What is sickle cell anemia?
Sickle cell anemia is a hereditary chronic hemolytic anemia caused by the production of Hb S as a result of a mutation in codon 6 of the beta globin gene. This mutation causes the hemoglobin to sickle when the red cell is deoxygenated.
What is the function of the red blood cell?
The main function of the red blood cell is to carry oxygen from the lungs to the tissues and then transport carbon dioxide back from the tissues to be expelled through the lungs. For the red blood cell to function, it depends on the red blood cell metabolism pathways, the membrane structure as well as the hemoglobin content. As the main function of the red blood cell is as an oxygen carrier, a mature erythrocyte is essentially a bag full of hemoglobins.
In a healthy adult, there are approximately 270 million hemoglobins in 1 red blood cell. The hemoglobin is a tetrameric structure of 2 alpha-like and 2 beta-like globin chains interconnected by specific points and each folded globin chain carries a heme peptide with an iron atom in the center. Each iron atom can carry 1 molecule of oxygen.
The alpha globin gene cluster is found on chromosome 16 while the beta globin gene cluster is found on chromosome 11. The genes in the cluster are arranged according to the order of development and at different stages of development, different hemoglobin subtypes are formed to have different oxygen affinities. For example, fetal hemoglobin or Hb F have a higher oxygen affinity compared to Hb A to allow for oxygen exchange between the mother and the developing fetus. However, Hb F switches to Hb A (at around 6 months after birth) which is more efficient in oxygen delivery once the baby is born.
What are hemoglobin disorders?
Disorders of the hemoglobin or hemoglobinopathies are mutations affecting the globin genes and are usually inherited. They can be loosely classified into structural hemoglobinopathies which is a qualitative disorder of the hemoglobin for example Hb S. In structural hemoglobinopathies, the hemoglobins formed are not able to carry oxygen as efficiently as the normal hemoglobins. The other group of hemoglobinopathy is thalassemia which is a quantitative reduction or absence of one or more of the globin chain production.
Pathogenesis of sickle cell anemia.
Genetically speaking, hemoglobinopathies are mainly autosomal recessive disorders where you will need two mutant alleles to be clinically symptomatic while carriers are generally asymptomatic.
Sickle cell disease is common among the Africans and also the Indians. The sickle red cells confer some protective mechanism against malaria and has allowed this faulty gene to persist historically. Even just one copy of the sickle gene is enough to offer some resistance towards malaria.
Sickle cell anemia is caused by a mutation in codon 6 of the beta globin gene, where the wild type glutamic acid has been changed to valine. Hemoglobin S (Hb S) is insoluble and forms crystals when exposed to low oxygen tension. Deoxygenated sickle hemoglobins tend to clump and polymerize into long fibers called tactoids. Initially, when the sickle hemoglobins clump together to form tactoids during the deoxygenation phase, the red blood cells are still reversibly sickled. But as more and more Hb S forms the long fibers, the red cells become irreversibly sickled and are unable to revert back to its biconcave shape. These red cell membranes are sticky and cause microvascular occlusions. They also cause vascular inflammation when they adhere to the vascular walls and in the spleen, there is a lot of hemolysis, congestion and infarction as these cells accumulate in the reticuloendothelial system to be destroyed.
What are the signs and symptoms of sickle cell anemia?
Signs and symptoms of sickle cell anemia include
(1) Manifestations of signs and symptoms 6 months after birth with hemoglobin switching predominantly from Hb F to Hb A, the adult hemoglobin.
(2) Acute problems in children for example painful swollen fingers or dactylitis or ulcers of the lower legs and splenomegaly but is often reduced in size later as a result of infarcts or autosplenectomy.
(3) The clinical expression of HbSS is very variable, some patients having an almost normal life, free of crises but others develop severe crises even as infants and may die in early childhood or as young adults.
(4) Chronic damage to the organs for example the kidneys or the liver and
(5) Growth impairment.
What are the complications of sickle cell anemia?
The hallmark of sickle cell anemia is severe hemolytic anemia punctuated by crises.
Crises may be vaso-occlusive, visceral, aplastic or hemolytic. Painful vaso-occlusive crises are most frequent and are precipitated by infection, acidosis, dehydration or deoxygenation for example, altitude, surgeries, deliveries, circulation stasis, exposure to cold or violent exercise. Infarcts can occur in any organs including bones, lungs and spleen. The most serious vaso-occlusive crisis is of the brain causing a stroke or the spinal cord.
Visceral sequestration crises are caused by sickling within organs and pooling of blood, often with a severe exacerbation of anemia. Severe complications include acute sickle chest syndrome which is the most common cause of death after puberty.
Splenic sequestration is usually seen in infants and presents with splenomegaly, falling hemoglobin and abdominal pain. Attacks tend to be recurrent and splenectomy is often needed.
