent increased turnover of erythrocytes may increase the demand for folate, causing folate deficiency. […] The body increases the production of fetal hemoglobin (HbF) to compensate for low levels of HbA in sickle cell disease. […] Hydroxyurea reduces the incidence of acute painful episodes and improves survival. […] Stimulation of erythropoiesis and increased fetal hemoglobin proportional reduction of sickled hemoglobin decreased red blood cell polymerization fewer vasoocclusive episodes.

• #40 Sickle cell disease – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/sickle-cell-disease/

  Hemolysis and the subsequent increased turnover of erythrocytes may increase the demand for folate, causing folate deficiency. […] The body increases the production of fetal hemoglobin (HbF) to compensate for low levels of HbA in sickle cell disease. […] Hydroxyurea reduces the incidence of acute painful episodes and improves survival. […] Stimulation of erythropoiesis and increased fetal hemoglobin proportional reduction of sickled hemoglobin decreased red blood cell polymerization fewer vasoocclusive episodes.

• #41 Sickle cell disease – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/sickle-cell-disease/

  Hemolysis and the subsequent increased turnover of erythrocytes may increase the demand for folate, causing folate deficiency. […] The body increases the production of fetal hemoglobin (HbF) to compensate for low levels of HbA in sickle cell disease. […] Hydroxyurea reduces the incidence of acute painful episodes and improves survival. […] Stimulation of erythropoiesis and increased fetal hemoglobin proportional reduction of sickled hemoglobin decreased red blood cell polymerization fewer vasoocclusive episodes.

• #42

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

  We have also gained incredible insights on the switch from fetal to adult Hb with identification of key regulating factors such as B-cell lymphoma/leukemia 11A (BCL11A) that together, with major advances in genetic and genomic technologies, have translated into genetic-based approaches for treating SCD. […] 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.

• #43

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

  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. […] 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.

• #44

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

  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. […] The amino acid sequence of -globin chain is sufficiently different from S such that little or no -globin takes part in the fiber formation, so the primary effect of HbF (22) is to simply dilute the intracellular concentration of HbS. […] Strategies that reduce HbS intracellular concentration, such as increasing HbF or the red cell volume (ie, mean corpuscular volume [MCV]), increase the delay time to sickling, while strategies that reduce adherence and shorten transit time should be therapeutic. […] 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.

• #45 Pathophysiology of Sickle Cell Disease

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

  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.

• #46 Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-03074-z

  Here, we defined sVOC as VOC that arises from the downstream processes caused by the initial VOC episodes. In this paper, we will summarize the mechanisms and pathophysiology of the chronic inflammatory processes associated with SCD, define and examine the molecular events of VOC and how they might promote sVOC, and propose a multipronged approach for the management of VOC episodes to prevent the development of sVOC. […] The mechanism of VOC is complex and yet to be fully dissected. However, it is most likely VOC occurs when the balance between the pathologic processes of SCD responsible for the ongoing inflammation and the hosts adaptive mechanisms is disrupted in favor of the pathologic processes. As a result, the host adaptive mechanisms are overwhelmed, and this leads to decompensation of the balanced state.

• #47 Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-03074-z

  VOC begins with increased sickling and interaction of the sickle erythrocytes with the endothelium in the post-capillary venules, either directly or by way of leukocytes adherent to the endothelium, leading to obstruction of blood flow that triggers a host of signaling cascades. […] Following the development of vaso-occlusion, several downstream pathologic processes are amplified beyond those that can be held in check by the host adaptive mechanisms. […] Among the many downstream events are the following five pathways, all of which result in a positive-feedback into the VOC process to induce secondary VOC: (1). Increased hemolysis produces more free heme and overwhelms heme scavenging mechanisms, precipitating the development of neutrophil extracellular traps that promotes a local prothrombotic condition. (2). Local hypoxemia caused by vaso-occlusion induces sickling of erythrocytes in the vicinity. (3). Cytokine release due to VOC activates leukocytes and platelets and increases their recruitment to the site of local tissue damage. (4). Increased enterocyte damage due to VOC further increases the gut permeability and worsens the translocation of luminal bacteria/bacterial products into the systemic circulation. (5). Stress induced by painful VOC leads to increased production of epinephrine and glucocorticoid response.

