Chapters Transcript Video Interpreting Abnormal CBCs in Children: A Practical Guide for Primary Care Hi, thank you, Maria, and uh thanks to the uh group for inviting me and um having me here to talk about abnormal CBC is something that's really, uh, that we think about all the time in our hematology clinic, and um I'm looking forward to the questions you guys have at the end and I'm happy to see some familiar names in the, in the webinar participants today. So, um, as Maria said, uh, my name is Maha Vissa. I'm one of the hematologists here at Children's Hospital, mostly in Oakland, but I work at both of our, um, children's hospitals as well as at the General Hospital in San Francisco. Care of adults with sickle cell disease. Um, and the topic of today's webinar is interpreting abnormal CBCs in children, a practical guide guide really for anybody taking care of, of patients. And I hope to cover, um, a couple of important topics here. Um, here are my disclosures. These are, um, to my knowledge, not impacting the content of today's, uh, presentation. So we came up with 3 learning objectives today. One is to identify the common differential diagnoses for anemia, thrombocytopenia, and neutropenia. I'll touch a little bit on some of the other, uh, white blood cell disorders that we might think of, but mostly neutropenia. Um, the second is to establish a systematic approach to evaluating cytopenias in the ambulatory setting. And um because this is probably the most common cytopenia that we deal with and the most common CBC abnormality, I do want to take a minute to talk a little bit more specifically about the examination, etiology and management of iron deficiency anemia and um some uh practical tips on the evaluation and management as well. So let's start with anemia. I like to go way back to basics on in determining like what on earth is even anemia, what's the definition? I think when we're all in medical school, we sort of get a um specific number in a numeric range that is um more pertinent to adults, but in pediatrics, we do have to take into account age-appropriate means. In newborns in particular, the hemoglobin means tend to be higher than in older patients, and there is a little bit of a nader around 2 to 3 months of life, uh, that recovers, um. And really the, the normal values which is set for the mean for age plus or minus 2 standard deviations does really vary by age, mostly in the first couple of years of life. So I encourage you to make sure that if you are sending a CBC to make sure that the reference range is specific for that age group and to, um, and if it's not, then we, you know, to look up the reference ranges, um, in some centralized resources. I believe this is from, um, Nathan Annosky as well as from Harry Elaine. The same thing applies to the MCV, the size of the red blood cells, um, and I think in medical school we learn about, you know, 80 to 100 being the normal reference range, but this range is very different in In small children, especially because of the impact of fetal hemoglobin on red blood cell size, fetal hemoglobin containing cells do tend to be much larger, it has to do with the hydration status of those red blood cells, and so an MCV that is technically in the normal range of somewhere in the 80s to low 90s, might actually be quite low for a newborn and indicate something like thalassemia trait or another hemoglobinopathy, that's driving the MCV down. So just something to be mindful of is that a um quote unquote normal CBC um may or may not be normal based on the patient's um chronologic and developmental age. When would we suspect anemia? I think this is something that is pretty common in the primary care setting. The symptoms might include pallor, fatigue, pika, um, if a patient is reporting significant bleeding, you might wanna consider whether it's significant enough to, um, impact the hemoglobin. And of course, if they're having palpitations, headache, or any other symptoms, um, there is significant overlap with some of these symptoms, in particular fatigue and headache with other etiologies, um, which are also very common, but anemia can be considered with any of these symptoms. On an exam, you might find a patient to be tachycardic, and you might observe pallor either in their skin or in their conjunctiva, and of course if they're bleeding, um, on your clinical exam, you can sort of quantify the um the degree of anemia that way as well. What's important to know though is that some patients, especially those with more of the chronic or subacute anemias, and most notably iron deficiency, may not have any symptoms. With the chronicity of the development of anemia, the symptoms might be either really subtle or they might not actually manifest at all, since this is more of an adaptive process. Um, and so, an asymptomatic patient with a very low hemoglobin isn't that surprising actually, um, and it's something that we all, I think, see regularly. When you are concerned about anemia, however, the initial workup may include things like a CBC, a reticulocyte count, a peripheral smear, and iron studies. I think that's a pretty, uh, standard first pass, um, but if your clinical suspicion for an underlying bleeding disorder, hemoglobinopathy is, um, is present, then sending other things like COAGs or von Mullerbrand factor, um, and hemoglobin electrophoresis may also be indicated, and hematology would be happy to sort of work with you on guiding that workup. One thing to note is that point of care hemoglobins tend to not be so great for um the diagnosis of, of anemia. I, I think of the point of care hemoglobin as a screening test, and so, um, if you are clinically concerned for anemia, then a screening test is probably not the right choice, you want to do a diagnostic test, and I would say that a point of care hemoglobin is usually not an adequate diagnostic test, whereas a venupuncture for a CBC would be an um adequate choice. Of course, the point of care is, is a good test to do. At first, just to verify your clinical suspicion. Um, and I, I already mentioned this, so I will skip over it, but the initial evaluation, including a CBC, venupuncture, reticulocyte, and iron studies is probably the best first thing to do. And here's sort of how I think about a framewise approach, uh, a stepwise approach to diagnosis of anemia of coming down to the etiology. The first thing is, of course, how low is the hemoglobin and is this patient stable. If this is a patient who's having hemodynamic compromise from their degree of anemia, then it doesn't really, um, matter upfront what the etiology is, we want to get that patient stabilized right away. The other thing to note is if there are other cell line abnormalities, in particular if there's significant elevation or depletion of the white blood cells, to be concerned for something like acute leukemia, and if the platelets are also affected, then this could indicate that this isn't just an isolated hemoglobin disorder, but perhaps a global bone marrow function disorder. And then of course our differential shifts into a different realm, where we're thinking more of marrow suppression, um, or marrow infiltration. But once we've identified that the hemoglobin is the only thing that's affected, that the red blood cells are the only cell component that is