Pathophysiological Basics of Sickle Cell Disease

Sickle cell disease or Sickle Cell Anemia (as it used to be called) is a disease of the red blood cells, which in inherited. It was first reported in Western Literature in 1910, when a midwestern physician described a patient from the West Indies who had an anemia, which was characterized, by unusually shaped cells. In the 1920s, it was shown that the change of these cells into the usual sickle shape was associated with conditions of low oxygen. The abnormal hemoglobin associated with sickle cell disease was first demonstrated in 1948, when the process of protein electrophoresis showed that the hemoglobin in patients with sickle cells was different than the average patient.

Pathophysiological Basics of Sickle Cell Disease

Before one can speak in depth on sickle cell disease itself, one must understand the basic pathophysiology which surrounds the condition. Hemoglobin is a protein carried by red cells, which carries oxygen from the lungs for delivery to peripheral tissues. It is composed of two similar proteins, alpha and beta. It is the coordinated action of the alpha and beta globin chains which allow the oxygen transport to occur. These two chains combine to form hemoglobin. During life, except during the very first week of embryonic development, one of the globin chains in an alpha. A developing fetus also has another chain which is a gamma globin; sometimes called non-alpha is present in the fetal circulation. The gamma globin is replaced shortly after birth with the beta, which then chains with the alpha.

When two alpha chains combine with two gamma chains, this is called Hemoglobin F, or the common hemoglobin of fetal circulation. Adult hemoglobin, formed of two alpha and beta chains is called Hemoglobin a. If one alpha and one non-alpha chain combine, then this two chain combination is called a dimer and it not functional enough to deliver oxygen to tissues.

Sickle cell disease is most commonly seen in patients from Africa, India, the Mediterranean and the Middle East. A genetic mutation caused there to be a change in one of the amino acids which build hemoglobin. While the alpha globin is normal, in sickle cell disease the beta unit has a substitution of valine for glutamic acid at position six on the amino acid chain. All the other amino acids in sickle and normal hemoglobin are the same.

The basis of this mutation is genetic in character. Since DNA determines the way amino acids are paired, it is a mutation within the DNA, specifically on chromosome 11, which is the gene that controls the production of the beta subunit, which causes the presence or absence of sickle cell disease. Because of the association with the chromosomes, sickle cell anemia is an inherited disease.

There are different expressions of this disease. If only one of the beta globins has a “sickle” gene and the other one is normal, then that person is considered a carrier for sickle cell disease. These people will not actually manifest the disease, but may pass it on to their offspring. This type of expression is called sickle cell trait. If both beta globin genes are affected, and have the substitution, then this patient has sickle cell disease. Inheritance is the only way of acquiring sickle cell disease.

Several factors are associated with the expression and variability of sickle cell disease. The presence of hemoglobin C. On it’s own generally causes no problems, a person who has two genes for the expression of hemoglobin C. can also have a relatively harmless disease called Hemoglobin C. disease. If the patient has C. And hemoglobin S, this is called Hemoglobin SC disease. This can cause a disease as severe as sickle disease. This condition may also coexist with sickle cell disease and cause a problem with red cell dehydration.

As we have stated the hemoglobin picks up oxygen in the lungs and releases it in the periphery. Normal hemoglobin molecules exist as single units within normal, red, disc shaped cells. Sickle hemoglobin also live as isolated units within the red cells when they are exposed to sufficient oxygen. but, in contrast to normal hemoglobin, when sickle hemoglobin delivers the oxygen to the tissues, the hemoglobin molecules have a tendency to stick together and form into long chains.

These chains cause the cell to bend in a crescent shape, or “sickle” shape, hence why the disorder is called sickle cell disease. When the cells are once again oxygenated, then the cell will resume its normal shape. As you can imagine, this causes the red cell to change shape many times over and over again. These changes cause physical damage to the red cell and the hemoglobin. Ultimately, the sickled hemoglobin gets to the point where it cannot revert to the single strands, but instead gets twisted into long braided bundles. The bundles get attacked to even larger and longer bundles which can stretch and change the shape of the cell. I found an interesting analogy on a sickle cell disease website which described the next process in this manner -“the bundles self associate into even larger structures which stretch and distort the cell. The analogy would be a water balloon that was stretched and deformed by icicles. The stretching of the balloon’s rubber is similar to what happens to the membrane of the red cell. Polymers tend to grow from a single start site, called a nucleation site, and often grow in multiple directions. Start shaped clusters of hemoglobin S. develop commonly.”

