Approach to Anemia: The Basics

Welcome back to Med Pods, the audio podcast from the Department of Internal Medicine at AFMC. In the first of its series, we had spoken to surgeon Captain Winnie Wilson, professor of medicine and neurologist in the department on a very important topic of stroke and its management. In the two-part series, we had discussed various causes of stroke as per age of the patient. We had discussed the pathophysiology, the mechanism by which stroke can happen and of course the various details of its management and complications. The feedback that we have received from undergraduate students and postgraduate residents is very heartening. We are happy to note that it has added value to the way they learn medicine and I am glad that this encourages us to do more in the process of creating educational material which is not just relevant but also credible coming from this institution. Today we have with us, Colonel Y Uday, professor of medicine and clinical hematologist in the Department of Internal Medicine at AFMC. Dr. Uday, an alumnus of AFMC, did his post-graduation from the same institution and went on to specialize in clinical hematology from the prestigious PGI-MER Chandigarh, a keen student of medicine who has a passion for teaching, has the ability to make even the most complex of topics easy for his students to learn and that's what makes him a very popular teacher amongst his students. It's great to have you with us today Uday and I am glad that you could spare time for us and I am sure with your brilliance in teaching and the way you simplify even the most complex topics, I am sure this podcast is going to be a pleasure to listen to for all the students and clinicians alike. Today we shall discuss this very important topic of enemia and as we understand amongst the various hematological problems that we face in clinical practice, there is no doubt that enemia remains the commonest amongst them. So let's start with the definition, how do you define enemia? Good morning sir, sir, as you rightly brought out, anemia happens to be one of the commonest global disorder the mankind is facing. We generally use the cut-offs of hemoglobin less than 11.5 gram per deciliter in females and hemoglobin less than 13.5 gram per deciliter in males. We can also use hematocrit cut-offs of less than 14 males and less than 35 in females but we generally prefer to use hemoglobin cut-offs. The adherence to a strict cut-off should not supersede the clinical judgment as applies for any other policy in clinical medicine. Good, so it's very important to remember these numbers 11.5 and 13.5 and from what I can understand you gave more importance to hemoglobin than the hematocrit which I would like you to qualify further that why should there be more importance given to hemoglobin? So historically, previously when we used to analyze hemoglobin values during our undergraduate days we all used to use test tubes and concentration by adding some chemicals to the test tube but lately this whole test tube technique has been modified or changed over or taken over by various electronic counters or what we call it as called as "coulter". Now the hemoglobin concentration in a coulter is directly determined whereas hematocrit is not directly determined it is calculated or derived by using some other parameters. So the coulter generally measures the RBC count by a flow technique and the mean corpuscular volume by a light scatter mechanism and then the hematocrit is derived from these two values by a mathematical calculation of RBC into MC divided by 10. As hemoglobin is directly calculated by the coulter we use the hemoglobin values nowadays more than the hematocrit. Okay, so that is good to understand and but you mentioned about this normal range of hemoglobin are these values sacrosanct or and can they be applied in all settings or is there any caveats to this? So it is a very important question as clinicians people need to understand that whenever we talk about certain values these are all statistically derived and when we derive a particular number we derive from a given population and the WHO when it derived its numbers it is not possible that it takes all gots across the world. Apart from this there are certain particular places where the hemoglobin could be actually lower than the ranges that we have spoken about. Some examples are like in pregnant ladies where they have got a huge increase in plasma volume expansion the hemoglobin a lower level of hemoglobin might still be normal. Secondly in older age group the values of hemoglobin and hematocrit in even a apparently healthy older adults are generally lower than those in the younger adults and the differences between males and females that are seen in younger adults are gradually decreased with increasing age. Intense physical activity so you are a marathoner and a runner you would understand that with every time that you run there are chances of March hemolysis there is increased dilutional anemia from increased plasma volume and apparent iron deficiency which is more common in individuals with high intense physical activity or endurance exceeds in these individuals again a hemoglobin value slightly lower than the values that we have spoken about can be considered as normal. Similarly we can have certain situations wherein the hemoglobin can artificially rise one in smokers because of a persistent stimuli by carbon monoxide and hypoxia there can be a rise in hemoglobin and these individuals would be having slightly higher values than the age and gender matched controls. Secondly as we are all in forces high altitude exposure 10 increase hemoglobin values across ages and genders. Thirdly androgens and the more commonly used SGLT2 inhibitors also have a phenomena of driving up the hemoglobin values in