What is Sickle Cell Anemia?

Sickle Cell Anemia: Stroke and Vaso-occlusion

Sickle cell anemia is a genetic disease affecting 70,000 to 100,000 African Americans (1). It is the most common cause for stroke in children (2). Strokes are much more common in children than adults for sufferers of this disease (3) with the average victim being around 6 years of age (2). About 11% of Sickle cell sufferers will experience a clinical stroke syndrome by age 20 (4). Usually arteries such as the middle cerebral and internal carotid are occluded (5). A well known study, STOP, The Stroke Prevention Trail in Sickle Cell Anemia, found that routine blood transfusions decreased incidence of stroke by about 90% (6). However, although incidence of life threatening massive stokes have decreased, cerebral infarcts were still taking place. The Cooperative Study of Sickle Cell Disease showed that 20% of 42 analyzed children had cerebral infarction (7). Another study showed that on average 17-22% of children with sickle cell will have subclinical evidence of cerebral infarction when imaged with a MRI (2). It is also now known that chronic transfusions do not prevent post stroke damage, or the progression of cerebrovascular disease (8). Another study of 27 randomly selected children who are not clinically affected by strokes, found 33% with mild retardation levels, which they compared to a published 1.45% for inner city black children (9). The study concludes that even though the patients do not suffer from stokes, they still have chronic hypoxia in their brain tissue. These findings demonstrate that even if incidents of strokes are decreased or nonexistent, the patients still have occlusion events.

     1. Solomon OA, Ohene-Frempong K. Beyond National Borders: A Global Perspective on Advances in Sickle Cell Disease Research and Management, and New Challenges in The Genome Era. [book auth.] B Pace. Renaissance of Sickle Cell Disease Research in the Genome Era. 2007, pp. 333-345.
     2. Hoppe, C. Defining stroke risk in children with sickle cell anaemia. 2005 : J. of the British Society for Haematology. pp. 751-766. Vol. 128.
     3. http://sickle.bwh.harvard.edu/scdmanage.html. [Online]
     4. Powars D, Wilson B, Imbus C, Pegelow C, Allen J. The Natural History of Stroke in Sickle Cell Disease. Am J Med, 1978. pp. 461-471. Vol. 65.
     5. Balkaran, B, Char G, Morris J, Thomas P, Serjeant G. Stroke in a Cohort of Pateints with Homozygous Sickle Cell Disease. J of Pediatrics, 1992. pp. 360-366. 120.
     6. Adams RJ, McKie VC, Brambilla D, Carl E, et al. Stroke Prevention in Sickle Cell Anemia. Control Clin Trials, 1998. pp. 110-129. Vol. 19.
     7. Kinney TR, Sleeper LA, Wang WC, Zimmerman RA, Pegelow CH, Ohene-Frempong K, Wethers DL, Bello JA, Vichinsky EP, Moser FG, Gallagher DM, DeBaun MR, Platt OS, Miller ST. Silent Cerebral Infarcts in Sickle Cell Anemia: A Risk Factor Analysis. The Cooperative Study of Sickle Cell Disease. Pediatrics. pp. 640-645. 103.
     8. Brousse V, Hertz-Pannier L , Consigny Y, Bresson J, Girot R, Mirre E, Lenoir G, Montalembert M. Does Regular Blood Transfusion Prevent Progression of Cerebrovascular lesions in Children with Sickle Cell Disease? Annals of Hematology, 2008.
     9. Steen RG, Xiong X, Mulhern RK, Langston JW, Wang WC. Subtlebrain abnormalities in children with sickle cell disease: relationship to blood hematocrit. Ann Neurol, 1999. pp. 279-286. 45.

Scientific Background

What is Hemoglobin?

Red blood cells are the means by which oxygen is delivered throughout the human body to tissues and muscles. It also removes the gases produced as a byproduct from physical processes. The red blood cell accomplishes this through the hemoglobin proteins it carries. Hemoglobin, so called due to the four heme groups, (i.e. iron) and globin a reference to a type of protein(1), can bind and release gases such as O2, CO and NO. It is a protein, made up of four smaller protein subunits labeled as α1, β1, α2, β2. Each subunit contains one iron atom that bonds an oxygen molecule in order to transport it from the lungs. The iron has eight alpha helical structures that surround it and this restricts each iron site to bind just one molecule from the two available molecular contacts (Figure I).

Figure I: Close up view of O2 bonded to Fe next to a helical protein structure(2).