decreased from the bone marrow, the next step is to identify the etiology, and the first step from that is looking at the size of the red blood cells, which we use the MCV to do. Microcytic, normocytic, and macrocytic anemias have um different differentials, and I'll go through those next, um, but as I mentioned before, those reference ranges for the uh size of MCV um can be different by age. So in a newborn, um, microcytic anemia is actually at a much higher MCV than in an older patient. And then finally, the reticulocyte count is one of the most important tools that we have to help us to identify what the etiology of anemia is. I have friends who make fun of me because anytime they, I ask, uh, they ask me a question, they, they tell me that I'm gonna ask them what the reticulocyte count is because it's something that's so, so, so valuable to hematology evaluation, um, when it comes to understanding the etiology. And what the reticulocyte count really tells us is whether or not the bone marrow is appropriately responding to. The degree of anemia. If you have significant anemia with an intact marrow, then there should be appropriate compensation for anemia with a proliferative reticulocyte response. So I think I, I run into a little trouble sometimes when we talk about quote unquote normal versus not normal reticulocyte count, because a normal reticulocyte count that falls within the reference range for someone who has severe anemia is by definition not normal. And so I tend to prefer the terms proliferative versus non-proliferative, and um, you know, you can look at your reference ranges and see if, if the reticulocyte count looks higher than the uh normal reference range, I would call that a proliferative response, versus non-proliferative being a relatively low, usually the absolute neutrophil count being sort of under 100,000. And again, low or normal reticulocyte count in an anemic patient is abnormal, uh, because the marrow has not compensated for the degree of anemia. Going through a couple of the differentials, microcytic anemia, of course, iron deficiency is the most common um cause of micro microcytic anemia, and other pertinent labs that might help corroborate this include a low ferritin, high TIBC or transferrin, um, high RDW or a wide RDW, this is the red cell distribution with, um, and a menser index, which helps us to distinguish, at least as a screening tool between iron deficiency thalassemia trait, is generally high. To take a step back from, for the menser index for a moment. In both thalassemia trait and iron deficiency, the MCV will be low. However, thalassemia trait tends to be a proliferative process where the RBC count is actually tends to be a little bit higher. Whereas in iron deficiency, this is a hypoproliferative process, there's a reduced production of red blood cells, and the RBC count is lower. So if both MCVs are the same, an RBC count that's higher will drive the denominator um up and your uh ratio will be lower, less than 13. You might also see an elevated reticulocyte count in thalassemia trait, but again, it's a screening tool, it's not necessarily diagnostic, and it might help us to distinguish, um, to determine whether or not we want to do additional testing for either iron deficiency or thalassemia trait. One thing that always annoys me is when I have made an assessment that this person has iron deficiency, but the story really doesn't, um, hold true. Like their diet is great, they've got plenty of leafy greens and meats, they're not having any blood loss, and so then you gotta think to yourself, OK, well, why on earth is this person iron deficient if there's no real good reason for iron deficiency? Thalassemia trait is uh important differential, and this can be either alpha or beta thalassemia trait that can cause marked microcytosis. And again, the menser index may be low in these cases and the reticulocyte count can be up. An electrophoresis is sometimes helpful, especially for beta thalassemia trait. Beta lives on the same gene locus as your other uh globin uh cousins like gamma globin and delta globin, and the hemoglobin A2, which is an alpha 2 delta 2 compound, might be slightly upregulated when there isn't sufficient beta globin to be produced. A normal hemoglobin A2 doesn't necessarily rule out beta thalassemia trait, but it's certainly, it certainly can be suggestive of beta thal trait if it's up. Since every hemoglobin that's produced um in the post embryonic life contains alpha globin, and alpha thalassemia trait is not diagnosable on electrophoresis, since all of your hemoglobins that are present in circulation will be decreased at the same proportion. And so, a normal electrophoresis doesn't necessarily rule out alpha thalassemia, it may point you in the direction of a beta thalassemia. Anemia of inflammation, um, used to be called anemia of chronic disease, um, but I think anemia of inflammation is a much more accurate term for what this is. This is generally a, um, process that starts off as a normocytic anemia and microcytosis is a late finding. And this is caused by, um, high hepcitin, this is a master regulatory protein for iron absorption, um, and hepcitin prevents the absorption of iron as well as the utilization of iron, um, in the system, and so it basically hides away iron. Um, in macrophages to reduce its availability for, um, the body basically just thinks there's there's an infection around. Again, this is one where if um the history doesn't necessarily fit with the picture, you do want to corroborate with this with some sort of history of chronic infection or inflammation. Things like a high ferritin, high ESR or other systemic illnesses may be at play. And I, the reason why I like the term anemia of inflammation is because anemia of chronic disease doesn't necessarily encompass the main driving factor. For example, depression is a chronic disease, but may not cause any systemic inflammation. Um, and so I think that this is a more descriptive factor of, uh, what's going on. These other two entities, lead toxicity and roblastic anemia are actually very rare, and we have seen an increase in the amount of um lead toxicity, but generally we don't attribute increased lead levels to um microcytic anemias. We probably want to be looking further than um just the lead unless it's exceedingly high for a very long time. So it is always pops up in our differentials for microcytic anemias, but I, I can't say that in Uh, in the time that I've been practicing as a hematologist, that this is the cause of anemia in a patient who doesn't have something else. Of course, somebody who's, who's having lead ingestion might also have iron deficiency because of PICA behaviors, etc. um, and so that's something to consider. And then seroblastic anemia is a genetic cause of anemia, which is extremely rare. Now moving on to the normocytic anemias, uh, this is where we have to do a little bit of an algorithm to determine what the etiology is, and so the first thing that I do when I see an anemia with a normal MCV is to assess the reticulocyte count. Is this a proliferative process or a non-proliferative process? A proliferative process with a high reticulocyte count generally indicates that there's peripheral blood loss or hemolysis with an intact compensatory response. The blood is