Chapters Transcript Updates in Management of Pediatric ITP Irem Eldem, MD, presents on emerging evidence on the efficacy, safety and mechanism of novel therapies for pediatric ITP. Um, I wanna thank everyone for joining Speaker Series tonight and say welcome. Um, we're happy to have you all join us. Um, before we get started, I wanted to say that this is Paula's last speaker series before she retires, so special congratulations to Paula. Um, tonight we have Doctor um Eldom, and tonight she'll be speaking on the topic of updates and management of pediatric ITP. And just a few reminders to please keep your mics muted and your cameras turned off during the lecture, and there will be time at the end for questions, and you're welcome to unmute them. Also a reminder that the credit is available only for the live session of speaker series, and whenever you're ready, doctor, I'll do you maybe again. Uh, thank you very much for inviting me. I'm uh very excited to be, um, together, and I'm sure maybe some of you will um and uh if not I'm very much looking forward to it and uh and congratulations, Paula, I just learned um I am uh one of the new uh pediatric hematology uh attendings in Saint Louis Children's Hospital and Uh, one of my focus areas, uh, in our hospital is immuno hematology and, uh, pediatric immune thrombocytopenia is one of those disorders. I will try to share the updates on the management, um, with, uh, a bit more on emphasis on um the mechanism of ITP. And also how we can work together to support and advocate for the families. So my objectives will be um to identify pediatric ITP clinical presentation mechanism, and how to diagnose, how to approach diagnosis, apply emerging evidence of the new normal therapies in pediatric ITP. And formalize the individualized treatment plans um for pediatric ITP patients based on the new recommendations, disease severity, and uh of course, patient preference, uh, and recognize the support needs for pediatric ITP patients and families. um uh and I'm also looking forward to hear your experience, um, in the community. Uh, and yeah, happy to, you know, um, talk about them, um, either you can intervene or at the end. So I would like to start with a case, um, but this case is just to show um just a snapshot of how a patient could present to your clinic. And uh because uh pediatricians, you know, nurse practitioners, um, PAs, those are the ones, uh, or nurses will be the ones who will actually, who will actually, who will actually will. Uh, who will diagnose the patients, and you were the ones who will, you know, foresee the case and will notice that there is something abnormal with this child and make the referral necessary referrals. So this is a 2.5 year old boy that you followed in your clinic previously healthy and presents with epistaxis for 15 minutes. And then when you, you know, continue your conversation, you'll learn that mom noticed some pettic also more bruising notice, especially at the school for the. It should be daycare for about a week. Um, then yesterday, um, the mom was really concerned because he threw up once and mom noticed a streak like blood, uh, when he threw up and also when you start to question more. She shared with you that he also had very dark color like black collar stool. And uh you learned that the patient had acute gastroentritis about 3 weeks ago, um, and in the family history, there was no like bleeding disorders such as hemophilia, bonelibra disease, or platelet disorders, and uh there was no other. Um, evidence of incidents of bleeding in the past for this child, and uh his growth chart looks healthy, his immunizations are up to date. On your exam, when you, you know, look at him, he seems happy, you know, he's been engaged with you, he's, you know, um, interactive in your exam, uh, and, but he's covered with bruising. And when you look at the lymph nodes, there is no enlarged lymph nodes and no hepatosplenomegaly otherwise unremarkable exam. And then you ordered the CBC um and explained that, you know, we're gonna do some little testing to understand uh what's going on. And even with the, you know, CBC test which uh will come back very soon. You found out that uh platelet count is significantly low, but when you look at the other cell lines, hemoglobin looks normal, uh, the size of red blood cells looks normal, MCV and white blood cell count, neutrophil count looks normal, but the platelet count was 24,000. Um, and the MPV, which shows the mean platelet volume, is 11.2. It is a little bit elevated than normal. And then, um, you reach out to Saint Louis Children's Hospital or close by Children Hospital and reach out to, you know, on call pediatric hemo physician, and they recommended, um, they will give some suggestions and, and then because the patient is clinically well appearing, um, you know, there are a couple of choices that we could do here. And at the end of this, uh, you know, session, um, I'm sure you will have a good plan about this, how to manage this case. Platelets, um, so platelets, uh, they are, if you look at the peripheral smear, uh, maybe you remember those are the red blood cells and let me try to. Uh, put my maybe pointer to help out. So those are the, I don't know if you could see my pointer, but the red blood cells look red with the uh mid paler, and those are the platelets. The platelets will be in, you know, purple granulation which supposed to be there because the absence will also goes with platelet function disorder. And, um, their mean platelet volume should be when you look at