• #48 Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-03074-z

  The ongoing inflammatory processes are further worsened if VOC occurs because VOC is invariably followed by ischemiareperfusion injury. […] The extent of the balance between chronic inflammatory processes and various adaptive mechanisms that maintain the equilibrium probably varies among different SCD individuals. […] Ongoing inflammatory processes not only render SCD patients to developing VOC, they also create a prothrombotic state. […] The current passive approach relies solely on supportive measures and wait for the spontaneous resolution of the VOC episodes. As a result, the duration of VOC is prolonged in patients who are caught in the vicious cycle of the pathology with the development of sVOC. A more aggressive approach that would treat the VOC instead is needed. […] Unless targeting the erythrocytes to protect the un-involved HbS erythrocytes from secondary sickling, successful treatment of VOC targeting of the downstream pathways requires multipronged approaches using combination therapy, just like treatment of malignant diseases using combination chemotherapy.

• #49 Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events | Journal of Translational Medicine | Full Text

  https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-03074-z

  The ongoing inflammatory processes are further worsened if VOC occurs because VOC is invariably followed by ischemiareperfusion injury. […] The extent of the balance between chronic inflammatory processes and various adaptive mechanisms that maintain the equilibrium probably varies among different SCD individuals. […] Ongoing inflammatory processes not only render SCD patients to developing VOC, they also create a prothrombotic state. […] The current passive approach relies solely on supportive measures and wait for the spontaneous resolution of the VOC episodes. As a result, the duration of VOC is prolonged in patients who are caught in the vicious cycle of the pathology with the development of sVOC. A more aggressive approach that would treat the VOC instead is needed. […] Unless targeting the erythrocytes to protect the un-involved HbS erythrocytes from secondary sickling, successful treatment of VOC targeting of the downstream pathways requires multipronged approaches using combination therapy, just like treatment of malignant diseases using combination chemotherapy.

• #50 Pathogenesis of Sickle Cell Anaemia | Encyclopedia MDPI

  https://encyclopedia.pub/entry/48960

  Sickle cell anaemia (SCD) is a life-threatening haematological disorder which is predominant in sub-Saharan Africa and is triggered by a genetic mutation of the β-chain haemoglobin gene resulting in the substitution of glutamic acid with valine. This mutation leads to the production of an abnormal haemoglobin molecule called haemoglobin S (HbS). When deoxygenated, haemoglobin S (HbS) polymerises and results in a sickle-shaped red blood cell which is rigid and has a significantly shortened life span. Various reports have shown a strong link between oxidative stress, inflammation, the immune response, and the pathogenesis of sickle cell disease. […] Leukocytes such as neutrophils, eosinophils, basophils, monocytes, lymphocytes, and platelets have been implicated in the pathogenesis of SCD, as evidenced by several studies. These cells are reported to be responsible for promoting inflammation, adhesion, and the painful crises characteristic of SCD. Even in the absence of infection, leukocytosis and immune activation is a common phenomenon.

• #51 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. Oxidative stress occurs due to an imbalance between the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the ability of antioxidant agents, including enzymes such as superoxide dismutases, catalase, and glutathione peroxidase, to neutralise them. […] 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.

• #52 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. Oxidative stress occurs due to an imbalance between the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and the ability of antioxidant agents, including enzymes such as superoxide dismutases, catalase, and glutathione peroxidase, to neutralise them. […] 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.

• #53 Pathogenesis of Sickle Cell Anaemia | Encyclopedia MDPI

  https://encyclopedia.pub/entry/48960

  The oxidative damage to lipids known as lipid peroxidation happens when membrane phospholipids are exposed to a hydroxyl radical and hydroperoxyl, which have been reported as the two most prevalent ROS affecting lipids. […] Inflammation is the body’s natural response to toxic chemicals, infection, and injury. Although it is difficult to determine the exact events that trigger the chronic inflammatory state in sickle cell disease (SCD), some mechanisms have been reported. The sources of inflammation in SCD include red cell alterations, haemolysis, vaso-occlusive processes, ischemia–reperfusion injury, infections, release of histamine, oxidative stress, thrombin generation and activation of complement. Many reported complications such as acute chest syndrome, stroke, leg ulcers, nephropathy, and pulmonary hypertension have been linked to inflammatory processes.

