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In 1910 James Herrick reported elongated, irregularly deformed red blood cells in some anaemic patients. Their erythrocytes had all kinds of strange shapes, some in the shape of a sickle, hence the name "sickle cell anaemia". A great deal of research was carried out in order to understand what the cause was. Sickle cells are much less flexible than normal erythrocytes. They therefore have difficulty in passing through capillary vessels, the diameter of which is often less than half the diameter of a red blood cell. Sickle cells are also optically birefringent, which indicates a regularly ordered structure within the cell. Since the contents of a red blood cell consist mainly of haemoglobin (95% of the proteins), the presence of an abnormal haemoglobin was soon suspected. In 1949 Linus Pauling and co-workers discovered that sickle haemoglobin carries a more positive charge than normal haemoglobin and the two species could be separated by electrophoresis. Consequently it was possible to isolate and study the abnormal haemoglobin.
Each molecule of haemoglobin consists of a tetramer consisting of 2 pairs of polypeptide chains to which a total of 4 haem groups (one haem group per globin chain) is linked. One molecule of haemoglobin therefore contains 4 proteins. Hb A contains 2 globin chains of one type (alpha) and 2 globin chains of another type (beta). Each alpha chain contains 141 amino acids while each beta chain has 146 residues. The type and the sequence of these amino acids is genetically determined. Depending on which 4 chains are present in the haemoglobin tetramer, the molecule is given its name.
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There are many haemoglobin variants:
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Normal |
Hb A |
® a 2 ß2 (alpha and beta) |
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Hb A2 |
® a 2 d 2 (alpha and delta) |
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Hb F |
® a 2 g 2 (alpha and gamma) |
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Pathological
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Hb S |
® a 2 ß2S |
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Hb C |
® a 2 ß2C |
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Hb E |
® a 2 ß2E |
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Hb H |
® ß4 (see a -thalassaemia) |
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Hb Barts |
® g 4 (see a -thalassaemia) |
The normal haemoglobins of a child or an adult are Hb A (97%), Hb A2 (2%) and Hb F (1%). Hb A contains 2 a -chains and 2 ß-chains. By a mutation in the genetic material (DNA), at various points in the chains a different amino acid than normal can be included. In 1957 Vernon Ingram in Cambridge discovered the mutation responsible for sickle cell anaemia. If by mutation, the 6th amino acid of the ß-chain (glutamic acid, negatively charged) is replaced by a different amino acid (valine, hydrophobic), Hb S is formed. As a result a hydrophobic site is formed on the outside of the folded mutated beta chain. With normal arterial oxygen tension there is no problem and the molecule transports the oxygen. In the capillary bed in the tissues the oxygen is released and deoxyhaemoglobin S is formed. This latter substance has several different properties. In deoxy-Hb S there is a second hydrophobic site on the surface. This site is concealed in oxy-Hb S. The site is complementary to the first. These two hydrophobic regions adhere to each other, resulting in a kind of polymerisation of the deoxyhaemoglobin S molecules. The hydrophobic valine on the surface makes the haemoglobin molecule somewhat less water-soluble if the molecule is not bound to oxygen. The concentration of haemoglobin in the erythrocyte (32-34 g%) does however require a very water-soluble molecule. The deoxyhaemoglobin S molecules start to come out of solution (precipitate). At low oxygen concentrations the deoxyhaemoglobin S molecules adhere to each other, forming long, rigid strands and thus deform the red blood cells making them more rigid. The molecules stick to each other in a definite pattern (like a crystal). This polymerisation reaction is relatively slow, giving a "delay time" or Td. The slower the circulation and therefore the longer the time before reoxygenation in the lungs, the more sickling occurs. Usually the transit time of a red blood cell in the microcirculation is less than Td and a major catastrophe is avoided.
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The main variables that affect sickling are the intracellular haemoglobin concentration, pH, the level of oxygenation and the percentage of Hb F. Sickling is accelerated by lack of oxygen, slow blood circulation, acidification and dehydration (a situation which is common with infections). The consequence of acidification is that Hb releases oxygen more easily and is thus deoxygenated: shift to the right of the Hb oxygen binding curve [i.e. %Oxy-Hb vs O2 tension]. The reduction in oxygen affinity of haemoglobin caused by a decrease in pH is termed the Bohr effect or Bohr shift. The formation of rigid Hb SS strands is counteracted by Hb F (efficiency of polymerisation is reduced). People with high concentrations of Hb F have far fewer symptoms than patients with low Hb F concentrations.
