A Mayo Clinic podcast for laboratory professionals, physicians, and students, hosted by Justin Kreuter, M.D., assistant professor of laboratory medicine and pathology at Mayo Clinic, featuring educational topics and insightful takeaways to apply in your practice.
This is Lab Medicine Rounds, a curated podcast for physicians, laboratory professionals and students. I'm your host, Justin Kreuter, a transfusion medicine pathologist and assistant professor of laboratory medicine and pathology at Mayo Clinic. Today we're rounding with Dr. Dr. Wysokinska, an assistant professor of medicine and consultant in the division of hematology and oncology at Mayo Clinic in Florida, to talk about clinical updates in thrombotic thrombocytopenic purpura. So what we often call TTP. Thanks for joining us today.
Thank you for having me over.
Oh, this is a great time. So for our audience, it's been about 10 years since we trained together and this is a nice reunion experience for the two of us to talk through. And actually we're talking about something that the two of us deal with and I'm wondering if you could help us set the stage for our audience. They may not be dealing with TTP. And so if you could maybe give us a starting point for what is thrombotic microangiopathy and how does that fit in or how does thrombotic thrombocytopenic purpura, gosh, a lot of mouthfuls here, how does that fit into this category?
Because of the mouthfuls, I may just resort to using the abbreviations that we use. So TMA for thrombotic microangiopathy and then TTP for thrombotic thrombocytopenic purpura. These are disorders, really they are disorders of clotting. They are disorders of the blood and of the immune system. So really what thrombotic microangiopathy is, it's a finding in the blood where you form small microthrombi in small blood vessels, which leads to ischemic changes. Concurrently because of these microthrombi, you see specific changes in the blood, on the blood testing. One of these, the classic finding is microangiopathic hemolysis, which specifically means finding of schistocytes. Schistocytes are sheared red blood cells. So when you look under the microscope, normally you see these nice round red cells shaped like a donut, but schistocytes really look like red cell fragments. They're like little pieces of the cell floating around. And when you see multiple of these schistocytes, we call it microangiopathic hemolysis.
Generally concerning finding is when you see at least two of these in high-power field. But overall, any, you should start kind of questioning if you see any of them. And concurrently, because of the consumption of clotting cells of platelets in these microthrombi, you also see decreased platelet count. So classically TMA will give you this microangiopathic hemolysis and low platelet count. Now the microthrombi generally it's not something you will see. The findings in the blood are indirect evidence of these microthrombi in the blood vessels. But as it often, for example, affects organs such as kidneys, on kidney biopsy, sometimes you can see these TMA, these microthrombi. And that's kind of the pathological finding that you will see.
And thrombotic thrombocytopenic purpura, TTP, is one of the subtypes of the TMA and it's one of what we would generally call maybe a primary TMA in that there is a very specific abnormality associated with this and very specific treatment. TTP occurs when there is a defect in a special enzyme called ADAMTS13. It's one of the metalloproteinases in the blood. What ADAMTS13 does is it cleaves, it breaks up von Willebrand factor multimers. And I may go back a little bit to explain what they do. So when first your body forms a clot, one of the first elements, one of the first stages of clot formation, is when platelets attach to von Willebrand factor multimers. Von Willebrand factor multimers normally are coiled up in the blood. They're large proteins, they open up and the platelets attach to them forming a clot.
So ADAMTS13I keeps the von Willebrand factor multimers the right size, so to speak. It cleaves them into these smaller, active pieces. Well, when you don't have enough of this enzyme, which is the primary problem in TTP, you form these ultra-large multimers, and what they do is the platelets, they actively catch the platelets, platelets attach to them, which leads to these strings of these clots in the microcirculation, which ultimately leads, again, to the microthrombi, the strings, the red blood cells, when they flow across these small blood vessels, they shear up. That's why we see the schistocytes and that's how you run into problems with TTP.
I really appreciate that for our audience. We have a diverse audience of laboratory professionals, clinicians and students. And I think probably for some people, TTP has been something that maybe they learn about in school. Because as you're saying, it's kind of a characteristic. But I really appreciate how, for our audience, you took that dive into that, to explain what do we mean? What is happening for patients in this condition? And I love that you're showing that's why. Why are we seeing schistocytes or sheared red blood cells is because of this idea of having these strings and clots that are just cutting these almost like, I don't know, what is it, like a cheese grater or something like that, cutting these red cells into pieces and then we see these fragments when we're looking at the peripheral sphere. So it's really kind of helpful I think to unpack that a little bit for the audience.
