Epidemiology And Pathophysiology Of Sickle Cell Disease Biology Essay

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IN October 1902, a peculiar anomaly in human red blood corpuscles came to notice in the histologic laboratory of the Ohio State University, Columbus, Ohio. Examination disclosed the fact that the colored corpuscles in the sample recently drawn by a student from his own finger that were elliptical and not circular (Dresbach M, 1904). Similar erythrocyte abnormalities were reported in North African Arab subjects shortly afterwards.(Edmond MM at al, 1905)

In November 1910 James B Herrick, M.D. (Professor Of Medicine, Rush Medical College, Chicago, Illinois; 1861-1954) published a detailed case report. This described a patient with jaundice, shortness of breath, lymphadenopathy, dark urine, leg ulcers, epigastric pain, and anemia associated with these same types of "peculiar elongated and sickle-shaped red blood corpuscles. (Herrik JB, 1910)

This classic report was the first unequivocal clinical description in Western scientific literature of sickle cell disease (SCD), a set of closely related hemoglobinopathies that have in common the inheritance of mutant hemoglobin S (fig. 1-1) Clinically, SCD is characterized by chronic hemolytic anemia, recurrent episodes of intermittent vasoocclusion and severe pain, progressive organ damage, and a striking variation of expression. . (Firth PG et al, 2004)

Fig. 1-1: Deoxygenated sickle cells: a peculiar anomaly in human erythrocytes (Firth PG et al, 2004)

In 1955, the first major review of the anesthetic implications of SCD acknowledged the high incidence of serious and potentially fatal exacerbations of the disease after surgical procedures. The avoidance of factors said to increase erythrocyte sickling and precipitate the vicious cycle has been the traditional foundation of anesthetic management of SCD. (Shapiro ND, Poe MF, 1955) 

The century after the discovery of the peculiar anomaly has seen an immense expansion in the understanding of the complex relationship between these peculiar erythrocytes and the clinical expression of the disease. (Firth PG et al, 2004)


Sickle cell disease (SCD) is a general name for a group of inherited conditions that have two features in common: sickle red cells in the blood and clinical illness as a result of having the abnormal erythrocytes. It was the first human disorder to be described at the molecular level. Worldwide,  300,000 children are born with SCD every year, and several million people are affected (Iheanyi Okpala, 2006)

The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, India and the Middle-East. (Weatherall DJ, Clegg JB, 2001 ) Migration of substantial populations from these high prevalence areas to low prevalence countries in Europe has dramatically increased in recent decades and in some European countries sickle cell disease has now overtaken more familiar genetic conditions such as hemophilia and cystic fibrosis. (Roberts I, de Montalembert M, 2007)

Three quarters of sickle-cell cases occur in Africa. A recent WHO report estimated that around 2% of newborns in Nigeria were affected by sickle cell anaemia, giving a total of 150,000 affected children born every year in Nigeria alone. The carrier frequency ranges between 10% and 40% across equatorial Africa, decreasing to 1-2% on the north African coast and <1% in South Africa. In middle east About 6,000 children are born annually with SCD, at least 50% of these in Saudi Arabia. (Awasthy N, Aggarwal KC, 2008)


Human Hb is a tetrameric molecule that consists of two pairs of identical polypeptide subunits, each encoded by a different family of genes. The human α and α-like globin genes are located on chromosome 16, and β and β-like globin genes are located on chromosome 11. The genes are present on both chromosomes in the same order in which they are expressed during development. During fetal life, the predominant type of Hb is HbF (α2γ2). During the postnatal period, HbF is gradually replaced by HbA (α2β2). HbA2 (α2δ2) is a minor adult-type Hb that accounts for less than 2.5% of the circulating Hb in normal individuals in adult life. Upon completion of the switch from HbF to HbA, patients with disorders of the β-globin genes start manifesting the clinical phenotype of their disease (Bank A, 2006).

Sickle cell disease is a hereditary hemoglobinopathy resulting from inheritance of a mutant version of the β-globin gene (βA) on chromosome 11, the gene that codes for assembly of the β-globin chains of the protein hemoglobin A. (Firth PG et al, 2004).

