Sickle Cell Anemia

Sickle Cell Anemia (SCA) is an inherited disease caused by a mutation in both copies of the hemoglobin (Hb) gene that results in the production of an abnormal hemoglobin protein called HbS. Mutation of only one copy results in the sickle cell trait. The symptoms and treatment strategies for SCA can all be traced back to the abnormal behavior of HbS in low-oxygen environments, in particular, the red blood cells (RBC) that carry the hemoglobin tend to change shape and flexibility. The abnormal RBCs are prone to early destruction (resulting in anemia) and tend to block small blood vessels (leading to pain and tissue damage). The abnormal gene and the disease it causes are highly prevalent in people of African descent and in populations where malaria is endemic.

SCA continues to motivate the study of abnormal hemoglobins, a class of diseases called the hemoglobinopathies. Normal adult hemoglobin, HbA, is a large molecule with four subunits, but many variant forms exist. Some of these variant forms cause disease, others don't. One normal variant is HbF (fetal hemoglobin), usually only present during gestation and shortly after birth, allows the fetus to acquire oxygen from maternal blood.

Careful study of individuals with SCA and sickle cell trait has given a highly detailed characterization of the abnormal HbS molecule and the gene encoding it. SCA became the first disease whose cause was traced down to the molecular level. Advances in understanding the disease have led to significantly improved treatments and outcomes for affected individuals. Nonetheless, SCA remains a significant cause of illness and early mortality. Sickle cell anemia also adds a significant economic burden, especially in areas such as Africa with high disease prevalence.

Contents 1 Other Names 2 Types 3 Causes 4 Diagnosis 5 Treatment 5.1 Treatment of anemia 5.2 Treatment of pain 5.3 Reducing painful crises 6 Cures 6.1 Bone marrow transplantation 6.2 Gene therapy 7 New Medicines 8 Prevention 9 Living with Sickle Cell Anemia 10 Caring for someone with Sickle Cell Anemia 11 Chances of Developing Sickle Cell Anemia 11.1 Complications 11.2 Related disorders 12 Clinical Trials 13 History 14 Epidemiology 15 Social Issues 16 Related Video from NHS Choices 17 References 18 External Links

Other Names

• Hemoglobin SS disease
• Hemoglobin S disease
• HbS disease
• Sickle cell disorders
• Sickling disorder due to hemoglobin S
• SCD

Types

SCA results from abnormal clumping of hemoglobin molecules in the presence of low oxygen. There are several variant forms of the disease based on the severity of symptoms and the exact structure of the affected hemoglobin molecules.

Causes

The manifestations of SCA can all be traced back to how the abnormal hemoglobin molecule encoded by a mutated version of the Hb gene (called hemoblobin S, or HbS) behaves differently than the normal hemoglobin, called HbA.

In sickle cell anemia, a lower-than-normal number of red blood cells results because sickle cells dare destroyed faster than normal red blood cells. Sickle cells last only about 10 to 20 days compared to the 80- to 120-day lifespan of a normal red blood cell. The bone marrow, which makes red blood cells, can't make new ones fast enough to replace the dying ones. The result is anemia. More specifically, the anemia is chronic, or long-lasting, and hemolytic, meaning that it results from accelerated destruction of RBCs as opposed to decreased production.

The other main manifestation of SCA is blocking of small blood vessels which causes tissue damage and pain. Normal red blood cells are smooth, round, and quite flexible. They move easily through blood vessels to carry oxygen to all parts of the body. Sickle-shaped cells don't move easily through blood vessels. Sickled cells are stiff and sticky. They tend to form clumps and get stuck in smaller blood vessels.

Diagnosis

Early diagnosis is important to allow early initiation of treatment and patient education. In unusual circumstances, the diagnosis can be made in early pregnancy based on DNA sequence results of samples taken from cells in the amniotic fluid or placenta. In newborns who are still producing significant amounts of fetal hemoglobin (HbF), the diagnosis may not be apparent from clinical signs or from looking at the blood under the microscope. In the US, many states offer a test for newborns that is based on mixing a blood sample with an oxygen-consuming chemical to induce sickling.

Many cases of SCA are diagnosed based on clinical findings (anemia and painful crises) and examination of RBCs under the microscope. To promote sickling, an oxygen-consuming reagent is added to a blood drop after it is placed on the microscope slide, just before examination.

