Sickle Cell Anemia

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Main pathology of sickle cell anemia and who gets it

Sickle cell anemia is an example of a hemoglobinopathy, which are a group of hereditary disorders caused by inherited mutations that lead to structural abnormalities in hemoglobin. Sickle cell anemia, the prototypical (and most prevalent) hemoglobinopathy, stems from a mutation in the β-globin gene that creates sickle hemoglobin (HbS). Normal hemoglobin are tetramers composed of two pairs of similar chains. On average, the normal adult red cell contains 96% HbA (α2β2), 3% HbA2 (α2δ2), and 1% fetal Hb (HbF, α2γ2). HbS is produced by the substitution of valine for glutamic acid at the sixth amino acid residue of β-globin. In homozygotes, all HbA is replaced by HbS, whereas in heterozygotes, only about half is replaced. Sickle cell anemia is the most common familial hemolytic anemia in the world(Kumar et al., 2014 pg 411)

On deoxygenation, HbS molecules form long polymers by means of intermolecular contacts that involve the abnormal valine residue at position 6. These polymers distort the red cell, which assumes an elongated crescentic, or sickle, shape. The sickling of red cells initially is reversible upon reoxygenation. However, the distortion of the membrane that is produced by each sickling episode leads to an influx of calcium, which causes the loss of potassium and water and also damages the membrane skeleton. Over time, this cumulative damage creates irreversibly sickled cells, which are rapidly hemolyzed by the body’s reticuloendothelial system as well as by destruction as they try to pass through fine capillaries. In sickle cell anemia the red blood cells become rigid and sticky and are shaped like sickles. These irregularly shaped cells can get stuck in small blood vessels, which can slow or block blood flow and oxygen to parts of the body.

The actual anemia of the illness is because of hemolysis, the destruction of the erythrocytes due to their shape. As much as the bone marrow tries to compensate by synthesis of new erythrocytes, it can not match the rate at which they are destroyed. Normal, healthy erythrocytes normally are in circulation for a period of 90-120 days unlike the sickled celled cells which last for a period of 10-20 days. (Sickle Cell Anemia, 2010)

Sickle cell anemia is an autosomal recessive genetic trait that is passed from the parents to the offspring. In parts of Africa where malaria is endemic, the gene frequency approaches 30% as a result of a small but significant protective effect of HbS against Plasmodium falciparum malaria. In the United States, approximately 8% of blacks are heterozygous for HbS, and about 1 in 600 have sickle cell anemia. Other ethnic groups which have high instances of the disease other than those of African descent, include Hispanic-American from Central and South America, people of Middle Eastern, Asian, Indian and Mediterranean descent. (Kumar et al., 2014 pg 411)

How is disease diagnosed and what are the necessary laboratory findings specific to this disease?

The most important laboratory test for sickle cell anemia is a complete blood count (CBC), specifically hemoglobin and hematocrit. A blood test can check for the defective form of hemoglobin that underlies sickle cell anemia. In investigation, hemoglobin level can be assessed, a peripheral blood smear is also done and a number of radiological tests such as X-Rays of parts such as the skull. In some countries, this blood test is part of routine newborn screening. But older children and adults can be tested, too. In adults, a blood sample is drawn from a vein in the arm. In young children and babies, the blood sample is usually collected from a finger or heel. The sample is then sent to a laboratory, where it’s screened for the defective hemoglobin. If you or your child has sickle cell anemia, your doctor might suggest additional tests to check for possible complications of the disease. If you or your child carries the sickle cell gene, you’ll likely be referred to a genetic counselor.

A complete blood count is done to access the level of hemoglobin in the patient. In a patient with sickle cell the hemoglobin level is reduced. According to Mayo Clinic 2022, normal values of hemoglobin in men is 13.2 to 16.6 grams per deciliter while in women is 11.6 to 15 grams per deciliter. In a patient with sickle cell the levels range between 6 to 8 grams per deciliter. The complete blood count also shows a high reticulocyte count, increased by 10% to 20%.

The blood film test is done to investigate and describe the appearance of the red blood cells, white blood cells and platelets as well as any abnormalities that may be seen in the slide. Normal, mature red blood cells are uniform in size ranging from 7-8 micrometers in diameter and do not have a nucleus as other cells do. They are round and flattened with a depression in the middle, biconcave. They are pink to red in color due to the hemoglobin inside the cells. When the appearance of red blood cells is normal, it is often reported as normochromic and normocytic. (Blood Smear, 2021). In sickle cell anemia however, the blood film is microcytic (reduced size) and hypochromic (less color). This is because in sickle cell anemia the red blood cells due to the presence of valine in the beta chain, the shape is affected and is sickle instead of the normal shape and size. It thus appears smaller and sickle shaped. The altered shape and size affect the blood cells capacity to carry the hemoglobin, thus less hemoglobin in the cells thus is hypochromic.