• #54 Pathogenesis of Sickle Cell Anaemia | Encyclopedia MDPI

  https://encyclopedia.pub/entry/48960

  The oxidative damage to lipids known as lipid peroxidation happens when membrane phospholipids are exposed to a hydroxyl radical and hydroperoxyl, which have been reported as the two most prevalent ROS affecting lipids. […] Inflammation is the body’s natural response to toxic chemicals, infection, and injury. Although it is difficult to determine the exact events that trigger the chronic inflammatory state in sickle cell disease (SCD), some mechanisms have been reported. The sources of inflammation in SCD include red cell alterations, haemolysis, vaso-occlusive processes, ischemia–reperfusion injury, infections, release of histamine, oxidative stress, thrombin generation and activation of complement. Many reported complications such as acute chest syndrome, stroke, leg ulcers, nephropathy, and pulmonary hypertension have been linked to inflammatory processes.

• #55 Pathophysiology of Sickle Cell Disease

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

  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.

• #56 Sickle Cell Disease, a Review

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

  This represents an intrinsic mechanism for inducing vascular disease, a common complication of sickle cell disorders. […] Repeated polymerization and depolymerization of hemoglobin can cause oxidative stress which has a role in the pathophysiology of hemolysis, vascular occlusion, and the resulting organ damage. […] 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. […] Sickle cell disease is a complex genetic blood disorder that affects multiple organs and systems. […] 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. […] A combination of these events and other processes promotes vaso-occlusion resulting in pain, end organ injuries, and failure in sickle cell disease.

• #57 Sickle cell disease (SCD) – McMaster Pathophysiology Review

  https://www.pathophys.org/scd/

  Sickle cells are mechanically weak and are prone to intravascular hemolysis. However, the more important mechanism leading to decreased red cell survival time is the extravascular hemolysis that occurs when inflexible cells are trapped in the spleen and phagocytosed by the reticuloendothelial system. […] Dysfunctional complement system has been proposed to contribute to the infectious complications in SCD, however, this has yet to be proven. […] Neurologic complications are related to vasoocculusive crisis and include strokes and silent strokes. The acute pulmonary complications of SCD, collectively referred to as the acute chest syndrome (ACS). It is defined as the appearance of new infiltrate with pulmonary symptoms, presence of fever, hypoxia and chest pain. Precipitants of ACS include infections, infarction and/or pulmonary fat embolism.

• #58 Sickle cell disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/sickle-cell-disease/

  Sickle cell disease is a group of disorders that affects hemoglobin, the molecule in red blood cells that delivers oxygen to cells throughout the body. People with this disease have atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle or crescent shape. […] The signs and symptoms of sickle cell disease are caused by the sickling of red blood cells. When red blood cells sickle, they break down prematurely, which can lead to anemia. Anemia can cause shortness of breath, fatigue, and delayed growth and development in children. The rapid breakdown of red blood cells may also cause yellowing of the skin and whites of the eyes (jaundice). Painful episodes can occur when sickled red blood cells, which are stiff and inflexible, get stuck in small blood vessels. These episodes deprive tissues and organs, such as the lungs, kidneys, spleen, and brain, of oxygen-rich blood and can lead to organ damage. A particularly serious complication of sickle cell disease is high blood pressure in the blood vessels that supply the lungs (pulmonary hypertension), which can lead to heart failure. Pulmonary hypertension occurs in about 10 percent of adults with sickle cell disease.

