Understanding Immune in Immune Thrombocytopenia

You are listening to the hematology podcast by Sanofi. Immune thrombocytopenia, ITP, is increasingly recognized as a complex immune-mediated disease rather than just a disorder of low platelets. In today's episode, we'll explore new developments in ITP, focusing on the role of Bruton Tyrosine kinase, BTK, in immune signaling, and how immunological mechanisms translate into the diverse clinical manifestations we see in practice. In this episode, we have two guests. Hendrik Friedrichsen is a consultant hematologist and clinical professor at the Odensee University Hospital and University of Southern Denmark. He is an expert in benign hematology, particularly immune thrombocytopenia and autoimmune hematitis. Rick Kapoor is MD, PhD, and research group leader at Sanquin Blood Supply Foundation, Amsterdam in the Netherlands. His research focuses on pathophysiology of immune mediated disorders or platelets and endocelium. This is the hematology podcast and I am Mats Meerup. So welcome to the hematology podcast. Hendrik, it's your second time. You're coming back here. Yeah, it was such a pleasure in the first time when we talked about TTP and so on. Thank you very much for having me back, Mats. It's a pleasure to be here. And you Rick, make your debut here in this podcast. Very welcome. Yeah, so I'm very happy to be here and I look forward into having nice discussions with you. It's actually the second podcast we have about TTP, which is interesting. I mean, this is obviously a hot topic now. Things are changing, concepts are changing. We understand it differently and we get new ways of treatment, which is interesting. So let's start out, basically. Could you start out with giving us a brief overview of what TTP actually is and why it's considered a complex immune mediated hematologic disorder? Yes, I can start. So thanks for this important question. So ITP used to be defined as idiopathic trombusopenic perpera. But since 2009, we have actually changed this into immune trombus adopenia. So still ITP. It does, we are now increasingly recognizing that it's not only a disorder of low-plated count, but it involves complex immune dysregulation with an important role for systemic inflammation. So it's an acquired autoimmune bleeding disorder and it has, we believe it develops through a loss of immune tolerance. We are immunosuppressive cells are impaired in their function and then somehow this results in the production of auto-antibody, second target platelets and diverse biological compartments, such as blood, spleen and liver, but also the platelet parental cells to make a carrier site in the bone marrow. So platelet auto-antibody can do it, but also cytotoxic T cells can do it as well. And by having this impact, we get a increased platelet destruction and a decreased platelet production, which together results in the development of trombus adopenia. And this is not, it sounds maybe straightforward, but this is a highly complex ophthalmology where there are multiple levels of immune dysregulation. So of course we have the loss of immune tolerance that I mentioned. We have the involvement of B cells, cytotoxic T cells, also macrophages that also can target the platelets. Secreted factor with the cytokines and other inflammatory parameters. We even think platelets themselves have an active role in this immune process as well, and more on that later. But it's important to realize that we still have many gaps in our understanding. And one of the challenges are that there's a high degree of heterogeneity in individual patients, not only regarding the biological mechanisms, as not every mechanism may be relevant in every patient, but this also usually impacts the disease-course trajectories, which may be newly diagnosed, persistent and some patients develop chronic ITP. But also we have heterogeneity-interputing responses. Some patients may respond to certain therapies, but others may relapse, and this may result in increased toxes as well, which may further increase the risk of bleeding. So yeah, this is a multi-layered immune dysregulation, which we still don't understand every aspect of it, but we know that there are certain important items, including important role for inflammation. That's a very good start. The diagnosis of ITP has been a little bit. I mean, it's been sort of a diagnosis of exclusion. How should we think about diagnosing ITP for Henrik? I don't know how many examples in medicine really has remained with such a vague definition that you have to exclude other causes of a specific phenotype to sort of rule in the diagnosis. But for many reasons, it has remained in ITP. So this is still the case, and really this is really, I think, one of the really major unmet needs in ITP to get it right sort of the first time to find a or a number of diagnostic tests that will make us more certain about why a specific patient has thermosythromatine opine. Yeah, because it means a lot to get their diagnosis right. You want to treat the patient for the right disorder, obviously, but also, I mean, you have to have some big lens for other developing disorders for other causes of thermosythromatine opine, yeah, for following patients. So there's so many implications to get the diagnosis right. So yeah, in many ways, it is a bit of a disappointment that we haven't really cracked that nut yet, but luckily, thanks to guys like Rick and other basic researchers, I think major progress is being made in terms of understanding the disorder. So I hope in my