Sickle cell disease is a disorder of hemoglobin formation in the red blood cells resulting in complications with circulation and blood supply to end organs. Blood is constituted of a fluid component known as plasma and cellular components such as white blood cells, red blood cells, and platelets. Each of the cellular components is carefully designed to serve a specific function. The red blood cells are primarily responsible for delivering oxygen from the lungs to other tissues and carbon dioxide to the lungs. The red blood cell is adapted by containing hemoglobin that binds oxygen and has a collapsible membrane to serve its gaseous exchange function.
Hemoglobin synthesis is dependent on the genetic information found within each individual. Hemoglobin is composed of two paired proteins known as globin chains. The alpha chain is always constant and can be paired with gamma, beta, or delta chain. The typical adult hemoglobin is composed of alpha and beta chains. A genetic change in the beta-globin gene results in exchanging a protein building block known as valine for the usual glutamate. The defective beta-globin chain results in hemoglobin, known as HbS. The inheritance pattern of the gene is autosomal recessive, meaning that it has to be inherited from each parent to present as a disease.
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Hemoglobin S is not as stable or insoluble as normal hemoglobin. In normal circumstances, low oxygen levels usually lead to minimal structural changes in the hemoglobin to allow for oxygen release. However, in sickle cell patient's low oxygen concentration, extremes of pH, or dehydration results in self oxidation of the hemoglobin that damages the skeletal and membrane structure of the red cell.
The permanent damage of the red cell's skeleton and the membrane causes the cell to change disk shape to an S or C- like shape, a sickling process. The sickling red cells cannot maneuver through smaller circulatory channels such as capillaries, which cause them to lodge these spaces (Kato et al., 2018). In larger vessels, the sickled cells are more likely to bind to other white blood cells, causing a build-up of a stationary cluster of cells causing the arteries' blockage. A vaso-occlusive crisis is the partial or complete occlusion of a capillary or larger blood vessel significant enough to cause clinical signs and symptoms in the patient.
Numerous organs play critical individual roles in ensuring oxygen is delivered to all the tissues in the body. For instance, the heart regulates blood pumping while the spleen ensures that only the best quality of circulating red blood cells remains in the bloodstream. Therefore, sickled red cells usually get trapped in the spleen and are broken down by white blood cells to release heme and globin used in making new red cells and other body processes. The breakdown of the red cells is known as extra-vascular hemolysis.
Free heme in the body is usually considered a foreign particle; therefore, an immune response can be mounted against it, resulting in inflammation of the vascular walls. Hemolysis of the red cell also causes depletion of an enzyme known as nitric oxide synthase. This enzyme removes harmful oxidation products from the body by converting the amino acid L-arginine to nitric oxide (Nader et al., 2018). Reduction in the synthase results in damage to the blood vessels due to impaired nitric oxide function. The free oxygen radicals will then react with the endothelium causing endothelial dysfunction. Additionally, the end product, nitric oxide, serves as a mediator for expanding the blood vessel lumen. A lack of nitric oxide will result in vasoconstriction, further predisposing the patient to an occlusive crisis.
The damage to the vessels and occlusion process will then present as symptoms in patients. The blockage of blood to an organ impairs the blood flow of essential nutrients such as oxygen needed for energy production in the cells, a process transiently known as ischemia. A prolonged lack of oxygen to tissues causes cell death through a process known as necrosis. The cell debris then initiates an immune response that results in releasing chemicals known as interleukins that stimulate the pain receptors. The areas of the body most affected area in the periphery due to reduced circulation in those areas. The patient will then present with painful swollen fingers, a condition known as dactylitis. Some patients may also present with hypersplenism, nephropathy, and respiratory complications
It is important to note that the vaso-occlusive episodes have specific environmental triggers such as travel to higher altitude areas, exposure to cold, demanding exercises, diarrheal infections causing dehydration, or any systemic infection. Infections will result in the release of chemicals known as cytokines that result in activation of the blood vessels' surface to express proteins that bind white blood cells and platelets known as selectins. The platelets and white blood cells then express similar selectins and bind to the blood vessel's surface. The sickled red blood cells also bind to the P-selectins and aggregate around the platelets interrupting blood flow resulting in downstream ischemia and infarctions.