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Red blood cells can loose water (dehydrate) in different ways. As their water content falls, the haemoglobin concentration increases. Loss of potassium (intracellular ® extracellular) with intracellular dehydration as a consequence plays an important part. The following transport mechanisms are important: so-called potassium chloride cotransport and Ca++-mediated potassium efflux. Potassium chloride cotransport is promoted by acidification. Sickling temporarily increases the intracellular calcium concentration, with subsequent potassium loss and, secondary to this, water loss. These dense SS cells are deformed and contribute substantially to vaso-occlusion and haemolysis.
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The sickling process also causes damage to various membrane proteins of the erythrocyte, thus promoting adhesion to the vascular endothelium. This makes circulation even more difficult. The degree of adherence is closely correlated to the severity of the disease. If there is inflammation, this "stickiness" can increase even more.
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An aspect of sickle cell disease that is not yet well understood is that despite the fact that the disease is based on a single mutation that substitutes a single amino acid in one protein chain in one cell type, there is a huge range of clinical manifestations. There are therefore clearly other additional factors that play a part, besides the tendency of haemoglobin S to polymerise under hypoxic conditions. One hypothesis is that the interaction between the sickle cells and the vascular endothelium plays a crucial part. Endothelial cells can be "activated", i.e. they can express all kinds of molecules on their membrane, under the effect of various inflammatory substances (cytokines, prostacyclins, etc). Such cells become "sticky" and promote local haemostasis (and possibly thrombosis). Sickle cell patients have a clearly increased number of activated circulating endothelial cells in their blood, mainly derived from the microcirculation. Individual variation in the expression of adhesion molecules may play a part in the variable clinical manifestations. There is also an increase in the number of adhesion molecules on the red blood cells. The local production of NO by the damaged endothelium falls.
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Nitric oxide (NO) produced by endothelial cells causes vasodilatation (effect is concentration dependent). NO reacts at least 1,000 times more rapidly with haemoglobin in free solution than with haemoglobin inside erythrocytes (NO reacts both with oxyhaemoglobin and deoxyhaemoglobin). Free haemoglobin in plasma will scavenge NO, thereby diverting nitric oxide from its homeostatic vascular function. This reduced bioavailability plays a role in the vascular pathology of sickle cell disease.
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What are the consequences of sickling?
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The sickle cell gene occurs in large parts of Africa and to a somewhat lesser extent in the Middle East (Saudi Arabia) and southern India. In West Africa, 5 to 25% of the population are carriers of the gene. In Central and East Africa heterozygotes occur with a frequency of from 20 to 40%. If 20% of the population are carriers of the gene, it follows that 1% of newborn children will be homozygous. Through the slave trade the sickle cell gene also found its way to North and South America.
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Heterozygous carriers are relatively protected against fatal P. falciparum malaria. They are of course infected just as often, but are less likely to die from the infection. If the malaria parasite is present within the erythrocyte, the red blood cell acidifies slightly. This is enough to promote sickling. Because of the damage to the membrane that then occurs, potassium flows out of the red blood cell, which is damaging to the parasite and the erythrocyte. The red blood cell is rapidly destroyed, for example in the spleen (heterozygotes have a normal spleen). Since heterozygotes in an endemic malaria area have a longer life expectancy than people with normal haemoglobin, it is thought that this has promoted the occurrence of sickle cell haemoglobin in Africa over the course of evolution. On the other hand, homozygous Hb S people have a very low life expectancy. There will therefore be a genetic equilibrium (see Hardy Weinberg equilibrium).
Sickle cell anaemia is a genetically determined disease. A distinction is made between three main groups: homozygotes, heterozygotes and double heterozygotes.
