The information at this site is a free service to the biomedical community and our members. The goal is to provide a source of current information on sickle cell anemia metabolism. The information and opinions presented are those of the authors. Comments and suggestions are welcomed.

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How Does Sickle Cell Cause Disease?

Sickle cell disease is a blood condition seen most commonly in people of African ancestry and in the tribal peoples of India. Clinically significant sickle cell syndromes also occur in people of Mediterranean and Middle Eastern background. Here, the most common problem is a combination sickle cell and beta thalassemia genes. The sickle cell mutation reflects a single change in the amino acid building blocks of the oxygen-transport protein, hemoglobin. This protein, which is the component that gives red cells their color, has two subunits. The alpha subunit is normal in people with sickle cell disease. The beta subunit has the amino acid valine at position 6 instead of the glutamic acid that is normally present. The alteration is the basis of all the problems that occur in people with sickle cell disease. The schematic diagram shows the first eight of the 146 amino acids in the beta globin subunit of the hemoglobin molecule. The amino acids of the hemoglobin protein are represented as a series of linked, colored boxes. The lavender box represents the normal glutamic acid at position 6. The dark green box represents the valine in sickle cell hemoglobin. The other amino acids in sickle and normal hemoglobin are identical.

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A Brief History of Sickle Cell Disease

Sickle cell disease has been known to the peoples of Africa for hundreds of years. In West Africa various ethnic groups gave the condtion different names.

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An Overview of Hemoglobin

This brief overview of hemoglobin is not meant to be comprehensive. The goal is to provide sufficient background to make this Web site useful to people unfamiliar with the area. More detailed sources are listed at the end of this file.

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Hemoglobin Synthesis

Hemoglobin synthesis requires the coordinated production of heme and globin. Heme is the prosthetic group that mediates reversible binding of oxygen by hemoglobin. Globin is the protein that surrounds and protects the heme molecule.

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Hemoglobinopathies

Hemoglobin is produced by genes that control the expression of the hemoglobin protein. Defects in these genes can produce abnormal hemoglobins and anemia, which are conditions termed "hemoglobinopathies". Abnormal hemoglobins appear in one of three basic circumstances.

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How Do People Get Sickle Cell Disease?

Sickle cell disease is an inherited condition. Two genes for the sickle hemoglobin must be inherited from one's parents in order to have the disease. A person who receives a gene for sickle cell disease from one parent and a normal gene from the other has a condition called "sickle cell trait." Sickle cell trait produces no symptoms or problems for most people. Sickle cell disease can neither be contracted nor passed on to another person. The severity of sickle cell disease varies tremendously. Some people with sickle cell disease lead lives that are nearly normal. Others are less fortunate, and can suffer from a variety of complications.

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Phenotypic Variation in Sickle Cell Disease: An Analysis

Everyone with sickle cell disease shares the same gene mutation. A thymine replaces an adenine in the DNA encoding the ß-globin gene. Consequently, the amino acid valine replaces glutamic acid at the sixth position in the ß-globin protein product (Ingram, 1956). The change produces a phenotypically recessive characteristic. Most commonly sickle cell disease reflects the inheritance of two mutant alleles, one from each parent.

by Errol L. Fields
Undergraduate Student, Harvard University.

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Malaria and the Red Cell.

For thousands of years malaria swept through the ranks of humankind like a scythe in the hands of an angry god. Falciparum malaria (P. falciparum) , transmited by the female anopheles mosquito is the most deadly of the four types of of the disease (the other three being P. vivax, P. ovale, and P. malariae). Each year, malaria attacks about 400 million people, two to three million of whom succumb to the illness. Most malaria victims are children. An understanding of the origin of sickle cell disease and several other red cell disorders requires knowledge of a few of the basics about malaria and something about the process called natural selection.

