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Types of Anaemia – Red Cell Disorders

by Paul Moss, PhD
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    00:00 chelation that can be given by . . . subcutaneous injections or through oral tablets.

    00:02 Now let us look at a range of diseases in which the anaemia is associated with red cells of a normal size, normocytic anaemia. One of the most common that we see in hospitals now is the anaemia of chronic disease, the anaemia of chronic inflammation. This is a very interesting background. Whenever there is chronic inflammation or infection within our body, the body sequesters iron within macrophages. It starts to shut down the flow of iron within the body. This leads to reduced iron level in the blood and reduction in haemopoiesis.

    00:44 You might ask why on earth thus the body do this, but it is almost certainly physiological evolutionary selected mechanism to limit the amount of iron available for pathogens like bacteria. Iron helps bacteria to divide and here is a mechanism of hiding it to way from bacteria. There are two pictures on the right showing examples of how this may happen.

    01:13 At the top we have a patient with rheumatoid arthritis and chronic disorders such as that are often associated with some form of mild anaemia and at the bottom you will see a bone marrow stain iron and the blue there represents the iron which is present within the reticuloendothelial cells.

    01:33 It has been taken in because of anaemia of chronic disease. It is quite a nice illustration of how iron really has to be very carefully regulated within our body. Now the treatment of anaemia of chronic disease is really to treat the underlying condition, treat Rheumatoid arthritis or perhaps the malignant disease or whatever it may be is leading to this condition and then the rest of the anaemia will sort itself out.

    02:08 Another important cause of normocytic anaemia is a renal disease because remember that the kidney produces erythropoietin, the major regulator of erythropoiesis. You will see on the right, the chart showing the very beautiful feedback mechanism for regulating erythropoiesis.

    02:29 In the bottom in green, the kidney acting as an oxygen sensor and producing erythropoietin whenever there is hypoxia releasing that which leads to increased erythropoiesis and the correction in the red cell mass. If the kidney is damaged, it may not be able to make erythropoietin and anaemia used to be a very severe problem in patients with chronic kidney disease.

    02:57 Unfortunately, we know a lot about erythropoietin now and are being cloned and can be produced as a molecule for injection and are widely used for patients with chronic renal failure and helps to increase that haemoglobin. Another time where you may see a normocytic anaemia is when the bone marrow cell is involved through other diseases. Now in this situation, you will also see a reduction in white cells and platelets. The bone marrow simply cannot produce enough normal cells. This can be due to a wide range of clinical problems.

    03:39 I have listed some there, infiltration with leukaemia, myeloproliferative disease and infiltration with carcinoma or aplastic anaemia. On the right, you will see that the fine biopsy of bone marrow and I do not know if you can recognise yourself. This is a difficult slide of what that may be, but in fact, that pink tissue is metastatic carcinoma not was leading to anaemia in this patient. Let us now turn to macrocytic anaemia where you have large red cells. The major cause here is a disorder called megaloblastic anaemia quite a long word again but we can easily understand it megalo-large, blast-the premature erythroblast. Look at the right-hand side and you will see those very large purple erythroblasts within the bone marrow. Why are they large? Essentially the vitamin deficiency here is limiting their ability to divide and replicate. So they are trying to expand and produce more molecules ready for division, but they simply do not make the final division, which is due to deficiency of vitamin B12 or folate. A characteristic feature within the blood film is shown at the bottom and you will see two white cells, which you will recognise as neutrophils.

    05:15 Now neutrophils have multilobed nuclei and you will see the more lobes you would expect normally after five, but in this condition, you can see more than that characteristic feature of megaloblastic anaemia. Now let us talk a little bit more detail about how this megaloblastic anaemia can arise. The most important cause which you need to know about is pernicious anaemia. This is now recognised as an autoimmune disease in which patients makes antibodies to the stomach to gastric parietal cells and to a protein called intrinsic factor, which is made within those cells. Remarkably, while B12 is absorbed within our food, it has to bind to intrinsic factor. The complex of B12 and intrinsic is then absorbed in the terminal ileum. You can see immediately that if your intrinsic factor is neutralised with antibodies, you would not be able to absorb B12 and I have mentioned that neuropathy can develop and that is certainly true. This disorder can lead to numbness in peripheral nerves and if untreated which thankfully we exceptionally where you see these days it can lead to very severe problems even blindness or dementia. I should mention before you the cause of the pernicious anaemia. This was a major cause of death of patients over 100 years ago. Treatment is very simple, vitamin B12 injections given every three months.