lifetime, we will sort of make it to get the diagnosis right the first time, but still nowadays, we actually have to rule out other causes of thermosythromatine opine as to find patients with ITP. You want to say something about your own, what you rule out, do you have a. Yeah, you get a lot of help with basic biochemical workup. Just see if you see a patient with isolated thermosythromatine opine that has luck enough that this person have had previous blood work, that's a very good indication where if the platelet count was normal previously and now it's very low and everything else is normal or close to normal, then it's a very good indication. But you have to rule out viral infections, hepatitis, CME, things like that. You have to consider other causes of autoimmunity, like, yeah, if patients have symptoms from the immune system, everybody's fearing cancer, but you have a very good indication that it's not if you're just looking on the normal platelet count, but yeah, you have to consider if it's a bone marrow disorder, and that would be my usual. Everything, always of course, consider the medications on thermosythromatine opine as you have to consider that as well. Nowadays, I think it's increasingly recognized that are some congenital thermosythromatine opineas that are not diagnosed until later, so you want to make sure, particular for persons not having had a normal platelet count previously, that it's not a congenital disorder. So genetic workup may are becoming increasingly recognized as a thing to consider, but not in standard sort of ITP diagnostic workup, but yeah, close to. Very good. So ITP is not only low platelets. Why should we look beyond platelet counts when assessing ITP? What does the patient experience of symptoms? Maybe I can continue. I mean, Briggs said it very beautifully that there is such a heterogeneity in the pathophysiology, and that of course plays into also the symptoms. There isn't a sort of very clear connection about that between these different mechanisms and presentations, but there are some. And obviously, I mean, you have to really think or listen to what patients say to you, they're complaining about fatigue, poor quality of life, bleeding symptoms, all that means a lot if you're planning to follow and treat the patients. And then of course, the comorbidity is extremely important. The lifestyle, is it a sedentary older person or is it an active older or younger person with other sort of demands and human states? So all that means something when you're planning a particular follow-up program, a particular therapy, how you should make yourself available to a patient. I've seen patients where I haven't maybe not before understood that they actually have more symptoms than one expects from low platelets, and I feel really guilty here. We have to learn. So let's move to the immunology. We have here a concept called multi-immune modulation. What does this mean in the context of ITP? Yes, a multi-immune modulation is a phrase that addresses this underlying immune dysregulation. So basically the complex disturbed communication that is happening in ITP due to the autoimmune triggers. And this communication is between several immune cells, but also within the cells themselves. And collectively they drive from a set of pinia and the clinical manifestations. So this basically this immune network of, yeah, communication network is multi-immune modulatory and accessible for particular therapies to utilize, yeah, this, understand and utilize this network to skew the balance towards the resolving of the autoimmunity. So we want to basically break the cycle that is responsible for the triggers that are inducing the, the ITP. So this may include the auto antibodies that are produced, but very importantly also the inflammatory status that is a key aspect in the disorder. You have already mentioned that the immune components of ITP is much more complex than we've thought like 20, 25 years ago when we thought just about these cells and antibodies. But you just repeat again what immune components are involved in ITP. Apart from the well-recognized B cells or auto reactive plasma cells that produce the playlet auto antibodies and the cytotoxic D cells that destroy, can also destroy the playlet or on omega-caricides and the secreted factors that are emerging in this, in this disorder that are pro-eventory in nature. One of the very important starting points basically is what we call the loss of immune tolerance where certain immunosuppressive cells get impaired in function. And how this happens actually we still don't really understand, but we know that there is an impairment and there's a certain skewing in these subsets, particularly signified by increased TH1 and TH17 cells and decreased T regulatory cells or T-REX. And this balance is very important, particularly these T regulatory cells that are not only impaired in numbers but also in their inhibitory function. And this somehow then results in targeting of the playlets and an omega-caricides during ITP. And one of the key components here is the inflammatory status because we know that under these conditions that there's a high disease activity, they are low number and are functionally active T regulatory cells in general increase TH1, TH17 cells, but there's also low TGF beta, low IL-10. And we know that when that is pro-eventory status it can shift upon certain therapies that are effective by reversing these relationships. So thereby increasing T regulatory cells, decreasing TH1, TH17 cells, increasing