The various diseases are summarized in table (1-1). SCD is inherited in an autosomal recessive fashion with standard mendelian inheritance. (Kevin J. Sullivian, Salvatore R. Goodwin, 2009)

Hemoglobin electrophoresis (%)





Hb A

Hb S

Hb F

Hb A2

Hb C

Sickle cell anemia (Hb SS)









Sickle β0 - thalassemia









Hemoglobin SC disease (Hb SC)









Sickle β+ thalassemia









Sickle cell trait (Hb AS)









Table (1-1): Severity and diagnostic testing for relevant sickle cell syndrome. (Kevin J. Sullivian, Salvatore R. Goodwin, 2009)

The classic, and the most widespread, genotype of SCD is the homozygous state of the mutant allele (βS βS), coding exclusively for hemoglobin S production. Heterozygous genotypes coding for hemoglobin S together with other hemoglobin variants or alterations in the regulation of the beta gene expression may result in symptoms of SCD. Several other genetic variants of SCD result from the interaction of different mutations of the human β-globin genes. When the βS gene interacts with the βC gene, the resulting sickling disorder known as HbSC disease is typically mild . (Platt OS, Brambilla DJ, et al, 1994)

When a βS gene interacts with a β-thalassaemia gene (a mutant β-globin gene that either fails to produce normal β-globin mRNA or produces it at markedly decreased levels), the severity of the resulting sickling disorder depends on the severity of the coinherited β-thalassaemia mutation. When the coinherited β-thalassaemia gene is completely inactive (i.e., β0-thalassaemia), the resulting sickling disorder known as Sβ0-thalassaemia tends to be of severity similar to that of homozygous HbSS disease. In contrast, when the coinherited β-thalassaemia gene is partially active (i.e., β+-thalassaemia), the resulting sickling disorder known as Sβ+-thalassaemia can have a spectrum of clinical severity. If the β+-thalassaemia mutation is mild, as with people of African descent, the resulting Sβ+-thalassaemia tends to be clinically mild. In contrast, if the β+-thalassaemia mutation is severe, as with Mediterranean populations, the clinical sickling disorder tends to be moderate (Gladwin MT, Kato GJ, 2005).

Identified genetic factors that alter the phenotypic impact of hemoglobin S include the expression of hemoglobin F, haplotype variation, and the coinheritance of α-thalassemia. The markedly increased but extremely variable production of hemoglobin F significantly affects the clinical effects of hemoglobin S. Production of fetal hemoglobin after infancy typically stabilizes at approximately 1% of the total hemoglobin in the general population. In contrast, the African haplotypes commonly express fetal hemoglobin concentrations of up to 15%, and typical production by the Asian haplotype is even higher at 8-30%. (Firth PG et al, 2004)


Many mechanisms contribute to the complex pathophysiology of sickle cell disease (SCD). Recent studies begin to demonstrate overlap among these seemingly unrelated processes.

The variable clinical spectrum of SCD is the consequence of multiple events and genetic susceptibility that goes beyond the occurrence of a single amino acid substitution in the beta globin chain of hemoglobin. Any attempt to identify the primary mechanism will certainly generate debate; however, it is clear that there are complex interrelationships among the many mechanisms discussed that make it difficult to argue that any single event occurs in isolation. (Kato GJ, Gladwin MT, et al, 2007)

Sickle cell disease refers not to a specific disease but to a variety of genotypes that share a common phenotype characterized by the production of a sickled erythrocyte on Hb deoxygenation, chronic hemolysis, recurrent vasocclusion, and ischemic end organ injury to virtually every organ system. All patients with a SCD phenotype share in common the inheritance of a mutant β- globin allele in which the 6th codon is altered, resulting in the substituation of valine for glutamine at the 6th amino acid position of the β- globin chain (Kevin J. Sullivian, Salvatore R. Goodwin, 2009)

The instability of hemoglobin S exposes the erythrocyte cell membrane to the destructive oxidant potential of intracellular iron. Under normal circumstances, the dangers of oxygen and iron are nullified primarily by the structure of hemoglobin. Iron-containing heme is contained within a hydrophobic globin pocket that constrains the reactivity of iron by shielding the heme from most external solutes. Consequently, heme tends to bind reversibly with oxygen in the ferrous (Fe2+) state rather than the ferric (Fe3+) state. In addition, the heme is compartmentalized by a globin coat that separates the iron from potential targets of oxidant damage in the cytosol or membrane. (Repka T, Hebbel RP, 1991)