the CBC, it's around. You know, 8 to 10 overall, I would say. So if it's about, especially, you know, 11, uh 10.5 and about we can call it as this is macro, uh, for, uh, you know, thrombocytopenia of the platelet count is also low, and we receive a lot of uh consults related to low platelet count and count and evaluation of the, you know, uh, careful. Very much important to us to make sure that the CBC, what is reported in the CBC, is really accurate when we observe, when we look under the microscope. The distribution of the platelets, 2/3 is only in the circulation. So when you look at 1/3 of the platelets, it will not be reflected on your CBC. So the rest will be in the spleen. Uh, spleen is the largest organ that captures the platelets, and that's why it will be really important when we're talking about the immune thrombocytopenia. The lifespan is short. It's similar to neutrophils. It's about 1 week to 10 days. That's why it's, it is very like pretty shorter than the red blood cells. If there is an immune destruction going on, and if the, you know, the life will be shorter, couple of hours, that's why it will be difficult for the bone marrow to keep up with the production. And this is uh a megacardiocy on the left side you're seeing, and that's how we see the bone marrow progenitors. It's a multinucleated cell, and then at the rim of the megacardiocy, you can see there are tiny platelets with endomyosis that they're going to be released to the circulation, and that's how we are seeing the platelets um and the and the peripheral blood. And here I would like to point out one very much important growth factor, thrombopoidin. It's mainly produced in the liver, and this is the main regulator of the thrombopoesis megacardioposis. A little bit of his theory about immune thrombocytopenia. Actually, the first case described in 1500s, um, and, but the doctor Gottlie Verhof, he's a German physician, he described. Two young patients pretty clearly and that still fits the clinical picture um in our in our day. He described two patients presenting with porpora and epistaxis. Uh, one of them get into remission on its own, but the other one had a relapsing and remitting course, and that's what we talk with the patients. It will, some of them will have a vaccine and pain in course. And even, you know, when we complete the treat them, um, there is a chance that mild fluctuations still could happen. About 100 years later, the mechanism of uh I thrombo described for this purpura and it was thrombocytopenia, and then in 1915 it was observed and you know, sinectomy improved the symptoms in a patient. And I will show in the next slide, but Washington University Saint Louis Barnes Jewish Hospital has an important actuary history related to ITP because the famous Harrington Hollingsworth experiment was done uh here in Saint Louis, and I will show you in a second. And in 1980s, the mechanism more explained to You know, uh, put it out there that there is platelet clearance increase and there is impaired platelet production and the steroids proposed for the treatment. So it's basically we have been talking about more on the treatment um. Beyond the surgery for the last 4050 years. And in 200 and after 2010, especially uh now we're talking about uh the thrombopoid and mimetics, and there are two medications that we can use in pediatrics and that really change the picture and the management. And this is Doctor Harrington. Um, the experiments showed that the platelet autoimmunity is caused by a circulating factor. And how did he find that out? With Dr. Holling's birth, they were two hematology fellows back in the 1950s, and uh what they did is they collected blood. From the ITP patients, and they inject the plasma of those ITP patients to volunteer actually um lab workers and volunteers, one of them was Doctor Harrington himself, and after injecting the platelet count in their other how to volunteers, you can see within a couple of hours, within 3 hours, the platelet count dropped down. And then Several days later, spontaneous recovery happened and uh I think I remember reading that um actor Harrington platelet count drops so down, and I don't know what what was the main trigger, but he even had a seizure um at that time. So, um. But he did fine afterwards and that was, you know, shared within the literature that there is something within the ITP patient's plasma that cause platelet or the immunity, and that could be also shared with the health to volunteers with injection of the plasma from ITP patients. A little bit about definitions that I would like to talk about after the history. Um, there is an international working group on ITP, and those are experts from different countries, and they come together. And around 2010, in order to standardize uh the terminology and the guidelines and the clinical trials, they changed the name from idiopathic thrombocytopenic purpura to immune thrombocytopenia. And as the name tells itself, it's more immune mediated and because purpura is not observed in some of the patients, that's how they uh define and in the, you know, if you look at the papers after that time, immune thrombocytopenia is the terminology we use. And also when it comes about uh the recovery phase, uh, we used to call it as acute and chronic ITP and 6 months was our landmark, but now we're telling like acute ITP less than 3 months old, and then it becomes persistent if it's lingering beyond 3 months, and then it becomes chronic if it's beyond 1 year after diagnosis. So this is an acquired autoimmune disorder of uh childhood. It could be seen as adults for sure, but uh in children because we don't do routine CBCs unless we have a reason, it might be sometimes tricky to call it as an acquired thrombocytopenia. So that's why the history will be important. Uh, but also it's helpful if they have already have another platelet count, CBC from uh prior visits. It's really good to compare for us, um, to make a better, uh, more accurate diagnosis. It's a platelet destruction and impaired platelet production goes together and um they they describe the platelet count to be less than 100. 