If someone has both a normal gene (from one parent) and a mutated gene (from the other parent), he or she produces both the normal haemoglobin (Hb A) and also the sickle cell haemoglobin (Hb S). The patient has about 2/3 Hb A and 1/3 Hb S. The person is then a carrier (heterozygote) and each red blood cell contains both Hb A and Hb S. Such erythrocytes are functionally normal and have the advantage that they provide relative protection against fatal Plasmodium falciparum infection. This explains the frequent occurrence of this condition in Africa (so-called sickle cell trait). Such heterozygotes lead a normal life. But they may well pass the gene on to their children.
If a patient has two identical mutated genes (homozygote), he or she cannot produce Hb A. After birth, the Hb F concentration falls and after 3 to 6 months, the red blood cells contain mainly haemoglobin Hb S. This has very important consequences.
Probability per child of having the different haemoglobins:
There are some important situations:
Vaso-occlusive complications
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Pain episodes |
in more than 70% of patients. |
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CVA |
in 10% of children; "silent" lesions with cognitive damage in 50-90%. |
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Acute chest syndrome |
in 40% of patients, more often in children. |
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Priapism |
in 10-40% of men. Severe cases lead to permanent dysfunction. |
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Liver disease |
in <2%. Multiple causes: hep B, C, iron overload. |
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Spleen sequestration |
in children < 6 years of age. Often preceded by infection. |
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Spontaneous abortion |
in 6% of pregnant women; less frequent in Hb SC. |
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Skin ulcers (leg) |
in 20% of adults; less frequent in Hb SC |
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Osteonecrosis |
in 10-50% of adults (often femur, humerus) |
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Proliferative retinopathy |
rare in sickle cell anaemia; in 50% with Hb SC. |
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Renal insufficiency |
in 5-20% of adults, often with severe anaemia |
Complications of haemolysis
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Anaemia |
haematocrit often 15-30%, higher in Hb SC. |
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Gallstones |
in the majority of adults, usually asymptomatic. |
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Acute aplastic crisis |
due to parvovirus B19. Sudden severe anaemia. |
Infectious complications
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septicaemia in 10% of children < 5 years. |
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Osteomyelitis |
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Escherichia coli septicaemia |
In adults often originating from infection of the urinary tract. |
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Note: Parvovirus B19
The name parvovirus B19 was given to a particular minute virus. There is no parvovirus B18 or B17 etc. Its nearest relatives are the replication-defective dependoviruses. The receptor molecule for parvovirus B19 is tetrahexosoceramide, a glycolipid (erythrocyte P antigen), which explains the cell tropism of this virus. Infection by this virus is followed by an acute depression in the production of red blood cells in the bone marrow. This is a transient event which is usually not of great clinical significance except in patients with severe haemolytic conditions. When the depression of the bone marrow lasts longer than the average life time of the red blood cells, severe anaemia will develop.
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Parvovirus B19 causes so called "fifth disease". It is an illness characterized by a mild rash and occurs most commonly in children. The ill child typically has a "slapped-cheek" rash on the face and a lacy red rash on the trunk and limbs. Occasionally, the rash may itch. The child usually has a low-grade fever, malaise, or a "cold" a few days before the rash becomes apparent. The child is usually not very ill. Pet dogs or cats may be immunized against "parvovirus," but these are animal parvoviruses that do not infect humans. Therefore, a child cannot "catch" parvovirus from a pet dog or cat, and a pet cat or dog cannot catch human parvovirus B19 from an ill child. Non-immune adults can also be infected. The person can be asymptomatic or develop the typical rash of fifth disease, with symmetrical joint pains and/or joint swelling. Most frequently affected are the hands, wrists, and knees. The joint pains and swelling usually resolve in a week or two, but may last several months. This should be distinguised from infections with hepatitis B or arboviruses such as Ross River virus or Barmah Forest virus.
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Individuals with sickle cell trait are generally asymptomatic and have no abnormal physical findings. Their laboratory evaluation often shows microcytosis, but is further normal with no anaemia, no evidence of haemolysis, and no laboratory abnormalities other than haemoglobin AS on haemoglobin electrophoresis. Many individuals will have decreased ability to concentrate their urine. There may be an increased incidence of urinary tract infection during pregnancy. Painless haematuria does occur in 1 to 4% of individuals with sickle cell trait. This complication is usually not a significant problem, however, a small minority of individuals may have recurrent haematuria requiring medical intervention, transfusion, and iron therapy. Complications such as splenic infarction, pain episodes, and sudden death may be induced by severe hypoxia, severe dehydration, and exertion at the limits of human endurance, e.g. at high altitudes.