the individuals. Now in individuals where they have high values we need to understand it may occasionally mask an underlying anemia whether it could be because of iron deficiency or b12 because of this fallacious rise of hemoglobin. That is very interesting to note and I think the take home message from this answer seems to be that the numbers do not apply across the board and we really need to see the clinical setting of the patient in which those values have been derived. Coming on to the next question is the definition of anemia different for different groups and are there any Indian cutoffs or anemia or are they universally applicable to everyone across the world. So there are two major studies which were done on this one in US and one by the national health survey which was conducted in even in India. What people found out when in US they looked at the database, Asians and African Americans generally have a hemoglobin lower of 0.5 to 1 gram per deciliter when compared to the other Americans native Americans or the white Americans. Similarly hemoglobin values across our country or in the Southeast Asian countries appears to be 1 to 2 gram percent lower when compared to the Americans or Europeans. Now this could be because of two particular phenomena one as we discussed when we draw Gaussian curves and when we look at the 95 percentile of the population fitting into a particular category our categories might be lower. Secondly as such the prevalence background prevalence of anemia could be higher in Africans and in Asians because of various vitamins and mineral deficiencies that they might be having per se a background very high prevalence of anemia or the alpha thalassinias which are not usually routinely studied they are very high in Africans and in Asian ancestry. So these two things can actually lead to a slightly lower hemoglobin values in our settings and in African settings when compared to European or American setting. Okay so there is no reason to have a different cutoff for Indians however considering the way these data have been derived and like you said earlier we need to individualize depending on which clinical setting they have been taken from. Moving on to the next as far as the age groups are concerned like in most criteria for values that we see in parameters that we assess we have different cutoffs for children. So is that applicable to older adults as well as in geriatric population? There is an increased frequency of anemia with ageing. So there were some suggestions in the past that maybe the standard hemoglobin values in the older age people might be lower because of a decreased bone marrow function when compared to actually there being anemia. So there was a national health and nutritional examination survey which was conducted but what was concluded was that the values which have been prescribed by WHO of 13.5 and 11.5 do also are applicable for the geriatric population and it is probably because the increased prevalence of home morbidities particularly chronic kidney disease or a nutritional deficiencies at this particular age group that these people might be anemic. So rather than leaving about geriatric population saying that they have lower normal it is ideal of it would be appropriate to evaluate every individual a geriatric individual with hemoglobin cutoffs less than the WHO defined values. So again in this age group as well we do not seem to have a different criteria from what I can understand but when an elderly person comes to us with anemia based on these cutoffs is the evaluation of these patients similar to the other adults or children or is it any different? There are certain disorders which are more common in geriatric age group. If we take a group of 100 individuals one third of them would be affected with nutritional deficiency another one third would have anemia of chronic disease or anemia of chronic inflammation which is now termed as functional iron deficiency as a cause and the last third will have unexplained causes or idiopathic causes wherein if we try evaluating them further most of these last third will have clonal hematopoietic disorders or what we call as chip disorders wherein there is some abnormality in the genetics and which is leading to a myelodysplasia or a decreased bone marrow function. Now understanding these causes a routine testing for any individual above the age of 60 years with anemia would include an appropriate kidney evaluation in the form of getting a creatinine done and calculating a EGFR doing iron stores or iron study evaluation in the form of serum iron, transferent, DIVC and phenitine values, evaluating vitamin B12 levels and in those patients who are what are suspected to have B12 deficiency and we are still finding equivocal B12 reports to do a methyl malonic acid level in these individuals and when all these are normal a folate level. So this would be an appropriate testing, there are few additional testings which would be required when we found everything else to be normal which includes one suspecting androgyne deficiency or as some people term it andropause which can lead to decreased levels of serum testosterone and that leading to isolated normosatechromachromic anemia. Second monoclonal gamopathies which can present routinely as a iron deficiency or a normosatechromia and third to look for clonal cytopenias. This would sum up the causes and the evaluation of a geriatric individual. So as a person ages the likelihood of an underlying pathophysiology for causation of anemia may actually get more complicated than the usual simple causes that we evaluate adults for and this could include anything from an underlying derangement of renal functions to an underlying malignancy. And keeping all this in mind while evaluating an elderly is likely to lead us to a cause