1000 in order to call it as ITP. The incidence is 50 to 10 and 100,000 children, and it could be isolated or it could be secondary to other triggers such as infections, other immune diseases, immune dysregulation and immunodeficiencies, or infections and drugs. Um, sometimes, not only the platelet will be affected, but you can see the other cell lines could get affected by the immune cytopenia, such as immune neutropenia and other immune hemolytic anemia, then we will call it as Evans syndrome. Uh, the likelihood of one year spontaneous remission is pretty high in children. So that's why I think the management is now changing more to be, you know, we'll talk about a little bit more uh later, um, but observation is now also included more often, uh, in the cases, uh, given there is a spontaneous remission chance, about 65-70%. And it depends on your diagnosis age. The earlier the diagnosis, the spontaneous remission will be higher. When it comes to adults, it is more difficult, and by 6 months, less than half of the patients will be in remission. So this is the diagram that shows the natural course of ITP in children versus adults, and this light purple shows that like the significant bleeding is more common in children. Than in adults. When we say significant bleeding, um, I will show you the bleeding assessment, like grade 3 and 4 that will cause a drop in the hemoglobin, that will require intervention and hospital visit hospitalization. But we're talking about more non-intracranial hemorrhage here because intracranial hemorrhage is more common in the adult presentation. Uh, the initial presenting platelet count will be really low, less than 20,000 with the acute onset, while an adult it's more insidious and chronic onset. And the treatment response, that's the beauty of pediatrics is uh usually more responsive, but we, we deal with uh lots of chronic cases for sure, given that we are the referral center, but oral treatment responses um better compared to the adult population. And there is a component of fatigue here that I want to talk about, especially on the chronic ITP. That will be important in transitioning of our patients as well, and you may need to address in your clinics too. Female to male ratio, it increases with adults and comorbidities will increase with adults. Now, what's the mechanism? Mechanism is important in ITP because that's what drives the treatment choice. Overall, in the simplistic uh schema on the right side, the platelet itself will be um bounded by the antiplatelet antibodies, high affinity IgG antibodies, and They will be um those platelets bound by the antiplatelet antibodies evil phagocytose by macrophages. My binding to FC receptor here. Uh, or they will be acting as an antigen presenting cell and present those plated epitopes to T cells that will drive that will trigger the uh. Increase cytokines and B cell differentiation to produce more other antibodies against the platelets. So, um, the rapid destruction will usually occur in the spleen itself or other liver and other tissues because of the phagocytosis, and this will exceed the megacardocyte production in the bone marrow. So there is an out of balance, out of proportion of destruction of platelets compared to the production of uh megacards, and sometimes megacardioy enzymes could be um uh the attack by the immune system as well. um, and interestingly, you know, we expect when the megacardiocytes will, uh, kind of behind the production. Uh, of the platelets, the thrombopotin levels supposed to increase, but that's not the case. The studies show that the main regulator thrombopoin, actual levels are normal, so which means that something is off here as well. Liver does not seem to sense to increase the TPO. So we talk about the pathogenic mechanisms and here, this is a schema that just just to show how the platelets will die because the immunoglobulins will bind and uh there might be some complement activation as well. Uh but the main mechanism here macrophages well phagocytos, the immunoglobulin bound uh platelets, and then. It will also present a CD for T cells that will induce a B cells to differentiate the plasma cell to produce more of the antibody production, and that could impair megacardioy maturation as well, and cytotoxic CDA T cells will be also responsible in the uh platelet death. Um, clinical presentation, I think, uh, you have, uh, I'm sure most of you, uh, have already seen, uh, those cases in their clinic, um, but like it will present with more skin and mucosal bleeds rather than what we see with hemophilia like hemorrhosis or internal organ bleeds. Um, there is, uh, you know, Amenorrhagia and GI hemorrhage, like our first case, for example, has some signs of GI hemorrhage, but I will explain usually the epistaxis, uh, that the child will swallow and it could irritate the stomach and they can throw up blood. It can cause some dark um stool too, but um this is still significant and this is also part of uh the