Hemoglobin is also a cooperative molecule. This means that when it binds one gas molecule to a site, the properties of the protein change so that it has a higher affinity to bind a second molecule, as well as for the third and forth. The process is also invertible, such that when one molecule is released, the others have a higher likelihood to leave. This process is necessary for life, because it allows the hemoglobin to effectively uptake O2 in the lungs and releases it in the blood stream.

When hemoglobin has no gas molecules bound, it is usually in the T-state (tense) configuration. The T-state is a quaternary structure of the molecule that allows it to have a higher stability when there are no ligands bound. When Hb has all four ligands bound, it is most likely found in the R-state (relaxed), a different quaternary structure that has a higher structural stability for more ligands. The T and R-states differ by a rotation of one set of subgroups (α1β1) by 15 degrees with respect to the other two subgroups (α2β2) (Figure II).

Figure II: The T to R-state rotation of hemoglobin dimers(3).

One way to study this system is through the MWC model (named after Jacques Monod, Jefferies Wyman & Jean-Pierre Changeux). According to this model the Hb molecule is either in the T or R state completely. It does not have a sub-combination of the two states that occurs for a certain number of ligands. With the absence of ligands, the molecule has a large probability of being in the more stable T state at any time. For one ligand, there is a slight increase in the probability for the R state to occur. At about 2 or 3 ligands, the time spent in the R-state can increase until it is more probable then T, depending on the system. For 4 ligands, it is generally in the R state, but always completely in one or the other. Having two configurations presents certain ramifications in the system. When the molecule is in the R state, the rate at which it can bind a molecule is increased by an order of magnitude. When the rate of binding a ligand is influenced by the presence of other ligands, the protein is referred to as allosteric. Hb is a cooperative allosteric protein, therefore it bonds each additional ligand with a greater affinity.

Sickle Cell Anemia, Mutation & Disease:

There are more than 300 genetic variations of hemoglobin among humans. Generally, the variations differ by just one molecular group (an amino acid residue). However, one small change among hundreds of amino acid residues can have far reaching consequences. One such example is the genetic disease Sickle Cell Anemia. In the two beta subgroups a negative amino acid residue Glu is replaced by a hydrophobic Val. This occurs on the outer surface of the protein. When sickle hemoglobin is non liganded (in a deoxy state), it is able to form polymers due to the new surface molecular contacts. This event is rate limiting because a nucleus, (several hemoglobin molecules bonded together) must stay together long enough to allow a 14 strand polymer to grow from them. After this, the rate of polymerization increases exponentially, because of heterogeneous polymerization (polymers forming on preexisting polymers, Figure III).

Figure III: The two pathways of polymerization.

If the formation of polymers continues inside the red blood cell, it is possible to harm components in, or deform the cell. This is detrimental to the life-span of the red blood cell, causing the anemic side effect. The polymers can also stiffen the red blood cell, making passage through a tight capillary difficult (Figure IV).

Figure IV: Passage through a capillary.

Sickle disease is found mainly in people of African descent; specifically those whose ancestors are originally from a malaria-infected region. In the United States alone, about 72,000 people are infected about 1 in 500 African Americans. Worldwide, 1 in 12 people of African descent are carriers. For a person to become infected, it is necessary to inherit two mutated genes, one from each parent. The parent can have the sickle cell disease by carrying two infected genes or can be a carrier with just one sickle trait gene. By carrying one mutant gene, the disease is only half expressed and is not enough to be harmful. If both parents are carriers, then they can each pass either a healthy gene or a mutated one. There is then a one in four chance of the child having sickle disease, and a fifty percent chance of becoming a carrier.

Sickle cell anemia is a life long debilitating disease. When a human baby is in the gestation period, they have fetal hemoglobin in their red blood cells. Fetal Hb is another variant of hemoglobin produced specifically by fetuses and is unaffected by the Sickle cell trait. After the child is born, fetal hemoglobin is replaced by normal adult hemoglobin, or in this case by sickle hemoglobin. This means the disease might not be noticeable until after the baby is born and already a few months old. When the disease is fully present, victims can develop a type of anemia resulting from the red blood cells having a shorter lifespan. This also leads to increased chances of infections, like pneumonia. Many more complications arise when blood flow is blocked in a capillary. If it occurs in the retina they can become blind; if it occurs in the extremities, like the fingers or toes, they might swell, or lose the function of the appendage. It is also possible for the person to permanently lose vision due to the lack of blood flow to the retina. Extreme complications include severe and acute chest pain, ulcers, stroke, and death.

     1. Nelson, DL, et al. Lehninger Principles of Biochemistry. p206.
     2. Lehninger. p213.
     3. Voet, D. Biochemistry. p228.