• #59 Sickle cell disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/sickle-cell-disease/

  Sickle cell disease is a group of disorders that affects hemoglobin, the molecule in red blood cells that delivers oxygen to cells throughout the body. People with this disease have atypical hemoglobin molecules called hemoglobin S, which can distort red blood cells into a sickle or crescent shape. […] The signs and symptoms of sickle cell disease are caused by the sickling of red blood cells. When red blood cells sickle, they break down prematurely, which can lead to anemia. Anemia can cause shortness of breath, fatigue, and delayed growth and development in children. The rapid breakdown of red blood cells may also cause yellowing of the skin and whites of the eyes (jaundice). Painful episodes can occur when sickled red blood cells, which are stiff and inflexible, get stuck in small blood vessels. These episodes deprive tissues and organs, such as the lungs, kidneys, spleen, and brain, of oxygen-rich blood and can lead to organ damage. A particularly serious complication of sickle cell disease is high blood pressure in the blood vessels that supply the lungs (pulmonary hypertension), which can lead to heart failure. Pulmonary hypertension occurs in about 10 percent of adults with sickle cell disease.

• #60

  https://journals.lww.com/hepcomm/fulltext/2025/05010/hepatobiliary_complications_in_patients_with.10.aspx

  Sickle cell disease (SCD) is the most common hemoglobinopathy. Patients with SCD are at high risk of hepatobiliary injury due to the ongoing vaso-occlusive and hemolytic process, iron overload from sickle cell treatment, including transfusions, iron chelation therapy, and comorbid conditions. Liver injury directly related to the sickling-related hemolysis and vascular occlusion includes acute ischemia, sequestration, and cholestasis. Hepatobiliary injury correlated more with hemolytic complications of SCD, including elevated right ventricular systolic pressure, acute chest syndrome, and leg ulcers, and less with vaso-occlusive pathology including retinopathy and avascular necrosis. […] Hepatobiliary complications are common in patients with SCD and require vigilance for identification. […] Hepatobiliary injury in SCD is known to be multifactorial, with inflammation as a result of the sickling and hemolytic process, ischemic injury from recurrent vaso-occlusive episodes (VOEs), endothelial injury, cholestasis, and iron overload due to hemolysis and transfusions contributing. This may suggest a common pathophysiology, whereby hemoglobin released in hemolysis sequesters nitric oxide, causing sinusoidal vasoconstriction and subsequent (1) hepatocellular ischemia, (2) further induction of sickling, and (3) transudation of fluid into the liver parenchyma causing congestion in a mechanism recently described as the congestive escalator. […] In the exploratory multivariable survival analysis, age, ALT elevation, ALP elevation, and TBili 103 mol/L predicted overall mortality.

• #61 Updated Mechanisms of Sickle Cell Disease-Associated Chronic pain

  http://transpopmed.org/articles/tppm/tppm-2015-2-024.php

  Sickle cell disease (SCD), a hemoglobinopathy, can cause sickling of red blood cells, resulting in vessel blockage, stroke, anemia, inflammation, and extreme pain. […] The interaction between sickled red blood cells and the vessel wall causes endothelial cell activation, which leads to the production of inflammatory mediators. These mediators are thought to play a role in SCD pathology. […] In clinical studies, SCD patients with chronic pain exhibit symptoms that suggest sensitization of pain pathways. […] Painful episodes increase during times of cold weather and windy weather, suggesting a possible cool/cold sensitivity in SCD patients. […] Increased nociceptor activation, a characteristic of sensitization, was found in SCD animal models. […] Peripheral sensitization may not be the only contributor to SCD associated chronic pain. Central sensitization, the phenomenon in which excitability of spinal cord neurons increases, may occur in SCD mouse models.

• #62 Updated Mechanisms of Sickle Cell Disease-Associated Chronic pain

  http://transpopmed.org/articles/tppm/tppm-2015-2-024.php

  Sickle cell disease (SCD), a hemoglobinopathy, can cause sickling of red blood cells, resulting in vessel blockage, stroke, anemia, inflammation, and extreme pain. […] The interaction between sickled red blood cells and the vessel wall causes endothelial cell activation, which leads to the production of inflammatory mediators. These mediators are thought to play a role in SCD pathology. […] In clinical studies, SCD patients with chronic pain exhibit symptoms that suggest sensitization of pain pathways. […] Painful episodes increase during times of cold weather and windy weather, suggesting a possible cool/cold sensitivity in SCD patients. […] Increased nociceptor activation, a characteristic of sensitization, was found in SCD animal models. […] Peripheral sensitization may not be the only contributor to SCD associated chronic pain. Central sensitization, the phenomenon in which excitability of spinal cord neurons increases, may occur in SCD mouse models.