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Chronic haemolysis manifests itself as pallor, mild jaundice, dark urine and retarded growth. There is hypertrophy of the bone marrow, which can often be seen in the cranium and the maxillae. But the expansion of the bone marrow is less pronounced than in homozygous ß-thalassaemia, possibly because less erythropoietin is produced than expected due to repeated kidney damage. Due to the constant interruption in the blood flow and the production of bilirubin, bilirubin gallstones are produced at a very young age (such stones are often not radio-opaque). There is splenomegaly up to about 5 years (afterwards there is atrophy because of the repeated infarctions of the spleen). The expansion of the bone marrow can usually be seen clearly by frontal "bossing", a pronounced curving of the forehead and by widely spaced teeth in the jaws. On an X-ray of the cranium, small canals in the diploë of the vault of the cranium and are known as a "hair-on-end" appearance.
Haematological crises sometimes occur. In children aged from 6 months to 3 years the spleen can sometimes swell acutely (sequestration of blood in the spleen), with sudden anaemia, hypovolaemia and shock as a result. Many do not survive this. Due to infections, such as malaria for example, hyperhaemolysis can occur. After certain viral infections (parvovirus B19) a period may follow during which the bone marrow does not form any new red blood cells (aplastic crisis). Bone marrow arrest can also occur if there is a marked folic acid deficiency.
Thrombotic crises are triggered by oxygen deficiency in the tissues, acidosis, slowed circulation, cold, dehydration, etc. For example: infections, fever, hypothermia, trauma, abortion. This is manifested most commonly as episodes of pain, but also, among others, as kidney infarctions (haematuria, papillary necrosis), priapism, atrophy of the spleen, bone necrosis (head of the femur, head of the humerus, metacarpals, vertebrae), CVA, chronic skin wounds (mainly on the shins), and proliferative retinopathy. Hand-foot syndrome is sometimes the first clinical manifestation. The child then has acutely painfully swollen hands and feet. Chronic damage to the vertebrae leads to biconcave vertebrae ("fish vertebrae") with a typical appearance on X-ray. Patients can develop a marfanoid appearance
[bodyshape can resemble Marfan, Klinefelter (XXY) and Stickler syndrome (marfanoid, but with vitreal degeneration and cleft palate)]. Due to kidney damage, patients with sickle cell anaemia usually have difficulty in concentrating their urine and are susceptible to dehydration. Hyposthenuria may become evident in childhood as enuresis. Glomerular sclerosis, manifested by proteinuria, progresses as patients age. Proteinuria is a potential harbinger of chronic renal failure but can be ameliorated by angiotensin converting enzyme inhibitors. Chronic renal failure occurs in up to 5% of patients with sickle cell anaemia. In case of haematuria, renal medullary carcinoma should be excluded, although it is not yet clear if there is an increased risk. Pulmonary infarctions contribute to acute chest syndrome, with pain, dyspnoea and a poor general condition. Children often feel pain and distress. The sequelae are often considerable. Small cerebral watershed infarcts may be clinically silent but produce cognitive defects shown by neuropsychiatric testing. Patients may also present with cerebral haemorrhage secondary to berry aneurysms and "moya-moya" vascular abnormalities, more commonly seen in adults. Hemiplegia can result from a cerebral infarction. Most patients with brain injury require long term transfusion therapy. Those children should be considered for bone marrow transplantation.
Ophthalmological problems tend to be more common in patients with high concentrations of haemoglobin (higher viscosity). Symptomatic disease usually occurs in adults. Occlusion of small retinal vessels with neovascularisation is asymptomatic until haemorrhage occurs within the vitreous. Detachment of the retina, more common in late disease, is a feared complication, and an important cause of blindness, together with occlusion of the central retinal artery. If possible, the patient should be evaluated on a yearly basis by an ophthalmologist. Fluorescein angiography followed by laser photocoagulation is an effective and safe treatment for retinal detachment. Occlusion of the central retinal artery leads to acute loss of vision. This is a medical emergency, for which urgent transfusion is imperative.