in most situations. So what are the usual causes of anemia that we encounter in clinical practice when we come to a general common age group that we encounter then? Sir it is a very interesting thing and to understand this phenomena I would like to take a simile or a metaphor from a car industry. So if I go on to a road and I look at a particular type of cars going on a road and on one fine day I find that the number of these particular cars or vehicles are decreased. The possibilities that I would think about the first possibility would be that there is a traffic police guy stopping all the vehicles or there is an accident which would have occurred up the road which is like a blood sense when they are not seen in the periphery. Something which is destroying or entrapping them upstream. Second is there a decreased factory production of this particular car. So the factory in this parlance as far as a blood sense is considered bone marrow. So is there a decreased marrow function or third like it happened during COVID there was a lot of problem with the raw materials which were not possible to be imported from different parts of the world. So is there a raw material deficiency which is like iron deficiency or a B12 deficiency in parlance with the anemia? So if we go in this sequence of raw material factory and something which is trying to destroy or entrapped what is available on the roads so then we can understand all the causes and that would explain the common causes of anemia. So anemia remains a very common clinical problem and we often encounter it in clinical practice. What makes it more difficult to sort of identify it in the early days of its evolution is the fact that most of the symptoms seem fairly non specific. So if you want to simplify it for our students I would like you to tell us what are the common symptoms of anemia with which patients usually present and what are the unusual symptoms where you should suspect that there could be an underlying anemia or a hematological disorder as a sort of cause for those symptoms. So as you very rightly brought out the biggest challenge in evaluating anemia happens to be most of the times the etiological cause of anemia or the symptoms and signs of the etiology super means the symptoms of a symptoms or signs of anemia per se. But if we have to delineate in an individual who does not have any over etiological symptom then anemia can present as fatigue wherein this is a very loose term wherein people would complain just of unusually being tired or weak or they would present as shortness of breath or disney on exertion which is probably because of the decreased oxygen carrying capacity of the individual. Patients can come with particularly the young girls who are in the pubertal age group or who have started having the menstrual cycles recently they frequently present with dizziness or lightheadedness especially on standing up quickly which is because of the postural fall. Cold hands and feet syndrome, poor circulation in situation in patients with anemia leads to patients roti liseh, sir haath hande prjaate hain. So cold hands and feet syndrome or people can come with unusual headaches or worsening of the headaches which are previously present or new migraine attacks. This is probably because of the low oxygen carrying capacity to the brain. Patients can also present with irritability, frequent changes in mood and difficulty in concentrating which most of the young children particularly in the age group of 5 to 15 with severe anemia present with and lastly patients can present with pale skin which is very visible or it is very overt to the family members which is primarily because of reduced red blood cells which can lead to paleness. So these are the common symptoms which are directly associated or caused by anemia per say without the etiologies being involved into it. Now there are certain symptoms of anemia wherein which can give us a clue towards the cause. One the most important being pika, in children they can present with eating or licking onto the walls, eating chop pieces and in adults it is seen as cryophrygy wherein the people are found to eat raw ice or chewing of the ice. So that is one symptom which is very common in patients with iron deficiency anemia. Similarly, leg cramps and restless leg syndrome in females gives a decent clue towards the iron deficiency anemia. Similarly, a patient with anemia when present with jaundice obviously leads us to any hemolytic process in the body and whichever the step of hemolysis it could be pre-epatic or post-epatic. So there could be different causes of hemolysis which can occur and that can lead to jaundice and anemia. So from the long list one can make out that obviously there is nothing very specific about these symptoms as far as a pointer towards anemia is concerned. But at least one of these symptoms sounds most non-specific especially when even the patients when they actually want to say that they have excessive fatigue they are not too sure what they actually mean and that it becomes equally difficult for the doctor to interpret this symptom of fatigue. So when a patient says that there is easy fatigability is that a symptom that one can directly correlate with anemia or do you think that it needs to be further broken down or there can be certain other reasons why a person may feel easily fatigued. It is a very aptly said fatigability is not a synquinon for anemia though easy fatigability most of the times people consider it that the patient is anemic because in Hindi most of the patients come up and tell us or in English they say we are fatigued. Fatigued can mean different things to different people. Now it could just mean excessive sleepiness, it could mean weakness which could be neurological non-neurological, it could just mean lack