The hemoglobin S. that appears in the sickling situation is only maintained as a polymer group by the weakest of forces. The association of valine with the beta chain makes the bands between the twisted hemoglobin structures very weak. Unfortunately, the polymerization that occurs in the sickling cells not only changes the shape of the cells but also makes the walls of the cells rigid. Sometimes the cells can become wedged in the smaller blood vessels, which can then cause micro-infarction to the local tissue. The end result is pain and often organ damage due to hypoxia. This damage to the red cells can also be the cause of the many complications of sickle cell disease. Free heme can be released from the cell during the repeated actions of polymerization/depolymerization and results in the formation of reactive oxygen compounds. Antibodies can develop to these compounds, which attack the red cells themselves and result in even more hemolysis and a greater degree of anemia than is already seen as a result of the red cell destruction.

The bone marrow tries to keep up production to replace the red cells destroyed in sickle cell disease, but in most patients it is generally not fast enough. As a result, the amount of bone marrow, which actively produces cells in the sickle cell patient, is much greater than in patients with normal hemoglobin.

How anemic the patient is will differ from patient to patient. A typical patient with sickle cell disease will have a hematocrit around 25%, whereas the normal hemoglobin patient will run around 45%. The method of expression of the disease can also affect the degree of anemia. For example, a patient who has hemoglobin SC disease (Where one beta globin is coded for S. And the other beta globin is coded for C) have higher hematocrits than patients who have both beta globins coded for S (Hemoglobin SS disease). Patients who have sickle cell trait have normal blood counts.

People with a family history of sickle cell disease are understandably concerned that they may have the disease themselves, and want testing. Routine blood cell counts (CBCs) cannot identify sickle cell disease. The best test for diagnosis is the hemoglobin electrophoresis that can detect the different hemoglobins and can also answer as to whether the patient has Hemoglobin C. Or thalassemia as well.

Most newborns in the United States are tested at birth for all these diseases.

Physical Manifestations of Sickle Cell Disease

The most common presentation of sickle cell disease in the adult is what is called a vasoocculsive crisis. This usually begins in response to some change in the body, such as a fever, being at a high altitude or even just from the temperature change on a hot day. There are times when it is not possible to identify what causes the crisis.

The most common presenting symptom is severe deep pain present in the extremities, usually in the long bones. Another common area of pain is the abdomen. The patient’s pain is usually very severe and may be accompanied by fever, malaise, and leukocytosis. This syndrome may last anywhere from a few hours to a few days and it will often begin quickly, and end just as quickly. Anemia is universally present, and in the patient who has not previously been diagnosed, this may be a diagnostic clue. As previously reported, the anemia is chronic and hemolytic. Megaloblastic changes may be seen due to the rapid cellular turnover as well as folate deficiency. In worst cases, there may be an aplastic crisis. This is often associated with an infection by Parvovirus B-19. The bone marrow’s replacement of the cells is disrupted. This usually manifests with a rapid drop in hemoglobin levels. Luckily, this condition is usually self limited, and the treatment is mostly supportive. Recovery is usually heralded by an increase in the reticulocyte count.

In children and in adolescents, sickle cell disease causes growth retardation, a delay in the manifestation of secondary sexual characteristics and sexual maturation, and usually results in the child being significantly underweight. It often happens in childhood that the spleen enlarges, especially in the first year of life, resulting from the sequestration of a large number of sickled cells within the spleen. This is a painful process. The spleen will then have repeated infarcts, and splenic function is impaired during the enlargement. Eventually, the repeated episodes of infarct leave the spleen fibrotic and it shrinks in size, becoming non-functional. In effect, this is called an autosplenectomy. The lack of spleen means that the patient with sickle cell disease suffers from an immune deficiency, and is particularly sensitive to encapsulated organisms like Streptococcus pneumoniae. Pneumococcal infections are common during the childhood of patients with sickle cell disease, as are infections with gram negative organisms in adult life.

Infants with sickle cell disease may often suffer from dactylitis, which causes painful swelling in the dorsum of the hand and foot. This can result in cortical thinning in the bones, and is not usually associated with erythema. Another syndrome called acute chest syndrome is seen, is which the patient has chest pain, fever; rapid breathing and pulmonary infiltrates are seen on chest x-ray. Acute chest syndrome is considered a medical emergency; as if it is not treated quickly it may lead to acute respiratory distress syndrome and death. The central nervous system is not immune from the effects of sickle cell disease. The most prevalent manifestation of central nervous system involvement is embolic stroke, which may have varying degrees of neurological involvement. The cardiovascular system can also be affected, since the chronic and recurrent hemolysis may lead to hemosiderin deposition within the myocardium, which in turn leads to dilation of the ventricles and congestive heart failure. The patient with sickle cell disease may also suffer from gallbladder disease, repeated infarction of the joints and bones, pulmonary hypertension from repeated micro infarction, renal failure secondary to loss of concentrating ability.