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Angioid streaks in sickle cell anaemia are common in the second and third decade. Those grey, brownish-red poorly defined streaks radiate across the fundus of the eye, lying beneath the retina and the blood vessels. The streaks are caused by breaks in the elastic tissues in the back of the eye. They appear similar to the changes one can see in pseudoxanthoma elasticum and Paget's disease of the bone, but in sickle cell disease, Bruch membrane calcification is not a common part of the pathology. If complications are likely, photocoagulation can be performed by an experienced ophthalmologist.
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Because of the repeated infarctions of the spleen, sickle cell anaemia patients over the age of 5 years no longer have a functioning spleen. The spleen remnant will be small and fibrotic. The spleen plays an important part in protecting against bacteria. Asplenic children are very susceptible to bacterial infections, including pneumococci (i.e. encapsulated bacteria, Streptococcus pneumoniae). Osteomyelitis caused by, among others, Salmonella and staphylococci, is common. Often it is difficult to distinguish between, for example pulmonary infarction and pneumonia, and between osteomyelitis and bone infarction. Local tissue infarctions and infections occurring together promote each other.
About 40% of sickle cell anaemia patients develop acute chest syndrome during their lives. This syndrome consists of a collection of problems, such as acute chest pain, dyspnoea, coughing, fever, hypoxaemia (average PaO2 71 mm Hg), leukocytosis and pulmonary infiltrates, mainly in the inferior lobes. This can develop into a full-blown ARDS (Acute Respiratory Distress Syndrome). People with chronic leukocytosis, high haemoglobin concentrations and a low Hb F concentration are at greater risk. Painful vertebrae, sternum and rib infarctions together with microvascular thrombosis and endothelial damage contribute to the development of acute chest syndrome. Bone marrow infarctions followed by fat embolism play a part. At necropsy, in 75% of fatal cases bone spicules are found in the lung. In 60% of patients with acute chest syndrome, fat-loaded macrophages are found in the broncho-alveolar fluid. Bone infarctions can be detected by bone scintigraphy with Technetium 99m medronate.
[The "m" in Technetium 99m refers to "metastable" and indicates a high-energy nuclear isomer of this element. The exited nucleus has a half-life of 6h, reverting to ground level Tc99 which has a half-life of 212,000 years. Because of this short half-life it has to be produced from Molybdenum99 just before using it]. This radioactive tracer is taken up by osteoblasts that are mobilised to repair the damaged bone. This sort of scan can of course only be carried out in large centres. Because of the pain in the chest wall, patients are able to breathe less deeply ("splinting") with hypoventilation, atelectasis and perhaps surinfection as a result. Hypoxaemia increases the adhesion of red blood cells to the endothelium, via the increased expression of the adhesion molecule VCAM-1 on the endothelium, which binds to protein α4β1 on the red blood cell. Breathing in regularly, as deeply as possible, is an important part of the treatment ("incentive spirometry"). The patient is asked to breathe in deeply 10 times and to do this every two hours while awake. The role of opioids in promoting hypoventilation is unclear, but probably not very important. If the pain cannot be alleviated with opioids in the first 24 hours after admission, treatment can be continued by switching to mid-thoracic epidural block. This increases the inspiratory capacity considerably, and within just a few minutes. By administering corticosteroids, one tries to reduce the inflammatory component in the pleura lying against the rib infarction in acute chest syndrome. The administration of oxygen, antibiotics and standard or exchange transfusion completes the treatment. The possible therapeutic role of breathing NO (nitric oxide) still has to be studied in more detail. In a good hospital, the mortality of acute chest syndrome is 2% for children and 5% for adults.*
During periods of unobstructed blood flow in patients with sickle cell disease, the blood contains several types of red cells: biconcave disks that, despite their normal shape, may be poorly deformable; cells that are irreversibly sickled even when oxygenation is adequate; and reticulocytes that are highly adhesive to endothelium and have a distinct, somewhat wrinkled appearance. Adhesive sickle cells can initiate vaso-occlusion by becoming attached to the endothelium of vessel walls. Thereafter, poorly deformable red cells begin to accumulate behind the site of adhesion, ultimately resulting in an occluded vascular segment containing many sickled red cells.