• #63 Updated Mechanisms of Sickle Cell Disease-Associated Chronic pain

  http://transpopmed.org/articles/tppm/tppm-2015-2-024.php

  The question remains as to what is causing enhanced peripheral and central sensitizations in SCD mice and patients. […] Elevated levels of ET-1 in the blood plasma of SCD patients and mice both during and after a vaso-occlusive episode suggest that this peptide may play a role in SCD associated pain. […] ET-1 may sensitize nociceptors by acting on transient receptor potential vanilloid 1 (TRPV1) channels, which co-localize with ETA receptors in peripheral nociceptors. […] The chronic nature of SCD associated pain may be attributed to a combination of both peripheral and central sensitizations.

• #64 Updated Mechanisms of Sickle Cell Disease-Associated Chronic pain

  http://transpopmed.org/articles/tppm/tppm-2015-2-024.php

  The question remains as to what is causing enhanced peripheral and central sensitizations in SCD mice and patients. […] Elevated levels of ET-1 in the blood plasma of SCD patients and mice both during and after a vaso-occlusive episode suggest that this peptide may play a role in SCD associated pain. […] ET-1 may sensitize nociceptors by acting on transient receptor potential vanilloid 1 (TRPV1) channels, which co-localize with ETA receptors in peripheral nociceptors. […] The chronic nature of SCD associated pain may be attributed to a combination of both peripheral and central sensitizations.

• #65 Newer Modalities and Updates in the Management of Sickle Cell Disease: | JBM

  https://www.dovepress.com/newer-modalities-and-updates-in-the-management-of-sickle-cell-disease–peer-reviewed-fulltext-article-JBM

  The blockages and reduced oxygen delivery result in episodes of acute pain, tissue ischemia, and organ damage. Further, repeated sickling and unsickling cycles damage the cell membrane, contributing to chronic inflammation and endothelial dysfunction. The various consequences of SCD, such as acute chest syndrome, stroke, pain crises, and multi-organ damage, are caused by the combined effects of these processes. […] The dysregulation of the von Willebrand factor (VWF) – ADAMTS13 axis is a key component of the pathophysiology of sickle cell disease and plays a significant role in its pathogenesis. Examining the effects of oxidative stress and chronic hemolysis, which aggravate organ damage and endothelial dysfunction, is another area of research. Through the reduction of hemolysis, oxidative stress, and inflammation, these treatments seek to slow down the course of the disease. Furthermore, the goal of therapies targeting sickle cell adhesion to the vascular endothelium and endothelial dysfunction is to avoid tissue ischemia and vaso-occlusion. Another important pathophysiological event in sickle cell disease is the polymerization of hemoglobin under deoxygenation, which causes red blood cell sickling and other complications. As a result, it has become a key objective to stop sickle hemoglobin (HbS) from polymerizing, which will stop sickle-shaped red blood cells from forming and lower the risk of vaso-occlusive crises. Furthermore, methods to enhance the synthesis of fetal hemoglobin (HbF) have attracted interest because HbF prevents HbS polymerization and lessens the symptoms of SCD. Since inflammation is essential to both chronic organ damage and vaso-occlusive crises, it also presents a target for intervention. It is possible that treating inflammation and its consequences will help SCD patients live better lives.

• #66 Newer Modalities and Updates in the Management of Sickle Cell Disease: | JBM

  https://www.dovepress.com/newer-modalities-and-updates-in-the-management-of-sickle-cell-disease–peer-reviewed-fulltext-article-JBM