So I guess what from your perspective, and as an expert that treats this, what's important for the laboratory professional, student and clinician to appreciate it about TTP? So I mean obviously it's given during medical school as a characteristic disease, but in practice, what's the important thing to know about it?
Yeah, no, it's a very good question. And I think because TTP without treatment carries such high mortality, it's 80, 90%. So we always have it on our radar and I think we always watch for these schistocytes on blood smear, especially if a patient presents with low platelets and hemolytic anemia, where either the laboratory testing reveals that there is hemolysis, low haptoglobin-elevated LDH, or somebody from the lab calls you to let you know, "Hey, I'm seeing schistocyte on the blood smear," or it's reported kind of in laboratory tests. So I think just keeping that on the radar as a potential diagnosis. I do think in our kind of experience seeing very diverse patient groups, transplant patients, patients with also other TMA syndromes like atypical HUS, in practice, probably most patients that we see with schistocytes don't have TTP. And nevertheless, it's always that syndrome that you have to rule out, that you have to act on and you have to act on relatively quickly.
So I think just keeping that on your radar, knowing that that's a possibility, is extremely important. And generally, we always appreciate a call from the lab, because usually the lab is the first line, that the smear is abnormal, there's low platelets, there is the hemoglobin, those always gets reviewed. We appreciate a heads-up from the lab team to let us know that they're seeing something concerning, specifically schistocytes. Because clinically we do, we definitely want to know about it. And then it's so important to know because the treatment has to be instituted very quickly. And that's when you come in, I think when we ask you for help, because TTP is caused by deficiency of this ADAMTS13 enzyme, and obviously it can be genetic. You just don't have a gene to produce good, adequate ADAMTS13. Or more commonly, you developed an antibody immunity against this enzyme and you're attacking it in a sense, and you don't have enough levels.
So the primary treatment is to replace the ADAMTS13, and also to remove the antibody. And that's where plasmapheresis comes in. So it's very important to get that started quickly because that's that standard of care. We will talk maybe later on that. Maybe not for the long future where we're soon going to have these additional treatment options that may replace plasma exchange. But still right now, obviously it's still very important to institute that treatment and that involves calling your blood banker or, I think, in different centers it may be, I don't know, nephrology who runs the plasma exchange, hematopathology, sometimes hematology runs the plasmapheresis. So you have to get that started, get the line in and get the treatment started quickly in addition to trying to eradicate the antibody. So I would say the vigilance, that's one thing. And two, knowing what to do once you have suspicion that it's TTP. And also, obviously, sending the testing for ADAMTS13.
It's so important. So I think top of mind hearing that, 80 to 90% mortality. I mean that just sends off alarm bells and also, I think, reinforces why is it a characteristic thing that we're talking about? So just what it can mean to a patient's life in terms of losing it. And the idea you're talking about the importance of initiating very rapidly, something like plasma exchange, plasmapheresis, to treat the patient. So this isn't something that like, "Hmm, let me sleep on this and cogitate and maybe after then ..." This is something that needs a little bit more of an urgent urgency to it. I also like that you highlight the vigilance of thinking about it. I wonder maybe for our audience, are there some common things that you mentioned like we see transplant patients that might have a thrombotic microangiopathy. So Dr. Wysokinska, is there a way that you sort of might rule out or decide, oh, I'm concerned about TTP. But are there some common ways that you're ruling it out? What do you do there?
Absolutely, and thank you for that nice question as a segue into the PLASMIC score. So there are prediction tools that we can utilize to predict, to define, how likely it is that our patient with TMA does have TTP. There are actually a couple of prediction models. I think the one that probably we use the most is the PLASMIC score, which is based on very, very specific clinical questions that help you narrow down, is this the patient you think that may have TTP? I think it's about six questions or so total, that take into account exactly, is this a transplant patient? Does this patient have malignancy? What is their kidney function? Do they have laboratory findings that support that there is a hemolytic process going on? It takes into account actually, patients MCV, so whether it's low or not.
