 Good day, everyone. So we will start our discussion. Actually, we will be continuing our discussion about anemia. So last time, we did talk about an introduction about anemia, what are the usual diagnostic tests that needs to be done for anemia. And then eventually we proceeded with your iron deficiency anemia, we did discuss anemia due to chronic disease. And at the same time, we also had a brief discussion about your hereditary hemochromatosis and hemocyderosis. And for the last part, last time, we did discuss about megaloblastic anemia. So before I start this topic, I hope that you are already finished with your video discussions with regards to those topics so that we can jumpstart immediately to our topic today, which is all about bone marrow failure. So bone marrow failure is one important thing that we need to discuss today first and foremost because bone marrow failure could also be attributed to anemia. So as we go along in a short while, we will be discussing different forms of bone marrow failure in which there will be diseases that will be discussed with regards to bone marrow failure. So let's start with the pathophysiology of bone marrow failure first. So failure of your bone marrow can actually arrive in different form. It can actually present itself as the same thing as bone marrow hypoplasia, but in reality there are actually different reasons or different pathophysiology and pathophysiological changes in our bone marrow that leads now to its failure. The first one is the destruction of hematopoeic stem cell as a result of injury by either drugs, chemicals, radiation, viruses, and autoimmune mechanism. So we all know that your hematopoeic stem cell are the progenitor cells of your blood cells such as your red blood cells, your white blood cells, and your platelets. So in cases of bone marrow failure, bone marrow failure is not always hereditary. Some of these are actually acquired due to exposure to a particular cellular injury brought about by drugs, chemicals, radiation, viruses, and in some cases autoimmune mechanisms. So this time there are autoantibodies associated with their destruction. In addition to that, there could also be a premature senescence and apoptosis of your hematopoeic stem cell as a result of genetic mutation. So we all know that your progenitor cells should actually perform its function of producing the blood cells that's needed by the body, but in cases of genetic mutation there can actually be a premature apoptosis or destruction of our hematopoeic stem cell. So here guys, you can see that they are not mature cells. They are already underwent apoptosis, hence there are no mature cells that are produced. Thirdly, we also have ineffective hematopoiesis caused by stem cell mutations. So we did talk about that with regards to anemia, it can either be insufficient erythropoiesis or ineffective hematopoiesis. So in effective hematopoiesis or erythropoiesis, there is a problem now with your progenitor cell. Intrinsic problems with regards to your cell. And it can also be due to deficiency in vitamin B12 or in your folate that are very much needed in DNA synthesis. And then now I will reference you back to our discussion with megaloblastic anemia. You all know that megaloblastic anemia can be because of vitamin B12 deficiency or folic acid deficiency. Both of which are very important components in DNA replication. Hence if there are deficiency in such vitamins like your folic acid, there will be ineffective hematopoiesis that will now lead to bone marrow failure. In addition to that, disruption of bone marrow microenvironment could also be a cause of your bone marrow failure. So remember that when we discuss your hematopoiesis, we did talk about the bone marrow microenvironment such as your stromal cells, your endoretical endothelial cells in the bone marrow. So if those mechanisms are disrupted, if the mechanisms are disrupted there, it can also lead to bone marrow failure. Next, decreased production of hematopoietic growth factors are related hormones. So you all know that for a specific type of cell to be produced, there are different stimulating factors, growth factors, cytokines, and most especially there are a lot of growth factors that are currently being produced in your bone marrow to stimulate the production of your blood cells. So in the case that there is a decreased production of those hematopoietic growth factors, there will also be a bone marrow failure in that case. And last but definitely not the least is the loss of normal hematopoietic tissue. So you all know that the active bone marrow that is capable of hematopoiesis is your red bone marrow. So in cases where we lost those hematopoietic tissue as a result of infiltration in the bone marrow with abnormal cells, that can also be a reason for bone marrow failure. With all