    07:07 You can also take high doses of oral pure B12 and hope you just manage to absorb enough.

    07:15 On the right, there is a tongue of somebody with pernicious anaemia is often described as PA and you can see of certainly is sore and some more swollen.

    07:25 Now the bottom I have mentioned folate deficiency. This is an autoimmune disease, but it can also occur when there are excess requirements for folate classically when somebody is pregnant or if they have a haemolytic anaemia and, here again, a simple tablet of folic acid will prevent all of the problems. Folate is used in the same biochemical pathways B12, which is why these two causes the same affect of megaloblastic anaemia. Let me now turn into another form of anaemia, haemolytic anaemia. This is a very interesting condition.

    08:08 We remember that red cells normally live for around 120 days. But if this is shortened due to haemolysis, destruction of red cells, then the bone marrow must respond to that by producing increasing numbers of red cells. Interestingly reticulocytes were slightly larger than red cells.

    08:27 So, in fact, the mean cell volume within the blood increases. So this anaemia can be macrocytic in some cases. Now the bone marrow can normally cope with a short lifespan of red cells until it goes below around 15 days and then really it just cannot keep up and anaemia is almost inevitable and that is haemolytic anaemia. Let us look at how that can present in the patient. Let us start with that figure on the right of somebody who I think you will agree is jaundiced. You can see the yellowness in the sclera of the eye. That is bilirubin.

    09:13 Why on earth would somebody with haemolytic anaemia become jaundiced? To understand that we have to think about how haemoglobin is degraded. We talked earlier about how it is synthesised and you will see the diagram on the left, how this occurs. The degradation of haemoglobin involves firstly the split into haem and globin. The globin is a protein and that is broken down into constituent amino acids. We are more interested in the haem.

    09:49 Again the iron has to come out and is recycled what is left is protoporphyrin and that is broken down into bilirubin and now you can see why patients may get jaundiced.

    10:06 That bilirubin is insoluble. It needs to bind to albumin and then it goes to the liver where it can be conjugated and excreted into the gut. Some of it is actually reabsorbed and can be passed out in urine. Haemolytic anaemias should be classified into two large groups. The disorders which arise because of an inherited abnormality and those which were required later in life. Red cells are relatively simple cells. As cells grow, they have a membrane, they have haemoglobin and they have some enzymes and indeed inherited causes of hemolytic anaemia can involve those three major components. Let us look at those three in turn. We now need to just look quickly at the red cell cytoskeleton because of course the shape of the red cell is defined by proteins within the cells that maintain its structure and you will see this cross section of a red cell at the bottom we have got proteins called spectrin, which form ankyrin within the cell and spectrin is anchored to the surface of the red cell through anchoring proteins and protein such as Band 3 and Band 4.1. So these are very critical proteins for maintaining red cell shape. What happens if you are born with an abnormality in the genes coding for some of these proteins such as spectrin or ankyrin. One of those disorders is hereditary spherocytosis. Have a look at that film on the right-hand side. Do you see anything unusual about it? I think what you might see is some cells which are very round and darker than normal red cells, very spherical and those are the cells of hereditary spherocytosis.

    12:21 These patients often are mildly anaemic. This is very variable disease depending on the severity of the mutation and how it affects the individual patient. Folic acid can be useful to maintain and support red cell production and if the patient is getting symptomatically anaemic with a low haemoglobin, then you can remove the spleen and splenectomy will solve the problem. It does not change the genetic defect, but it stops the spleen from taking out the slightly different spherical red cells. We have to be careful because there are always associated with taking out the spleen particularly in children and you have to balance the anaemia against this slight, but definite risk of infection following splenectomy.