being destroyed outside of the marrow, but the marrow is able to respond to that effectively. Um, and when I see that there is a high retic count, and I'm suspicious for hemolysis, the next step is to evaluate whether it's an immune versus a non-immune process, and I will remind you all about the direct coombs or the direct anti-globulin tests that we can do to determine whether there's an antibody coating the red blood cell surface, um, where if it's positive, that indicates that antibodies are present on red cells and might be contributing to the degree of hemolysis. If the DAT is negative, the immuno, the uh there is not a concern for an immune hemolysis, then we got to consider non-immune causes, and this further breaks down into potential red cell defects like hemoglobin disorders and membrane disorders, and extrinsic causes such as TTPHUS, the things where the red blood cells actually quite healthy, but there's something external that's causing a shearing and breakdown of the red blood cells. And here's my differential diagnosis chart for the normocytic anemias. Again, the differential for a non-proliferative or a low slash inappropriately normal reticulocyte count includes acute bleeding. Anemia of inflammation, and this is usually the early um anemia of inflammation is a normocytic process. Um, marrow suppression, and I'll call out um parvovirus B19 as a viral illness that generally has a predilection just for red blood cells, whereas some of the other viral infections might also cause thrombocytopenia or leukopenia. One thing I didn't include on the slides here is that marrow can be suppressed by many of the medications that we routinely use as well, things like antibiotics, anti-seizure medications, and of course in the HOC world, chemotherapy. Uh, can cause suppression of the bone marrow, and so medications and viruses tend to be a more common marrow suppression findings that lead to a normocytic anemia. And then this entity called transient erythroblastopenia of childhood or TEC is definitely worth considering. This is something that generally happens in younger patients, usually in the like 2 to 5 age range, like the preschool age range, um, and it's not very well understood, but thought to be a post-viral phenomenon where we're having transient. Um, reticulocytopenia is usually a profound reticulocytopenia, like almost no reticulocytes to be seen, and we often catch these patients at their hemoglobin nadir. This does tend to be a slightly quicker process than something like iron deficiency, and so patients probably do end up more symptomatic with pallor, fatigue, difficulty with, um, feeding, etc. And so these patients we're generally catching at their nadir when they're sort of starting to get on the recovery, and we might need to transfuse them to support and then rely on their outpatient. Um, follow up to ensure that their hemoglobin is recovering at the appropriate rate. I would probably send a Parmavirus um PCR in these patients to make sure that uh this is uh idiopathic TEC and not a specific um etiology. And moving on to the proliferative um differentials in which the reticulocyte count is high, again, autoimmune hemolytic anemia is indicated by a positive Coombs test or positive DAT indicating that there's an immune process. There's other antibodies that can cause immune hemolysis, but this is the most common, is a warm autoimmune hemolytic anemia caused by an IgG against kind of non-specific red blood cell glycoproteins. In the non-immune realm, we think of intrinsic factors, membrane disorders like spherocytosis or elliptocytosis, enzyme disorders like G6PD deficiency or pyrobate kinase deficiency, and hemoglobinopathies like hemoglobin CC disease or sickle cell disease. Non-red cell disorders, again, these are three-letter acronyms, the microangiopathic hemolytic anemias, where the poor red cells are just trying to do their job, but they end up getting sheared by um something interfering from the endothelial surface, and TTP that would be um platelet complexes that are bound to von Willebrand disease multimers, um, and then DIC of course that's similarly, uh, clots within the peripheral, um, bloodstream are causing some hemolysis. I always find this kind of fun to go down this, this pathway to determine what's my ideology and use different specific tests to, to point us in the right direction. Of course, the clinical history is very important. A couple of other differentials for a very low reticulocyte count, I've already mentioned Parvavirus B19 and transient erythroblastopenia of childhood. A couple of other things that I would mention are diamond black fin anemia. This is a congenital red cell aplasia and generally presents with severe anemia very early in life, usually within the first year. Um, and so these patients end up becoming transfusion dependent, and there are other ways to manage this as well. Um, viral suppression, infiltrate a bone marrow disease such as leukemia, and severe immune hemolysis may also be invoked. Severe immune hemolysis indicates that the antibodies are so potent that they're actually destroying the reticulocytes as well. And so even though the bone marrow is intact, those cells that are being produced are immediately destroyed. Um, this is a really rare condition, and, but we have seen it, um, in the past leading to hospitalization due to severe hemolysis. And lastly, thinking about the macrocytic anemias, um, we can differentiate these between the megaloblastic and non-megaloblastic, that is more of a bone marrow finding, so it's not quite as evident on the peripheral blood smear, um, so it's a little bit more of a pathologic diagnosis than a clinical one, but the megaloblastic changes indicate that there's some imbalance between nuclear and cytoplasmic maturation, and this is generally because of the delay in DNA synthesis due to nutrient deficiencies, specifically B12 and folate. The nucleus is trying its best to create new purines and to undergo its metabolism, and then the cytoplasm is just kind of like waiting for it, so it gets bigger and bigger and eventually it gives up and spits out the nucleus, and you have a larger red blood cell. This is happening in other um bone marrow cells as well, which is why we see the hyper segmented neutrophils in B12 deficiency. This is an indicator that the um nucleus of those cells is growing out of proportion to the cytoplasm. B12 and folate deficiency are the most common causes of megaloblastic anemia, and some medications that that have an impact on those pathways like methotrexate or 6 mercaptopurine, which are commonly used in our leukemia and sometimes in rheumatology treatments, um, can cause a macrocytic anemia as well. The non-megaloblastic, so this is more of, um, it's not quite that change in the nuclear and cytoplasmic maturation, but other etiologies for the cells to be large. Uh, one includes high fetal hemoglobin, and so generally infants aren't anemic, but they will have macrocytosis because of high fetal hemoglobin. Um, this is also true for patients with, say, sickle cell disease on hydroxyurea. Sometimes we actually look at the MCV to assess whether the patient's adherent or not, because we expect that the fetal hemoglobin that's induced by hydroxyurea for people with sickle cell disease will drive up