Sickle Cell Disease: Pathology and Implications
1. Introduction to Sickle Cell Disease
Atypical RBCs in SCD result from mutation(s) in the human HBB gene that encodes for the β-hemoglobin subunit at position 6, changing the amino acid from glutamic acid to valine to produce hemoglobin S (HbS). Sickle cell trait (SCT; HbAS: the carrier state for SCD) results from inheritance of HbAS from one parent and a normal β-globin gene (HbA) from the other parent and is generally asymptomatic. Symptomatic SCD arises from inheritance of HbS from each parent (HbSS). Other clinical manifestations of SCD result from SCD along with co-inherited alpha linked thalassemia, other heterozygous SCD mutation(s) (HbSC, HbSE) or β-globin gene deletions plus a single SCD mutation. Clinical manifestations of SCD are categorically classified as either acute vaso-occlusion/vaso-occlusive crises (VOC) or chronic complications, unfortunately there is limited consensus in classifying each of these complications and this review details the most recent classification efforts.
Sickle cell disease (SCD) encompasses a group of inherited red blood cell (RBC) disorders characterized by the presence of atypical RBCs (sickle-shaped or crescent-shaped erythrocytes) in circulation. The presence of RBCs with this distinct morphology, which results from polymerization of hemoglobin S (HbS) and the formation of intracellular tactoid crystals, promotes several of the cardinal features of sickle cell disease: vaso-occlusion and hemolytic anemia. While it was first described more than a century ago, SCD has re-emerged as a global health problem with more than 300,000 affected births expected by year 2040. Indeed, this disease is of high interest as it affects millions worldwide but not everyone is seriously affected. While the genetic basis of SCD is well understood, the consequence of the resulting changes on RBC physiology, the molecular details of vaso-occlusion, and the genetic modifier(s) for disease severity remain the subject of extensive research.
2. Genetic Basis of Sickle Cell Disease
The dramatic and disabling manifestations of the sickling process result from a delicate and stunning interplay of mechanical, inflammatory, oxidant, and protein-protein interactions. The altered flow due to the stress on the RBC, increased leukocyte adhesion to the endothelium, altered RBC properties following the polymerization of hemoglobin S, enhanced oxidant production, circulatory blockage, and an array of activated pro-inflammatory and pro-adhesive mediators together produce the full range of sickle cell clinical symptoms. In particular, the vascular endothelium plays a key role by not only serving as the initial site of adhesive interactions but also by modifying multiple inflammatory pathways following alteration of cell-cell interactions that can initiate a cascade of permeability changes.
Sickle cell disease (SCD) is a monogenic disorder caused by a mutation in the beta-globin gene, which leads to the production of an abnormal variant hemoglobin called hemoglobin S (the normal beta hemoglobin is termed A). When deoxygenated, hemoglobin S assumes a gelatinous form, resulting in the characteristic sickling of red blood cells (RBC). The sickling process occurs in a precisely chain length-dependent manner, such that the developing, nascent sickle fibers are initially soluble and accumulate within RBC until a discrete length (generally <30). At that point, the fibers become insoluble and distort the shape of the RBC. The change in shape alters the electrophoresis of the cell, while the increased RBC rigidity leads to vaso-occlusive events, particularly in the microvasculature. This results in end organ damage and the full range of clinical complications seen in sickle cell disease (SCD) patients. Over time, in a slow and irreversible manner, these vaso-occlusive processes result in end organ damage, eventually leading to a reduced lifespan when compared to the general population.
3. Pathophysiology of Sickle Cell Disease
5-hydroxymethylphthalavyldioxotetrahydrofuran (IkappaB kinase inhibitor) administration blocks NF-kappaB-mediated transcription and enhances biological nitric oxide availability in a model of sickle cell disease in the rat and, in doing so, diminishes vascular inflammatory processes in those animals. Therefore, the pathology in sickle cell patients might, in part, be mediated by the activation of NF-kappaB. Transcription factors of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) are sequestered inactive in the cytoplasm by binding to the inhibitory protein, IkB. The activation of this transcription factor occurs through the release of IkB from the inhibitory complex and the translocation of the free NF-kB to the nucleus. NF-kB mediates the inflammatory response, cellular proliferation and apoptosis, and has been associated with hormonal dysregulation, hypertensive pathology, allergic reactions, neoplasia, and neurodegenerative disease.