of energy, it could mean decreased exercise tolerance, it could mean a psychological phenomenon of just feeling low or feeling down or a patient might be actually complaining about this neon exertion. So fatigue can be very different in different people so it is always good when a patient complains of easy fatigability or khakavad. It is a good idea to dwell into it and to understand what does patient want to convey by saying fatigue. Now the common causes for fatigue can vary from anemia to depression to hypothyroidism to sleep apnea to cardiopulmonary disorders to medications to supplement effects which are common causes of where the fatigue. Now most important nowadays most elderly people for hypertension are commonly on beta blockers and fatigue happens to be one of the common side effects of beta blockers which is generally seen. As a basic workup for fatigue other than CBC to look for anemia we also should do some biochemistry, thyroid profile and age-appropriate screening like evaluation for any malignancies or for any viral infections such as HIV or hepatitis C. So it could mean anything and everything so as you rightly said sir it is good to dwell into detailed history when a patient says easy fatigability. How very rightly said in fact just today in the clinic that I was having for the undergraduate student there was a question on fatigue and it took me a long time to actually explain what are the various types of problems that can actually manifest as the symptom of fatigue in a patient and I think that is one place in clinical evaluation of the patient where history taking is so relevant and no amount of artificial intelligence can actually help unless the doctor can talk to the patient and really understand what is that underlying cause for fatigue is. Coming on to the next important aspect of anemia evaluation is moving on from history to examination. Patients with anemia can have various signs and it would be very relevant for you to explain that what are the clinical signs that one must look for in patients with anemia which will point towards not just confirming the presence of anemia but also pointer towards the underlying cause. The clinical signs as we discussed in symptoms also we can have two types of signs one which are specific just to low hemoglobin and second for the etiology. Now when we look for signs which are secondary only to low hemoglobin as in the symptoms we had cold feet and cold hand syndrome so the skin may be cool to touch. Palar of congenitiva is a very important sign as far as anemia is concerned. Patients can have pachycardia to compensate for the oxygen carrying capacity and which in turn can lead to a high output heart failure or just can present with systolic flow murmur in patients with severe edema particularly when the hemoglobin values are less than 5 or 6 gram per deciliter. Now palar of mucous membranes that is the nail beds or the parma creases suggest that the hemoglobin values are less than 9 milligram per deciliter. Now these are certain things which are specific only to low hemoglobin but if we need to look at etiology of anemia we need to consider it into three categories. One, if a child is presenting to us with anemia then the commonest things that we should think about are inherited causes and thus a good general physical examination in the form of any dysmorphisms, any absent thumbs or bony abnormalities, any absent parma creases or if the patient is having any other syndromic features in the form of cavelules, spots, keratin dysfunctions will give us a guide towards either being phanconies anemia, dyskeratosis congenital, Schwarzmann syndrome. Now the second group in the children happens to be the storage disorders for anemia. So a pediatric patient coming with anemia, you need to look at organomegaly and if the patients have got organomegaly early in life, so either we are looking at a storage disorder or we are looking at a hemoglobinopathy wherein it is leading to extra medullary hematopoiesis. If it comes to adults, a good head-to-toe examination, a hair fall, presence of a tongue examination for looking for baldness of the tongue or furrowing red beefy tongue is important. Pedoscopy, which is a lost art in the clinical medicine, has got important clues in patients with anemia wherein severe anemia can itself lead to hemorrhages but patients with B12 deficiency can actually present with rock spots. Similarly, any organomegaly in adults or any features of mineral or vitamin deficiencies like angular, helosus, and stomatitis can give a clue or a scum skin findings for any particular B-complex deficiency can tell us about the etiology of anemia. So from what I can understand is that anemia although a very simple looking problem considering the non-specificity of its clinical presentation, as well as the amount of clinical examination in detail that one has to do to reach a conclusion, remains a very important clinical issue that needs to be understood very well by students and by the practice inclinations. So from you as an expert who handles these cases on a regular basis, I would like to know how do you approach a case of anemia when it comes to you. So an approach to a case of anemia particularly would depend sir on two important things other than the history and the physical examination to identify features that we have discussed still now. So there are certain other things that we should definitely do is one is to take a good treatment history to understand what are the medications or the medical conditions that the patient was suffering from. Secondly, a family history particularly for in India because we host the maximum number of globinopathies in the Asian countries. So a thalassemia or a sickle cell disease or any other siblings in the family or the parents or cousins suffering