Both these defense mechanisms (checks on the reactivity with oxygen and the separation of heme from targets of oxidant damage) are interrupted by the instability of hemoglobin S. The loss of hemoglobin structural stability increases the rate of globin denaturation and deterioration of the protective hydrophobic shield, increasing oxidation of heme to methemoglobin, the ferric state of heme. (Hebbel RP,et al, 1988)

Free iron and iron-containing compounds accumulate in the cell membrane, partly because of abnormal interaction between hemoglobin S and membrane phospholipids and proteins. Endogenous oxidant stress is consequently targeted directly to sickle cell membrane structures. Increased membrane-iron compounds result in denaturation and aberrant clustering of membrane surface proteins, abnormal cation permeability, and the disruption of normal phospholipid membrane asymmetry. The loss of the stabilizing β6 amino acid charge in hemoglobin S therefore disrupts the erythrocyte's globin defenses against the oxidant perils of large quantities of intracellular iron present in the heme. (Aslan M, et al, 2000)

Increased cell membrane iron disrupts the transmembrane ion transport pathways, leading to pathologic cell dehydration. Cellular dehydration is essential for the deformation or sickling of the deoxygenated erythrocyte. Sickling is caused by widespread polymerization and gelation of hemoglobin S after deoxygenation (fig. 2-2). Because gelation does not occur instantaneously on deoxygenation, sickling occurs after a delay time required for sufficient intracellular polymerization to deform the cell. The delay time of most cells is greater than the circulation time required to return to the pulmonary capillaries and reoxygenate. Typically, approximately 10% of erythrocytes sickle reversibly, and a further 10% circulate in an irreversibly sickled state. Delay time is extremely sensitive to intracellular hemoglobin concentration because the progress of aggregation and precipitation from solution is catalyzed by the formation of the polymer nuclei that exponentially accelerate gelation. Severe cell dehydration, present in older cells, is required to increase hemoglobin concentration and decrease the delay time to within a single systemic circulation time. Reversible cell sickling exacerbates the process of dehydration, resulting in irreversibly sickled cells that remain deformed throughout the circulation. Sickling is therefore consequent not only on the insolubility of deoxy-hemoglobin S but also on cellular dehydration arising from previous membrane damage secondary to hemoglobin S instability. (Firth PG, Head CA, 2004)

Disruption of the erythrocyte cell membrane results in increased adherence of rigid, iron-laden erythrocytes to the vascular endothelium, exposing the endothelium to increased shear and oxidant stress. Adherence is mediated predominantly by a wide variety of adhesion molecules expressed by the erythrocytes and endothelial cells. In addition, structural membrane changes diminish erythrocyte deformity and increase fragility, shortening red cell lifespan, hastening erythrocyte turnover, and increasing the proportion of reticulocytes. This young erythrocyte group expresses increased amounts of adhesive proteins compared with the overall erythrocyte population. High erythrocyte turnover therefore combines with the direct effects of cell membrane changes to produce abnormally adhesive cells. This heightens mechanical and oxidant stress on the vascular endothelium. (Hebbel RP, Vercelloti GM, 1997)

Fig. 2-2. Cellular consequences of Hemoglobin S. Hemoglobin S is both unstable and insoluble as a result of the loss of the negative charge. The two features act in concert to disrupt the erythrocyte and the surrounding environment.

In addition to the obvious shape changes that result from the formation of intracellular hemoglobin polymers, cumulative evidence has provided new insight into the pathophysiology of SCD and several interrelated pathways have been identified. (Miguel R. Abboud and Khaled M. Musallam, 2009)

Sickle cell disease (SCD) is as much a disease of endothelial dysfunction as it is a hemoglobinopathy that triggers erythrocyte polymerization. Increased expression of adhesion molecules on erythrocytes and endothelial cells, interactions with leukocytes, increased levels of circulating inflammatory cytokines, enhanced microvascular thrombosis, and endothelial damage are all thought to contribute to obstruction of the arterioles by sickled erythrocytes. Nitric oxide (NO) is a free radical and a potent vasodilator that regulates vascular homeostasis. Interestingly, NO has properties that can impact every aspect of SCD, from decreasing platelet activation and adhesion receptor expression on the vascular endothelium, to decreasing vascular smooth muscle proliferation, limiting ischemia-reperfusion injury, modulating endothelial proliferation, and regulating inflammation. Given the crucial role of NO depletion in endothelial dysfunction, it is not surprising that NO dysregulation is a common denominator among varied mechanisms of sickle vasculopathy. NO is produced in the endothelium from its obligate substrate L-arginine, which is converted to citrulline by a family of enzymes, the NO synthases (NOS). Although NOS expression and activity is increased, SCD is characterized by a state of NO resistance, NO inactivation, and impaired NO bioavailability. Under conditions of increased hemolysis, inflammation and/or oxidative stress, the compensatory upregulation of NO likely becomes overwhelmed and ineffective. Vascular dysfunction is the end result, due to complex and multifactorial interactions that ultimately manifest as the clinical phenotypes of SCD (Claudia R. Morris, 2008)