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Pulmonary hypertension is a feared complication in chronic and severe haemolytic anaemias, such as thalassemia major, congenital sferocytosis and paroxysmal nocturnal haemoglobinuria. Pulmonary hypertension occurs in about one third of all patients with sickle cell disease. Chronic haemolysis and asplenia are considered to be the links between the haemolytic anaemia and the high intravascular pressures and oblitarative changes. Asplenia increases the circulation of platelet-derived mediatiors, which promotes pulmonary microthromboses and adhesion of erythocytes to the endothelium. Haemolysis results in the release of free haemoglobin, which scavenges nitric oxide and catalyses the formation of reactive oxygen species. Cell breakdown also releases red-cell arginase, which limits the availability of arginine to nitric oxide synsthetase, resulting in a relative deficiency of nitric oxide. Nitric oxide (NO) is a very important regulator of vascular tone. Routine clinical and laboratory findings are not sensitive enough to pick up the early changes. Echocardiography can identify people who have tricuspid regurgitant jet velocity of more than 250 cm/second. This measurement correlates well with the development of pulmonary hypertension.
Heterozygotes
Since normal and mutated beta chains are produced equally rapidly, it might be expected that heterozygotes would have ±50% Hb S and ±50% of Hb A. However, because alpha chains bind somewhat more easily to the normal beta chains than the mutated forms, there is a relative excess of mutated beta chains in the tetramers. The excess mutated chains are then destroyed. As a result, most heterozygotes have about 35% Hb S rather than 50%, and about 65% Hb A. The diagnosis of sickle cell trait is established by haemoglobin electrophoresis, isoelectric focusing or HPLC.
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Homozygotes
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There is severe anaemia (usually Hb 6-9 g%) with considerable reticulocytosis. A blood smear of a homozygote shows a great many sickle cells, in contrast to that of a heterozygote. The diagnosis can be confirmed by haemoglobin electrophoresis. On electrophoresis it can be seen that most of the haemoglobin consists of Hb S (often more than 80%); the remainder consists of Hb F and Hb A2. Of course, no Hb A can be found. There is often thrombocytosis and leukocytosis.
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A sickling test can also be carried out in vitro (Emmel’s test). In this, a drop of blood is placed on a glass slide. This is covered with a coverslip and the edges are sealed with some vaseline (no more contact with the air). As time goes by and the oxygen in the blood falls further (due to the metabolism of the cells), red blood cells will sickle. This test can be accelerated by adding a drop of sodium metabisulphite to the blood.
Since Yuet Wai Kai and Dozy in 1978 carried out the first direct analysis of foetal DNA for the prenatal diagnosis of sickle cell anaemia, there has been an explosive growth in this science (looking for polymorphism via restriction enzymes, hybridisation techniques, PCR). Hb S (ß6 Glu® Val) is caused by a A® T substitution in the second nucleotide of the sixth codon of the ß-globin gene. The mutation destroys the identification site of restriction endonucleases such as Mnl I and Dde I. These hi-tech techniques are at present beyond the reach of third world countries.
Analyses are performed on DNA from foetal cells obtained by chorionic villus sampling (CVS) in the first trimester, perhaps as early as the 10th gestational week. As an alternative approach, amniocentesis under echographic guidance can be performed safely in the l6th gestational week, a time when there is sufficient amniotic fluid. These sampling methods result in a far lower rate of foetal demise than the foetal blood sampling method practiced previously, and their use now is nearly universal. It is common practice to initiate tissue culture as a backup source of foetal DNA in case insufficient DNA for analysis is obtained initially. The emphasis on methods of early sampling to safeguard against unacceptable delays in diagnostic testing have encouraged the use of CVS as the method of choice for foetal sampling. However, the use of CVS before 9 weeks’ gestation is associated with increased rates of limb reduction anomalies. Moreover, when CVS is used for sampling, confined placental mosaicism may result in mistaken diagnoses of heterozygosity in homozygous fetuses. CVS is not recommended until after 10 weeks’ gestation, and diagnoses of heterozygosity must be confirmed by amniocentesis later in pregnancy.