the, the MCV. Stress erythropoiesis, so if someone is chronically anemic and they're creating a high amount of fetal hemoglobin, or if they have some sort of marrow dysplasia or marrow failure, um, that can also cause a high fetal hemoglobin, and oftentimes the MCV is high in those patients. Patients with a high reticulocyte count might have a slightly higher MCV and um that's because reticulocytes just are larger in general than mature red blood cells. Some medications can cause a high MCV such as anti-epileptics and antibiotics, and, and systemic conditions like thyroid disease, liver disease, and alcohol use might also drive up the MCV, but these are a little bit less common in children, especially in the primary care setting. So I think we're gonna share these slides with you, but I've just summarized the differentials for anemia, the at least the most common ones, um, for you here, and this is a, a chart that I often just cognitively use as a framework for assessing anemia, um, and coming to a diagnosis based on different evaluations. And I, um, hope that this is helpful for you in your primary care setting. I'm gonna take a little bit of a detour into specifically iron deficiency anemia, which is a topic that's, you know, that I think about a lot because we get a lot of referrals for iron deficiency that's either refractory to um treatment or that is um difficult to understand the etiology for. So iron deficiency is the most common nutritional deficiency in the world. There's an estimated prevalence of about a third of the world population that is iron deficient, um, and not all of those cases are associated with anemia, but many of them are. About 15% of US toddlers are estimated to be iron deficient, and about 5% have associated anemia. And these numbers, the prevalence of this is, uh, why we do general screening in our pediatric population, um, at age one and sometimes at age two as well. There are some risk factors including poverty, some ethnic minorities, low birth weight, prematurity, and obesity. And this is just to point out that there are some health disparities that play a role in the both evaluation and management of iron deficiency. So iron deficiency anemia does affect some racial ethnic groups more than, uh, white children, including Latinx and Asian-Americans, and these disparities are more profound on a global health level. There's many risk factors, and we have to keep that in mind when we're assessing for iron deficiency. Iron absorption, you know, why is iron deficiency so common? Absorption of iron is actually very regulate tightly regulated and highly inefficient. Most of the iron that we consume is not appropriately, uh, is not absorbed, and that's for a good reason, cause iron overload can also cause, um, a lot of problems for the system. The most common causes for iron deficiency, I think by far in little kids, it's inadequate dietary intake. Most of the iron containing foods are not that appealing to little kids, including um vegetables and meats, um, and so a restricted diet might be the most obvious cause, and I'll talk a little bit more about some other dietary causes as well. Excess blood loss in someone who has a good diet could be a contributor as well, and this is generally seen in our patients who have excess menstrual blood loss, um, but other causes of blood loss like GI or occasionally things like epistaxis could cause, um, anemia with iron deficiency as well. Less commonly, we have issues of impaired absorption. I think of inflammatory bowel disease or celiac disease being the most common sources of this, but there can be other GI conditions that uh we collaborate with our gastroenterology colleagues on. Anemia and inflammation again can cause sort of more of a functional but eventually uh systemic iron deficiency, and then there are rarely primary disorders of iron metabolism, but these are really only invoked when all of the other causes are ruled out. A couple of unique features to iron deficiency are pika or pagophagia. This is the eating of non-food items, which generally resolves pretty quickly after repletion, and you can see this young lady from Google Images who's eating ice. I would be curious if she's iron deficient. She doesn't look that pale to me. And as I mentioned before, iron deficiency anemia might actually be totally asymptomatic, and many of the patients that were um diagnosing with iron deficiency might have been diagnosed just based on screening rather than on um a diagnostic evaluation. Inadequate dietary intake is probably the most common reason we see in little kids, um, excess cow's milk being the most common, I'll talk about why, but vegetarian or vegan diets as well as restrictive eating patterns might also be invoked, and so if these are, um, if you have a patient who you suspect might not have sufficient iron in their diet, it's probably a good idea to check their iron status, even if they're not necessarily anemic, because iron deficiency can cause other problems beyond anemia, including neurocognitive changes, behavioral changes, etc. And poor cow's milk, you know, cow's milk is so, so, so important when it comes to the good fats, calcium. Like there's a lot of great nutrition that comes with cow's milk. So why does it get such a bad rap in the iron deficiency world? First, uh, milk has low iron content and pretty low bioavailability of the limited amount of iron that's actually in it. Um, and if kids are drinking a ton of milk, it might cause some occult GI bleeds. I say in infants here, but it's possible for this to happen in older children as well. The most important factor I think in my mind is that if a kid is drinking a ton of milk, then it's possible they're just not eating other iron-rich foods cause they're full. Um, and so it's, it's a little bit of a both medical and behavioral intervention when it comes to reducing their cow's milk intake. It's to introduce other foods that might have some iron in them. The other thing to mention is that Um, calcium might actually inhibit the absorption of iron, and so if even if a kid is eating a substantial amount of iron, but it's always with cow's milk, they might not be absorbing it as effectively. So in general, we, we uh counsel to avoid cow's milk and infants, um, altogether, um, and over age one, we do ask to restrict, um, milk intake to less than 24 ounces a day in toddlers and older children. I personally have a 15 month old, so I know that this can be really, really difficult for parents who are transitioning from breast milk or formula to cow's milk cause kids love cow's milk and it can be pretty tough to, to limit it and push other foods. So I empathize, but this is probably one of the most common reasons we see kids end up in the hospital for Um, severe anemia related to iron deficiency is excess cow's milk. The other thing to consider is excess blood loss with menorrhagia being the most common. Uh, one thing I've learned is the way that we ask about menstrual blood loss can be, um, Can inform how we think about the amount of blood really and what I really like this, this is called a pictorial bleeding assessment chart or PBA, uh, which you can Google or you know we have dot phrases within our, our, our EPI system as well that really helps to quantify and, and objectively determine