Sickle Cell Disease Pathology
1. Introduction to Sickle Cell Disease
S/β-thalasemia (compound heterozygote for a β0-thalassemia with HbS) is a very frequent condition, and although sickle cell disease patients share similar pathologies, different molecules are involved in the Hb-F regulation and a broader morphological variety of red blood cells is found in these patients. Heterozygous patients of sickle cell disease are called trait, and are another important focus of research, as in some condition, these patients also become symptomatic. Hb is not only involved in the transport of O2, but also influences the blood viscosity, forming crystals upon deoxygenation. These crystals tend to adhere to the membrane of the RBC, increasing the hemolytic rate, and diminishing the deformability of these cells, which increases their life span and promotes organ infarctions.
Sickle cell disease (SCD) is the first “molecular disease”. SCD patients carry one of several mutations in the gene encoding for the β-globin subunit of the adult hemoglobin. Homozygosis for the so-called “S” mutation (HBB glu6val) is named SCA (SS). Other genotypes involve the HBB locus, and can give rise to a broad variety of clinical conditions where anemia and vaso-occlusion give the most relevant symptoms. Hb is a four subunit molecule, which in its adult form (HbA) is a heterodimer of two α-globin chains and two β-globin chains. The β-globin genes are located at chromosome 11 (11p.15.5). Several mutations are known to affect this gene, yet the HBB glu6val (βs) leads to the most common form of sickle cell disease (SCD).
2. Genetic Basis of Sickle Cell Disease
Sickle cell mutations have occurred multiple times in different geographical areas, but only a few have been fixed and spread in human populations. The high frequency of this allele in African and Indian populations, with balanced selection, suggests that the heterozygote has an advantage against other genetic disorders, particularly severe malaria caused by P. falciparum. Similarly, in malarious areas of the world, the heterozygous condition resulting from a combination of other hemoglobinopathies like thalassemias, thalassemia with O-Arab allele, and HbE gene are also observed, which have some advantage against severe malaria cases. Science has provided many pieces of evidence for the beneficial effect of both the heterozygous and homozygous states over the age-old malaria in geographical areas that are malarious. Moreover, this sickle cell gene confers a high degree of resistance to P. vivax, another important causative organism of malaria in human beings.
Sickle cell disease is due to a point mutation in the beta-hemoglobin gene, resulting in the replacement of the amino acid glutamic acid by valine at position 6 of the beta-globin chain. The gene encoding the beta-globin chain has 3 exons and 3 introns, spanning a length of 6.5 kb on the short arm of chromosome 11. The presence of 2 alleles of the HBB gene, one from each parent, determines a person’s genetic status for the beta-globin chain. The mutation in codon 6 of the beta-globin gene manifests in the homozygous condition and results in sickle cell disease. However, the presence of 1 normal allele along with a mutated allele results in the carrier status without many symptoms. However, some of these carriers may show intermediate conditions, displaying milder symptoms, also known as sickle beta thalassemia disease with genetic complexity.
3. Pathophysiology of Sickle Cell Disease
It has for many decades been recognized that, in the context of the disease SCD, circulating red blood cells assume the morphology of the ‘sickle’ shape. A global perturbation is therefore initiated, due to blood flow disturbances and obstruction in the microvasculature of the vascular beds of many diverse organs, often referred to as vaso-occlusions. In terms of pathophysiology, in SCD, the RBC becomes stiff and adherent to the endothelium and the then ensuing dynamic cell adhesion that is triggered in the inflamed vasculature of the patient. Sickle RBC cell adherence to multiple substrates involves a cascade of sequential, rapid and simultaneous cooperative events mediated by the binding of adhesion molecules. Data from multiple laboratories, over multiple years, suggest that the sickle RBC displays with multiple adhesion events and has a dynamic cusp/flag “molecular memory” in RBC-exchange transfused patients too, something that may increase the clinical rate of vaso-occlusions, irrespective of the genome driven genetic “transport” defects, or whether the patient is in the steady state or undergoing a vaso-occlusive crisis (VOC) at the time observational data on RBC molecular adhesion is obtained.