The next test is the sickle cell solubility test which is aimed at screening individuals 6 months old or older. They are not diagnostic and are not used for newborn screening. The tests detect the presence of hemoglobin S but do not distinguish between sickle cell disease and trait. (Sickle Cell Tests, 2021). This test investigates how well the protein molecule in the red blood cells, hemoglobin, dissolves in the reagent solution used in the test. A negative test is normal. It means your hemoglobin is normal. This solution here gives a clear solution due to the absence of the hemoglobin S. A positive hemoglobin test result, indicates that the screening test detected the presence of Hemoglobin S or sickle hemoglobin, which may mean you carry the sickle cell trait. These results are a preliminary screening. The mixture of hemoglobin S in the solution influences the results such that its presence gives the solution a turbid appearance, due to the precipitation of hemoglobin S.

Another test done is the hemoglobin electrophoresis test. Hemoglobin electrophoresis is a test that measures the different types of hemoglobin in the blood. It also looks for abnormal types of hemoglobin. Normal types of hemoglobin include: Hemoglobin (Hgb) A, the most common type of hemoglobin in healthy adults. (Medical Tests, 2021) In adults, these are normal percentages of different hemoglobin molecules: HbA: 95% to 98% (0.95 to 0.98) HbA2: 2% to 3% (0.02 to 0.03) HbE: Absent. The test will help them find any abnormal types of hemoglobin in your blood. These could be a sign of disorders including: sickle cell anemia. This test is used to confirm the diagnosis where there will be no HbA, 80-95% Hb S and 2-20% Hb F.

There other tests which are used to diagnose the sickle cell genes before birth. This helps diagnose the unborn baby through sampling of amniotic fluid through amniocentesis to look for the sickle cell gene.

X-Rays and MRIs are some of the radiological tests done to investigate sickle cell anemia. Imaging is done to investigate the effect of sickle cell on the musculoskeletal system. These effects include, extramedullary hematopoiesis, osteonecrosis, dactylitis (hand-foot syndrome), myonecrosis and osteomyelitis. MRI is the best method for detecting early signs of changes in bone marrow due to acute and chronic bone marrow infarction, marrow hyperplasia, osteomyelitis and osteonecrosis. X-Ray finings found include lung consolidation affecting the lower lobe(right more than left) in adults while in the pediatric population the middle lobe is affected.(Ramirez, 2019..medscape sickle cell imaging)

Significant signs and symptoms of the disease

According to Mayo Clinic 2021, sickle cell has the following signs and symptoms:

Anemia. Sickle cells break apart easily and die, leaving you with too few red blood cells. Red blood cells usually live for about 120 days before they need to be replaced. But sickle cells usually die in 10 to 20 days, leaving a shortage of red blood cells (anemia). Without enough red blood cells, your body can’t get enough oxygen, causing fatigue.

Episodes of pain. Periodic episodes of pain, called pain crises, are a major symptom of sickle cell anemia. Pain develops when sickle-shaped red blood cells block blood flow through tiny blood vessels to your chest, abdomen and joints. Pain can also occur in your bones. The pain varies in intensity and can last for a few hours to a few weeks. Some people have only a few pain crises a year. Others have a dozen or more pain crises a year. A severe pain crisis requires a hospital stay. Some adolescents and adults with sickle cell anemia also have chronic pain, which can result from bone and joint damage, ulcers, and other causes.

Swelling of hands and feet. The swelling is caused by sickle-shaped red blood cells blocking blood flow to the hands and feet. Dactylitis, painful swelling in your hands or feet, is often the first symptom babies and young children with sickle cell disease exhibit. Your child may have sickle cell disease if you notice: increased fussiness, swelling, tenderness, or redness in their hands or feet, avoiding grabbing or holding items, avoiding walking or standing

Frequent infections. Sickle cells can damage your spleen, leaving you more vulnerable to infections. Doctors commonly give infants and children with sickle cell anemia vaccinations and antibiotics to prevent potentially life-threatening infections, such as pneumonia. Both children and adults with sickle cell disease are functionally asplenic, making them susceptible to infections caused by encapsulated bacteria, such as pneumococci. (Kumar et al., 2014 pg 413)

Delayed growth or puberty. Red blood cells provide your body with the oxygen and nutrients needed for growth. A shortage of healthy red blood cells can slow growth in infants and children and delay puberty in teenagers.

Vision problems. Tiny blood vessels that supply your eyes can become plugged with sickle cells. This can damage the retina — the portion of the eye that processes visual images — and lead to vision problems.

Some conditions can be mistaken for sickle cell and they include beta thalassemia. It inherited condition that affects hemoglobin, the protein in red blood cells that carries oxygen to different parts of the body. Affected people have a different change (mutation) in each copy of their HBB gene: one that causes red blood cells to form a “sickle” or crescent shape and a second that is associated with beta thalassemia, a blood disorder that reduces the production of hemoglobin. Depending on the beta thalassemia mutation, people may have no normal hemoglobin (called sickle beta zero thalassemia) or a reduced amount of normal hemoglobin (called sickle beta plus thalassemia). (GARD,2014). While beta thalassemia is caused by a defect in the beta-globin gene, controlling the production of the beta-globin chains of hemoglobin, sickle cell disease is caused by a defect in hemoglobin itself with the presence of abnormal hemoglobin S.