the things that I have said here today, we will actually be discussing them in accordance now to all their diseases. So there are specific diseases whereby you will be seeing all of this. So guys, I will be mentioning the diseases and then the characteristics of a particular disease. And then eventually, all of these here right now on your screen, these pathophysiological changes in your bone marrow can contribute to those diseases. Not necessarily all of them but one of these is actually the reason why we have bone marrow failure in such diseases. So we will be starting with the first one and that is your aplastic anemia. So aplastic anemia is being characterized by your peripheral blood pancytopinia. So again when I say pancytopinia, this is the overall decrease of all types of blood cells. Be it RBC, platelets, WBC, all of them are decreased in your peripheral blood smear, in your peripheral blood rather. So we also have reticulocytopinia. So reticulocytopinia is also observed in a plastic anemia. At the same time, bone marrow hypocellularity is also observed. So later on, I'll be showing you a picture of a normal, normal cellular bone marrow and a hypocellular bone marrow. In addition to that, there is also a depletion in your hematopoietic stem cell. So obviously since your bone marrow is already in hypocellular state, there will also be a decrease in your hematopoietic stem cell. So again, pancytopinia in the presence of hypocellular or a plastic bone marrow is always expected, okay, is always expected. Although this name might be misleading sometimes because it implies that anemia is the only problem since we're calling a plastic anemia as it is, as a plastic anemia. But in reality, all other blood cells like your WBC, specifically your neutrophils and also your thrombocytes are decreased in number. So a plastic anemia is not just the red blood cells that is decreased, but also other blood cells such as your WBC and your thrombocytes. So your a plastic anemia can actually be acquired or inherited, okay? It can actually be acquired or inherited. So 80 to 85% of the cases are actually acquired, okay? So if we say acquired, you actually are exposed to a particular compound or simply it's just idiopathic, okay? So with regards to acquired, 70% of the cases of your acquired 70% of all the cases of a plastic anemia are actually idiopathic. So there are no known costs on to this. So it's like leaving your ex. I already told you that. So even if you leave your ex, you'll still look like you're dead. If you ask your friends, why did you break up? It's idiopathic, okay? It's an idiopathic effect. So moving forward, let's go to the second one. It can also be secondary, okay? So when I say secondary, you are exposed to a particular drug, chemical, radiation, virus that might cause a plastic anemia. So we have here chemicals such as your cytotoxic drugs, your benzene, your radiation, you're endosyncratic. Later on, I'll be explaining what endosyncratic secondary a plastic anemia is all about. It can also be your viruses, okay? So your viruses like your Epstein-Barr virus or your EBV, your hepatitis virus could also cause it and your human immunodeficiency virus could also cause a plastic anemia. Miscellaneous conditions such as your paroxysmal nocturnal hemoglobinuria or your PNH is also associated with a plastic anemia, autoimmune disease and pregnancy, okay? And pregnancy. So inherited cases, on the other hand, can also account to around 15 to 20 percent, okay? 15 to 20 percent of the total, what do you call this? Total cases of a plastic anemia could also be inherited. So it can be in the form of your Phanconi anemia, your dyskeratosis congenital and your Swachman-Diamond syndrome, which will all be discussed briefly later on. So the laboratory findings with your a plastic anemia as we said earlier, we have pancytopenia. So meaning to say low RBC, you also have leukopenia. So selective fall specifically in your granulocytes, okay? In your granulocytes, in your thrombocytopenia as well. And unlike other bone marrow-related diseases, when it comes to a plastic anemia, there are no abnormal cells in the peripheral blood smear. So meaning to say, it's not like leukemia where we have immature cells, okay? Immature cells or abnormal cells in the peripheral blood smear. Here, what actually happens during a plastic anemia is that there are not enough cells in your body. Okay? There are not enough cells in your body. And as you can see, bone marrow shows hypoplasia, okay? Hypoplasia. So meaning to say, even the hematopoietic stem cell are low in number inside your bone marrow. What I also want to highlight that with regards to a plastic anemia, this type of anemia is appearing to be a normalcytic, normal chromic red cells. Your red cells are normal chromic and normalcytic, although