SCA can also be diagnosed by a process termed electrophoresis in which suspect and normal Hb samples are subjected to an electric field, which causes them to migrate through a gel. Sickle hemoglobin moves differently than normal hemoglobin. Hemoglobin electrophoresis is typically used in diagnosing older children and adults.

Treatment

SCA requires a comprehensive treatment plan with several goals in mind: the oxygen-carrying capacity of the blood must be maintained (i.e., the anemia must be treated), the pain associated with blood vessel blockage must be treated, and the incidence and severity of occlusive crises must be minimized.

Treatment of anemia

Standard treatment of the anemia of SCA is blood transfusion. The donor RBCs contain normal Hb and last much longer in the body than do the patient's own RBCs. In addition, having adequate oxygen delivery to the kidney reduces erythropoietin production, which in turn slows down RBC production by the bone marrow.

Treatment of pain

Painful crises often affect the joints and sometimes require aggressive use of analgesics; including very strong narcotic analgesics such as morphine,but these drugs can be addictive and therefore are used with precaution.

Reducing painful crises

Minimizing the number and severity of occlusive crises is a prime goal of long-term management. Three approaches have been considered:

• Inhibition of HbS polymerization. Polymerization is formation of a larger molecule from smaller ones. This often affects the shape and function of the final molecule. This approach has not yielded practical therapeutic options, since there is so much Hb in the body (about 400g) and no safe and effective drugs to inhibit polymerization of HbS have been found.

• Reduction of intracellular Hb concentration. Normal Hb remains dissolved inside the RBC at a very high concentration; this concentration is easily measured and often reported as mean cell hemoglobin concentration, or MCHC. If an RBC contains HbS, this strategy suggests vigorous hydration to make sure every RBC has enough water to keep the HbS dissolved.

• Pharmacologic induction of HbF. A major advance in treatment of SCA resulted from the realization that fetal hemoblobin HbF interferes with polymerization of HbS. This is probably the reason that infants, who still produce significant quantities of HbF, remain asymptomatic for several months. Treatment with the anticancer drug hydroxyurea causes a dramatic increase in HbF production in adults, in whom HbF has been shut off since infancy. This decreases the severity and frequency of damaging blockages of blood flow. The mechanism by which hydroxyurea results in HbF production remains a subject of active investigation.^[1]

Cures

Bone marrow transplantation

Bone marrow transplantation can be a very effective treatment for sickle cell anemia, but the procedure requires an appropriate donor. It is expensive and risky and only appropriate in severely-affected individuals.

Gene therapy

Gene therapy is being studied as a possible treatment for sickle cell anemia. Researchers are looking to see whether a normal gene can be planted in the bone marrow of a person with sickle cell anemia, and thus cause the body to produce normal red blood cells. Researchers also are studying the possibility of treatment to turn off the sickle cell gene or turn on a gene that makes red blood cells behave normally.

New Medicines

New medicines being studied are:

• Butyric acid. This is a food additive that may increase normal hemoglobin in the blood.
• Clotrimazole. This is currently used to treat fungal infections. This medicine helps prevent the loss of water from a red blood cell and can keep the cell from turning into a sickle cell.
• Nitric oxide. This may make sickle cells less sticky and keep blood vessels open. People with sickle cell anemia have low levels of nitric acid in their blood.

Prevention

People at high risk for sickle cell anemia and who are planning to have children may want to consider genetic counseling beforehand. The diagnosis of sickle cell trait can be made based on each parent's DNA and allows estimation of the risk of having a child with SCA.

If known carriers want to have their own children, a procedure called pre-implantation genetic diagnosis can improve the chance that the children will have normal hemoglobin. Eggs from the mother and sperm from the father are mixed together in a laboratory dish. The eggs that become fertilized are checked for sickle cell anemia. Fertilized eggs that don't have sickle cell genes are then implanted in the mother's womb. This is an expensive procedure with a non-negligible failure rate.

If a pregnancy is already in progress, cells can be taken from the amniotic fluid for genetic testing.

Living with Sickle Cell Anemia

With good health care, many people with sickle cell anemia can live productive lives, have reasonably good health much of the time, and live longer today than in the past. Many people who have sickle cell anemia now live into their forties, fifties, or even longer.