Beta Thalassemia Sickle cell anemia

Defect in the beta globin gene, controlling production of the beta globin chains of hemoglobin Sickle cell diseases is a defect in hemoglobin itself with the presence of an abnormal hemoglobin S.

In beta thalassemia, the mutation in hemoglobin‘s beta subunit, results in less hemoglobin protein being made In sickle cell disease, an abnormal hemoglobin protein; hemoglobin S, is made, but it doesn’t function correctly

They both have certain signs and symptoms including tiredness, shortness of breath, pale, skin, slow growth and many more due to their similar effects of reduced oxygen delivery to peripheral tissues.(Beta Thalassemia, 2019)

Genetic component of the disease and likelihood of inheritance

The incidence of sickle cell disease is not related to one’s gender since it is transited as an autosomal recessive disorder. (Ceglie et al., 2019). If one parent has the sickle cell trait and the other does not carry the sickle trait at all, then none of their children will have sickle cell anemia. There is a one in two chance that any given child will get one copy of the sickle cell gene and thus have the sickle cell trait. It is equally likely that any given child will get two of the normal hemoglobin genes that be completely unaffected.

If both parents have the sickle cell trait, there is one in four chance that any of the children would be born with sickle cell disease. There is also a one in four chance that any given child could be completely unaffected. There is a one in two chance that any given child born will have the sickle cell trait. If one parent will have the trait and the other has the sickle cell disease, there is one in two chance that any given child will have the disease and a one in two chance that one child will get the sickle cell trait; in this case no child is unaffected. If one parent has sickle cell anemia and the other is unaffected, all the children will have the trait but none will be affected.

How is the disease commonly treated in the medical community?

Since the disease is an inherited one, there is no permeant cure for it. There are measures present; supportive care, however to help in management and alleviate problems or complication brought about by sickle cell anemia. As a result of improvements in supportive care, an increasing number of patients are surviving into adulthood and producing offspring. Of particular importance is prophylactic treatment with penicillin to prevent pneumococcal infections. Approximately 50% of patients survive beyond the fifth decade. By contrast, sickle cell trait causes symptoms rarely and only under extreme conditions, such as after vigorous exertion at high altitudes. (Kumar et al., 2014 pg 413)

A mainstay of therapy is hydroxyurea, a “gentle” inhibitor of DNA synthesis. Hydroxyurea reduces pain crises and lessens the anemia through several beneficial intracorpuscular and extracorpuscular effects, including (1) an increase in red cell levels of HbF; (2) an anti-inflammatory effect due to the inhibition of white cell production; (3) an increase in red cell size, which lowers the mean cell hemoglobin concentration; and (4) its metabolism to NO, a potent vasodilator and inhibitor of platelet aggregation. (Kumar et al., 2014 pg 413)

Encouraging results also have been obtained with allogeneic bone marrow transplantation, which has the potential to be curative. bone marrow transplants are difficult to obtain because of the specific HLA typing necessary. Ideally, a close relative (allogeneic) would donate the bone marrow necessary for transplantation. Some gene therapies are under development that would alter the patient’s own bone marrow stem cells ex vivo, which can then be transplanted back into the patient after chemotherapy eliminates the original unmodified cells. Blood transfusion is also used in the management of sickle cell disease in acute cases and to prevent complications by decreasing the number of red blood cells (RBCs) that can sickle by adding normal red blood cells.(Kaiser, 2020).

complementary and alternative medicine (CAM) to control pain. CAM treatments differ from traditional medical treatments because they are not based in science. They do not replace traditional medical treatments but may provide additional pain relief. They imclude, massage, exercise, eating well and a balanced diet, acupuncture, yoga, Tai chi and reiki. (SCD, 2021)

REFRENCES

Joseph E Maakaro(November 2, 2021) Sickle cell disease. https://emedicine.medscape.com/article/205926-overviewKumar, V., Abbas, A. K., & Aster, J. C. (2015). Robbins and Cotran pathologic basis of disease (Ninth edition.). Philadelphia, PA: Elsevier/Saunders.

TESTIMG.COM.( November 9, 2021) Blood Smear https://www.testing.com/tests/blood-smear/#:~:text=The%20results%20of%20a%20blood,be%20seen%20on%20the%20slide.&text=Normal%2C%20mature%20red%20blood%20cells,as%20most%20other%20cells%20do

Kaiser J (5 December 2020). “CRISPR and another genetic strategy fix cell defects in two common blood disorders. https://www.science.org/content/article/crispr-and-another-genetic-strategy-fix-cell-defects-two-common-blood-disorders

Corinna L. Schultz, MD(August 2019).Hematology (Blood Disorders) at Nemours Children’s Health https://kidshealth.org/en/parents/beta-thalassemia.html

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