Aplastic crises occur as a result of infection with parvovirus or from folate deficiency and are characterised by a sudden fall in hemoglobin which usually requires transfusion.
Hemolytic crises are characterised by an increased rate of hemolysis with a fall in hemoglobin but a rise in reticulocytes and usually accompany a painful crisis.
Complications of sickle cell anemia include acute chest pains when certain areas of the chest have their blood supply cut off, infections as the spleen is overwhelmed with destroying the abnormal red cells and also autosplenectomy when the spleen dies due to lack of blood supply. Stroke when certain parts of the brain do not receive enough blood and the same goes for organ failures like kidney failure, ulcers, eye damage and many more. All depends on where the microvessels get blocked or occluded. Other complications include brain infarcts, retinopathy, pulmonary hypertension, acute chest syndromes, cholelithiasis, autosplenectomy, chronic renal failure, obstetric complications, priapism, bone infarcts, osteomyelitis, chronic leg ulcers, dactylitis and generally widespread painful vaso-occlusive crises.
How do I test for sickle cell anemia?
General laboratory tests
In laboratory investigations, a sickle cell anemia patient with homozygous sickle cell mutation will have moderate anaemia with reticulocytosis count in the full blood count. Moderate anisopoikilocytosis with polychromatic cells and sickled erythrocytes can be seen in the peripheral blood film.
Specific laboratory tests
There will be a positive sickle solubility test. Elevated bilirubin and raised serum lactate dehydrogenase when there is high red cell destruction in a crisis. PCR will show a positive sickle mutation and infarcts like the brain infarcts can be detected using the Doppler ultrasonography. Hemoglobin electrophoresis and high performance liquid chromatography will reveal presence of haemoglobin S and also an elevated Haemoglobin F.
How is sickle cell anemia treated?
In spite of all the pain, the treatment of sickle cell anemia is largely symptomatic. Patients are given prophylactic oral penicillin to prevent infection, and told to always hydrate themselves and given painkillers, oxygen and antibiotics in painful crises. Regular blood transfusions are not required as this is a qualitative disorder and not quantitative. Current curative treatment is bone marrow transplantation, however, it is difficult to find a HLA-matched donor. Gene therapy is on the horizon as there are already clinical trials ongoing to cure this disease.
Below is the synopsis of sickle cell anemia.
Definition of sickle cell anemia
A hereditary chronic hemolytic anemia caused by the production of Hb S (a qualitative hemoglobin defect due to a β-globin gene codon 6 mutation [glutamic acid → valine])
Epidemiology of sickle cell anemia
Most frequent in Africa, Middle East and India
Inheritance pattern of sickle cell anemia
Autosomal recessive disorder.
Signs and symptoms of sickle cell anemia
- Symptoms appear after 6 months of age when hemoglobin switching occurs
- Acute problems in infants and children i.e. severe infections, acute chest syndrome, splenic sequestration and stroke
- Generalized impairment of growth and development in children with chronic hypoxia
- Chronic organ damage in adults
Types of crises in sickle cell anemia
- Sickling crises (vaso-occlusive / painful / infarctive)
- Hemolytic crises (marked increase in hemolysis)
- Aplastic crises (associated with parvovirus B19 infection)
- Sequestration crises (sudden trapping of blood in the spleen or liver leading to rapid enlargement of the organ and drop in haematocrit resulting in hypovolemic shock)
Pathophysiology of sickle cell anemia
Complications of sickle cell anemia
Confirmatory / Diagnostic tests for sickle cell anemia
- Sickling test
- Hemoglobin electrophoresis
- High performance liquid chromatography (HPLC)
- DNA mutation test (PCR)
- Peripheral blood smear (screening)
Laboratory diagnosis of sickle cell anemia
Full blood count and Peripheral blood characteristics in crises
Full blood count: Moderate anemia, increased reticulocyte count
Peripheral blood smear: Moderate anisopoikilocytosis, polychromatic cells, sickled erythrocytes
Other important investigations and expected results of sickle cell anemia
- ↑ unconjugated bilirubin
- ↑ urine urobilinogen
- ↓ serum haptoglobin
- Pigment bilirubin gallstones
Treatment and management of sickle cell anemia
- Prophylactic penicillin
- Pneumococcal and meningococcal vaccine
- Avoid dehydration, hypoxia and circulatory stasis
- Active treatment for bacterial infections
- Oral / IV fluids, analgesics, oxygen, exchange transfusion and ventilatory support during painful crises
- Transfusion when necessary
- Bone marrow transplantation
- Regular cerebral blood flow surveillance and prophylactic transfusions
- Hydroxyurea for adults
- Splenectomy in splenic sequestration crises