how many, um, how severe bleeding is. Um, there is a score associated with this, I think for pads or tampons that are very minimally soaked, you get like 1 point and um. The menstruating individual can indicate like how many pads or tampons they have that with each of these different soaking um severity, so 1 point for each of these, 5 points for each of these, and 20 points for each of these fully saturated pads as well as if they have clots or flooding and A high bleeding score, I think above 100 or so every day on, on any given day generally suggests that this person could have a bleeding disorder. Um, and so you definitely can ask really specific questions. I like to ask other questions like, do you ever need to leave class to change a product? Do you ever need to wake up overnight because you're worried about leaking? Those also help me to understand, you know, somebody might be changing 10 pads a day, but if they're really lightly soaked, that might not be the same story as someone who's changing 10 very soaked pads every day with leaking and clotting. If someone is really truly not having excess menstrual blood loss, then you can consider other bleeding, uh, symptoms like GI bleeding or epistaxis, but these are a little bit less common and generally more obvious, um. The assessment of menorrhagia might be more of a key, cause someone who says, no, I don't bleed a lot, might actually be bleeding a lot, especially if they have family members who also have heavy bleeding, and that's the only frame of reference they have. If someone is learning from their mom, yeah, this is how many pads is normal, their mom might also have a bleeding disorder that's gone undiagnosed. And then we also have to think about, could there be a bleeding disorder, and that's sort of a separate talk, but I just wanted to comment on um some of the etiologies that might lead to excess bleeding. So the first related, the first category is platelet-related abnormalities, so thrombocytopenia or platelet dysfunction, quantitative and qualitative platelet disorders are worth considering, and then von Muillibrand disease being the most common inherited bleeding disorder, um, all impact platelet function and disorders of any of these can lead to bleeding. Further down in our clotting cascade, any inability to decrease to form a fibrine clot, so this is either decreased or absent clotting factors such as in hemophilia, as well as inhibitors to our factors, or dysfunctional factors such as in fibrogen dysfibringenemia. These can all cause a decrease in the fibrine clot formation. And then we can have increased clot breakdown. There are some disorders in which clots are formed adequately, but they're broken down a little bit too quickly, disorders of fibroanalysis. And then of course, the coagulation cascade and platelets aren't the only thing that are needed. We also need an intact vasculature and um um. And our collagen vascular system and so any disorders of the scaffold for clots to form such as Ehler Stanlos, etc. could also cause um clinical bleeding. And I mentioned this already, but the evaluation of menstrual bleeding does need to be a little bit more specific, and I often prepare your, my patients to say, I'm gonna ask you some sensitive questions about this, and, you know, I, I wanna make sure that patients are comfortable asking, answering those questions honestly. Um, and sort of creating an environment which, um, talking about this is safe and for the purpose of helping them feel better, um, often I feel like is pretty helpful and having their family in the room can be helpful, but sometimes these are questions that are a little bit more, um, honestly answered with an adolescent who is on their own. Um, I also just acknowledge how weird it is for me as a non-menstruating individual to be asking these questions, so I think normalizing it and really getting, uh, a sense of building trust with the patient can be important for a sensitive conversation like this. If there is an identification for heavy menstrual bleeding, things like hormonal therapy, surgical interventions, and IV, um, iron or transfusion could be implicated as well. And so similarly from a, I, I made this just figure looking at different causes for bleeding that we might need to consider. Of course local causes, things like vascular anomalies, trauma, fibroids or IBD can be considered, but if you're worried about a systemic cause of bleeding disorder, this is sort of our differential that again is a separate talk about bleeding, um, but I'll leave here for you as a reference. Going back to iron deficiency, um, you know, iron is meant to be stored for the maintenance of erythropoiesis, and the storage is really what, um, we use to determine whether someone is iron deficient. Um, when the stores are depleted, erythropoiesis begins to slow, and that's why we see the labs change in a pretty predictable order. The first thing to drop is the ferritin, the storage form of iron, followed by the hemoglobin, and then the MCH or MCB. When iron is repleted, they correct in the opposite order, um, and, uh, that is something that we can monitor in the outpatient setting to make sure that our iron repletion is appropriate. Um, and again, as I mentioned, iron deficiency isn't only um impacting hemoglobin, it can also impact growth, immunity, and neurodevelopment. Severe iron deficiency, we also know is a risk factor for thrombosis, in particular cerebral venous sinus thrombosis, and we have to keep in mind that other differentials could exist. Just because someone has thalassemia doesn't mean they can't also have iron deficiency. Vice versa, so an ongoing assessment, um, after initiation of iron repletion is really important to make sure that we're actually correcting it and we're having a good sense of what their baseline hemoglobin status is. Um, I think that this is a repetition of what I've mentioned before. The expected lab abnormalities in somebody with iron deficiency, of course, include low hemoglobin, low MCV, and a low MCH, a wide RDW, and we tend to think of iron deficiency as an, um, hypoproliferative anemia, so a low or inappropriately normal, uh, reticulocyte count, and then this is what our iron studies would look like. Generally, a low ferritin, low iron saturation, a high transferrin or TIBC. And a normal or high serum iron doesn't necessarily rule out iron deficiency because that's a little bit more of a transient finding. One thing to mention is that if a patient does have a concurrent inflammation, for example, all the kids I've taken care of recently for evaluation of iron deficiency have had a cold, and colds can rise the ferritin inappropriately, and so a normal ferritin doesn't necessarily rule out iron deficiency, uh, but a low ferritin is always suggestive of iron deficiency. So how do we screen and prevent? Of course, you guys are much more aware of this in primary care settings than in hematology cause we're seeing the patients you refer to us, but iron deficiency is screened regularly, generally at 1 year and sometimes at 2 years as well, and of course, uh, when there's any symptoms. A diet history should account for adequate iron intake and the recommended amount varies by age, but I feel like most of us can generally get a sense of severe restriction or um