The patient may lose vision due to retinal vascular infarcts. Leg ulcers are also a common painful issue, and because of the poor circulation associated with this disease, healing is poor and infection common.

Adult females who become pregnant and who have sickle cell disease are also at high risk. For these women there is a very high rate of miscarriage. Placenta previa and abruption are common due to hypoxia and infarction. The babies born to sickle cell disease mothers are often premature and have a low birth weight due to incompetent placental function.

Treatment options for Sickle Cell Disease

Because so much is known about the genetics and pathophysiology of sickle cell disease, the causes of the physical manifestations are well understood. None the less, there is no cure. In managing the patient with sickle cell disease, the goal is to avoid crises when possible, and manage symptoms as they occur. The vasoocclusive crisis is treated with vigorous hydration and analgesics. Patients are usually given intravenous fluids in sufficient amount to correct any dehydration. This is usually best managed on an inpatient basis. Pain management usually requires the use of opiates. Morphine continues to be the drug of choice in the acute crisis, while non-steroidal anti-inflammatory drugs like ibuprofen can be used for the chronic and bone pain. It may also be helpful to use certain drugs like tricyclic antidepressants, which tend to have a synergistic effect with pain management and may reduce the need for opiates. Vigorous attention to prevention of infection is also important. Every patient with sickle cell disease should receive the pneumococcal vaccine at age 2 with a booster shot at age 5 to reduce incidence of pneumococcal infection. Some children are even placed on prophylaxis with penicillin during infancy, until such time as they can receive the vaccine. Adult patients are best treated with broad spectrum antibiotics empirically until therapy can be tailored to the causative organism by culture and sensitivity. There is some thought that allogenic bone marrow transplantation can cure this disease, but there are so many risks associated, and so few matched donors, that this does not, in most cases, represent a feasible plan.

While several drugs have been tried for the treatment of sickle cell disease, the only drug which is currently approved by the FDA for the treatment of sickle cell disease is hydroxyurea, which increases the production of hemoglobin F, thereby retarding sickling This medication can decrease the frequency and severity of vasoocculsive crises, reduce chronic pain and lead to a better quality of life. Unfortunately, hydroxyurea is a potentially carcinogenic medication, and its long-term effects have yet to be seen. Patients who currently use hydroxyurea must have frequent blood tests with careful attention for the presence of luekopenia and thrombocytopenia. In order to qualify for this drug, the patient must have at least 6 painful crises in a year, severe chronic pain which is unresponsive to conventional methods of control, acute chest syndrome or a history of stroke.

The patient’s mental well being, in light of this chronic and potentially disabling disease must also be considered. The patient may benefit from referrals to pain management experts, social workers, psychiatrists and physical therapists, substance abuse counselors, and vocational rehabilitation workers.


Patients who suffer from sickle cell disease have a chronic, disabling and potentially life threatening disease which manifests almost from the time of birth. This disease may be one of the most studied, and possible one of the most well understood on a pathophysiological basis, but still no cure exists. Patients require comprehensive care and careful attention to prevention of crises.


Bailey, K; Morris, JS; Thomas, P; Serjeant, GR. 1992. Fetal hemoglobin and early manifestations of homozygous sickle cell disease. Arch. Dis. Child. 67:517-20.

Charache, et. al. 1995. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J. Med 332:1317-22.

Platt, OS; Brambilla, DJ; Rosse, WF; Milner, PF; Castro, O; Steinberg, MH; Klug, PP. 1994. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N. Engl. J. Med 330: 1639-44.

Powars, D, et al. 1993. Sickle cell anemia. Beta’s gene cluster haplotypes as genetic markers for severe disease expression. Am. J. Dis. Child. 147:1197-1202.

Powars, D, et. al. 1994. Beta-S gene cluster haplotypes modulate hematologic and hemorheologic expression in sickle cell anemia. Use in predicting clinical severity. Am. J. Ped. Hematology-Oncology 16:55-61.

Seltzer, WK; Abshire, TC; Lane, PA; Roloff, JS; Githens, JH. 1992. Molecular genetic studies in black families with sickle cell anemia and unusually high levels of fetal hemoglobin. Hemoglobin 16: 363-77.

Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, Davies SC, Ohene-Frempong K, Bernaudin F, Matthews DC, Storb R, Sullivan KM. 1996. Bone marrow transplantation for sickle cell disease. N Engl J. Med 335: 369-376.

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