Caring for someone with Sickle Cell Anemia

Vigilance, close communication with health care providers, aggressive infection control, and prevention of painful episodes are mainstays of treatment. In addition, there are several recommendations for caring for children with SCA:

• Daily penicillin up to age five.
• A flu shot every year after six months of age.
• A regular vaccination against pneumonia. (This is also given to children who don't have sickle cell anemia.) Children with sickle cell anemia also get two doses of a stronger pneumonia vaccination after two years of age. Doses of this stronger vaccination are given several years apart.
• Vaccination against meningitis after the age of two.

Chances of Developing Sickle Cell Anemia

SCA is inherited as an autosomal recessive condition, meaning that individuals must inherit a gene coding for the abnormal HbS protein from both parents to show signs of the disease. For this to happen, both parents must carry the HbS gene, i.e., the mother and father must both be carriers. In a family with both parents carrying the HbS gene, the children will represent a mix of those who have inherited zero, one, or two copies of the disease gene. About 25% of their children will carry two copies of the HbS gene and have the disease, about 50% will inherit a single copy of HbS and be carriers, and about 25% will have zero copies of the HbS gene and be unaffected.

Complications

Complications can arise from anemia, from blood vessel blockage, or from the cumulative effects of treatment. The main anemia-related complication is fatigue, often profound, and exercise intolerance. Cumulative effects of multiple transfusions include an increased risk of infections, iron overload, and an increased risk of some cancers from hydroxyurea treatment. Finally, since sickle cells can block blood vessels and prevent oxygen delivery anywhere in the body, the complications seen in SCA run (literally) from head to toe. Several specific examples are listed:

• Hand-Foot Syndrome. When sickle cells block the small blood vessels in the hands or feet, pain and swelling along with fever can occur. One or both hands and/or feet may be affected at the same time. Pain may be felt in the many bones of the hands and feet. Swelling usually occurs on the back of the hands and feet and moves into the fingers and toes. This may be the first sign of sickle cell anemia in infants.

• Splenic (Sequestration) Crisis. The spleen normally filters out damaged RBCs at the end of their normal lifespan. In SCA, the spleen may become painfully enlarged from engulfing large numbers of abnormal RBCs.

• Infections in both children and adults with sickle cell are a significant concern, since one of the spleen's normal functions is assisting in fighting infections. Pneumonia is the most common cause of death in young children who have sickle cell anemia. Meningitis, influenza, and hepatitis are other infections that are common in people with sickle cell anemia.

• Acute Chest Syndrome is a life-threatening condition linked to SCA. It's similar to pneumonia and is caused by an infection or by sickle cells trapped in tiny blood vessels in the lungs. People with this condition usually have chest pain, fever, and an abnormal chest x ray.

• Delayed Growth and Puberty. Children with SCA often grow more slowly and reach puberty later than other children. Adults with SCA are often small in stature.

• Stroke. Sickled RBCs that block vessels supplying the brain can cause a stroke. This type of stroke occurs mainly in children. The stroke can cause learning disabilities or more severe problems.

• Eye Problems. The retina, a thin layer of tissue at the back of the eye, is supplied by small blood vessels that are susceptible to occlusion. Inadequate blood supply to the retina can weaken its attachment to the back of the eye (resulting in detachment), or parts of the retina can die, causing blindness.

• Priapism. Males with sickle cell anemia may have painful, unwanted, and prolonged erections called priapism. This happens because the sickle cells stop blood flow out of an erect penis. Over time, priapism can damage the penis and lead to impotence.

• Gallstones. When red blood cells die, they release their hemoglobin, which the body breaks down into a compound called bilirubin. When there is too much bilirubin in the body, stones can form in the gallbladder. Gallstones can cause steady pain that lasts for 30 minutes or more in the upper right side of the belly, under the right shoulder, or between the shoulder blades. The pain usually occurs after eating fatty meals. People with gallstones may have nausea, vomiting, fever, sweating, chills, clay-colored stool, or jaundice (yellowish color of the skin or whites of the eyes).

• Ulcers on the Legs. Sickle cell ulcers (sores) usually begin as small, raised, crusted sores on the lower third of the leg. Leg sores occur more often in males than in females and usually appear between the ages of 10 and 50.

• Pulmonary Arterial Hypertension (High Blood Pressure). Damage to the small blood vessels in the lungs makes it hard for blood to flow through them. This causes blood pressure in the lungs to increase. Elevated pressure in the lungs can put excess strain on the right side of the heart and lead to heart failure. Excessive shortness of breath is an important symptom linked to this problem.