decreased in number. So here we can say that, as I said last time, your anemia can actually be a cause of either low RBC count or a defect in the RBC in itself, okay? Aside from that, if you can see with regards to a plastic anemia, your neutrophils also appear normal. Your neutrophils also appear normal. Okay? Your neutrophils appear normal. So in addition to that, okay, in addition to that, let's go now to the acquired plastic anemia first. So we all know that idiopathic is the first reason, okay? Majority of it are actually idiopathic. Secondly, it's because of secondary, we call it secondary a plastic anemia. So this is now due to the exposure to drugs, chemical, radiation, or infections of viruses such as your Epstein bar, your HIV, and your hepatitis viruses, okay? Your hepatitis virus. So here, okay, in the secondary a plastic anemia, you can see on box 19.3, the selected drugs reported that have a rare association with idiosyncratic secondary a plastic anemia. Wow, it's already being read. Idiosyncratic secondary a plastic anemia. So what is idiosyncratic secondary a plastic anemia? So it is a condition, it is a rare condition in which there is a combination of both genetic and environmental factors, interceptable individuals. So it is both, it's like a merge, it's like a merging of idiopathic and secondary causes. So there's an internal factor within your body that is not known, but at the same time, you're also exposed to such secondary, to such compounds like your drugs, chemicals, and radiation that actually amplify your chances of having a plastic anemia. So let's just say that you're already able to start with, okay? You're already able to start with, and then the legal crush is still there. So it's a double whammy, right? So you're already able to start with, and then the legal crush is still there. There's no legal legal response, right? So that's how it happens in a plastic anemia. Both the genetic and the environmental factors are in there. That's why it now progresses to become now your idiosyncratic secondary a plastic anemia. So again, it's a combination of both genetic and your environmental factor, okay? Your environmental factor. So moving forward, okay? Moving forward with your acquired a plastic anemia, so we all know now that your lab, some of the laboratory findings is of course your pancytopenia, your hypocellular bone marrow, and in some cases, you can also observe macrositic red blood cells alongside with the normalcytic. So we actually have a diagnostic criteria for a plastic anemia. We have the moderate a plastic anemia, the severe a plastic anemia, and the very severe a plastic anemia. So as you can see, with regards to their bone marrow, hypocellular bone marrow, plus at least one of the following, okay? Either neutropinia, thrombocytopenia, or a decrease in your RBC and your reticulocytes. In your severe a plastic anemia, there's a bone marrow cellularity of less than 25%, plus two of at least, at least two of these cases, such as your neutropinia, thrombocytopenia, and also the decrease in your RBC and your reticulocyte. But more specifically with regards to very severe, very severe a plastic anemia, all of these things are now present in your patient. So that's very important for us to actually identify this type of anemia because it can really be fatal in our patients, okay? For our patients. Having said that now, this is actually the appearance of a normal, okay? This is a neuromocellular bone marrow, so you can see you have adipose here, you have your yellow bone marrow, but majority of it are actually your red bone marrow that are capable of hematopoiesis. Unlike now, in cases of acquired a plastic anemia, as you can see, there's already a shift from, there's already a shift from red bone marrow to now becoming your yellow bone marrow. So it's not a regression, because the regression is yellow bone marrow to red bone marrow. So this one is an evident case of a plastic anemia, okay? An evident case of a plastic anemia. So before we move forward to the inherited forms of a plastic anemia, so let's take a quick breather first. So inhale, okay, everyone. Hold, exhale. So hold one more time. Okay, so inhale all the, inhale all the positivity and the energy. So hold it, okay? Now exhale all the stress, the bad vibes that you're feeling right now. So hold. Okay, for the last time, inhale. Okay, exhale, hold. Exhale. And of course, hold. And now you can breathe normally. So again, let's start and let begin our discussion about inherited forms of a plastic anemia. So with regards to inherited forms of a plastic anemia, these are actually present at an early age. So unlike your acquired plastic anemia, of course, it's normal up until you're exposed to some factors that will cause the development of a plastic anemia in your system. But with regards