Sickle Cell Anemia

BACKGROUND/ ABSTRACT

Individual with sickle cell anemia have abnormal hemoglobin molecules. The Hemoglobin molecule in their de-oxygenated state begin to aggregate with one another to form long sickle shaped fibers, which converts the healthy biconcave shape of red blood cells into sickle shapes. These sickle-shaped red blood cells con aggregate and clog tiny capillaries, resulting in

1.      Painful Swelling

2.      Impaired blood flow

3.      Increased risk of stoke (poor blood flow to the brain)

4.      Increased risk of pathogenic infections (Poor circulation)

5.      Increased risk of severe bacterial infections due to loss of functioning spleen tissue

6.      Cerebral infarction occurs in children and cerebral hemorrhage in adults.

7.      Decreased immune reaction due to hypersplenism, leg ulcer and many more.

In addition, these abnormal red blood cells have a shorter life span. This means they will die at a quicker rate and this can lead to a decrease in the beta chains of the hemoglobin.

Glutamate 6 ----------à  Valine 6

In normal hemoglobin glutamate 6 is located on the surface of the B-chains. This is not a problem because the polar glutamate can easily interact with polar environments. The b subunits of the normal hemoglobin have a polar residue at the 6th position. That can interact well with the polar water molecules found in the blood plasma.

In the abnormal hemoglobin, the non-polar valine in the 6th position would rather interact with other non-polar molecules rather than without H2O. If another deoxyhemoglobin is near, Valine 6 can interact with either Valine 88 or Dhenylalanine (Charache S, Terrin ML, Moore RD, et al, 1995). This is a genetic disease that for the most part this was out as an original survival instinct.  From the equatorial climate and the antibodies that sickle cell helps to destroy malaria parasites. Bone marrow transplant is the solution, but in most cases, this weakens the immune system that leads to other diseases that can cause death. This disease is prevalent in the African American culture, one would think being displaced in a climate such as the Americas contributes to why the sickle cell gene has caused so much pain to descendants of the African diaspora.

The symptoms of sickle cell anemia present after an infant is four months old (Clark PA, 1984). They can vary with some people having mild symptoms and others having difficult symptoms that cause them to be hospitalized for treatment (Platt OS, Brambilla DJ, et al 1991). The most common signs and symptoms are linked to anemia and pan. Other signs and symptoms are linked to the disease’s complications. The most common symptoms of anemia is fatigue (feeling tired or weak). Other symptoms include:

·         Shortness of breath

·         Dizziness

·         Headache

·         Coldness in the hands and feet

·         Pale skin

·         Chest pain

Sickle cell crises is the sudden pain throughout the body, this affects the bones, lungs, abdomen and joints. A sickle cell crisis occurs when a sickled red blood cells form clumps in the bloodstream, blocking blood flow through the small blood vessels in the limbs and organs and causing pain and organ damage. Along with this excruciating pain, chronic pain as well can occur, lasting for months and severe limiting patients’ daily activities. 

Fig 1. Increase in life expectancy of patients with sickle cell anemia in the U.S. (Dewitt LD, Wechsler LR, 1988)

The graph above displays that with different western medical treatments people with sickle cell anemia can experience a longer life expectancy. The methods and actions that have been taken over the years has increase the life expectancy of those who are ill and eased the difficulty of having the disease (Nuttall GA, Cook DJ, 1996). There are still research being done as to more effective treatments and cures.

Other symptoms and complications include:

·         Hand-foot syndrome – Swollen hands and feet caused by sickle-shaped cells blocking blood flow out of the hands and feet. This may be the first sign in babies with the condition.

·         Jaundice – A yellowing of the skin and eyes occurring due to liver damage

· 

Fig 2. Sickle cell disease related mortality rate in the U.S from 1983-2002

This chart shows how far treatment and prevention for sickle cell anemia have some over the years. The infant mortality rate used to be nearly 250,000 and decrease to 78,000 in 2002. This shows how the advancement in medicine is helping people with the disease (Serrador JM, Pcot PA, et al 2000). This chart directly shows how western biomedicine has been used to "enhance" the lives of people with sickle cell.

Diagnosis

         Sickle cell anemia is diagnosed through a blood test to check for hemoglobin S. The defective form of hemoglobin that underlies sickle cell anemia. In the united states, this blood test is part of routine newborn screening done at the hospital. In adults, a blood sample is drawn from a vein in the arm. In young children and babies, a blood sample is usually collected from a finger or heel. The sample is then sent to a laboratory, where it is screened for hemoglobin S (Murray RF, Soble A, 1974). If the screening test is negative, there is no sickle cell gene present. If the screening test is positive, additional tests will be done to determine whether one or two sickle cell alleles genes are present. People with one allele (sickle trait) have a fairly small percentage of hemoglobin S while people with two allele  (sickle disease) have a larger percentage of the defective hemoglobin.

Fig 3. Sickle Cell traits and how the gene can be inherited. (Samuel-Reid JH, 1994)

Treatments

Half-matched transplant  Physician-scientists at Johns Hopkins have developed a procedure called a half-matched bone marrow transplant that has been successful in “curing” sickle cell anemia. Rather than wiping out a patient’s immune system before transplanting donor bone marrow, doctors administer just enough chemotherapy to suppress the immune system, which keeps patients from rejecting the donated marrow without harming their organs. And, the procedure expands the potential donor pool, making more patients eligible for the transplant. 

Normally, doctors look for a donor who matches a patient's tissue type, specifically their human leukocyte antigen (HLA) tissue type. HLAs are proteins — or markers — found on most cells in the body.