  The blockages and reduced oxygen delivery result in episodes of acute pain, tissue ischemia, and organ damage. Further, repeated sickling and unsickling cycles damage the cell membrane, contributing to chronic inflammation and endothelial dysfunction. The various consequences of SCD, such as acute chest syndrome, stroke, pain crises, and multi-organ damage, are caused by the combined effects of these processes. […] The dysregulation of the von Willebrand factor (VWF) – ADAMTS13 axis is a key component of the pathophysiology of sickle cell disease and plays a significant role in its pathogenesis. Examining the effects of oxidative stress and chronic hemolysis, which aggravate organ damage and endothelial dysfunction, is another area of research. Through the reduction of hemolysis, oxidative stress, and inflammation, these treatments seek to slow down the course of the disease. Furthermore, the goal of therapies targeting sickle cell adhesion to the vascular endothelium and endothelial dysfunction is to avoid tissue ischemia and vaso-occlusion. Another important pathophysiological event in sickle cell disease is the polymerization of hemoglobin under deoxygenation, which causes red blood cell sickling and other complications. As a result, it has become a key objective to stop sickle hemoglobin (HbS) from polymerizing, which will stop sickle-shaped red blood cells from forming and lower the risk of vaso-occlusive crises. Furthermore, methods to enhance the synthesis of fetal hemoglobin (HbF) have attracted interest because HbF prevents HbS polymerization and lessens the symptoms of SCD. Since inflammation is essential to both chronic organ damage and vaso-occlusive crises, it also presents a target for intervention. It is possible that treating inflammation and its consequences will help SCD patients live better lives.

• #67 Newer Modalities and Updates in the Management of Sickle Cell Disease: | JBM

  https://www.dovepress.com/newer-modalities-and-updates-in-the-management-of-sickle-cell-disease–peer-reviewed-fulltext-article-JBM

  The blockages and reduced oxygen delivery result in episodes of acute pain, tissue ischemia, and organ damage. Further, repeated sickling and unsickling cycles damage the cell membrane, contributing to chronic inflammation and endothelial dysfunction. The various consequences of SCD, such as acute chest syndrome, stroke, pain crises, and multi-organ damage, are caused by the combined effects of these processes. […] The dysregulation of the von Willebrand factor (VWF) – ADAMTS13 axis is a key component of the pathophysiology of sickle cell disease and plays a significant role in its pathogenesis. Examining the effects of oxidative stress and chronic hemolysis, which aggravate organ damage and endothelial dysfunction, is another area of research. Through the reduction of hemolysis, oxidative stress, and inflammation, these treatments seek to slow down the course of the disease. Furthermore, the goal of therapies targeting sickle cell adhesion to the vascular endothelium and endothelial dysfunction is to avoid tissue ischemia and vaso-occlusion. Another important pathophysiological event in sickle cell disease is the polymerization of hemoglobin under deoxygenation, which causes red blood cell sickling and other complications. As a result, it has become a key objective to stop sickle hemoglobin (HbS) from polymerizing, which will stop sickle-shaped red blood cells from forming and lower the risk of vaso-occlusive crises. Furthermore, methods to enhance the synthesis of fetal hemoglobin (HbF) have attracted interest because HbF prevents HbS polymerization and lessens the symptoms of SCD. Since inflammation is essential to both chronic organ damage and vaso-occlusive crises, it also presents a target for intervention. It is possible that treating inflammation and its consequences will help SCD patients live better lives.

• #68 Newer Modalities and Updates in the Management of Sickle Cell Disease: | JBM

  https://www.dovepress.com/newer-modalities-and-updates-in-the-management-of-sickle-cell-disease–peer-reviewed-fulltext-article-JBM

  The blockages and reduced oxygen delivery result in episodes of acute pain, tissue ischemia, and organ damage. Further, repeated sickling and unsickling cycles damage the cell membrane, contributing to chronic inflammation and endothelial dysfunction. The various consequences of SCD, such as acute chest syndrome, stroke, pain crises, and multi-organ damage, are caused by the combined effects of these processes. […] The dysregulation of the von Willebrand factor (VWF) – ADAMTS13 axis is a key component of the pathophysiology of sickle cell disease and plays a significant role in its pathogenesis. Examining the effects of oxidative stress and chronic hemolysis, which aggravate organ damage and endothelial dysfunction, is another area of research. Through the reduction of hemolysis, oxidative stress, and inflammation, these treatments seek to slow down the course of the disease. Furthermore, the goal of therapies targeting sickle cell adhesion to the vascular endothelium and endothelial dysfunction is to avoid tissue ischemia and vaso-occlusion. Another important pathophysiological event in sickle cell disease is the polymerization of hemoglobin under deoxygenation, which causes red blood cell sickling and other complications. As a result, it has become a key objective to stop sickle hemoglobin (HbS) from polymerizing, which will stop sickle-shaped red blood cells from forming and lower the risk of vaso-occlusive crises. Furthermore, methods to enhance the synthesis of fetal hemoglobin (HbF) have attracted interest because HbF prevents HbS polymerization and lessens the symptoms of SCD. Since inflammation is essential to both chronic organ damage and vaso-occlusive crises, it also presents a target for intervention. It is possible that treating inflammation and its consequences will help SCD patients live better lives.

