Sickle Cell Anemia

Department of Medicine, University of Georgia

MD4230E: Hematology, Transfusiology

Dr. Elene Dolmazashvili

Juma Awar

4/11/2022

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Introduction

Sickle cell disease is a group of inherited disorders, of which homozygous hemoglobin S (HbSS) and

HbSβ0 thalassemia or sickle cell anemia (SCA) are the most common and clinically severe phenotypes.

Under hypoxia, acidosis or dehydration conditions, HbS polymerizes and forms linear elongated fibers

that distort red blood cells (RBCs), leading to a chronic hemolytic anemia and acute episodes of pain due

to Vaso-occlusive (VOC) obstruction of blood flow and tissue ischemia. The ensuing

ischemia/reperfusion injury leads to the generation of reactive oxygen species and endothelial cell

activation with increased adhesion molecule expression, and activation of neutrophils, monocytes and

platelets leading to a chronic inflammatory state in SCD. Additionally, intravascular hemolysis of sickle

RBCs leads to nitric oxide (NO) depletion by cell-free Hb, contributing to endothelial dysfunction.

Moreover, the RBC membrane is damaged by deoxy-HbS polymerization through lipid peroxidation

leading to phosphatidylserine exposure, and generation of a hypercoagulable state. These mechanisms

contribute to the development of chronic organ damage including sickle nephropathy, pulmonary

hypertension, avascular necrosis of bone, chronic lung disease and ultimately to a shortened life

expectancy.

Pathophysiology

The sickling process within red cells occurs as direct consequence of the substitution of a single

nucleotide (A to T) in the codon for amino acid 6. The change converts a glutamic acid codon (GAG) to a

valine codon (GTG). However, valine is a hydrophobic amino acid. During deoxygenation, valine

hydrophobicity attracts hydrophobic regions of adjacent β-chains facilitating the polymerization of

hemoglobin molecules. Formation of Hb aggregates is a thermodynamically unstable event, and under

particular conditions, the number of molecules aggregating significantly increases and reaches a critical

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mass, known as the critical nucleus, after which point addition of further molecules to this compound

generates a stable complex. As this progresses, the reaction becomes autocatalytic and heterogeneous

nucleation occurs on the surface of pre-existing polymers, leading to robust polymer generation, causing

erythrocytes sickling. Polymerization progression is affected by oxygenation, 3-diphosphoglycerate (2,3-

DPG) concentration, pH, temperature, saline concentration and carbon monoxide.

Diagnosis

Preconception, antenatal, and neonatal screening programs are important in the clinical care and public

health management of SCA. The most common approaches to diagnosis in high-income countries

include gel-based or capillary electrophoresis, high-performance liquid chromatography, and isoelectric

focusing. All are sensitive in identifying affected individuals but are limited by their inability to reliably

distinguish HbSS from HbS/β0-thalassemia. However, most neonatal screening programs involve testing

during the first week of life, when the expression of adult hemoglobin (and, therefore, HbS) is still low,

which leads to problems with reduced sensitivity. This has prompted the development of new

approaches that include tandem mass spectrometry, DNA diagnostics (including Taqman PCR and

sequence analysis of specifically amplified HBB genes), and next-generation sequencing analysis.

Although these increasingly sophisticated methods are now entering clinical practice in high-income

countries, few are readily available to the majority of patients in low-income regions. For many years,

the mainstay of diagnosis in these regions has been the sodium metabisulfite sickling test or commercial

variations of it; however, these tests cannot reliably distinguish carriers from affected patients. Several

alternative, point-of-care approaches are currently under development, of which the most advanced—

an antibody-based lateral-flow assay marketed under the name of Sickle SCAN—is now commercially

available.

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Symptoms

Sickle cell anemia can manifest in any organ of the body. Common and important manifestations are

presented here.

Anemia. The patients often have a relatively stable but low Hb value. However, this may decrease

secondary to blood pooling in the spleen, due to aggravated hemolysis, or transiently decreased bone

marrow production (even aplastic crisis) associated with infection. 

Pain episodes (Vaso-occlusive episodes). Vaso-occlusive episodes with accompanying pain in affected

parts of the body are the most characteristic of the disease, and cause 90 percent of all hospital

admissions in adults. Cool weather, fever and dehydration increase the risk. 

Infections . Patients with sickle cell anemia are particularly vulnerable to infections caused by capsule-

bearing bacteria, eg Streptococcus pneumoniae and Haemophiles influenzae. The cause is repeated

infarcts in the spleen, which lead to functional asplenia. Globally, infections are the leading cause of

death in children with sickle cell disease, although these infections have decreased in the Western world

thanks to vaccinations and antibiotic prophylaxis.

Acute chest syndrome. Acute chest syndrome is defined as a new radiological pulmonary infiltrate in

combination with fever, cough, increased sputum production, tachypnea, dyspnea and/or new

hypoxia. This condition is the most common cause of death in adult patients with sickle cell disease. The

etiology of acute chest syndrome in children is usually lung infection, while in adults the etiology is more

often unknown or multifactorial. 