excess milk intake based on a pretty basic general diet history. A couple of comorbidities can be implicated here too, of course, nutritional intake might cause other deficiencies such as folate or B12. A bleeding disorder must be evaluated as well, because just repleting iron in someone who's having ongoing bleeding is sort of creating a vicious cycle where we're just chasing the iron. Um, similarly, if there's GI bleeding, we might need a GI workup to, um, ensure that iron repletion is gonna be successful. Other comorbidities like hypothyroidism or intrapulmonary hemorrhage, um, this is idiopathic pulmonary hemosiderosis, might also be implicated, and I just mentioned these to say that treating iron deficiency with iron alone might not necessarily correct the global problem that's leading to iron deficiency. And so when it comes to the management, most iron deficiency is managed in the primary care setting. Um, it's only when, um, either that is ineffective or there's something unusual about the case where hematology is getting involved, but generally oral iron supplementation, dietary modifications, and control of bleeding, um, are the key management strategies. Um, but for more severe anemia or symptoms of iron deficiency, acute care management might be needed. Unfortunately, there really is no consensus on appropriate ED or inpatient management, and that's something that we've been trying to work on here at Children's, and I'll show you an example of um a workflow that we've designed here just to understand, you know, does this patient need to be admitted, and if they are admitted, sort of what's, what's the appropriate dispo, whether they go to the ICU to the hematology floor, or to the general floor. Um, and what are kind of the, what's the role of transfusion, what's the role of intravenous iron and oral iron? I think that the goals of inpatient management are important for me to, to name here. Of course, we want to make sure that we're identifying the underlying cause of iron deficiency. It really bothers me when a patient is determined to have iron deficiency, and I can't understand why, because treating iron deficiency does not treat the cause of iron deficiency. Um, if a patient does develop the degree of anemia that requires inpatient admission, then I sometimes think that oral iron, like just telling someone to start taking oral iron, probably isn't that helpful because chances are that's already been tried in the outpatient setting and it hasn't been effective. So we maybe need to address either social barriers, nutritional barriers, developmental barriers, or other reasons why this patient has gotten to the point where they needed to be admitted for the management of iron deficiency anemia. And that's why we generally recommend an IV iron um infusion, at least one, if not a total correction of their iron deficit while in the inpatient setting, because that'll give us some time to correct their anemia, correct their their iron, and give a little bit of time for the dietary or bleeding modifications to take place, which of course, say it's a kid who has severe autism or restrictive eating might not be able to be implemented right away over overnight. And so we definitely want to make sure we're um Addressing those and creating a plan for full correction of iron deficiency and close follow-up either in hematology or in the primary care setting. This is a lot of collaboration between our teams. And I, I like to make this key point that iron deficiency is actually anemia is three different problems. Correcting anemia alone with say a transfusion does not actually address iron deficiency, and it certainly doesn't address the cause for iron deficiency. And treating with iron alone doesn't cause, doesn't address the cause either. So if someone continues to bleed or someone does not modify their diet, we're, we're really just kind of putting a band-aid on, on the problem. And so, I think that addressing all three of these issues, anemia, iron deficiency, and whatever is causing iron deficiency is the only way to successfully correct iron deficiency, um. And prevent it from occurring after initial management. All right, so moving to the opposite end of anemia, just talking for briefly about erythrocytosis, which um I actually got a consult this morning about erythrocytosis. Um, this is an elevated hemoglobin that's almost always secondary to some sort of chronic hypoxic conditions. The most common reasons what we see in children are things like sleep apnea, congenital heart disease, chronic lung disease, high altitude, or smoking. Hopefully smoking is something that we less commonly see in children, but you never know, um, especially vaping, etc. But so the first thing that we definitely evaluate when a patient is sent to us to look at persistently high hemoglobin is um whether they ever have hypoxia and looking at their heart and lungs as an etiology. A couple of less common um etiologies specific and these cause more of a primary erythrocytosis are high affinity hemoglobin, so hemoglobin variants that have a hard time releasing oxygen, and so, Um, the erythropoietin demand is, is quite high. Um, epo-secreting renal tumors, um, again, really, really uncommon, but something definitely to consider if you could check in a person with a normal hemoglobin should have a relatively low EO level or erythropoietin level, uh, so if that's high, then that's certainly something to be worried about. And then myeloproliferative disorders like polycythemia vira, again, really, really uncommon in children, um, but certainly not unheard of, especially if there's a family history. Urgent evaluation should be done if there are any vasomotor symptoms. This includes things like headache, flushing, pruritus, dizziness, and early satiety. I actually sent an email about getting one of these exact patients into my clinic ASAP, um, because the family reached out to me saying that, hey, the labs are pretty stable, but my kid doesn't feel good. And so those are things where the consequences of erythrocytosis, including, uh, cerebral venous sinus thrombosis or just this flushing. Um, must be evaluated soon. So for persistent elevated hemoglobin without symptoms, it's pretty appropriate to refer to him for evaluation, but I would say urgent evaluation is necessary for anybody else. And in the last 10 minutes or so, I am going to um talk about the other cell lines. I think anemia is probably the most um clinically relevant, but of course we see platelet and white blood cell abnormalities as well. So briefly about platelets, uh, the first thing that I think of when it comes to thrombocytopenia is uh mechanisms of, uh, is what is the mechanism. So I, I look at these different buckets, impaired production. Consumption, destruction, or sequestration. I'll talk a little bit about some etiologies of these. So from a production standpoint, um, the first thing that we want to make sure we're not missing is some sort of infiltrative bone marrow process like leukemia, and oftentimes the presenting finding of leukemia is nosebleeds or gum bleeding or easy bruising because of thrombocytopenia. Um, as I mentioned, for red cells, many infections, medications, etc. can also suppress the bone marrow, and so think about any of those. Um, congenital thrombocytopenias