Sickle cell disease is an autosomal recessive inherited disorder involving a glutamine to valine substitution at position 6 of the hemoglobin beta chain. At physiologic conditions, this leads to the aggregation of HbS and distortion of deoxygenated erythrocytes into their classical sickle-like shape. Such rigid, sickled erythrocytes can occlude the fragile postcapillary venule and, when it occurs, generate its characteristic painful crisis. The vascular occlusion can even occur in small arterioles in certain conditions referred to as “sludge”. Transient, repeat bouts of vascular obstruction result in ischemia/reperfusion injury to the vessels and tissue and promote a chronic vascular inflammatory process in sickle cell patients. Further complications are often difficult to manage, and only a few therapies attend to the root cause of the disease.
4. Clinical Manifestations and Complications
Acute anemia is usually related to multi-organ damage “crisis.” This is due to hypovolemia induced by capillary obstruction, acute hemolysis in patients who do not normally have high hemolysis rates in comparison with HbS populations of moderate or mild severity, and alloimmunization. Neurological manifestations are very common in SCD, especially strokes, which precipitate other neurological disorders or can have a silent presentation, leading to other severe lesions such as infarctions or aneurysms. Ischemic strokes are associated with stenosis precisely at the middle cerebral artery and infections. If the stroke is the product of a silent cerebral ischemia or a multiple infarctions syndrome and leukoencephalopathy. Subarachnoid hemorrhages (SAH) are a serious condition that accounts for 3% of all stroke syndromes in sickle patients. This is an unusual condition, about 6% of all stroke syndromes attributed to vasculopathy, in the general population, with high mortality and morbidity, reaching up to 40%. SAH has a positive association with high blood viscosity, inflammation, and fibrosis, more frequent in the sickle cell population, and higher hemolysis rate, with possible future diagnostic parameters.
Symptomatology of sickle cell disease (SCD) is diverse and depends on haemoglobin (Hb) phenotype, age, and geographic location. HbSS is the most common form of SCD, and manifestations are observed soon after the loss of fetal Hb (HbF) and its replacement with HbS. Most symptoms begin at very early ages, such as recurrent pain episodes, dactylitis, and anemia. Anemia is present from early on and can be chronic or acute. Chronic anemia leads to compensatory erythroid hyperplasia. Due to high hemolysis rates, the release of cell-free Hb (Hb index) is higher than in other hemolytic anemias. As a result, hepcidin levels are reduced, which increases intestinal iron absorption, leading to an increase in iron availability to erythroblasts. Consequently, it is usual to observe hemosiderosis in populations with poor access to effective chelation therapy. Associated with chronic anemia are leg ulcers, which result from ischemic areas lacking normal production of new blood vessels. They usually recur but can profoundly impair the quality of life.
5. Management and Treatment of Sickle Cell Disease
The indications for ischemic stroke and remarkable abnormal vessel wall abnormalities seen on the magnetic resonance imaging (MRI or MR angiographic (MRA) cranial vessel study indicate HCT. Features of firm organ damage are the suvation of a significant concomitant disease with SCD. Revamping the minor and most devastating consequences of SCD. Renal dysfunction and severe avascular necrosis, left ventricular eccentricity index greater than 2, or left ventricular diastolic dysfunction in fullness on the echocardiography test and decline in the forced expiratory volume over one second (FEV1) and forced vital capacity (FVC) on pulmonary function tests. Previous overexposure to greater than 100cc/m2 of blood therapy or 15 units and age is another indication. Radiological significant liver iron overload with transferrin saturation more than 75% and liver iron content (LIC) more than 5mg/gm of dry weight on liver biopsy. Feminization or clinically significant spleen sequestration crisis in a patient who is over 6 years not using hydroxyurea, and which was followed in less than 5 years by symptomatic sickle cell disease. Any patient who has failed treatment with hydroxyurea.
Hematopoietic stem cell transplantation (HCT) is curative in SCD patients without significant organ dysfunction before transplantation. When the indications and performing correctly, it is the most superior treatment with superior outcome in terms of event-free survival, organ function, rule growth, and nonexistence of end organ organurt. The main indications of undergoing HCT are defined by abnormal transcranial Doppler velocity measurements.
Management of SCD is done by disease modifying and symptomatic management of complications and symptoms. The disease modifying includes hematopoietic cell transplantation (HCT), while hematopoietic stem cell gene therapy is a promising future treatment. Hydroxyurea (Hydroxycarbamide) has been an important drug with potential disease modifying effect that reduces sickling, decreases hemolysis, decreases the total WBC and platelet count (most important for preventing thrombosis in SCD), and increases HbF. It has been shown to decrease the frequency of vaso-occlusive events (VOEs), acute chest syndrome, etc., and death in adults with SCD. Thus, almost every adult with Hb SS should be on hydroxyurea, which is a safe long-term drug (over 17 years of use) with most of the toxicities related to short-term rise in the MCV or other cytopenia been related to high dose or to excess declining reserve of myeloid or erythroid elements as might occur in very chronic severe anemia of any cause.