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Office Location: Disque Hall - Room 923 Office Phone: 215-895-1517 Email Address: day23@drexel.edu LinkedIn Profile: Donna Yosmanovich	What is Sickle Cell Anemia? Sickle Cell Anemia: Stroke and Vaso-occlusion Sickle cell anemia is a genetic disease affecting 70,000 to 100,000 African Americans (1). It is the most common cause for stroke in children (2). Strokes are much more common in children than adults for sufferers of this disease (3) with the average victim being around 6 years of age (2). About 11% of Sickle cell sufferers will experience a clinical stroke syndrome by age 20 (4). Usually arteries such as the middle cerebral and internal carotid are occluded (5). A well known study, STOP, The Stroke Prevention Trail in Sickle Cell Anemia, found that routine blood transfusions decreased incidence of stroke by about 90% (6). However, although incidence of life threatening massive stokes have decreased, cerebral infarcts were still taking place. The Cooperative Study of Sickle Cell Disease showed that 20% of 42 analyzed children had cerebral infarction (7). Another study showed that on average 17-22% of children with sickle cell will have subclinical evidence of cerebral infarction when imaged with a MRI (2). It is also now known that chronic transfusions do not prevent post stroke damage, or the progression of cerebrovascular disease (8). Another study of 27 randomly selected children who are not clinically affected by strokes, found 33% with mild retardation levels, which they compared to a published 1.45% for inner city black children (9). The study concludes that even though the patients do not suffer from stokes, they still have chronic hypoxia in their brain tissue. These findings demonstrate that even if incidents of strokes are decreased or nonexistent, the patients still have occlusion events. 1. Solomon OA, Ohene-Frempong K. Beyond National Borders: A Global Perspective on Advances in Sickle Cell Disease Research and Management, and New Challenges in The Genome Era. [book auth.] B Pace. Renaissance of Sickle Cell Disease Research in the Genome Era. 2007, pp. 333-345. 2. Hoppe, C. Defining stroke risk in children with sickle cell anaemia. 2005 : J. of the British Society for Haematology. pp. 751-766. Vol. 128. 3. http://sickle.bwh.harvard.edu/scdmanage.html. [Online] 4. Powars D, Wilson B, Imbus C, Pegelow C, Allen J. The Natural History of Stroke in Sickle Cell Disease. Am J Med, 1978. pp. 461-471. Vol. 65. 5. Balkaran, B, Char G, Morris J, Thomas P, Serjeant G. Stroke in a Cohort of Pateints with Homozygous Sickle Cell Disease. J of Pediatrics, 1992. pp. 360-366. 120. 6. Adams RJ, McKie VC, Brambilla D, Carl E, et al. Stroke Prevention in Sickle Cell Anemia. Control Clin Trials, 1998. pp. 110-129. Vol. 19. 7. Kinney TR, Sleeper LA, Wang WC, Zimmerman RA, Pegelow CH, Ohene-Frempong K, Wethers DL, Bello JA, Vichinsky EP, Moser FG, Gallagher DM, DeBaun MR, Platt OS, Miller ST. Silent Cerebral Infarcts in Sickle Cell Anemia: A Risk Factor Analysis. The Cooperative Study of Sickle Cell Disease. Pediatrics. pp. 640-645. 103. 8. Brousse V, Hertz-Pannier L , Consigny Y, Bresson J, Girot R, Mirre E, Lenoir G, Montalembert M. Does Regular Blood Transfusion Prevent Progression of Cerebrovascular lesions in Children with Sickle Cell Disease? Annals of Hematology, 2008. 9. Steen RG, Xiong X, Mulhern RK, Langston JW, Wang WC. Subtlebrain abnormalities in children with sickle cell disease: relationship to blood hematocrit. Ann Neurol, 1999. pp. 279-286. 45. Scientific Background What is Hemoglobin? Red blood cells are the means by which oxygen is delivered throughout the human body to tissues and muscles. It also removes the gases produced as a byproduct from physical processes. The red blood cell accomplishes this through the hemoglobin proteins it carries. Hemoglobin, so called due to the four heme groups, (i.e. iron) and globin a reference to a type of protein(1), can bind and release gases such as O2, CO and NO. It is a protein, made up of four smaller protein subunits labeled as α1, β1, α2, β2. Each subunit contains one iron atom that bonds an oxygen molecule in order to transport it from the lungs. The iron has eight alpha helical structures that surround it and this restricts each iron site to bind just one molecule from the two available molecular contacts (Figure I). Figure I: Close up view of O2 bonded to Fe next to a helical protein structure(2). Hemoglobin is also a cooperative molecule. This means that when it binds one gas molecule to a site, the properties of the protein change so that it has a higher affinity to bind a second molecule, as well as for the third and forth. The process is also invertible, such that when one molecule is released, the others have a higher likelihood to leave. This process is necessary for life, because it allows the hemoglobin to effectively uptake O2 in the lungs and releases it in the blood stream. When hemoglobin has no gas molecules bound, it is usually in the T-state (tense) configuration. The T-state is a quaternary structure of the