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Sickle Cell Trait

Sickle cell trait usually is not regarded as a disease state because it has complications that are either uncommon or mild. Nevertheless, under unusual circumstances serious morbidity or mortality can result from complications related to polymerization of deoxy-hemoglobin S. Such problems include increased urinary tract infection in women, gross hematuria, complications of hyphema, splenic infarction with altitude hypoxia or exercise, and life-threatening complications of exercise, exertional heat illness (exertional rhabdomyolysis, heat stroke, or renal failure) or idiopathic sudden death (1-4). Pathologic processes that cause hypoxia, acidosis, dehydration, hyperosmolality, hypothermia, or elevated erythrocyte 2,3-DPG can transform silent sickle cell trait into a syndrome resembling sickle cell disease with vaso-occlusion due to rigid erythrocytes. Compound heterozygous sickle cell disease can be mistaken as uncomplicated sickle cell trait, particularly when an unusual globin variant is involved.

By John Kark, M.D. (formerly of the Uniformed Services University of the Health Sciences, Bethesda, MD.)
Howard Universty School of Medicine
Center for Sickle Cell Disease

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RED CELL DEHYDRATION IN PATHOPHYSIOLOGY AND TREATMENT OF SICKLE CELL DISEASE.

Cells with a markedly increased Hb S concentration are a prominent feature of sickle cell disease, as a consequence of the loss of K, Cl and water from the erythrocyte. The extreme dependence of polymerization kinetics on Hb S concentration means that these dehydrated erythrocytes rapidly sickle when deoxygenated. Blockade of K loss from the erythrocyte should, therefore, prevent the increase in Hb S concentration and reduce erythrocyte sickling. Detailed knowledge of the mechanisms leading to cell dehydration makes this a viable therapeutic option. Two ion transport pathways, the K-Cl cotransport and the Ca²⁺-activated K⁺channel play prominent roles in the dehydration of sickle erythrocytes. Possible therapeutic strategies include inhibition of K-Cl cotransport by increasing red cell Mg²⁺content and inhibition of the Ca²⁺-activated K channel by oral administration of clotrimazole.

by Carlo Brugnara, M.D.
Departments of Pathology and Laboratory Medicine
The Children's Hospital

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Transition of Patients with Sickle Cell Disease from Pediatric to Adult Care

Transition is a constant element of life. The process begins at birth and ends at death. Some transitions (for instance, becoming a parent) are more difficult than others (e.g., learning to drive). Some transitions, such as school graduations, are abrupt and marked by ceremony. Other transitions are gradual with less well-defined boundaries (becoming middle-aged, for instance).

People with chronic illness face the same transitions. Additional issues arise that most healthy people never encounter, however. Children with chronic illness that stretches into adulthood face the same challenges of adolescence as their healthy counterparts. The challenges are more complex and intertwined with other formidable tasks, such as finding new care providers and institutions. People with sickle cell disease often need help and guidance as they cross life's stream that separates childhood and adulthood.

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How Do People Get Thalassemia?

Thalassemia is an inherited condition. The genes received from one's parents before birth determine whether a person will have thalassemia. Thalassemia cannot be caught or passed on to another person. The clinical severity of thalassemia varies tremendously depending on the exact nature of the genes that a person inherits.

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Sickle Cell Disease

Sickle Cell Disease is a group of inherited red blood cell disorders. Normal red blood cells are round like doughnuts, and they move through small blood tubes in the body to deliver oxygen. Sickle red blood cells become hard, sticky and shaped like sickles used to cut wheat. When these hard and pointed red cells go through the small blood tube, they clog the flow and break apart. This can cause pain, damage and a low blood count, or anemia.

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Sickle cell anemia

Sickle cell anemia is a hereditary disorder that mostly affects people of African ancestry, but also occurs in other ethnic groups, including people who are of Mediterranean and Middle Eastern descent. More than 70,000 Americans have sickle cell anemia. And about 2 million Americans - and one in 12 African Americans - have sickle cell trait (this means they carry one gene for the disease, but do not have the disease itself).

Sickle cell anemia occurs when a person inherits two abnormal genes (one from each parent) that cause their red blood cells to change shape. Instead of being flexible and round, these cells are more rigid and curved in the shape of the farm tool known as a sickle - that's where the disease gets its name. The shape is similar to a crescent moon.

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