• #69 CRISPR Sickle Cell Gene Therapy: Approaches, Challenges, and Progress

  https://www.synthego.com/crispr-sickle-cell-disease

  More recently in December of 2023, the FDA approved the first CRISPR-based therapy, called Casgevy. Developed by CRISPR Therapeutics and Vertex Pharmaceuticals, Casgevy specifically targets the BCL11A gene to treat sickle cell disease and beta-thalassemia. […] Treating sickle cell anemia with CRISPR involves an ex vivo procedure known as gene-edited cell therapy, where hematopoietic stem cells are extracted from the patient, corrected, and then replaced. […] One of the main approaches to CRISPR sickle cell gene therapy is to repair the mutation in the adult hemoglobin gene responsible for sickle cell disease, causing the healthy, normal form of adult hemoglobin (hemoglobin S) to be produced. […] The preclinical development of Dr. Dever’s β-globin gene-editing method is complete, and the method proves to be incredibly efficient and reproducible, allowing for mutation and analysis of precise genomic locations in weeks. Clinical trials are the next steps toward the implementation of this treatment.

• #70 CRISPR Sickle Cell Gene Therapy: Approaches, Challenges, and Progress

  https://www.synthego.com/crispr-sickle-cell-disease

  More recently in December of 2023, the FDA approved the first CRISPR-based therapy, called Casgevy. Developed by CRISPR Therapeutics and Vertex Pharmaceuticals, Casgevy specifically targets the BCL11A gene to treat sickle cell disease and beta-thalassemia. […] Treating sickle cell anemia with CRISPR involves an ex vivo procedure known as gene-edited cell therapy, where hematopoietic stem cells are extracted from the patient, corrected, and then replaced. […] One of the main approaches to CRISPR sickle cell gene therapy is to repair the mutation in the adult hemoglobin gene responsible for sickle cell disease, causing the healthy, normal form of adult hemoglobin (hemoglobin S) to be produced. […] The preclinical development of Dr. Dever’s β-globin gene-editing method is complete, and the method proves to be incredibly efficient and reproducible, allowing for mutation and analysis of precise genomic locations in weeks. Clinical trials are the next steps toward the implementation of this treatment.

• #71 CRISPR Sickle Cell Gene Therapy: Approaches, Challenges, and Progress

  https://www.synthego.com/crispr-sickle-cell-disease

  More recently in December of 2023, the FDA approved the first CRISPR-based therapy, called Casgevy. Developed by CRISPR Therapeutics and Vertex Pharmaceuticals, Casgevy specifically targets the BCL11A gene to treat sickle cell disease and beta-thalassemia. […] Treating sickle cell anemia with CRISPR involves an ex vivo procedure known as gene-edited cell therapy, where hematopoietic stem cells are extracted from the patient, corrected, and then replaced. […] One of the main approaches to CRISPR sickle cell gene therapy is to repair the mutation in the adult hemoglobin gene responsible for sickle cell disease, causing the healthy, normal form of adult hemoglobin (hemoglobin S) to be produced. […] The preclinical development of Dr. Dever’s β-globin gene-editing method is complete, and the method proves to be incredibly efficient and reproducible, allowing for mutation and analysis of precise genomic locations in weeks. Clinical trials are the next steps toward the implementation of this treatment.