to inherited forms of a plastic anemia, these are actually present during birth already, okay? So there is a progressive bone marrow failure, okay? A progressive bone marrow failure. And patients with inherited or, yeah, inherited or hereditary, a plastic anemia, do have characteristic physical malformations or stigma. So there are some abnormality with regards to their stature or even with regards to their physical appearances, okay? So moving forward, okay? Moving forward, so there are different forms of a plastic anemia that were mentioned in your rodac. So we have phanconi anemia. We have your dyskeratosis congenital and your swashman, your swashman-bodean diamond syndrome, okay? So let's start with phanconi syndrome. So phanconi syndrome was first discovered by Dr. Guido Phanconi in 1927. So phanconi anemia is actually a chromosome instability disorder characterized by a plastic anemia. So physical abnormalities and cancer susceptibility are also observed in patients with phanconi anemia. So during phanconi anemia, you could actually observe the following to our patient. So first and foremost, it is an autosomal recessive genetic disorder and this is due to chromosomal breakage, okay? Chromosomal breakage, okay? Chromosomal breakage. So this is common in your Ashkenazi juice. So I'll tell you what Ashkenazi juice is. So these are these are juice, obviously, that are intermarrying. So intermarrying among their relatives. So I guess if you have read some stories, Ashkenazi juice marries their children. So closely related relatives. So your phanconi anemia have clinical features such as short stature. So we also have strabismus strabismus or the abnormal alignment of the eyes. Okay? Abnormal alignment of your eyes. So you can also observe low set ears. Frequent infections positive or they can also be have they can also have deafness and there are some abnormality with regards to their thumb. Abnormal thumbs are sometimes absent their thumb. So phanconi anemia is actually characterized by low red cells white blood cells and also your platelets and also your platements and usually usually the phanconi anemia is characterized by low red cells white blood cells and also your platelets and usually the common the common treatment for this is bone marrow replacement. Okay? Your bone marrow replacement. So I just want to say don't know if you have watched the movie of Ding Dong Dante Angelica Panganiba and Angel Locsin and Zangio Morudo. Angel's daughter has a plastic anemia. Okay? That's why they need bone marrow transplant. So I just want to say okay? And in addition to that okay? In addition to that phanconi anemia cells during phanconi anemia cells have higher have greater number of characteristic chromosome break end ring chromosomes. So this indicates if there are a lot of chromosomal breakage this indicates that the cells actually have increased so it's faster to destroy. So that is for your phanconi syndrome guys. Okay? That is for your phanconi syndrome. Let's move on now to your Swashman Bodien let's go now to your diskeratosis congenital. So your diskeratosis congenital obviously is also a form of a plastic anemia. So if I say a plastic anemia automatically the clinical features such as your pancytopinia the hyposellular bone marrow all are present the things that I am only adding are the things that are not yet been mentioned in other diseases which makes this particular disease unique by itself. So in your diskeratosis congenital it is characterized by muco-coutinous abnormalities okay? Mucocoutinous abnormalities bone marrow failure and pancytopinia that's what I said earlier. So the typical clinical presentation involves a triad of abnormal skin pigmentation okay? A triad of abnormal skin pigmentation aside from that we also have these trophic nails and oral leukoplakia. So leukoplakia is the deposition of that white black here on the side of your on the side of the buccal cavity of your on your buccal cavity obviously. So with regards to diskeratosis congenital patients that has dc okay? The patients that has dc are actually also prone to cancer okay? They are also prone to cancer but in addition to that okay? In addition to that they are also involved in some that our patients can have as a wide range of multi-system abnormalities ranging from your pulmonary fibrosis, liver disease developmental delay, short stature, microencephaly immunodeficiency dental caries and even periodontal disease. So that is for the diskeratosis congenital. So again this is a form of inherited aplastic anemia. Last but definitely not the least is your Swashman Bodian Diamond syndrome. Your SBDS is a multi-system disorder that is characterized by pancreatic insufficiency, cytopenia skeletal abnormalities and a predisposition for hematologic malignancy. So patient with Swashman your SBDS