THDGF beta , TH17, and TH17 cells, decreasing THDGF beta, low IL-10, but collectively creating an anti-inflammatory status which is paralleled by increased placid counts. So I think one of the very important aspects here is that we want to achieve this shift from pro-inflammation to anti-inflammation by resolving this immunological disbalance. We have some important concepts that are new to me that I would like you to explain. Can you explain the role of NLRP3 in flammasome and the net formation in ITP? Yes, so the LRP3 in flammasome, it's a crucial intracellular protein complex of the innate immune system and it can form in response to pathogens or cellular damage. When this is activated we get the production of pro-eventory cytokines and for the ephemous zone, particularly IL-1 beta and IL-18 and this LRP3 in flammasome expression and activity is at least we know from at least four studies and more are emerging that this activity is increased in patients with ITP with active disease compared to controls or patients with ITP in remission. And we also know that this activation of the NLRP3 in patients with ITP may also promote the T17 response. So this is something we don't want because this will also stimulate this balance that is the basis of the loss of immune tolerance. Regarding the nets, I'm sure everyone is familiar with them but just very briefly, neutrophil exhaler traps or nets, they are basically, you can call them weapon-like structures that are composed of DNA, histones, a lot of proteins such as antimicrobial proteins and they are released by activated neutrophils. So basically this DNA is expelled out of the cell and this can have a beneficial effect in certain settings. For instance, this can be very beneficial in sepsis where pathogens can be trapped by these nets and in this process we call netosis, the production of these nets. However, there's also a downside that in certain settings these nets can also be toxic and they can also contribute to thrombosis and autoimmune disorders. We believe that this may likely be, yeah, this advantage is affecting ITP. I think more studies have to really further look into the role of the nets in ITP but at least there are two studies that have clearly shown that patients with ITP have increased net formation, signified by certain markers such as citronellated histone 3DNA or cell 3DNA and this reflects basically the status of neutrophil activation and its contribution to inflammation. And we also know that inflammatory status is then linked to these certain neutrophil markers that are increased. And we know that also for instance, platelet neutrophil interactions may also drive this release of these nets. We also know this very well from other disorders that this is possible. But in the end these nets are likely in ITP related to the promotion of thrombosis and further immune dysregulation. Okay, very good. Brutantyrusine kinase is something we know from other areas of hematology but it's also considered a critical player in immune signaling in ITP. Could you tell us about that? Yeah, so Brutantyrusine kinase or BTK, it's a crucial enzyme. We originally know from the, from his role in the B cell receptor signaling pathway and that it plays a pivotal role in B cell development, activation and antibody production in general. But BTK, it may be particularly relevant in ITP because it acts on several cellular levels. So one is indeed the classical B cell where it may be responsible for auto antibody production. So I played with auto antibodies. But BTK is also important for the functionality of macrophages. And as I briefly mentioned, they are also very important in inducing antibody mediated platelet phycosytosis. So the cellular uptake of platelets by these macrophages and BTK plays an important role in this as well. And as I previously talked about the inflammation, we also know that the BTK is important for activation of the NRP3 AFermisome. And thereby also the IO1 beta and IO18 secretion and subsequent immune response that comes from that furthermore, also the net also, BTK plays a role also in that in relation to the stimulation of fnetosis. So these are already key aspects of role of BTK which signifies a critical role of that signaling pathway on several levels of immune deaths regulation in ITP. And how does BTK inhibition relate to multi-immune modulation? Well, multi-immune modulation is then, it's tapping into all these various cellular network communications in the cell and between the cells. If one would utilize this and try to target the BTK, it will also, it may also affect the auto antibody production, the phycosytosis capacity, but also inflammation activation, neutrophil activation and also the communication between all these different cells, particularly as well. For instance, platelets may also enhance neutrophil activation and the doses. So BTK can be, it's an example of a signaling molecule that can be targeted in order to at least disrupt this immune dysregulatory cycle. So we have quite a few immunological targets here. How can we do different mechanism of action influenced treatment response? Yeah, I wish I knew that. I mean, it's really the million dollar question. I think we really lack some biomarkers to choose the right treatment for the right patients, but it's really good news, all the sort of advances that have been made in understanding biology as Rick emphasizes because it has also resulted in therapeutic targets evolving and therapies for these reactions. So I mean, we have a multitude now