The best characterized clinical consequence of NO scavenging because of intravascular hemolysis is pulmonary hypertension (PHT). Approximately one-third of adults with SCD have at least mild PHT. Progressive PHT produces right ventricular failure and eventual cor pulmonale. SCD patients with even mild elevations of tricuspid regurgitant jet velocity of 2.5 m/s or greater have an approximately 10-fold relative risk for early mortality, even higher with concurrent left ventricular diastolic dysfunction. Markers of high pulmonary pressure, including high tricuspid regurgitant jet velocity or elevated serum N-terminal probrain natriuretic peptide (NTproBNP), are the most sensitive predictors of early death in SCD. (Gladwin MT, Sachdev V, et al, 2004)

Because NO is known to play a role in normal penile erection, it is paradoxical that chronically impaired NO bioavailability in SCD is associated with priapism. Perhaps more importantly, this pathobiology suggests that efforts to control hemolytic rate may reduce priapic activity. (Bialecki ES, Bridges KR, 2002)

The evidence linking stroke to hemolysis is more circumstantial and less definitive. In several studies of stroke in SCD, stroke was associated with lower Hb concentration. Supporting a link between hemolytic rate and stroke risk, in children with SCD and abnormally high transcranial Doppler velocities, is the fact chronic transfusions simultaneously reduce the hemolytic rate, plasma-free Hb levels, and the risk for stroke. (Lezcano NE, Odo N, et al, 2006)

A self-reported history of stroke is associated with PHT in patients with SCD. A characteristic profile of particularly severe hemolysis seen in most SCD with PHT is noted. There are many similarities in the epidemiological, physiological, and histopathological features of these two complications of SCD, and it is intriguing to hypothesize that, like PHT, part of the pathophysiology of cerebrovascular disease might involve impaired NO bioavailability. (Gladwin MT, Sachdev V, et al, 2004)

Serum lactate dehydrogenase (LDH) is released from the erythrocyte along with free hemoglobin and arginase. As such, LDH represents a convenient biomarker of intravascular hemolysis and NO bioavailability associated with mortality that Kato and colleagues found helpful in identifying the clinical subphenotypes of hemolysis-associated vasculopathy. ( Kato GJ, Gladwin MT, et al, 2008)

Both hemolytic rate and splenectomy (surgical and functional) are associated with RBC membrane damage, phosphatidylserine exposure at the RBC membrane surface, activation of tissue factor, and thrombosis. Splenectomy removes a large portion of the reticuloendothelial system, lowering the overall hemolytic rate, possibly shifting some of the hemolysis from extravascular to intravascular compartment. This hypothetically would prolong circulation of abnormal RBCs with cell surface phosphatidylserine, which are implicated in hemostatic activation. (Atichartakarn V, Angchaisuksiri P, et al, 2002)

The biochemical consequences of hemoglobin S therefore extend well beyond the structure or shape of the erythrocyte. The entire vascular milieu of the sickle erythrocyte is drastically altered. It is these widespread and diverse biochemical changes, rather than simply isolated alterations in erythrocyte characteristics, that produce the clinical features of SCD. (Firth PG, Head CA, 2004)

High HbF levels reduce the incidence of some subphenotypes of SCD, like osteonecrosis, acute chest syndrome, and acute painful episodes. HbF level has not been associated with protection from PHT, stroke, or priapism. This is paradoxical, because HbF expression in patients with SCD is well known to be associated with decreased overall hemolysis. The solution to the paradox may lie in the remarkably high rate of intense hemolysis in the fraction of RBCs that fail to express HbF. In addition, potential associations of HbF with these subphenotypes may also be obscured by analytical approaches that fail to account for the interactions of many other genetic modifiers with HbF. The principal observed clinical benefits of HbF are on the viscosity-vasoocclusive phenotype, potentially because of the anti-sickling effect of HbF. (Steinberg MH, 2005)