are pretty rare, um, with Scott-Aldridge is some, you know, like a board, boards one which has small platelets, uh, this congenital amega carocytic thrombocytopenia, Fanconi anemia, all these other bone marrow failure syndromes can be invoked. Aplastic anemia is another one, as well as nutritional deficiency. Severe B12 deficiency doesn't just cause macrocytic anemia, it can cause a pancytopenia. And so again, isolated, um, platelet production issues versus a global marrow production process help us to distinguish this differential. Most of these impact all the cell lines except for things like CMV or Wiscott Aldridge, which may be more platelet specific. From a consumption or sequestration standpoint, I, I lump these even though they're kind of different, um, consumption indicates to me a pretty sick patient, so sepsis, DIC, and hypersplenism, um, are causes for this. And then, in a well-appearing patient, you might want to consider an ultrasound or an exam to just determine what your spleen looks like, but a large spleen does, um, end up sequestering quite a bit of platelets, and patients with hypersplenism for various reasons, either EBV or Um, you know, thalassemias, they might be thrombocytopenic because of not really thrombocytopenic, but functionally thrombocytopenic because of sequestration into the spleen. Um, patients that have hadomegaly might also have sequestration as well. Platelet destruction is something to consider too if there is a um consideration that the bone marrow is intact. Sometimes I look to other parameters like the mean platelet volume, which is often reported on a CBC but may not be reported if the platelet count is quite low, or some labs do provide something called an immature platelet fraction. I think of this as kind of a um. Analog to reticulocyte count in red cells for platelets where um the analyzer can actually determine if there's granules or things that suggest that the platelets are immature, and these indicate that they're like new baby platelets that are very big and very sticky, um, and tend to be very good at clotting. So even if the um the platelet count is quite low, these large platelets tend to reduce the risk for bleeding quite a bit. The most common form of this is ITP or immune thrombocytopenia, which is often idiopathic but can be secondary to some sort of um underlying autoimmune process like lupus, um. And that sort of tends to um be evaluated based on clinical context. In a little kid after a virus, we generally think of it as a primary idiopathic ITP whereas it's if it's an adolescent or there's other features of autoimmune conditions, um, then a secondary process could be considered. In newborns, we also consider um autoimmune or autoimmune thrombocytopenia. These are either maternal antibodies that have crossed through the placenta, so getting a maternal history of um thrombocytopenia can be helpful, and autoimmune is generally when the baby's platelets, um, and the mom's platelets have different antigens, and, uh, the, the baby develops antibodies against those antigens. Non-immune processes, again, this is similar to our um anemia of non-immune uh normocytic anemia, some microangiopathic hemolytic anemias can consume platelets pretty quickly, um, von Mullerbrand disease, there's one type that does consume platelets as well as some vascular anomalies, which is less of a disseminated intravascular coagulation, more of a localized intravascular coagulation, um, Casselbach-Merrick syndrome being the most common. Um, and I mentioned a little bit about ITP already, but this is most commonly postviral, but can be under associated with some underlying autoimmune conditions or some infectious processes. I always think of the three H's HIV, hepatitis C, and H. pylori. So for refractory cases or cases where the underlying etiology is to be determined, I often send these infectious testing. Generally, the clinical findings are mild, including petechia and mucosal bleeding, but rarely life-threatening bleeding can occur. Um, and the reason why it doesn't occur as, as much life-threatening bleeding with, um, ITP as it does say in a patient getting chemotherapy and has a low platelet count is because these large platelets tend to be, um, stickier. They're like new brand new, uh, eager eager platelets, and they're pretty good at clotting. When it comes to the treatment, um, we generally go by bleeding symptoms rather than what the platelet count is, and treatment is generally indicated for patients who have mucosal bleeding, um, because there is a slightly higher risk for those patients to develop severe bleeding, um, if not treated. But for petechia alone and a low platelet count with no symptoms, it is actually pretty reasonable and now becoming more accepted to observe those patients with regular follow-up. The natural history in most cases is for the thrombocytopenia to resolve within weeks to months, um, but if thrombocytopenia is persisting beyond one year, that's when we call it chronic thrombo ITP. The first line treatments, the first line that is generally recommended is steroids, although recent data have invoked the use of thrombopoietin mimetic agents like L-thrombopag. Uh, we're using a little bit less IVIG now, mostly due to the side effect and cost profile, and there's ongoing studies looking at the cost effectiveness of different first line treatments. When all of these have been exhausted, there are some agents that can be used as refractory agents like rituximab, other immunosuppression, and sort of a last ditch effort is splenectomy because the platelets are going to the spleen to be reduced and um. Or to be destroyed and uh if the spleen isn't there, then the platelets are just tagged with antibodies and not necessarily going to be destroyed. Qualitative platelet disorders could be considered as well, but this generally doesn't cause an abnormal platelet count, um, but just to say that there are some differentials to be considering in a patient who has a normal platelet count, but with clinical bleeding symptoms, including medications, simple ones even like SSRIs, NSAIDs, aspirin, or anticoagulants, von Wallbrand disease, uremia, and occasionally rare congenital conditions, things like Bernard Solier and um Glansman's. And one thing to consider is also pseudothrombocytopenia. This is actually due to um spurious thrombocytopenia that occurs in the lab, um, and this doesn't cause any clinical bleeding symptoms. Some people for whatever reason have anti-EDTA antibodies. EDTA is a preservative inside a purple top tube that can cause platelet clumping in vivo, and so, uh, sorry, in vitro, this is a typo here, I apologize. Um, there is no in vivo clumping, and so functionally it does not cause any bleeding symptoms, and to confirm this, you can actually send a platelet count in a different tube, usually we do a blue top tube, which is what we send our coags in, um, and this should not have any EDTA in it, and you won't get the clumping, and this is what a smear might look like. So you might also look at the, when you see thrombocytopenia, sometimes I look for a comment from the pathology lab or from the um lab to see are there platelet clumps, because that might indicate that this isn't really a real thrombocytopenia. It's pretty uncommon, but we do think