would give us a good clue about the etiology. Now we then thereafter have to decide about is it acquired in nature or inherited in nature. The inherited we have already spoken about for considering for the acquired causes. We need to take good history for the dietary practices though in Indian parlance when people say I am a non-vegetarian that actually does not mean anything because if they eat once a week non-vegetarian food or they eat eggs once a week really is not going to help them for wheat well or other iron component from the heme component of the non-vegetarian diet. So dietary practices and taking the good details for that any travel history any history of chronic infections tuberculosis being very common in the country and in females particularly taking a good menstrual history to understand that number of parts that the lady changes or the duration of the bleed in every cycle would help us in identifying the cause. One important thing other than these acquired things is to look at chronicity of anemia is it acute in nature or is it chronic in nature because the etiologies would be very different and thereafter to go for any specific causes particularly to rule out hemolysis wherein we would have a directed portions of any history of jaundice gallstones any dark urine or anemia which occurs particularly on exposure to certain types of foods or drugs exposure will give us a good idea about hemolysis being a cause of this other than this other systems that is kidney or liver when involved can lead to anemia because of the indirect causes. So this in general would be the history and the physical examination from the etiology point of view that we would like to take in a patient who routinely come to us in an Indian practice. So that again adds to the fact that I just mentioned is that approaching anemia requires a very strong clinical acumen both in history taking and examination and of course the understanding of various ways in which anemia can develop in a patient. But in practice often we do not get patients of anemia who come to us with some symptoms or signs it is often a blood report that they come to us with and the patients are absolutely okay. So in such situations how do you approach a patient whose hemoglobin is low has anemia but has no overt signs or symptoms. In this subset of patients who are already diagnosed as a case of anemia based on some blood report a good complete blood count and when I mean a complete blood count it means the values of the three cell lines that is hemoglobin, TLC and platelet to understand is it one cell line afflicted or other cell lines being afflicted along with a retic count and a PBS would be one mark of the evaluation. Now here when other cell lines are afflicted it clearly tells us that there is a problem in the factory and it is just not the hemoglobin which is the red cell line which is getting affected others can be affected. So either it is a problem in the factory or it is a problem post factory in the form of destruction in the periphery in the form of some hypersclinism or something which is eating away all the three cell lines. A peripheral blood smear tells us about any atypical cells being present. So that gives us a good idea about parasites and atypical cells and retic count is something which tells us about the marrow functionality because a person who has got appropriate retics that means that the factory is functioning well. So this is one group of tests which will tell us broadly about what are we looking at. Now the second part of it once we have understood that this is only an immune there is no other problem with the factory or something which is affecting other cell lines then the other things which will affect which will allow us to classify the etiology would be a combination of MCV and RDW. So the volume of the cell whether it is microcytic, normocytic or macrocytic and the red cell distribution bit that means what is the character of the cells which are there. Is there an isopropylocytosis, are we having a mixed bag of different types of cell or is it only one type of cell which is present. Based on these two characters that is CBC, TBS and reticon one side and MCV and RDW on the other side we should be able to classify 99% of the patients with aegymia. So you have just added a few more parameters to further complicate matters and anemia although remains a common and simple clinical problem. What greater understanding of this disorder has made is that we now actually understand how cells especially the red blood cells change as far as their size, their pattern of structure and based on that we are able to actually sort of predict what kind of anemia this patient may be having. So let us take it one by one you mentioned about reticulocyte count from my understanding reticulocyte count mirrors what is happening inside in the bone marrow and is a sort of a simpler way to pick up that from a plain and simple blood sample. So how do you actually evaluate a patient just based on the reticulocyte count that you get on the hemoglobin? Sir so we have now discussed that if we are looking at isolated red cell line disorders then we use reticulocyte count as you rightly said for the marrow functionality. Now there are two possibilities either we do not have adequate retics or we have adequate reticulocyte counts. In those individuals who do not have got adequate reticulocyte count it means that it is a case of bone marrow failure syndrome. Now bone marrow failure can occur because either the raw materials are not reaching the factory such that the factory is not able to function. So in all the micronutrient deficiencies will have low retics. Second there can be some infections like parvoviral infections which lead to maturation arrest of the red cell line. So from an electroblast