things especially in toddlers, we need to monitor carefully. Hematuria in teenagers, um, we recently actually had such a case that it was a severe bleeding that we needed to admit and, you know, require prolonged hospitalization. Um, but bruising petii and those are the purpura and some peticing here and the bruising are the main presentation, and then will come the mucosal bleeds and then other severe bleeds. The most common age we do see is like 2 to 6 years old, and also when they become teenagers, the other immune diseases uh might start and that's another predisposed uh peak age. It's usually followed by a viral in or immunization. But even the viral illness will, you know, uh wean off or, you know, even several weeks after immunization, the platelet counts could still linger in the low ranges. Intracranial hemorrhage, I think this is for sure the most scary part, and it is very rare, it could happen. I think I did see, um, like I would say two cases. And um for like the last 10 years that I have been uh following similar kids and intracranial hemorrhage that usually presents with acute neurologic deficit, and those children um usually have less than platelet count, less than 10,000. And um it could be usually seen with other comorbidities, like if a child has other comorbidities, not only the pediatric ITP that's also predisposes them to other bleeding. So there are other coagulation pathway might be disrupted too, and it's uh 1 in 1000 reported incidents in the pediatric ITP patients. And we talk about the severe bleeding is that being more common in children, um, but when I say severe bleeding, um, I will show you the bleeding assessment in a second. So we talk about is a diagnosis of exclusion, uh, because low platelet count in children could happen in various reasons. So the tests really help us. We order, um, you know, first physical exam, we make sure that we keep a good bleeding, uh, diary and notes regarding which parts are affected in taking pictures, clinical pictures on the chart as needed. And then looking into, is there anything that will tell me is that this could be any inherited thrombocytopenia, for example, that will go with um skeletal abnormalities, any underlying kidney issues, any dysmorphic features, and, and also like need to consider inherited bone marrow failure syndromes and also, of course, malignancy is always in our mind and make sure that we're not missing any. Pathologies, um, and if you remember at the beginning of the case that I mentioned, those children look OK. they engage with you and they will be still playful, they will be still smiling. On the other side when it comes to, you know, malignancies or other chronic issues, um, that they will look realistic and the platelet count will, uh, you know, low counts will follow that. Um, This CBC diff and reticulocyte count is important because to make sure there is no ongoing hemolysis in addition to that, or there is no ongoing like neutropenia and cell lines are not affected, um, or are we seeing any blasts? That's why periphe smear is part of the workup and here you can see very large platelets. This is a giant platelet almost at the same size of red blood cell, we call it as giant. And this is very typical, that shows that the bone marrow was under stress and just releasing a large plates doesn't have enough time to release the small ones, um, and that shows um uh a destruction process going on. CMPLDHuric acid, other bleeding tests like PTTIN or fibrinogen, and we do some infection workup to see if there is any underlying trigger. Um, and to plan for the management immunoglobulin levels, they are to, uh, make sure there is no hemolysis component. And on the, you know, future, uh, follow-ups or depending on, you know, uh, age of the patient and other multisystemic involvement, um, you could order ANA C3, C4 evaluation for lupus, um, especially the other and CVID. Uh, common variable immune disease that we need to consider. And uh some families asked like, should we get and see antiplatelet antibodies, but those are like not uh a high specificity, but not sensitivity and it's not generally recommended to order because even if they are negative, it will not exclude the diagnosis. So we said ITP is a diagnosis of exclusion because uh what does not cause a low platelet count in a child um and especially in the hospitalization environment, um, the mechanism could be increased platelet destruction or abnormal platelet distribution or decreased platelet production. And the list is pretty, you know, thick as you can see here. That's why taking a good history, is there any underlying disease like Digeorge syndrome is associated with microthrombocytopenia. Is there any like thyroid issues? Is there any medication that was used recently? And um any recent transfusion history, um, again, um, neonatal part will be important because newborns also could present with Uh, immune thrombocytopenia that could be auto or autoimmune depending on mom's platelet counts. Infections are the big group, um, CME, EBV, HIV. We are seeing lots of, uh, it's a, you know, viral season as you um follow in your clinics, and respiratory viral swab will help out. And, um, and the conception that we usually see at the setting of the hospital ICU if they're having. Um, you know, DIC picture and a sepsis, hemolytic uremic syndrome, HLH, uh, traumatic macroangiopathy, or if they have like a mechanical valve or uh emo circulation could trigger um thrombocytopenia. And hypersplenism is the other thing that we need to pay attention