Related disorders

There are many diseases related to variations in hemoglobin structure, collectively called hemoglobinopathies.

Clinical Trials

SCA remains an active area of clinical research. There are several promising projects to establish the safety of new therapies or improve the efficacy of known ones. Clinical trials can be found at:

• Sickle Cell Anemia Clinical Trials
• National Heart Lung and Blood Institute.

Several projects are of particular interest:

• "Retroviral Vector Mediated Globin Gene Transfer to Correct Sickle Cell Anemia or Thalaassemia." This is an attempt to deliver the correct version of genes that are defective in SCA or thalassemia to stem cells taken from human patients. The modified human stem cells will be tested in mice as a first (safety) step to determine whether or not the modified genes are being expressed.

Pulmonary hypertension is being addressed in at least two studies that examine the effects of drugs commonly used for erectile dysfunction:

• Cialis will look at the effect of tadalafil (Cialis) on pulmonary hypertension and priapism.

• Viagra will examine the effect of sildenafil (Viagra) for pulmonary hypertension.

History

SCA has likely been present in human populations for thousands of generations. Different mutations probably arose independently in Africa and the Arabian peninsula. The persistence of these mutations may be due in part to the survival advantage conferred on heterozygotes, whose RBCs are less susceptible to invasion by malaria parasites than are normal RBCs.^[2]

The peculiar shapes taken by diseased RBCs were first described in 1910 in a dental student from Grenada. ^[3] Since the appearance of RBCs in the microscope was so different from anything seen before, there was uncertainty as to whether this represented a new disease or if the findings were due to the bizarre presentation of an already-known disease. As more and more cases were described, however, SCA was described as a disease in and of itself. ^[4]

Technological advances in the early 20th century allowed discovery of the molecular basis of SCA, which was an important landmark in molecular medicine. Indeed, the difference between HbS and normal HbA comes down to a single amino acid in the Hb molecule, which can be traced back to a single point mutation in the DNA that codes for the beta subunit of the Hb tetramer. SCA was the first disease to be described at this level and understood as "a molecular disease." ^[5]

Epidemiology

About 8% of black Americans are heterozygous for HbS. That is, these people carry the sickle cell trait, and the disease occurs in about 1 per 500 births in this population. Hispanics are also affected with a disease frequency of about 1 per 1,200 births. In areas where malaria is endemic, the number of carriers approaches 30%. About 2 million Americans have the trait and about 70,000 people in the US have the disease, with about 90% of patients surviving to age 20 and about half surviving to age 50.

Social Issues

The difficulties presented by SCA pervade every aspect of a person's life and in many cases lead to psychological and social problems.^[6] People with SCA often experience social difficulties and stigma, especially with respect to obtaining adequate pain management. One study in 2007 showed that sickle cell patients seen in three emergency departments received pain medications 70 to 75 minutes later than recommended by the American Pain Society.^[7]

Related Video from NHS Choices

Pamela, 18, was born with sickle-cell anaemia, a genetic blood disorder. She describes how to cope with the disease on a daily basis, and explains why it is important to raise awareness of the condition.

References

1. ↑ Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008 Mar 27;358(13):1362-9. Full Text | PDF
2. ↑ Desai DV, Dhanani H. Sickle Cell Disease: History And Origin.The Internet Journal of Hematology. 2004. Volume 1 Number 2. Full Text
3. ↑ Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscules in a case of severe anemia. Arch. Int. Med. 1910 6:517-521.
4. ↑ Sydenstricker VP. Further observations on sickle cell anemia. JAMA. 1924 83:12-15.
5. ↑ Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia, a molecular disease. Science. 1949 110:543-548.
6. ↑ Edwards CL, Scales MT, Loughlin C, et al. A brief review of the pathophysiology, associated pain, and psychosocial issues in sickle cell disease. Int J Behav Med. 2005;12(3):171-9. Abstract | Full Text | PDF
7. ↑ Tanabe P, Myers R, Zosel A, et al. Emergency department management of acute pain episodes in sickle cell disease. Acad Emerg Med. 2007 May;14(5):419-25. Abstract

External Links

Sickle Cell Disease Association of America

Sickle Cell Foundation of Georgia

Sickle Cell Information Center