till the time it is forming a mature RBC there can be a maturation arrest which can occur and in such situations the retics will not perform and later mature RBCs will not perform. So reticulocytopenia or geroretics would again suggest that the patient might be a case of maturation arrest or what we call as pure red cell eplasia because of parvoin infections or any other causes. The third possibility is a case of aplastic anemia wherein the marrow is totally vacated because of either a cytotoxic injury, radiation injury or a viral suppression or a T cell immune mediated problem wherein the marrow has completely been vacated or the factory is totally dysfunctional. So that again leads to reticulocytopenia. So our causes of decreased retic counts or inadequate reticulocyte response are one decreased raw material, bone marrow failure, maturation arrest with features of pure red cell eplasia or a aplastic anemia. Now the issue comes when we have got high retic counts. Then we need to see whether these reticulocytes which are higher in number, are they proportionately higher to the anemia or not. So when a patient has got anemia in any individual the marrow will try to pump out more and more cells and this pumping out the immature cells are thrown out of the marrow early into the circulation. So, whenever we take reticulocyte count we have got two calculations, mathematical calculations that we do. The first calculation is known as corrected reticulocyte count wherein we divide the reticulocyte count by the number of days of life of a retic. On an average retic stays in the periphery for 2.1 days. So if I have got anemia, so I have got retics for today, I have got retics for tomorrow. So when I am evaluating tomorrows I have got two populations which are from two different days. The actual number of retics which the marrow is throwing out is only the total retics divided by 2 which happens to be the corrected reticulocyte count. The second correction is what is known as a reticulocyte index. That is corrected reticulocyte count we divide it by the actual amount of duration or the hemoglobin correction that needs to take place. So we do it in two ways, one for the anemia the degree of anemia and second for the lifespan of the reticulocyte and putting together we finally come to a figure which is known as reticulocyte index and this final figure that we have is what we take for the marrow functionality. If the final figure reticulocyte index is less than 2.5 we call it that the marrow is not pumping adequate number of adequate response to the anemia and if it is more than 2.5 we say that it is adequate and if it is more than double of 2.5 we say that it is most probably haemolysis wherein we are going to have excess number of reticulocytes which are present in the periphery. The other parameters that you mentioned was about the mean corpuscular volume. Now you can also classify anemia based on MCV as either microcytic, normalcytic or macrocytic anemia. So based on MCV how do you approach anemia? So after we have decided that the bone marrow is functioning normally or not thereafter we shift on to MCV. Now we have got as you said microcytic, normalcytic or macrocytic. So when we say microcytic so in Indian parlance we take cutoffs from 75 to 80 below that particular number are considered as microcytic anemia. Prevalence wise the commonest cause of microcytic anemia in our country happens to be iron deficiency or thalassemia traits or beta thalassemia trait which can lead to a small size RBCs. Now if a patient has got iron deficiency anemia one the RBC size will be smaller second the number of RBCs which are produced will also be low in number. So we have got something known as a menzer index wherein we divide the MCV by RBC in million and if this is less than 13 then we call it it is probably because of a thalassemia trait and if it is more than 13 we call it as iron deficiency. These happens to be iron deficiency and thalassemia traits put together happen to be around 90 percent of the microcytic anemia in our country and of the two iron deficiency is 70 percent and 20 percent is thalassemia traits. Other causes of microcytic anemia which needs to be considered are citroblastic anemia particularly in children, lead poisoning which is gradually getting lower and lower because of lead free utensils, lead free paints that we are using and lead free petrol that we are using. So otherwise lead poisoning, chronic infections or severe protein deficiencies. So this is the microcytic component of it. Now if the MCV is more than 100 to 105 and in some books even they say more than 95 pentatons then we call it as macrocytosis. The commonest cause for a macrocytic anemia is a dissociation between the genetic material that is the nucleus and the cytoplasm and that happens when the nucleus is not the genetic material is not being correctly made and it happens in patients with B12 and folate deficiency because these two elements or these two particular components are required for a good genetic makeup of a cell and whenever that is not being properly the cell increases because the cytoplasm keep forming and the nucleus is not forming. So there is a nuclear cytoplasmic dissociation which takes place and that leads to large cells. So the commonest causes are other than folic acid and B12 deficiency happens to be liver diseases, hypothyroidism or in a newborn very they generally have larger sized cells. So these are the cause for macrocytic anemia. Having macrocytic anemia or microcytic anemia is very easy because we have got defined causes. Rest anything and everything which are not fitting into these particular causes can lead to normalcytic or a combination of iron plus B12 deficiency can lead to normalcytic. So the most difficult ones to be treated are