because large enlarged spleen will uh chew up some of the platelets. And then, uh, not the least, not the last, but not the least is the decreased platelet production, especially there is infiltrated bone marrow process going on like a storage disorder, malignancy, um, you cannot believe what iron deficiency. Uh, causes thrombocytopenia in children, we did have like severe iron deficiency anemia cases that came along with significant uh thrombocytopenia, yeah. For sure inherited bone marrow syndromes are something that we need to. And then comes the question the families will ask like, oh, should we do a bone marrow evaluation? So, a lot of studies done in the past about this, but oral and pediatrics, it's not necessary if CBC is stone cold good except the thrombocytopenia. Um, because like if you do a bone marrow, you could see they could be increased, they could be normal, they could be decreased, so it will not give you. An idea, but it will help you to rule out like a malignancy or a bone marrow disor failure disorders or any other infiltrated processes or or sometimes infections as well, and storage disorders like Goa disease or HLH. So if you think that there are like multiple cytopenia, it doesn't fit your typical ITP picture, relapsing or refractory. Uh, ITP course, uh, multisystemic involvement, and before sinectomy, especially, uh, um. We're not doing uh sinectomies uh that much anymore, but, uh, before committing such a big surgery, I, I think uh it will be helpful to do a bone marrow evaluation. Bleeding assessment. So WHO has a bleeding scale, but there are different bleeding scoring systems out there. If you have a good routine, good system, it will work um because um still the standardization process is going. But WDHO bleeding scale, grade 0 is no bleeding, grade 4 is a hemodynamic severe instability, severe bleeding, CNS bleeding. So this is the uh spectrum of bleeding and then comes in between, the patients usually present grade 1 or 2. Rarely grade 3 and and then 4. So we usually do see, I would say, um, grade 1 and 2 in the presentation of ITP. And, and most of the patients like this patient, for example, had epistaxis less than 30 minutes. I think 2030 minutes is oral, but we expect to be OK, but if it's beyond that, uh, or it's a cluster epistaxis, that will be abnormal and I would put it in grade 2. Piti, uh, you know, bruising. The grade one, but if you're seeing more than like um 2.5 centimeter icymosis, then it is, it will be great. 2. And then uh we look into uh you know, any hemoglobin drop. If it requires red blood cell transfusion and it's described more than 2 g this a liter drop, it will be grade 3. So this is the severity, and when it comes, uh, the site of the bleeding, it's important to note where was the bleeding because, you know, there's always, um, I know that it's in your mind not accidental trauma when a patient, pediatric patient presents to a clinic and uh we usually. Uh, really need to give reassurance to schools or daycare in our ITP patients because sometimes, you know, the daycare daycare will call the family, you know, or, you know, there will be a concern raised, oh, is there an NAT process going on? No, uh, this is an ITP kit, so we need to give uh Reassurance letters and how to manage those situations to schools, but of course in the clinic when we're first seeing the patient, this is one of the differential. That's why it's important to note where the bleeding is. It's called wet purpura, but mucosa bleeds like subconjuncti gum bleeding. And lips, tongue, and if you don't look at it, the family will miss it. So it's important to look at the gums, buckle mucosa, a blisters there, lips and tongue, um. And, uh, and making sure a good, you know, naked exam is needed, not to miss any area of uh bleeding site and asking specific site questions because if you ask, is there any bleeding, sometimes the families may not, you know, remember, uh, at that moment. So asking female teenagers, um, how are your menstrual. Periods, how are they longer than 7 days, you know, are you changing pad more than every, uh, more often than every 3 hours, um, and for males, especially, do you see blood, uh, when you pee? It will be important. And when we are doing the bleeding diary, the families, we recommend them to keep, but also, uh, we keep it in our notes. Is there an upcoming surgery or procedure? Is there recent, uh, any activity, uh, any infection, immunization history that will go along with those bleeding symptoms and is any intervention required? You know, grade 12 will be medication, antifibrinolytic, uh. Or requiring visit, but when it comes grade 34, which will be, you know, severe bleeds that will require hospitalization, and it will be, you know, maybe ICU management, maybe surgical intervention or transfusions. OK, I think, um, now I will, uh, kind of on the last part, we'll uh talk more about the uh clinical spectrum and the management. Um, although ITP presents with bleeding symptoms, it's a heterogeneous spectrum of disease, and remember, 80% will be primary, but 20% of the patients, they have something underlying. Uh, abnormal with their immune system. So this is the part that we shouldn't miss and that's why we monitor them closely at our clinics. Um, and here, This is a good schema that shows how uh the treatment response varies depending on where the immune tolerance defect is. If the immune tolerance defect starts in the bone marrow cells or at early age, they usually present with other autoimmune diseases like Alps, autoimmune