molecule that allows it to have a higher stability when there are no ligands bound. When Hb has all four ligands bound, it is most likely found in the R-state (relaxed), a different quaternary structure that has a higher structural stability for more ligands. The T and R-states differ by a rotation of one set of subgroups (α1β1) by 15 degrees with respect to the other two subgroups (α2β2) (Figure II). Figure II: The T to R-state rotation of hemoglobin dimers(3). One way to study this system is through the MWC model (named after Jacques Monod, Jefferies Wyman & Jean-Pierre Changeux). According to this model the Hb molecule is either in the T or R state completely. It does not have a sub-combination of the two states that occurs for a certain number of ligands. With the absence of ligands, the molecule has a large probability of being in the more stable T state at any time. For one ligand, there is a slight increase in the probability for the R state to occur. At about 2 or 3 ligands, the time spent in the R-state can increase until it is more probable then T, depending on the system. For 4 ligands, it is generally in the R state, but always completely in one or the other. Having two configurations presents certain ramifications in the system. When the molecule is in the R state, the rate at which it can bind a molecule is increased by an order of magnitude. When the rate of binding a ligand is influenced by the presence of other ligands, the protein is referred to as allosteric. Hb is a cooperative allosteric protein, therefore it bonds each additional ligand with a greater affinity. Sickle Cell Anemia, Mutation & Disease: There are more than 300 genetic variations of hemoglobin among humans. Generally, the variations differ by just one molecular group (an amino acid residue). However, one small change among hundreds of amino acid residues can have far reaching consequences. One such example is the genetic disease Sickle Cell Anemia. In the two beta subgroups a negative amino acid residue Glu is replaced by a hydrophobic Val. This occurs on the outer surface of the protein. When sickle hemoglobin is non liganded (in a deoxy state), it is able to form polymers due to the new surface molecular contacts. This event is rate limiting because a nucleus, (several hemoglobin molecules bonded together) must stay together long enough to allow a 14 strand polymer to grow from them. After this, the rate of polymerization increases exponentially, because of heterogeneous polymerization (polymers forming on preexisting polymers, Figure III). Figure III: The two pathways of polymerization. If the formation of polymers continues inside the red blood cell, it is possible to harm components in, or deform the cell. This is detrimental to the life-span of the red blood cell, causing the anemic side effect. The polymers can also stiffen the red blood cell, making passage through a tight capillary difficult (Figure IV). Figure IV: Passage through a capillary. Sickle disease is found mainly in people of African descent; specifically those whose ancestors are originally from a malaria-infected region. In the United States alone, about 72,000 people are infected about 1 in 500 African Americans. Worldwide, 1 in 12 people of African descent are carriers. For a person to become infected, it is necessary to inherit two mutated genes, one from each parent. The parent can have the sickle cell disease by carrying two infected genes or can be a carrier with just one sickle trait gene. By carrying one mutant gene, the disease is only half expressed and is not enough to be harmful. If both parents are carriers, then they can each pass either a healthy gene or a mutated one. There is then a one in four chance of the child having sickle disease, and a fifty percent chance of becoming a carrier. Sickle cell anemia is a life long debilitating disease. When a human baby is in the gestation period, they have fetal hemoglobin in their red blood cells. Fetal Hb is another variant of hemoglobin produced specifically by fetuses and is unaffected by the Sickle cell trait. After the child is born, fetal hemoglobin is replaced by normal adult hemoglobin, or in this case by sickle hemoglobin. This means the disease might not be noticeable until after the baby is born and already a few months old. When the disease is fully present, victims can develop a type of anemia resulting from the red blood cells having a shorter lifespan. This also leads to increased chances of infections, like pneumonia. Many more complications arise when blood flow is blocked in a capillary. If it occurs in the retina they can become blind; if it occurs in the extremities, like the fingers or toes, they might swell, or lose the function of the appendage. It is also possible for the person to permanently lose vision due to the lack of blood flow to the retina. Extreme complications include severe and acute chest pain, ulcers, stroke, and death. 1. Nelson, DL, et al. Lehninger Principles of Biochemistry. p206. 2. Lehninger. p213. 3. Voet, D. Biochemistry. p228.
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