normalcytic, normochromical anemias. So let us not go into the specific disorders which present as normalcytic anemia because I understand it is a wide spectrum and often we are left with actually no reason why a patient has this kind of anemia. So we will address those aspects when we come to those specific disorders when we talk about them. Anemia being such a common disorder it presents often to patient, the doctors who are dealing with various other subspecialities or a general practitioner. So let me know what are these situations where you expect that the doctor to whom this patient has presented with anemia should refer this patient to you as a clinical hematologist because these are situations which require a more specialized approach. So this is a very very important topic that you have actually queried about. Now slowly even in army we are seeing that people refer iron deficiency anemias to hematologist and it takes so much of effort on the part of the soldier and on the part of the units to spare manpower to be referred for simple disorders like iron deficiency anemia or B12 deficiency anemia. It is not that these are inferior disorders which I am not always should not see but the factor is these are such simple things that the initial management and in the garden variety of iron deficiency and B12 anemias a general physician or a MD practitioner or a MD medicine should be able to handle. Now there are peculiar situations where we definitely request that people should refer cases of anemia immediately to hematologist that is some hematological emergencies when you find pancytopenia where all three cell lines are affected and particularly severe pancytopenia where it platelets are less than 20,000 TLC is less than 1000 or absolute neutrophil count less than 500 with severe anemia as anemia less than being 6 gram per deciliter. So three cell line affliction and severe low cut off numbers is an hematological emergency because that might reflect a plastic anemia and the patient needs to be addressed fast otherwise they might develop community acquired infections. Second if the peripheral blood smear is showing any atypical cells suggestive of blasts or immature myeloid or lymphoid forms such patients should be referred to hematologist immediately. Next the pancytopenia which occurs with hemolysis thrombosis or bleeding that means they are actually harboring something very serious so anemia or cytopenia is coming with hemolysis thrombosis or bleeding should be immediately referred to a hematologist. And lastly micro angiopathic hemolytic anemia or MAHA as we commonly say wherein a peripheral blood smear is showing cystocytes or individual has got any of the clinical manifestation of thrombotic micro angiopathies which routinely are DIC, hypertensive emergencies or TTP or HUS in such situations patient should be sent to hematologist urgently without any further delay. Now there might be some other situations other than emergency situations wherein there is a diagnostic uncertainty that means there is anemia despite of you managing or trying to evaluate the best way possible and you are not able to come to a conclusion or the anemia is not improving such patient should definitely be referred or when we have an older individual who has got a normal B12 and a folate level but he has got anemia or bisytopenia or pancytopenia. So elderly people above age of 60 years with more than one cell line afflicted and for the benefit of the patient and a better continuity of care it is better to refer these patients to hemat centers. I think that is a very exhaustive and almost near complete answer for a question which is not simply answered because there are a lot of such situations where actually the clinician who encounters such patients may not be too sure however what I can understand is that any red flag sign which makes the anemia look sinister or where the underlying evaluation requires a specialized center I think these are situations where they should be no delay because underlying condition needs to be diagnosed as early as possible. So just revising this the aspects that we have discussed in this podcast I think we have been very simplistic to start with as far as the condition of anemia when would you call a patient to be having anemia? What are the usual comments of anemia that you encounter and how easy it is to actually miss anemia because the symptoms are so nonspecific clinical signs are often not contributory as far as the basic evaluation of anemia is concerned but even with the abnormal report there are a lot of indices which can actually point towards the underlying etiology as well as the type of anemia that the patient may be having. So to have a deep understanding of all these aspects makes a clinician more adept at diagnosing such conditions, identifying situations which may be sinister and require immediate referral and a deeper understanding of why anemia happens in various age groups is what I think this podcast will address and I must really thank Colonel Uday for having simplified such a complex topic in such a brief time that he has spoken to us on. This topic requires revision and I request the students to actually go into the detail aspects of it, read about it and come back to us if there are any aspects which they need greater clarification on. In our future podcast on the same topic we would be addressing individual types of anemia which would require a greater understanding of the causes of that particular condition and how to manage which we will address in the subsequent podcast. Thank you very much Dr. Uday. Thank you sir. Thanks for this opportunity and I really hope that this would help both the undergraduates and post graduates if we instigate them to read about anemia before we go on to the future podcast. Thank you sir.