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Assaying foetal cells in the maternal circulation offer hope for safer sampling in the future. Foetal blood sampling is used only in centers where DNA-based testing is unavailable. The Hb S and Hb C genes can be detected directly in foetal DNA samples. Tests using polymerase chain reaction (PCR) provide are sensitive, rapid and simple. PCR provides greater amounts of DNA for analysis, often obviates the wait for tissue culture growth, and shortens the time for diagnosis to days rather than weeks.
Apart from bone marrow transplantation, there is no curative therapy at present. Haematopoietic stem cell therapy and gene therapy remain possibilities for the future. The suffering of children can however be lessened. An important new development is the possibility of stimulating the induction of haemoglobin F by drugs. Hb F contains gamma chains instead of beta chains (structure a 2 g 2 ). Hb F has a greater affinity for oxygen than Hb A. This helps the foetus to draw oxygen from the mother’s blood. The reason for this increased affinity is that Hb F binds 2,3-diphosphoglycerate less strongly than Hb A.
[See oxygen dissociation curve: H+, CO2 and 2,3-DPG shift the curve to the right and thus promote the release of oxygen to the tissues forming deoxy-Hb]. Hb F inhibits the polymerisation of deoxy-Hb S. This inhibits the sickling of red blood cells. In Bedouins in Saudi Arabia and in India there are many people with Hb SS and congenital persistence of haemoglobin F. They have few clinical problems. This is why efforts are made to use various drugs (alone or in combination) to increase the level of Hb F. After birth, the genes for the gamma chains are less active because they become methylated. This is reversible however. First of all 5-azacytidine was tested, an antineoplastic substance that interferes with DNA methylation. This product increases the concentration of Hb F. This is no longer used. The cytotoxic drug hydroxyurea (Hydrea®) was recently approved by the American FDA for the treatment of sickle cell anaemia. It stimulates the expression of the gamma globin chain genes. It can be used in prevention (not in an acute crisis). The toxicity is known from its use in myeloproliferative disorders, but acceptable (mainly leukopenia, 80% of people). At present there are no indications of an increased incidence of chromosomal abnormalities or leukaemia in people who have used hydroxyurea for two years. Hydroxyurea clearly reduces the frequency and the severity of the attacks. The optimum dosage and duration still has to be determined individually (? 15 mg/kg/day as a starting dose – to be increased in steps according to the clinical symptoms; 1 to 1.5 gram/day is often necessary). The effect of hydroxyurea can only be seen after several months. About a third of patients treated with hydroxyurea show no increase in the Hb F. If there is no response within 3 to 6 months, the medication should be discontinued. It is possible that hydroxyurea works by mechanisms other than an increase in the Hb F. There is a clear correlation between the number of white blood cells and the pain crises. It is possible that the mild neutropenia caused by hydroxyurea in this way contributes to the clinical response. Patients who take hydroxyurea often report a more rapid improvement than can be explained by the increase in foetal haemoglobin. This may be due to the fact that hydroxyurea is oxidised by haem and therefore NO is produced. There is also a reduced expression of adhesion molecules (e.g. VCAM-1), as a result of which red blood cells adhere less easily to the endothelium. The SS cells become less "sticky" during therapy with hydroxyurea.