• #72 CRISPR Sickle Cell Gene Therapy: Approaches, Challenges, and Progress

  https://www.synthego.com/crispr-sickle-cell-disease

  The second approach to CRISPR sickle cell gene therapy involves a gene knockout, switching off the gene that suppresses fetal hemoglobin. This method causes fetal hemoglobin (hemoglobin F) to be expressed, replacing the mutated adult hemoglobin. […] CTX001, also referred to Casgevy, is one such investigational new drug application, co-sponsored by CRISPR Therapeutics and Vertex Pharmaceuticals, to treat sickle cell disease. […] Another CRISPR-based approach to treating sickle cell anemia is epigenetic editing. A 2017 study found that fetal hemoglobin expression is mediated by epigenetic factors, with a genetic variant delaying the switch from fetal hemoglobin to the adult form. […] One of the most media-covered clinical trials was CTX001 (Casgevy), an autologous gene-edited cell therapy developed by CRISPR Therapeutics and Vertex Pharmaceuticals. This CRISPR cell therapy clinical trial for treating sickle cell disease involves restoring the expression of fetal hemoglobin to alleviate the symptoms of sickle cell disease and beta-thalassemia. […] GPH101 uses gene editing to correct the mutation present in the HBB gene of sickle cell disease patients and restore normal hemoglobin expression.

• #73 FDA D.I.S.C.O.: L-glutamine for sickle cell disease | FDA

  https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-l-glutamine-sickle-cell-disease

  Sickle cell disease is an inherited hemoglobinopathy in which sickled RBCs become lodged in small vessels leading to ischemia. The resulting vaso-occlusion causes painful crises and tissue damage that cripple the quality of life of these patients and often lead to hospitalizations. Vaso-occlusion can lead to sequelae like strokes, acute chest syndrome, hepatic crisis, and bone infarction. […] Although the mechanism of action for L-glutamine is not fully understood, its use in sickle cell disease is based on its antioxidant activity. It increases NAD redox potential in sickle red blood cells through increasing the availability of reduced glutathione. This may lessen oxidative damage in sickle red blood cells. […] The primary endpoint was the number of crises during the first 48 weeks on study treatment. A sickle cell crisis was defined as a visit to a medical facility for sickle cell disease-related pain that required treatment with a parenteral narcotic or parenteral ketorolac.

• #74

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

  These therapies are anticipated to be cost-prohibitive, and ensuring everyone has access would be a substantial challenge. […] 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. […] P-selectin on the endothelial surface mediates abnormal rolling and static adhesion of sickle erythrocytes to the vessel surface. […] 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.

• #75

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

  These therapies are anticipated to be cost-prohibitive, and ensuring everyone has access would be a substantial challenge. […] 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. […] P-selectin on the endothelial surface mediates abnormal rolling and static adhesion of sickle erythrocytes to the vessel surface. […] 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.

• #76

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

  The breakdown of sickle cell red blood cells releases heme, which activates inflammatory proteins that result in vaso-occlusion. […] Elevated interleukin-6 (IL-6) plays a role in the inflammation associated with ACS. […] Hydroxyurea has shown a reduction in the incidence of VOCs, ACS, hospitalizations, and the need for blood transfusion. […] Hydroxyurea prevents or reduces the progression of chronic organ damage like cerebrovascular complications and sickle cell nephropathy, which correlates with mortality benefits. […] Crizanlizumab has shown a reduction in annual VOC rate by 45% but the evidence for a reduction in ACS, priapism and nephropathy still needs better substantiation. […] Voxelotor raises Hb levels, improves red-cell deformability, and reduces blood viscosity by inhibiting HbS polymerization.

• #77

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

  The breakdown of sickle cell red blood cells releases heme, which activates inflammatory proteins that result in vaso-occlusion. […] Elevated interleukin-6 (IL-6) plays a role in the inflammation associated with ACS. […] Hydroxyurea has shown a reduction in the incidence of VOCs, ACS, hospitalizations, and the need for blood transfusion. […] Hydroxyurea prevents or reduces the progression of chronic organ damage like cerebrovascular complications and sickle cell nephropathy, which correlates with mortality benefits. […] Crizanlizumab has shown a reduction in annual VOC rate by 45% but the evidence for a reduction in ACS, priapism and nephropathy still needs better substantiation. […] Voxelotor raises Hb levels, improves red-cell deformability, and reduces blood viscosity by inhibiting HbS polymerization.

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