okay? Patient with SBDS have peripheral cytopenia so decrease as well the pancreatic secretions that's why okay? That's why they can also have malabsorption eventually okay? They can also have malabsorption. So having said that now those three are the inherited forms of aplastic anemia but before I finally end this discussion about aplastic anemia there are also other forms of blood or bone marrow failure aside from aplastic anemia and these are number one your pure red cell aplasia, your congenital this erythropoietic anemia your myelophytic anemia and your anemia of chronic kidney disease. So let us start with your pure red cell aplasia. Your pure red cell or your PRCA is a rare disorder of erythropoiesis characterized by a selective and severe decrease of your erythroid precursors in an otherwise normal bone marrow. So here with regards to your red cell aplasia the only okay? The only thing decrease is your red blood cell that's why we call it your pure red cell aplasia okay? Your pure red cell aplasia. So patients with PRCA have severe anemia which are still normalcytic by nature and they are characterized to have reticulocytopenia okay? Reticulocytopenia so obviously reticulocytopenia is lower because to start with there is a severe decrease in your erythroid precursors okay? Erythroid precursor so normal WBC and platelet counts are observed in patients with PRCA and your PRCA can actually be acquired or congenital okay? Acquired or congenital. So again during pure red cell aplasia red blood cell production is suppressed with little to no abnormality found in your WBCs and your platelet. So I want you to remember guys that congenital pure red cell aplasia is also called as your black your diamond black anemia. Your diamond black fan anemia is also known as your congenital pure red cell aplasia and your acquired pure red aplasia can also be observed. So again my two form your acquired and your congenital so now let's try to differentiate your fan conny anemia and your diamond black fan anemia your fan conny anemia is a form of a plastic anemia meaning to say all cells, all blood cells are decreased unlike your diamond black fan which is a pure red cell aplasia only your red blood is depleted. Your brown skin pigmentation is only seen in your fan conny thumb abnormalities are seen in your fan conny renal abnormalities also in fan conny anemia and in your peripheral blood fan conny anemia is characterized by pancytopia your diamond black fan anemia is characterized by a decrease in RBC alone with little to no abnormalities in your leukocytes and your thrombocytes. So that is your pure red cell pure red cell aplasia. Second on the other forms of bone marrow failure is your congenital dyseretropoietic anemia so your congenital dyseretropoietic anemia is characterized by your refractory anemia reticulocytopia and at the same time at the same time at the same time your at the same time hyper cellular bone marrow or this time this time bone marrow failure doesn't just talk about low bone marrow like in a plastic anemia it also talk about hyper cellular bone marrow it's true, isn't it better if you have hyper cellular bone marrow it's also good not good because in hyper cellular bone marrow there is ineffective erythropoiesis meaning to say there are these plastic changes in your erythroblast there are these plastic changes in your erythroblast so to start with you won't learn because there are these plastic changes in your in your red blood cells so it means abnormal growth and development that will now cause abnormality that will now cause abnormality in your red blood cells in addition to that we also have your refractory anemia which is which is part which is actually a part of your yellow dysplastic syndrome so with regards to with regards to refractory anemia with regards to refractory anemia this is observed not only in your cda not only in your cda but in other yellow dysplastic diseases what do you call this other dysplastic diseases yellow dysplastic diseases rather so in addition to that in addition to that when we say congenital this erythropoietic anemia it can actually appear it can actually appear in what do you call this in other forms but before I move forward let me elaborate refractory anemia so when we say refractory anemia this is an anemic condition an anemic condition that is not associated with another disease so most probably it just is caused by a different a different factor so with regards to refractory anemia they can be successfully treated through blood transfusion that is when it comes to refractory anemia they can be corrected with blood transfusion so your congenital dyserythropoietic anemia on the other hand can actually be classified into three forms they can be classified into three forms such as your cda1 which is characterized with a cdan1 