Vaso-occlusive crises pose a significant risk to the patient, and treatment is indicated. The primary treatment used is hydroxyurea (Nader et al., 2018). However, hydroxyurea does not target the underlying immediate pathogenesis mechanism of occlusion. Hydroxyurea functions by increasing fetal hemoglobin, which is more stable under low oxygen tension than hemoglobin S. Administration of hydroxyurea does not entirely rule out the possibility of a vaso-occlusive crisis. Other therapies have proven effective in targeting the immediate causes of vaso-occlusion. Tinzaparin acts to inhibit clot formation that may contribute to vaso-occlusion, while propranolol plays a role by allowing for vasodilation. Therefore, such therapies can be used as an adjunct to hydroxyurea administration.
The likely process demonstrated in the trial study (Ataga et al., 2017) is vaso-occlusion, primarily secondary to endothelial activation and cell adhesion to the vascular walls. The medication assessed in the study is Crizanlizumab, which is conventionally known as ADVAKVEO, which is administered as a once a month treatment. For every kilogram, the patient weighs 5mg is given; therefore, a 70kg patient will be given 350mg. The drug is given through venous access over 2 hours. It is administered at the beginning, after two weeks, and then every month after that. However, the underlying trigger of the crisis has to be treated. For instance, administer antibiotics for infections. Intravenous fluids are given for those that are dehydrated and counseling for travelers or sports enthusiasts.
Crizanlizumab is an artificial antibody that has an affinity to bind to a single antigen. The antibody is designed to target the surface, as mentioned above, protein P-selectin. It binds to the protein preventing interaction with P-selectin ligand 1. P-selectin ligand 1 is a glycoprotein found on the surface of blood cells and binds to activated endothelia in the vessel wall (Abadier & Ley, 2017). Administration of Crizanlizumab blocks this interaction preventing occlusion via aggregation of cells.
Crizanlizumab administration may result in infusion site reactions such as swelling and edema. Once the protein reaches the systemic circulation, it may be recognized as a foreign body in some individuals triggering an immune reaction. The immune reaction will present more commonly as nausea, low-grade fever, joint and back pain. Other patients may present with abdominal pain, urinary tract infections, vomiting, and diarrhea. Of importance to note is that the drug inhibits aggregation of platelets and white blood cells to activated endothelium. The inhibition may interfere with physiological responses such as chemotaxis (movement of white blood cells to infection sites) and platelet adhesion, leading to serious adverse effects such as infection or sustained hemorrhage.
A comparison between the risks of adverse effects and the utility of the therapy ought to be done. Clinical trials have shown no adverse effect that was uniquely occurring in patients who received Crizanlizumab compared to the control group that received a placebo. Additionally, the study analyzed the effectiveness of Crizanlizumab administration was forty-five percent lower incidences of vaso-occlusive crises than the placebos. While the study mentions an adverse hemorrhagic reaction in one patient, it does not highlight the effects on immune responses (Ataga et al., 2017).
Crizanlizumab is, therefore, an effective drug in the prevention of sickle cell vaso-occlusive crises with the adjunct of hydroxyurea. It also proves useful as a single high dose administration. Studies on Crizanlizumab have not highlighted the effects of the drug on immune responses in preventing transmigration of white blood cells to inflammatory sites. Does such a knowledge gap pose questions such as whether the patients would present with classical inflammatory signs such as temperature in the event of an infection? Are they at risk of developing septicemia?
References
Abadier, M., & Ley, K. (2017). P-selectin glycoprotein ligand-1 in T cells. Current opinion in hematology , 24 (3), 265-273.
Autauga, K. I., Kotlar, A., Kanter, J., Liles, D., Cancado, R., Friedrich, J., ... & Gualandro, S. (2017). Crizanlizumab for the prevention of pain crises in sickle cell disease. New England Journal of Medicine , 376 (5), 429-439.
Kato, G. J., Piel, F. B., Reid, C. D., Gaston, M. H., Ohene-Frempong, K., Krishnamurti, L., ... & Vichinsky, E. P. (2018). Sickle cell disease. Nature Reviews Disease Primers , 4 (1), 1-22.
Nader, E., Grau, M., Fort, R., Collins, B., Cannas, G., Gauthier, A., ... & Hot, A. (2018). Hydroxyurea therapy modulates sickle cell anemia red blood cell physiology: Impact on RBC deformability, oxidative stress, nitrite levels, and nitric oxide synthase signaling pathway. Nitric Oxide , 81 , 28-35.