lymphoproliferative syndrome, antiphospholipid syndrome, Evans disease syndrome, or uh lupus. Um, and if it's in the differentiation phase, like there's a skewed perip B cell subset, then it will present with combined variable immuno deficiency. CLL is for adults, and we do see a lot of patients after transplant or after like congenital heart disease that they are uh thymus is removed as well that will create. Uh, problems in their B cell, uh, subset differentiation, and we do see ITP in those patients or in cancer survivors too. And then comes the last part, if there is a problem in the peripheral immune response, it will like HIV, hepatitis C, um. Uh, whereas the MMR and their vaccines as well, CMV infection, especially in adults H. pylori and then childhood ITP, but their response overall, this group, uh, will be better compared to having a problem on your central immune tolerance. And more cell types will be affected here. What about the management? Uh, the management of ITP, uh, I think it's shaped by, um. Uh, over the last 40 years, but especially within the last 10 years with the TPO memetics, uh, we're now using more agents. Uh, in 2019, American Society of Hematology published guidelines, um, about how to manage pediatric patients, and it's a pretty actually uh thick guideline, but if you look at if you review and I shared my references at the end, you will see that. Pediatric page only like for 2 pages, but the rest is adults. So we are still uh in the phase that we need to collect more data on the pediatric patients. I will and I will briefly mention 1st and 2nd line therapies, 3rd and 4th lines will be more, I think the management uh. More immunosuppressive therapy and finally will be splenectomy, which I think we're trying to avoid as much as possible. There are two main reasons. One, the infection risk pretty much increases. The second thing is, uh, there is still failure risk after splenectomy. Um, and when we are reading the recommendations, you will see either strong or conditional, and that will drive uh our management and decision. So the first question in 2019, experts come together and ask in the guideline, should we manage pediatric new diagnosis, outpatient or inpatient? And when you look at if the platelet count is 220,000 less than that, and if there are no wet purpura, no mucosal bleeds, it is OK, it is recommended outpatient management. So, um, and this is also, uh, not a strong recommendation, and you should, as pediatricians, we always need to consider what environment my patient lives in. Is there any social concern? Is there any uncertainty about my diagnosis? Uh, do they live far away? Can they come up to their follow up? Because once we send them home, they should be able to follow up it in the schedule with the hematologist urgently within the next 1 to 2 days. So that's how we decide uh outpatient versus inpatient decision. If they have more than 20,000 platelet counts and no bleeding symptoms or mild, again, outpatient management within 2 to 3 days follow up with hematology would be OK. And then um what about what to do? So, new diagnosed ITP child playly count less than 20,000 who has only skin manifestations, large, you know, uh, i, bruising, um. Only skin manifestations and the bruisings are not like, uh, I would say uh not painful, not larger than 3 centimeter, um, and if you come to that point, they usually have it purpura, then our recommendation, uh, is observation over treatment. But again, the observation should be followed with the hematologist and regularly and for those children, um, we do depending on, you know, their platelet count, their symptoms, we do a follow up in the clinic and the labs frequently like twice a week or once a week or depending on the child's symptoms. For example, recently, I can give you an example. We had a patient who presented um like 10 year olds, and he, sorry, he was 7 years old. He presented with a platelet count of 25,000 with only bruising and pettic eye. We decided to monitor the patient without any intervention and observe in our clinic further guidelines, and then a couple of weeks later, about a month later, he came back after a scooter injury with the prolonged bleeding from the wound. So although we were observing up to that point now, uh, because there is an injury, you know, happened, uh, we called the child back to our clinic, we scheduled next day, we're able to do that and then um we can accommodate every day of the week and um. The platelet count repeat was 9000, so I decided to go ahead and treat the patient. And what's gonna be the treatment here? Uh, it is corticosteroids. It used to be IVIG. Uh, as the first, uh, line, but now we're doing more outpatient management and, you know, um, at the end of the day, IVIG, uh, something that requires infusion, we can give it outpatient in our center as well and the infusion center, but it's still still requires pre-authorization. It comes with some, you know, um, still some side effects and uh it's an intravenous medicine. That's why, uh, in as an efficacy, you know, uh there was no benefit, one or the other, corticoster is if your patients for for sure good a candidate for that, right? There will be times that we're not able to use steroids such as a patient with the diabetes will not be a good candidate, or um, you know, a patient with a hypertension will not be a good candidate. And the length of the treatment is maximum 7 days in the new ITP diagnosis. We're not, uh, it's not recommended to give longer than that and we're already giving it quite a