Pulmonary hypertension. 30 percent of adult patients with sickle cell anemia suffer from pulmonary

hypertension, and the complication is a strongly negative prognostic factor. The exact pathophysiology is

not clear, but pulmonary hypertension usually occurs without evidence of pulmonary embolism.

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Venous thromboses. 25 percent of adult patients with sickle cell anemia develop venous

thromboembolism. This means that patients with sickle cell anemia have as high a risk of developing

venous thrombosis as patients with congenital deficiencies of endogenous coagulation

inhibitors. Impaired flow, vasoconstriction, impaired fibrinolysis, activation of the coagulation cascade

and activation of endothelium and platelets are considered to be some of the causes. Phospholipid

antibodies occur, possibly due to exposure of phospholipid surfaces in damaged erythrocyte

membranes. Patients with sickle cell anemia have also been found to have lower levels of protein C and

S, which may be due to increased consumption of the factors secondary to coagulation activation in the

vessels.

Cerebrovascular disease. Ischemic stroke is a common cause of morbidity and mortality in sickle cell

disease. Subtle brain parenchymal changes can contribute to the cognitive impairments that sometimes

develop.

ischemia. Treatment with erytrapheresis and acetylsalicylic acid (ASA) led to regression of the patient's

symptoms.

Leg ulcers. Leg ulcers are relatively common and probably occur due to reduced circulation secondary to

"sickling" of erythrocytes in the small blood vessels.

Treatment

Current treatment options focus largely on best supportive care, including blood transfusions and pain

medication. Hydroxyurea, with its proven efficacy in reducing sickle cell crises and improving survival,

should also be considered standard care, but it is grossly underutilized. Hydroxyurea is the first of just

two U.S. Food and Drug Administration (FDA)–approved drugs to treat sickle cell disease (SCD) by

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inhibiting the HbS polymerization that causes sickling. The clinical effectiveness of hydroxyurea is due to

the induction of fetal hemoglobin (HbF) production by a still unknown mechanism. HbF is composed of

two α-globin chains and two γ-globin chains. The amino acid sequence of HbF is sufficiently different

from HbS that little or no HbF takes part in fiber formation, so the primary effect is to dilute HbS.

Even a small decrease in the intracellular HbS concentration is therapeutic because of the enormous

sensitivity to concentration during the period before HbS fibers appear (delay time), allowing more cells

to escape the capillaries of peripheral tissues, where oxygen is delivered, before sickling occurs

A second drug that inhibits sickling, voxelotor, was approved by the FDA in November 2019. Voxelotor

preferentially binds to the high–oxygen affinity, nonpolymerizing R conformation of HbS, reducing the

concentration of the polymerizing T conformation at every oxygen pressure. However, HbS molecules

bound with the drug are in a conformation that delivers very little oxygen to tissues, in a disease

characterized by decreased oxygen delivery. So, although patients taking voxelotor show modest

increases in hemoglobin concentrations, it is not necessarily an indication of decreased anemia because

the increase in hemoglobin is about the same as the concentration of the drug-bound, non–oxygen-

delivering hemoglobin. Moreover, there is no current evidence of a decreased frequency of sickle cell

crises, and the effects on organ damage and survival are yet to be determined. However, the increase in

hemoglobin is accompanied by decreased markers of red blood cell rupture, indicating reduced sickling.

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References

Kjellander, C., Sennström, M. K., Stiller, V., & Ågren, A. (2015). Sicklecellanemi ger skiftande symtombild

och hög morbiditet--Allvarlig prognos vid världens vanligaste genetiska sjukdom [Sickle cell anemia

causes varied symptoms and high morbidity. Serious prognosis in the most common genetic disease in

the world]. Lakartidningen, 112, DCPM.

https://lakartidningen.se/klinik-och-vetenskap-1/artiklar-1/klinisk-oversikt/2015/03/sicklecellanemi-ger-

skiftande-symtombild-och-hog-morbiditet/

Pace, B. S., Starlard-Davenport, A., & Kutlar, A. (2021). Sickle cell disease: progress towards combination

drug therapy. British journal of haematology, 194(2), 240–251. https://doi.org/10.1111/bjh.17312

Piccin, A., Murphy, C., Eakins, E., Rondinelli, M. B., Daves, M., Vecchiato, C., Wolf, D., Mc Mahon, C., &

Smith, O. P. (2019). Insight into the complex pathophysiology of sickle cell anaemia and possible

treatment. European journal of haematology, 102(4), 319–330. https://doi.org/10.1111/ejh.13212

Tisdale, J. F., Thein, S. L., & Eaton, W. A. (2020). Treating sickle cell anemia. Science (New York,

N.Y.), 367(6483), 1198–1199. https://doi.org/10.1126/science.aba3827

Williams, T. N., & Thein, S. L. (2018). Sickle Cell Anemia and Its Phenotypes. Annual review of genomics

and human genetics, 19, 113–147. https://doi.org/10.1146/annurev-genom-083117-021320