of immune modulatory treatments that are efficient in patients and having their particular advantages and disadvantages. So I mean, the multitude of treatment options that has evolved along this increasing understanding is really good news because patients have different diseases. Their heterogeneity is something to consider in biology, but of course, also in their comorbidity in the multitude of drugs that people take may have different advantages in combining with other treatments. So altogether, this means a lot for choosing the right treatment for the right patient, but we cannot yet do a specific biomarker profile to say this particular treatment should be considered for a patient. So we have to rely on that translational researchers like Rick, increase the understanding for focal emissions to choose treatments. And a lot of options is always a good thing if you have to consider treatment. Some patients even have to have multitude of therapeutic hits to actually increase their platelets. So in many ways, it's really an advantage. But it's not only increasing platelets. Why is it important to address both objective and subjective outcomes? Oh, yeah, that's a very good point. I mean, along the increasing understanding and the increasing treatment options that diseases become more complex in many ways because we have most sure of options. But we're also increasingly recognizing that patients have a lot more symptoms than just platelets and bleeding. There is in particular psychiatric manifestations or psychological manifestations like fatigue and sciatism and depression. You have to consider that. Patients may, I mean, just have fatigue. It may be really have a major impact on their lives. And some of that is actually responsive to some of the drugs that are available. Some of the quality of life reductions do improve with treatment with increasing platelets accounts. But also, you have to make both the patient and yourself aware what is actually the burden of disease for a particular patient to choose the right treatment. Some treatments are subcutaneous injections, some are IV infusions, some are timely-limited and some are ongoing. And all of that is at play when you choose the treatment for a particular person. I mean, you have to remember, it's a very sort of basic research, but you have to remember that patients are not their disease. They're persons with a disease and they have a life outside the 10 minutes. You see them in hospital. They have kids and grandparents and jobs and all that. So is this what personalized care in ITP looks like? Ah, yeah. It is. The trouble is that clinics are always busy. You have a long list and all that. So the easy way is just to look on the platelet counts and CDO bleeding and you're reasonably okay. And then the patient is fine in your view and you have to see the next patient within a few minutes. But if you wish to understand the sort of burden of disease on a particular person, you have to use some more time. You have to ask them, how does this influence your life? I mean, do you worry? And what do you worry about and all of that? Do you have to do that once in a while and sort of integrating all of these things, maybe quality of life tools in your daily clinical work? It's something you have to consider and it's something you have to do at some stage, but it's not easy. Now, it's a challenge. So Rick made a fantastic overview of new immunological insights in this disease. Do you think these insights could actually improve our diagnostic approach to ITP? Yeah, I would say yes, definitely. And I think Rick would say the same, but I'm happy to hear his view. We have to, I mean, this must at some stage play a role in how we make the diagnosis. What do you think, Rick? Yeah, I completely agree with you, Anne Rick, because I think it's very important that we try to shed light on what type of ITP patients we are in fact dealing with. Because I think this is one of the major problems because not all ITP patients are the same. So we have to better profile this from a diagnostic point of view, and for which I think these immunological insights are extremely valuable. So we know that, okay, we have this type of ITP patients that may benefit from this type of treatment. So on one hand, I think it's important we understand these biological mechanisms of the pathophysiology, and in parallel we need to also keep better understanding how our therapies work because they may be more multifunctional than we realize. So as everything, it gets more and more complex as we get better. So how do these immunologically insights translate into clinical practice? What monitoring strategies should clinicians adopt to cover all the aspects of this disorder? I think it's a very good question, and it's really something you have to consider because knowing that it's complex immune dysregulation that is underlying, something that looks very sort of simple, just low platelet counts, maybe you really have to consider what are the challenges for a person. You have to consider what are their risks of infections, for instance, in terms of their disorder, in terms of their lifestyle, in terms of their frailty. So all of that is really a play, and I mean, just remembering we are almost forgot about it, but Spanectomy used to be a very sort of fashionable treatment. Some decades back, it's still used very little, and it's going down. But remembering the risks with Spanectomy, it's obvious that you have to consider that there may be risks, there may be benefits from any