big dose. And if when you are leading the guideline, I really like the way how they phrase it. Here it says children with newly diagnosed ITP who have non life threatening bleeding and or health related quality of life is affected, should receive treatment. So they're also assessing the life quality and that's I think makes Shared decision with the families because uh parents obviously do not want to leave a toddler, um, you know, even uh with like bruising and less than 20,000, I think in those situations we uh more lean towards the treatment. And then, uh, the 2019 ITP guidelines recommend if the ITP lasted more than 3 months and who did not respond to first line therapies, and they have non life threatening bleeding, they should receive TPOmimetics or rituximab and Uh, if you come to, you know, TPO memetics also do not work. Rituximab or sinectomy. But as I said, um, we usually, I think, managing most of our patients without not coming to that point, uh, with the current treatment options. So the mechanism of steroids and IVIG, how it works, it will decrease the. Uh, antigen presentation, uh, it will decrease autoantibody production, um, and, uh, and also it will, uh, rescue the impaired regulatory cells that will be important in the ITP management. Uh, rituximab itself will also address the mature already formed B cells, but because it's a quite immunosuppressive theory, we try to, you know, keep it at the very end of our list as the management. And Trombopo mimetics, these are uh approved in 2015 and 2018 by FDA for children about one year old. uh El Trombo pack, um. Is the one that could be given oral and it has liquid option to powder option. One thing is we need to be careful with the diet uh because it interacts with calcium containing uh foods. Romiplastin is the other one, and um it will, you know, they bind to the same receptor. And they mimic the TPO thromboplatin, which is the main regulator, um, and then will induce more platelet production. Rmoplasm is given sub Q and, uh, you know, some people who do not respond to al thrombobach could respond to romoplastin. That's possible, um, uh, but also we need to work with the insurance to see which one works better, uh, with the insurance as well. And then I would like to also talk a little bit about the severe bleeding part because, you know, this could happen, it will be very rare, but when it happens, I think the management um Because it's emergent, uh, intervention is necessary and there are long term, you know, follow up, um, also will be important, and, um, I'm sure you know, it will affect, uh, you know, the, it will cause some chronic issues that comes with it. Hopefully not that if it could intervene at the right time with right management. Uh, it's important to, you know, find out those patients and give the treatment at the right time to them. That's why ITP actually uh makes the families very much worried and the management sometimes could be really stressful. Uh, but when we see a patient with, you know, life threatening severe bleeding, um, it could be in the initial presentation as well, but we give everything as much as possible. We start um transfusions, platelets and red blood cells, and also ITP directed therapies at the same time, and you can see. The response to IVIG will be faster. Platelets, we need to give, you know, multiple times as uh the system body continues to destroy them. Corticosteroids will be, you will be seeing the peak a little bit later than IVIG and Tpomimetics also will take several days and weeks to see the maximum effect. And here, I try to summarize uh what does a response mean, how does it look like? Complete response is when, you know, platelet count is about 100,000 and you're not seeing any bleeding. They could be still on a medication, but no response means that it's still less than 30,000 and or not increased more than 2 times from the baseline platelet count, and response will be in between. And here time to initial response, as I said, IVIG will have the fastest response, but when it comes to retux, it will be the latest. Um, and on the right hand side you can see, uh, because we received those consults, what should we do before a procedure in those patients like today we just received a call. I think it's really important to be in touch with the hematologist as soon as possible because giving a platelet transmission will not fix this patient. And in order to come up with an effective treatment plan, we need to be aware of it. Like I would say several weeks before, I usually give 2 to 4 weeks in advance in order to make a good follow-up plan and communication with the teams. And the big question is, like, should we observe or treat, uh, I think it's very, I understand very stressful just to observe. Uh, that's why it's important to be managed by the experts in the field, because not every center, even they have him on, uh, you know, some, uh, cases will require expertise. It's important to reach out to the uh right people. That's why those referrals will be important. And here the important thing is we're not treating the platelet count here. Uh, we're, and I have like, we still have patients that they're in like 10s or twenties and they have a normal lifestyle, uh, at least as much as possible, they continue to uh resume their activities. Uh, here the questions come is, are we seeing any bleeding symptoms? Because goal of therapy here is controlling the bleeding symptoms rather than on a goal of platelet count. And the families and children need confidence that they are