The immune system uses these markers to recognize cells that belong in the body versus those that do not. The closer the match between a patient's HLA markers and the donor’s, the better for the patient. In most sickle cell cases, doctors looked for a nearly full match prior to bone marrow transplantation (Vichinsky EP, 1991). This was extremely difficult because in many cases, the person with the closest match, such as a sibling, may also have carried the sickle cell gene. The Hopkins procedure requires just a half-match, meaning that a patient’s parents or children could be suitable donors. With this option, doctors estimate that more than half of patients have potential matches. Three days after the transplant, a patient is given a high dose of a drug called cyclophosphamide, which “re-boots” the immune system. The cyclophosphamide spares the donor's stem cells and allows them to establish new blood cells and a new immune system. The budding immune system is re-trained to see the patient's body as friend, preventing the patient from rejecting the transplanted bone marrow. Doctors estimate that a large percentage of patients treated this way may never have sickle cell disease again (Wasta V, 2017). In March 2009, the Johns Hopkins bone marrow transplantation team successfully cured a 31-year-old woman of the disease using bone marrow donated by her mother.  

Sickle cell infusion center   Johns Hopkins operates a Sickle Cell Center for Adults that provides comprehensive care including regularly scheduled outpatient visits, screening for hydroxyurea eligibility, genetic counseling, pain management, education, wound care and social services. The Center in June 2008 opened a sickle cell infusion center to rapidly treat patients battling crises.

 Bone marrow transplant / Stem cell transplant  A bone marrow transplant gives a patient healthy stem cells – immature cells that grow into different parts of the blood – taken from the bone marrow (the soft, spongy tissue inside bones) of a healthy donor who does not have sickle cell disease.

Most patients get high doses of chemotherapy, radiation, or both, before the bone marrow transplant to kill non-functioning marrow and make room for new stem cells to grow. Doctors deliver the stem cells through a tube injected into the bloodstream. They find their way into the bone marrow and begin reproducing to make healthy new blood cells. While receiving stem cells, patients may experience pain, chills, fever, hives, chest pain or other symptoms.

Blood Transfusion   During a red blood cell transfusion, red blood cells are removed from a supply of donated blood and then given intravenously to a person with sickle cell anemia. Blood transfusions increase the number of normal red blood cells in circulation, helping to relieve anemia. They can decrease children’s risk of stroke. 

Fig 4 Pie chart showing the underlying causes of anemic heart failure

During a transfusion, a technician will hang a bag containing the blood product you are receiving from a pole, then insert a narrow tube into a blood vessel in your arm. The healthy blood from a donor will drip from the bag through the tube and into your vein. The procedure usually takes about one to two hours, depending on what blood component(s) you are receiving. Most people do not experience side effects from the procedure (Tegeler CH, Ratanakorn et al 1999). Possible side effects include fever, allergic reaction or infection. Transfusions also increase the buildup of iron in the body, which, untreated, could lead to organ damage.

    Conclusion

Genetic counseling and support for parents of newborn infants with sickle cell anemia has reduced the mortality from pneumococcal sepsis. Growth, nutrition and educational performance require close monitoring (Olivieri NF, Vichinsky EP, 1998). Ischaemic stroke is one of the most devastating problems in children and early detection is now possible. The Stroke Prevention Trial in sickle cell anemia (STOP) study showed that screening by transcranial doppler ultrasound reduces the incidence of stroke. Finally the use of patient controlled analgesia devices is effective for improved narcotic delivery. Non-steroidal analgesic can be an excellent adjunct to narcotic. Hydroxyurea has been shown to be effective in the prevention of pain and other complications of Sickle cell anemia.

Fig 5 An example of spectral Doppler frequency display of the middle cerebral artery. (Dewitt LD, Wechsler LR, 1988) 

Trans-cranial Doppler (TCD) ultrasound provides rapid, noninvasive, real-time measures of cerebrovascular function (Bishop CC, Powells S, et al, 1986). TCD can be used to measure flow velocity in the basal arteries of the brain to assess relative changes in flow, diagnose focal vascular stenosis, or to detect embolic signals within these arteries. TCD can also be used to assess the physiologic health of a particular vascular territory by measuring blood flow responses to changes in blood pressure (cerebral autoregulation), changes in end-tidal CO2 (cerebral vasoreactivity), or cognitive and motor activation (neurovascular coupling or functional hyperemia). TCD has established utility in the clinical diagnosis of a number of cerebrovascular disorders such as acute ischemic stroke, vasospasm, subarachnoid hemorrhage, sickle cell disease, as well as other conditions such as brain death. Clinical indication and research applications for this mode of imaging continue to expand. 

Pain in adults with sickle cell disease is the rule rather than the exception and is far more prevalent and severe than previous large-scale studies have portrayed. It is mostly managed a home; therefore, it prevalence is probably underestimated by health care providers, resulting in misclassification, distorted communication, and undertreatment. Increasingly overburdened emergency departments are not the most appropriate setting in which to manage pain that requires close monitoring and careful opioid dose titration. In 1973, the average life span of  patient with sickle cell disease was 14 years but after thirty years the development of comprehensive care models, day hospitals and ongoing research has increased life expectancy to 50 years. 

Work Cited/ References

1.  Bishop CC, Powell S, Rutt D, Browse NL. Transcranial Doppler measurement of middle cerebral artery blood flow velocity: a validation study. Stroke. 1986;17(5):913–915. [PubMed]
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