mutation that is found on your chromosome 15 you also have your cda type 2 your cda type 2 is also known as your hereditary erythroblastic multinuclearity with positive acidified serum or your hempass your hempass so your cda2 or your hempass is the most common form of congenital dyserythropoietic anemia so in this case RBC display hemolysis in the acid serum test which is also known as your hams acidified serum test and they do not lies they do not lies with sugar water test or your sucrose hemolysis test so the hempass antigen is your antigen eye so much of that when you reach your blood banking but for now that's what I want you guys to remember that with regards to cda type 2 that is also known as your hempass hereditary erythroblastic multinuclearity with positive acidified serum test why is it positive acidified serum test because it lies on these hams acidified test so lastly we have your cda which is the least common form of your congenital dyserythropoietic anemia so last but definitely not the least we go now to myelophytisic myeloph myelophytisic anemia I don't know if I am pronouncing it correct if it is myelophytisic anemia or myelophytisic anemia but either which I want you to take this home with you that you understand during your myelophytisic anemia you have a hypo proliferative anemia meaning to say your bone marrow also failed but this time it is actually because of the replacement of your bone marrow hematopoietic stem cell by your malignant cell by your malignant cell so in this case in this case during myelophytisic anemia your cancer will attach the size to your bone marrow your cancer will attach the size to your bone marrow thereby originally your bone marrow that is capable of hematopoietic are already becoming hypo proliferative because of the replacement of these abnormal cells usually it is actually being seen in cancer such as your breast cancer prostate cancer and even in your lung cancer it is very common in that 3 form of cancers so in this case cytopenia is due to an increase cytokines and growth factors that suppresses hematopoiesis that in return it will destroy the stem cell the progenitor cell and the stromal cell so in short along side with your bone marrow microenvironment ok so all of those were destroyed because of increased cytokines and growth factor that aims to suppress your hematopoiesis sir what happened it's because of the abnormal and malignant cells that are invading or replacing your bone marrow and in a sense this type of anemia is also normalcytic normochromic anemia normalcytic normochromic anemia I have known people with prostate cancer that metastasize to bone cancer they call it bone cancer at that time because the tumor cells have already infiltrated the bone marrow so again common in breast prostate and lung cancer so last but definitely not the least ok for the end of our part 1 of this discussion we also have anemia of chronic kidney disease so last time we talked about anemia due to chronic inflammation or disease this one is anemia due to chronic kidney disease so anemia of chronic kidney disease so this is actually a complication of your chronic kidney disease ok why is that so you all know that your kidney is actually the main organ producing your erythropoietin so meaning to say if your kidney is no longer functioning well even its function to to produce your erythropoietin is already inadequate now leading to anemia in addition to that increased urea or blood urea nitrogen inside your blood due to incapacity due to the due to the disrupted filtration capacity of your kidney during uremia or increased urea levels inside your blood erythropoietin is inhibited and in addition to erythropoietin being inhibited increased then your RBC fragility due to urea so what do you mean by that increased urea content in your blood urea content in your blood urea content in your blood and eventually because of dialysis for patients that have chronic kidney disease they have chronic blood loss they have chronic blood loss and also iron deficiency as well they also have iron deficiency they also have iron deficiency so that is for anemia of chronic disease so in this particular discussion we did discuss your bone marrow failure from your eplastic anemia both the acquired and inherited or the hereditary we also did talk about other forms of bone marrow failure such as your diamond black fan anemia aside from that we did talk about your congenital dyserthropoietic anemia your myelophytistic anemia and your anemia of chronic kidney disease so with that thank you so much guys for listening please take note that there is also another video this is just part one of our discussion for today so please proceed to the next video and then afterwards we will be meeting for our discussion through our google meet for today thank you so much