about it to make sure that we're actually working up a real thrombocytopenia and not a spurious one. And then thrombocytosis, um, to comment on the opposite end, is almost always reactive or inflammatory. Um, thrombopoietin, which is made in the liver, is an acute phase reactant, and so platelet counts do increase, um, in the setting of inflammation. But some things to think about could be asplenia. Again, about a third of our platelets at any given time are sequestered in a normal sized spleen, and so if you don't have a spleen, then there's nowhere for those platelets to get sequestered, and you can have a high platelet count as a result. Some myeloproliferative disorders like essential thrombocytosis and myelofibrosis can lead to an increased platelet count, so we definitely want to think about those. Very uncommon in kids, but worth considering, and then severe iron deficiency can cause thrombocytosis as well. I always think of it as like the bone marrow can't produce red cells, so it tries to produce something else instead, and EPO might have some impact on platelet production. For reactive thrombocytosis, treatment is often not required, but aspirin could be considered if you have a platelet count that's above 1000 or so with a primary marrow pathology. And lastly, just in the last minute or two, I'm gonna talk about some white blood cell abnormalities. Um, so leukocytosis is almost always reactive, but if there's a concerning clinical picture, or an absence of a very differential, so there's like severe neutropenia and really nothing else, um, then you might want to think about. Uh, leukocytosis that's pathologic like leukemia, so looking at a high abnormal lymphocyte or a blast count could indicate a leukemia picture when the white blood cells are really high, so a smear review is probably very important. Leukopenia can be concerning when it's associated with other um conditions like um. And and if the patient is getting recurrent serious infections, so it may be less concerning if it's chronic and if the patient is otherwise clinically well. And focusing a little bit more specifically on neutropenia, different labs have different reference ranges for this. The ANC is generally less than 1500 is what I consider to be neutropenia, but some labs might call it less than 1000. Um, prolonged functional neutropenia can increase the risk for bacterial or fungal infections, so someone with a low neutrophil count that doesn't have any of these symptoms may not necessarily have true neutropenia. And some concerning symptoms do include fever, mouth sores, GI symptoms, specifically weight loss, um, skeletal abnormalities or severe infections. These are, um, questions that I ask about to determine whether I need to work up a neutropenic patient more specifically. And there's a broad differential, um, from a congenital and acquired standpoint, the congenital ones include severe congenital neutropenia, Schwachman-Diamond syndrome, other bone marrow failure syndromes, and cyclic neutropenia, and I'll just mention this stuffy antigen associated neutrophil count, um, in the next slide, but something that's definitely emerging as a more common cause for low neutrophil counts. Um, medications, viral illnesses, and autoimmune or what we, you know, used to call chronic benign neutropenia are also considered, not necessarily a pathology. But again, the history of infectious, uh, infections, poor growth, uh, GI issues, mucositis, oral lesions, and a family history could direct your diagnostic workup. I'll mention this, uh, condition which used to be called benign ethnic neutropenia. We're using this term now called duffy null associated neutrophil count. Duffy antigens are red blood cell antigens that are actually pretty commonly absent in individuals of sub-Saharan African descent, and this is because these act as a chemokine receptor for malaria species to enter red blood cells. What it causes is actually a reduction in the circulating neutrophil count, not necessarily true neutropenia. Um, and so I think that The fact that this is attributed to an ethnic group isn't necessarily that helpful, and the fact that it's not really neutropenia, we're just calling this the expected neutrophil count with somebody who has this phenotype, um, is a more kind of accurate, uh, count. You might have noticed that the acronym for this is DAN, which I always find kind of funny, um, but when you hear us say daffinil associated neutrophil count, that is an indication that this is a neutrophil count that's actually pretty normal for an individual with this red blood cell phenotype. And not necessarily um an abnormality. And how funny, I just got a message about a Duffy antigen test for a patient that I took care of, like one moment ago, so that's opportune. Lymphocytes are um also often abnormal on a CBC. Lymphocytosis or atypical lymphocytes may be seen with common viral illnesses such as EBV and lymphopenia may be transient from acute viral infections, but might be more persistent, so. Some medications might induce leukopenia, such as steroids, rituximab, or chemotherapy, and it's important for those patients who are on chronic steroids or um immunosuppressive treatments to be on prophylaxis for infections that might result as a uh might happen as a result of prolonged neutropenia like uh PJP or PCP. For persistent lympho lymphoenia that is unexplained, you might wanna work up a little bit further, things like HIV malignancy, or autoimmune disorders can cause uh lymphopenia as well. So, in general, my approach to evaluation of leukopenia is looking at the differential first. For an isolated neutropenia, we wanna make sure that um we're getting a history of any infections or growth issues. If it really is a benign uh history, then we can consider uh Duffy antigen associated neutrophil count or autoimmune neutropenia, uh, which is not necessarily a pathology, and I always tell patients that testing for this with antineutrophil antibodies has a pretty low sensitivity and specificity unless we're looking for an underlying immune condition, um, and so we don't send antineutrophil antibodies to confirm benign autoimmune neutropenia. If there are associated symptoms, then hematology referral is indicated so that we can do a genetic evaluation as well as a potentially a bone marrow evaluation. And then I, I've also mentioned here the isolated lympopenia can indicate specific viral infections, uh, malignancy, um, medications, and, uh, family history and other symptoms may guide management as well. So I think this is my last slide and I'm happy to take questions. Uh, in general, I would say that abnormal CBCs are often explained by very common conditions like infections or iron deficiency. Those sometimes can be more concerning, so we generally take a stepwise approach to, um, any cytopenia. For anemia, it includes review of the MCV, reticulocyte count, and other cytopenias. With regards to iron deficiency, the management includes both iron supplementation and mitigation of the underlying cause. Just treating with iron does not treat what's causing the iron deficiency. And CBC abnormalities often benefit from collaborative evaluation between primary care and hematology, so we welcome your referrals and uh with that, I am glad to take any questions. Created by
