Overview of sickle cell anemia
Sickle cell anemia is a group of blood disorders typically inherited from a person’s parents. The most common type is known as sickle cell anaemia (SCA). It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells.
This leads to a rigid, sickle-like shape under certain circumstances. Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain (“sickle cell crisis”), anemia, swelling in the hands and feet, bacterial infections and stroke. Long-term pain may develop as people get older. The average life expectancy in the developed world is 40 to 60 years.
Sickle cell anemia occurs when a person inherits two abnormal copies of the haemoglobin gene, one from each parent. This gene occurs in chromosome. Several subtypes exist, depending on the exact mutation in each haemoglobin gene. An attack can be set off by temperature changes, stress, dehydration, and high altitude.
The care of people with sickle cell anemia may include infection prevention with vaccination and antibiotics, high fluid intake, folic acid supplementation, and pain medication.n Other measures may include blood transfusion and the medication hydroxycarbamide (hydroxyurea). A small percentage of people can be cured by a transplant of bone marrow cells.
Symptoms of sickle cell anemia
- Anemia. Sickle cells break apart easily and die, leaving you without enough 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).
- Episodes of pain. Periodic episodes of pain, called 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.
- Painful swelling of hands and feet. The swelling is caused by sickle-shaped red blood cells blocking blood flow to the hands and feet.
- Frequent infections. Sickle cells can damage an organ that fights infection (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.
- Delayed growth. Red blood cells provide your body with the oxygen and nutrients you need 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 may become plugged with sickle cells. This can damage the retina — the portion of the eye that processes visual images, leading to vision problems.
- Haemolytic crisis: Haemolytic crises are acute accelerated drops in haemoglobin level. The red blood cells break down at a faster rate. This is particularly common in patients with coexistent G6PD deficiency. Management is supportive, sometimes with blood transfusions.
- GENETICS: Normally, humans have haemoglobin A, which consists of two alpha and two beta chains, haemoglobin A2, which consists of two alpha and two delta chains, and haemoglobin F, consisting of two alpha and two gamma chains in their bodies. Of these three types, haemoglobin F dominates until about 6 weeks of age.Afterwards, haemoglobin A dominates throughout life. In people diagnosed with sickle cell disease, at least one of the β-globin subunits in haemoglobin A is replaced with what is known as haemoglobin S. In sickle cell anaemia, a common form of sickle cell disease, haemoglobin S replaces both β-globin subunits in the haemoglobin.Sickle cell conditions have an autosomal recessive pattern of inheritance from parents. The types of haemoglobin a person makes in the red blood cells depend on what haemoglobin genes are inherited from her or his parents. If one parent has sickle cell anaemia and the other has sickle cell trait, then the child has a 50% chance of having sickle cell disease and a 50% chance of having sickle cell trait. When both parents have sickle cell trait, a child has a 25% chance of sickle cell disease; 25% do not carry any sickle cell alleles, and 50% have the heterozygous condition.
Sickle cell gene mutation probably arose spontaneously in different geographic areas, as suggested by restriction endonuclease analysis. These variants are known as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian. Their clinical importance is because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.
The gene defect is a single nucleotide mutation (see single-nucleotide polymorphism – SNP) (GAG codon changing to GTG) of the β-globin gene, which results in glutamic acid (E/Glu) being substituted by valine (V/Val) at position 6. Haemoglobin S with this mutation is referred to as HbS, as opposed to the normal adult HbA.
This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structures of haemoglobin in conditions of normal oxygen concentration. However, under low oxygen concentration, HbS polymerizes and forms fibrous precipitates because the deoxy form of haemoglobin exposes a hydrophobic patch on the protein between the E and F helices (Phe 85, Leu 88).
Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as Africa, the Mediterranean, India, and the Middle East. Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.
The malaria parasite has a complex life cycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely, making the Plasmodium parasite unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite to digest Hb in the first place. Therefore, in areas where malaria is a problem, people’s chances of survival actually increase if they carry sickle cell trait (selection for the heterozygote).
Tests to detect sickle cell genes before birth
Treatment and management
TRUE LIFE CURE SICKLE CELL STORY
There is a cure for sickle cell disease
I was surprised when chatting recently with Leslie Lehmann, MD, clinical director of the Stem Cell Transplantation Program at Dana-Farber/Children’s Hospital Cancer Center (DF/CHCC). She turned to me and asked, “Did you know there’s been a cure for sickle cell disease for nearly 40 years?”
I had to admit that I didn’t. I’ve always thought of sickle cell—a painful and debilitating disease caused by an inherited mutation that makes red blood cells stiffen into a characteristic sickled shape—as a chronic disease to be managed, not one that could be cured.
I’m not alone in that belief. Lehmann often asks this question when she give talks for medical students, residents and other physicians. Their reaction is puzzlement, then a shaking of heads.
The cure is there, though. It’s a stem cell (aka bone marrow) transplant. The catch is that it’s not available to everyone—but for reasons that Lehmann thinks can be overcome.
Children and adults with the condition often receive treatment that alleviates symptoms or prevents complications (e.g., transfusions for anemia or strokes, penicillin to prevent infections, hydroxyurea to decrease pain crises and acute chest syndrome).
But none of these treatments address sickle cell’s root cause: the inherited mutation, which scrambles the gene for the adult form of hemoglobin. Hydroxyurea can force the body to stop making adult hemoglobin and instead make fetal hemoglobin (the form we produce during development and shortly after birth, and which never carries the sickle cell mutation). But it needs to be taken for life and it doesn’t work for everyone.
A stem cell transplant cures the disease by removing its source. Patients are “conditioned” with chemotherapy to completely destroy the hematopoietic (blood forming) stem cells in their bone marrow (including the ones that produce the malformed red blood cells). Doctors then rebuild their blood with healthy stem cells from a matched donor that doesn’t have the sickle cell mutation.
Stem cell transplants are often employed in blood and other cancers, but in sickle cell they’re currently available to a limited number of patients with truly severe disease. One reason is that they’re complicated and risky; many patients are too sick to tolerate the conditioning process, or their bodies don’t accept the donor cells.
A less intense form of stem-cell transplant may make cures possible for more children.
Then there’s the awareness issue. “Many physicians who see children with sickle cell don’t know if their patients are candidates for transplant,” Lehmann notes. “In turn, most families aren’t aware that it could be an option.”
Third is the “matched donor” requirement. “The matching requirements for a transplant in sickle cell are different from those in cancer,” Lehmann explains. “Right now only children with a sibling with identical but non-sickled red blood cells can qualify for a transplant. Only about 14 percent of patients are likely to have a match like that.”
But that may not always be the case. Lehmann is running the DF/CHCC arm of a clinical trial that could make non-related donations possible, as they can for many other kinds of transplants. Called the SCURT (Sickle Cell UnRelated Transplant) study, the trial tests the combination of a less intense (and therefore potentially safer) conditioning regimen and stem cells from unrelated donors.
“In cancer, less intense or ‘minimally ablative’ techniques let us eliminate just enough of a patient’s immune cells to avoid transplant rejection,” Lehmann says. “We think that we can achieve the same results for patients with sickle cell.