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Antibiotics, transfusions (normal or exchange transfusion), oxygen, pain control with paracetamol-codeine, ibuprofen or morphine analogues. Hyperbaric oxygen therapy ("caisson") is usually not available. Sufficient fluid should be administered because the kidneys have difficulty in producing concentrated urine. Often 3 to 4 litres a day are given (adults), if possible orally, otherwise IV. Severe acidosis is best corrected quickly, but conservatively, with bicarbonate, although no spectacular results can be expected. Wound healing, surgery in the case of osteomyelitis and a need for convalescence after CVA depend on the clinical context. Incentive spirometry is important in acute chest syndrome. In the case of rib or tissue infarctions, and also in chest disorders, it is important that the patient is urged to breathe deeply (10 maximum inspirations) at regular intervals, e.g. every two hours. This prevents atelectasis. Dexamethasone reduces inflammation of the pleura (area lying against rib infarction). Haematuria caused by a sickle cell crisis can be improved by the diuretic furosemide (Lasix®). The administration of hypotonic fluid also brings about an improvement. Both cause a fall in the osmotic substances in the kidney, as a result of which sickling occurs less quickly. The polymerising of Hb S is promoted strongly by dehydration. The higher the salt concentration in the blood, the more quickly the cells sickle. Desmopressin (DDAVP) is a substance which among other things lowers the salt content in the blood (hyponatraemia). By osmosis the red blood cells swell somewhat and the concentration of deoxy-Hb S falls. It is given as nasal spray/drops (0.1 –0.4 ml per day) or can be given IM or IV (1 to 4 m g per day; 1 ampoule = 1 ml = 4 m g). The price is however too high for developing countries. Moreover, its therapeutic role is controversial.
Priapism is a persistent and painful erection
[Lat. priapus, God of procreation]. It is not associated with sexual stimulation. It is an important complication of sickle cell disease. By adulthood, 90% of males with sickle cell anaemia will have had a least one episode of priapism. Other causes of priapism are leukaemia, multiple myeloma, tumour infiltration, amyloidosis, CO poisoning, lesions of the spinal cord, "high-flow" priapism secondary to an arterial rupture and the side-effects of some medications (excessive use of papaverin, phentolamin, prostaglandin E1 and other drugs). The blood that flows into the corpora cavernosa of the penis has difficulty leaving the organ due to venous thrombosis. Because of acidification and hypoxia, sickling of red blood cells increases still further. The corpus spongiosum of the glans and the area round the urethra are not involved. If priapism persists longer than 4 hours, surgery is definitely required. Persistent priapism (>24 hours) results in fibrosis and impotence. As an initial treatment the patient can be made to go up and down stairs in order to divert blood flow to the leg muscles (the "steal mechanism" principle) or have external compression of the perineum applied, perhaps with ice. General measures such as hydration, (exchange) transfusion and analgesics are necessary. Pharmacologically, an intracavernous injection with the alpha agonist phenylephrine can be administered at 100-500 µg per dose, to be repeated. It is best to prepare a diluted infusion (10 mg in 500 ml in a 0.9% physiological saline solution) and use 10-20 ml of this every 5-10 minutes for intracavernous administration. The needle must be placed laterally in the penis so as to avoid damage to the urethra and the nerve bundle. A nerve block to the base of the penis can be carried out with 1% xylocaine without adrenaline (syn. lidocaine without epinephrine). About 20-30 ml of blood can be aspirated by inserting a 19G or 18G needle for 2 to 10 hours. Sometimes treatment can be carried out successfully with terbutaline (Bricanyl®), a selective β2-agonist that is administered orally (5 mg) or subcutaneously (0.25-0.5 mg). Methylene blue (1-2 mg/kg slow IV) can be used, but can cause haemolysis in G6PD-deficient people. If the measures described above are not effective, surgery must be carried out.
Many homozygous sickle cell patients have to undergo surgery due to complications of their illness (mainly cholecystectomy or orthopaedic surgery) or for other reasons. Perioperative complications are common in patients with sickle cell anaemia. During anaesthesia, the operation itself and in the post-operative phase hypoxia must be avoided. Perioperative hypoxia, tissue hypoperfusion and acidosis can trigger vaso-occlusive crises and cause organ dysfunction (mainly acute chest syndrome and pain crises). Pre-operatively, an exchange transfusion can be given. Aggressive transfusion can be carried out in order to try to bring the Hb S% below 30%. It is probably better to transfuse conservatively with fewer blood units (to bring the Hb to about 10 g% or haematocrit = 30%). This is also effective in preventing problems and results in fewer complications (severe haemolytic reactions, considerable alloimmunisation, infections).
It is best to keep the mother’s haemoglobin level above 12 gram % (by transfusions). Pregnant homozygous sickle cell anaemia patients are rare in Africa. Hydroxyurea is contra-indicated in pregnancy.