From a molecular genetics perspective, the HbS disease is a deceptively simple single-gene recessive disorder, where a substitution in the β-globin gene results in the single amino acid change of valine replacing glutamine. As depicted in Figure 20.2, at the phenotypic level, the disease is characterized by its clinical heterogeneity and pronounced organ dysfunction and broad range of complications, caused by vaso-occlusion and hemolysis, and initiated by the cross-linking of polymers of deoxygenated sickle hemoglobin in the red cell. Besides its being a genetic disorder and from the clinical perspective, the SCD is a global health issue, that is both complex in its pathology and costly to manage, and represents a global public health power incognita, due to a complex interplay of biological, social, ethnic and environmental factors. The past decade or so has indeed seen several ‘converging crises’ in dealing with the various aspects of sickle cell disease in the developed and developing world.
4. Clinical Manifestations of Sickle Cell Disease
Most adults with severe SCD are transfusion-dependent, and these individuals must maintain Hb levels above 9 or 10 g/dL to prevent further complications. The U-shaped mortality curve seen in transfusion-dependent patients highlights the fact that risks of alloimmunization, iron overload, and other morbidities from recurrent transfusions can offset the benefits of maintaining a higher Hb level. To combat these risks, alternative methods of reducing sickle Hb and vaso-occlusion are under development, including the most recognized approach of simply generating more of the most common non-sickle allele of the Hb beta chain, HbA. The BCL11A gene encodes a protein important for the production of HbF in adults. Adults of African descent, in particular, who have high levels of HbF are usually clinically asymptomatic, regardless of whether they produce sickle Hb or not in the adult erythrocyte pool. Each of the complications seen in adults with SCD relates to some extent to the altered flow properties of erythrocytes that contain sickle HbS.
Adult patients with severe forms of sickle cell disease (SCD) are usually faced with anemia and other complications related to chronic blood transfusion. Most patients with SCD suffer frequent pain episodes, which are commonly treated with opioids. Some SCD patients at steady-state have vaso-occlusive crises (VOC) that do not necessitate hospitalization. These crises are treated with oral pain medications and resolve without intervention within hours to days. Classical acute chest syndrome, splenic sequestration, and priapism are the most serious pathologies of SCD. Each of these clinical manifestations of SCD can be life-threatening and typically necessitate hospitalization of the affected individual. Acute kidney injury from hemoglobinuria occurs in SCD patients, particularly in those with sickle cell trait who are challenged for adequate fluid intake in a hot environment.
5. Complications and Management of Sickle Cell Disease
SCD is associated with decreased life expectancy in all afflicted individuals. Physician monitoring of patients serves to treat their pain adequately and to diagnose and address life-threatening complications such as splenic sequestration, neurological sequelae, or infection. The condition can be cured in children with bone marrow or stem cell transplantation, but this is a high-risk endeavor, limiting use to only a few individuals and depends on the immediate availability of an appropriate donor and the wait period for full restoration of the hematopoietic immune system, which may be associated with opportunistic infections. The goal of treatment is to ameliorate the symptoms, the valuable red cell lifespan of 120 days, resulting in increased mortality with significant drops in hemoglobin concentration in low finances, research to find an appropriate cure, and early diagnosis of traits and newborn genetic testing for subsequent disease preventions. A number of main therapeutic interventions improve the survival and quality of life for individuals whose sickle cell status is characterized by hemoglobin. Beneficial treatments include regular red blood transfusions for the prevention of stroke in childhood, as well as to alleviate secondary end-organ damage (cardiac and kidney), ameliorate pain, impact hemolytic anemia, decrease acute chest syndrome and stroke, prevent complications of frequent hospitalization, alleviate the effect of hypoxemia on proliferation and activation of T-cells, and vaccines to protect the immune-compromised sickle cell patients against encapsulated bacteria.
Sickle cell disease (SCD) is a genetic blood disorder that alters the shape and physical properties of red blood cells from the normal biconcave disk to a rigid, nonspherical, and crescentic form. This distortion, known as sickling, occurs in response to hypoxia, dehydration, or exposure to a variety of cell-activating substances. Continued cycles of sickling and unsickling make the sickle cells rigid and adhesive, leading to cellular stasis and occlusion of the small capillary vessels. Occlusion of the microvasculature and resultant tissue ischemia and infarction leads to the clinical picture associated with sickle cell anemia, which includes episodes of severe pain classified as vaso-occlusive crises, anemia, tissue necrosis, and inflammation leading to avascular necrosis of bones, acute lung injury and chest syndrome, acute and chronic organ damage, scheduled appointments to the emergency room for the debilitated condition, and increased susceptibility to some bacterial infections.
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