treatment in terms of risks of infections, risks of thambosis, which also is something to consider, along, of course, the sort of basics, the bleeding risk that you have to want to balance, all of that. So I think these insights, and particularly also the understanding of the sort of downstream complications really improves the possibilities for making personalized medicine for a particular patient. Very good. So now at the end here, my last question for both of you, what future directions excite you most in ITP research? I think we have a lot of exciting directions that are upcoming. I think, of course, the Holy Grail is, of course, that we are in search of a biomarker, of course, and now I think we have realized that there will be no single biomarker, but maybe a collective set of markers in particular type of ITP patients. I think that's how we need to see it. And to be able to be able to find something like that, like a signature that can predict, you know, the disease, course, or trajectories or the therapeutic responses, I think now we are getting some exciting tools to do so. And this includes, like, the omics technologies, where you can have genomics, transcriptomics, proteomics, meta-belomics, all processes that can signify a certain phenotypic cellular change, links to a certain disease outcome. And I think studies are now more and more emerging that are starting to look at this. But they remain challenging because we need to also carefully think about the methodology on one hand, but also which type of ITP patients do we include in our analysis, what control groups do we have? So we need to be cautious here in order to conduct these type of studies. But I think this is one exciting, I think, direction. If you don't mind, I can just briefly touch on to other, I think, very exciting directions that are upcoming. And one is actually where we always look at platelets as the victims in ITP, the targets that are being destroyed. But I think now we are learning very wise and insightful lessons that platelets also are not only victims, but they may in fact be also a role in their own fate. Because they also harbor immunological functions, not directly homostatic but immunological functions. And these can be pathogenic in ITP due to certain pathogenic interaction with the immune cells, but they may also be beneficial for instance in certain therapeutic responses, platelets may become activated, release certain factors, giving one example, DGF beta, which may for instance help in reparation of this loss of immune tolerance by acting on certain impaired immunosuppressive cells. So I think also involving the platelet in this immunological equation will actually broaden our vision on the whole multi-minimulatory landscape. And one final one I really like to mention also is that all these immunological processes, of course, the question is what's the trigger? How are they emerging? What is the cause of it? And I think one very exciting direction here may be the gut microbiome, which we know from many other disorders, also other autoimmune disorders, we know that it can be a driver of immunological responses. And we hypothesize also that this may be an important role also in ITP, where it is, yeah, gut microbiota composition may be perturbed, and that this may potentially be a key in getting more insight into this heterogeneity in ITP on individual patient level. So I think we have a lot of lots of work to do, but I think we can make important steps in the upcoming period. - And Rick, something to add? - Yeah, I mean not a lot, though. I'm not really not a lab researcher, I'm sure well aware, but I have to say I actually fully agree with Rick that the really exciting thing is going on in the lab these years, but also, of course, the translation into the new therapeutic targets, the immune modulating therapies that are coming out really looks extremely powerful and extremely efficient, and that's going to be very, very exciting. And then of course, I mean, I always lecture that in ITP is of course in any disease, but in ITP particularly important not to make the treatment worse than the disease. And I think some years back, we have actually in some instance made the treatment worse than the disease with some of the older treatments that have really had really a heavy load on patients well being. And I hope, and I think that many of the new stuff that are coming out will make it more efficient, maybe for a shorter period, and then relieve patients on the burden from some of the toxicity. So that's where I'm really, that's where I'm putting my money and hope for the future. There's one last thing I want to add here also, I think, in able to get there, I think it's very important that we keep collaborating within the field, also on international level, to collectively be able to get there faster than we would if we would pursue it on our on our own. And I think, I'm very happy to be involved with that and work with people like Henrik, you know, because I think this is this is the way forward. Yeah, fully agree of course, yeah. Good final point, very good. So guys, thank you a lot. This was fantastic. Henrik, you always give such a clear clinical perspective. And but I must in particular, complimentary for giving such a clear overview of these difficult immunological aspects that I think our listeners will enjoy a lot. Thank you so much to both of you. Thank you very much. Yeah, thank you too. Thanks for having us. You have just listened to the hematology podcast by Sanofi. [BLANK_AUDIO]