    13:15 There are other examples of inherited abnormalities of the red cell membrane. One of those I have listed as hereditary elliptocytosis and yes you are right, the red cell does look elliptical and not disordered. Let us look at another inherited abnormality of the enzymes this time. One of the important ones is glucose-6-phosphate dehydrogenase a long word and this is more common in people from the Mediterranean and African region. Why? Because the heterozygous disorder can provide can protection against severe malarial infection. This is X-linked and patients need to avoid factors that precipitate the crisis of acute anaemia in this condition.

    14:06 Sometimes it is drugs, bizarrely sometimes it is kidney beans, fava beans and now it can trigger a crisis. Just look on the right of the green boxes there and you will see that coming in from the right what we call oxidant stress. If drugs, infection, or fava beans lead to oxidation within the red cells, the lack of sufficient G6PD activity can lead that oxidation damaging and killing of a red cell and as you work away down through that dark column you will see that inadequate production of NADPH and . . . leads to oxidation damage.

    14:58 Another enzyme disorder is pyruvate kinase deficiency. Again a similar, but rare disorder.

    15:05 Finally, the third inherited cause of haemolytic anaemia inherited haemoglobinopathies.

    15:13 These are very common. I am pretty sure that they have been selected during evolution because heterozygous state although it is not clinically insignificant in the patient, it provides protection against severe malaria. Malaria has had a big influence on the genetic makeup of people who live in malarial regions. But unfortunately, homozygous forms, a bad gene from your mom and your dad can be very severe disorders. Let us look particularly sickle-cell disorders in this case. Again on the right, an electrophoretic analysis of globin.

    15:53 On the top, we have normal person haemoglobin a dominating with a small amount of haemoglobin F. The next one down sickle-cell anaemia, a mutation in the beta chain. So there is no normal haemoglobin A. What we have is haemoglobin S. I will show you on the next slide what that does to red cells. The third one is a sickle-cell trait. This is the heterozygous state. One normal beta globin gene and one sickle beta-globin gene and here we see lower levels of haemoglobin A and some haemoglobin S. That is largely asymptomatic and at the bottom for . . . those of haemoglobinopathies is someone who has a sickle beta gene and haemoglobin C beta gene and you will see now you get haemoglobin C as a normal A.

    16:52 Sickle-cell anaemia is a very severe disease. In that slide, you will see at the bottom left a classic sickle-cell similar to the size that are used for cutting corn. Now sickle-cell anaemia leads to sickling of red cells during periods of hypoxia. When the blood is deep within capillaries and becomes hypoxic, the haemoglobin stacks up and leads to sickling of cells. This can block the blood vessels and that can lead to a range of clinical problems largely due to infarction and hypoxia of tissues further down. Treatment of sickle-cell anaemia, if needed, is with red cell transfusions provide the normal blood or with drugs such as hydroxycarbamide, which is shown to be quite effective. Finally in haemolytic anaemia, let us consider those disorders which are acquired, but not inherited are developed in life and I think the major one I want to focus on is the auto-immune haemolytic anaemias where the body makes antibodies against the red cells. Two types of antibodies are made, IgG antibodies, which you will know a quite high-affinity antibodies. They bind at 37 degrees and that is sometimes known as 'warm' antibodies. Look at the top two pictures on the right. On the left, you will see something that we saw similar to you saw a few slides ago, spherocytes. That is the characteristic feature of autoimmune haemolytic anaemia and you noticed more reticulocytes as well, slightly bluish cells. On the right, you will see a stain for reticulocytes and that is because the body is responding due to the haemolytic anaemia.

    18:45 The second type of antibody they can be produced is IgM. These are less strongly binding.

    18:52 They often need lower temperatures to act, sometimes known as 'cold' antibodies. But that very powerful at agglutinating red cells look at the slide at the bottom of the picture, you see those clumps of red cells they have been agglutinated by these IgM antibodies.

    19:13 These are sometimes found in older people who have plasma cells in the bone marrow producing these IgM antibodies and they can be triggered by infection as well.


    About the Lecture

    The lecture Types of Anaemia – Red Cell Disorders by Paul Moss, PhD is from the course Hematology: Advanced.


    Author of lecture Types of Anaemia – Red Cell Disorders

     Paul Moss, PhD

    Paul Moss, PhD


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