The clinical hallmark of SCD is intermittent, recurrent, acute episodes of severe pain, known as vasoocclusive crises (VOC) or pain crises. It is generally accepted that ongoing acute ischemia, vasoocclusion, and infarction are the central causes of pain, although nociceptive pathways and changes have not been extensively studied. Although the precise pathophysiology of VOC is incompletely characterized, acute changes in the endothelial regulation of flow and hemostasis are thought to be the key steps in the initiation and progression of vasoocclusion (fig. 2-4). (Firth PG, Head CA, 2004)

Activation of the vascular endothelium involves the increased endothelial expression of adhesion molecules, stimulating the binding of neutrophils and the release of proteolytic enzymes. Endothelial activation is triggered by insults such as infection, surgical stress, or, possibly, subclinical episodes of recurrent microvascular ischemia-reperfusion. Endothelial activation may be induced directly or via the elaboration of inflammatory cytokines and mediators by monocytes and macrophages. Platelet activation and aggregation, as well as fibrin deposition on areas of endothelial damage, may be additional early pathophysiological mechanisms during the development of VOC. Expression of adhesion molecules increases erythrocyte endothelial adhesion (and possibly impairs flow) sufficiently to allow microvascular sickling. The triggering event therefore impacts primarily on the endothelium, shifting the procoagulant and anticoagulant balance of the circulation towards hemostasis. The abnormal response to stressors seen in SCD is the result of the acute exacerbations of chronically deranged endothelial biology and physiology. (Kual DK, Hebbel RP, 2000)

Fig. 2-4. Pathophysiological model of vasoocclusive crisis (Firth PG, Head CA, 2004)

The VOC is therefore an intricate pathophysiological process thought to involve vasoconstriction, leukocyte adhesion and migration, platelet activation and adhesion, and coagulation. The considerable weight of evidence indicating the central role of endothelial and vascular dysfunction arises not only from the extensive biochemical, animal, and clinical data on SCD but also from related data on the role of inflammation in other vascular disorders such as unstable coronary angina and atherosclerosis. Although the precise significance and interaction of these various mechanisms remains to be defined, VOC is clearly more than a simple case of "log jamming" of the microvasculature by sickled cells. (Keaney JF, Vita JA, 2002)

Given the historical emphasis on the hypothesis of erythrocyte sickling as the dominant initiating event of VOC, the details of some longstanding clinical observations on the effect of hypoxia are of particular interest to the anesthesiologist. During a study of the effects of hypobaric hypoxia on American airmen with SCT published in 1946 a volunteer with a clinical diagnosis of SCD was exposed to decompression to 411 mm Hg for 30 min. Despite a reported arterial oxygen saturation of 74%, the subjected tolerated the hypoxemia "even better than. . .control subjects." (Firth PG, Head CA, 2004)

More recently, three series described a total of 37 cases of occlusive orthopedic tourniquet use for patients with SCD. There were no cases of ACS and only one episode of bony pain, with a causal relationship to tourniquet use not established. Prolonged survival with coexistent SCD and cyanotic heart disease has been reported, whereas people with the end stages of sickle cell lung disease survive with chronic baseline hypoxemia. Severe global and regional hypoxia, and presumably by extension increased erythrocyte sickling, does not therefore invariably produce a pain crisis. (Firth PG, Head CA, 2004)

In contrast, ascents to altitude and prolonged aircraft flights of several hours' duration are well-documented triggers of acute SCD-specific complications. Prolonged exposure to acute moderate hypoxia therefore appears to induce symptoms. Ascent to altitude imposes an adaptive pressure on the body's oxygen-delivery systems. The vascular endothelium, which regulates blood flow, is a central component of the oxygen delivery chain. Pathology induced by high altitude arises when the degree of hypoxic stress exceeds the body's adaptive capacity. Endothelial dysfunction is thought to be the origin of high-altitude pulmonary and cerebral edema, as well as acute mountain sickness. (Hackett PH, Roach RC, 2001) 

Ascent to altitude may therefore place an adaptive strain on the vascular endothelium, an interface in SCD that may be vulnerable to inflammatory damage during hypoxic stress. A speculative explanation for these paradoxical clinical observations would therefore support the concept that changes in the erythrocyte environment, rather than simply an isolated acute increase in erythrocyte sickling, are needed to trigger acute symptoms.(Platt OS, 2000)