supported in school and are safe to return to most activities. And that's why we recommend preventive lifestyle modifications like avoiding high impact sports until we make sure platelet count. In a safe zone, wearing protective equipment, and then uh assessing female patients, especially if they're having any menstrual bleeds. Regular dental visits because gum bleeding will be important, we should avoid, you know, and dental procedures they usually will need that. It's better to prevent any, you know, carries in advance. Avoiding platelet function disturbing agents, like when we are seeing those patients, if they are running fever, we always tell them not to take any ibuprofen or aspirin for sure, uh, and Tylenol in the management. And uh immunizations, uh, we, we usually recommend to resume immunizations, uh, if they are not acutely sick or febrile. Um, it's just the IVIG part of that, you might have a little bit blunted response to live vaccines, that's why it's recommended to delay the live vaccines like MMR 6 to 8 months later, but if in your uh you know, population you're seeing endemic cases, it's OK to give us's just Uh, be ready to maybe will require another dose 6 to 8 months later when you repeat the titers because they may not develop enough immunity. Um, And if the platelet count is like around 20-30,000 is generally safe to do the injection is just make sure to, you know, uh, press, uh, put you know pressure after those IM and prefer subQ injections if possible. And we wanna make sure that we provide a good school action plan. We write letters to schools and school nurses to feel that, you know, um, they know what to do as a first aid and first aid will be the same as you do any child, but it will require prompt communication with uh the hematologist and, you know, um, and a healthcare facility. And I wanna wrap up with this uh uh finally with this new clinic, some ITP patients will require further investigation because they will become chronic. They will have refractory ITP. They will have other cytopenias, multisystemic involvement, more excessive or severe bleeding symptoms or positive like immune disorder history. So those are the patients that we evaluate together with immunology and our immune cytopenia clinic, um, and, and that's why. It's important to, you know, monitor long term for those patients. Uh, yes, I feel so bad interrupting. I just wanted to let you know we only have 4 minutes left till 7 o'clock, and you do have one question in the chat, um, and I'll also need to put the QR code up for everyone to scan, so, um, if you could wrap up in just a minute or two, that'd be great. No, thank you, you're doing great. Uh, yeah, sorry about that. I think I really love the topic and I think here, finally, I would like to share um Shared decision toolkit, this is a really good resource to share with the families and um you can share with your ITP patients as well. They could, you know, um keep it handy, what to pay attention when they are having low platelet count. And this is, you know, as a group, shared decision and team efforts, um, and the patients will be embraced by, you know, you and and as pediatricians, by the school team, their family, and uh the hematology team. And these are very good uh support groups, uh, especially women and girls with blood disorders Foundation. They have great resources. I watched a couple of their YouTube videos by experts before this talk preparing for this talk, and PDSA also has very good uh advocacy groups and resources for ITP patients. So I think uh right now uh we're gonna continue to implement new ITP directed therapies and uh it's a shared decision uh with patients how to treat, how to manage them. And currently we need more clinical molecular essays to predict which patients are at higher risk of bleeding or will uh be more chronic and also health equity, like, can anyone access those treatments will remain to be challenged and things that we need to continue to work on. Thank you very much and I'm happy to take uh any questions you have. Please ask questions or you can email me anytime later as well if you have questions too. Thank you so much. Um, there is a question in the chat. I don't know if you um can navigate there. Um, so I, that's a great question. Uh, 5000 guidelines use 20,000 to direct care. If count on initial visit is 5000 should be treated to prevent ICH. So yeah, I recommend to refer all of those for sure kids for a referral to hematology. Um, so 5000 platelet count, uh definitely requires. Uh, urgent evaluation and the bleeding symptoms will be important. So those patients usually have uh vetorpura and we tend to bleed and depending on their bleeding symptoms, we either do outpatient or inpatient. Uh, does this explain the question? You all are welcome to unmute if you'd like for any more questions, um. Yes, please ask me 2 more questions. If you'd want, um, Doctor Eldha, you're welcome to put your email in the chat. Um, thank you so much for speaking for us tonight. We really appreciate it and um I'll put in the chat as well what we can expect for next month for our speaker series. Thank you. Thank you all for joining. Have a great evening. Thank you, Doctor Eldon. We really appreciate your time. Thank you very much for joining. Oh, it looks like we got one more question for you. 00 wait, no, sorry, you were replying. Yeah, I replied and I also shared my email. OK, great. Thank you. Created by Presenters Irem Eldem, MD Pediatric Cancer, Blood Disorders (Hematology) Cancer (Oncology) View full profile