So based on that, you add these points up and you come up with a score, and if the score is five or higher, it puts the patient into that intermediate higher risk category where you think, yes, I should pull the trigger on some of on the management or on starting plasmapheresis, on starting immunosuppression. Additionally, as part of evaluation, obvious, you want to send ADAMTS13 testing, which once its back may help you guide the next step. Do you need to continue with plasmapheresis? Is it really TTP or is it one of these other processes? And then you can back off some of these more intense therapies like plasmapheresis or other treatments.
So as I hear you there, it sounds like the PLASMIC score, and I think we can link to that in the show notes for listeners, but it almost is functioning the way, I guess I'm thinking about a lot of people might be used to the 4Ts score for thinking about HIT or heparin-induced thrombocytopenia. And, I guess, would you think of the PLASMIC score as a similar thing, as a tool somebody can use to evaluate the likelihood that they have TTP?
I think so. And with the newer ISTH guidelines that maybe, updates at the recent ISTH meeting, I do think that probably will be definitely incorporating it, incorporating it more, and it's definitely something we utilize in our clinical practice. So yeah, I think definitely a big part now of the initial assessment of these patients.
Right on. And so how are things changing and what's evolving in the practice of TTP?
Yeah, so exciting things are happening. We talked about red plasmapheresis, which is a great way to remove the antibody and replete ADAMTS13. But it really increases the level of the enzyme to the safe levels, in that the whole microthrombi process stops, but still the level remains low. And we know for patients with TTP long-term, those that have the thrombotic processes controlled, they have normal platelet count, but even if they remain at low ADAMTS13 level, they tend to have more cardiovascular thrombotic complications later on. So there is something about controlling the acute process, but also long-term consequences for these patients that we're now finding out may be tied into the ADAMTS13 level by itself. So there are some novel therapies that are coming out. One of these is recombinant ADAMTS13 which was FDA approved, I think, in late 2023, for patients with congenital TTP, so those that have a defect in ADAMTS13. There's over 200 of these multiple mutations identified that leads to this process.
It's a very rare disorder. So these are not huge clinical studies. Nevertheless, patient's treated with this recombinant ADAMTS13 in a prophylactic and on-demand treatment had very nice responses in treatment of these acute TTP episodes and in reducing the risk of them having any acute TTP events. So this is a very exciting kind of a novel treatment options for these patients. Also, I do believe around May 2024, there was a case report also in New England Journal of Medicine, of utilizing this approach in a patient with acquired, so with more common immune TTP. Which is what we see more commonly in our practice. This is [inaudible 00:17:21] autoimmune TTP with development of this ADAMTS13 antibody. It was a patient that was refractory to standard treatment options, plasmapheresis, sorry, plasma exchange, steroids, immunotherapy, caplacizumab which we'll touch on shortly, that responded really well to this compassionate use of recombinant ADAMTS13.
So I do believe there is a clinical trial now looking at this as a kind of a standard option in addition to plasmapheresis in immune TTP. So we'll probably have evidence in the near future that it can be used upfront and it might be in the future used instead of a plasma exchange for these patients. So that's kind of an exciting development with TTP. Additionally, a drug called caplacizumab, which has been approved for a TTP for a while now. And I think there is still a little bit of a debate in its role upfront. When you look at the guidelines from International Society of Thrombosis and Hemostasis, it is suggested to be used upfront in all patients with TTP. It is given just before starting plasma exchange and then afterwards for about 30 days total. It does reduce the duration of plasma exchanges. It helps with some of the risk of certain complications.
There is some evidence that maybe it reduces risk of death in certain kind of meta-analysis. It is, however, relatively expensive, not available everywhere, and there is a slightly higher bleeding risk. Actually, maybe I should explain that what caplacizumab does is it blocks the binding of Von Willebrand factor to platelets. So as you can imagine, that's what we want because that's causing the problems, but by itself it also increases bleeding risk. So there is that seen in clinical studies with very rare cases of serious bleeding.
So I think there is concern, justifiably sometimes, about using caplacizumab upfront, and I think we're still working maybe on refining where should we be using it. And I think certainly in patients who have quite pronounced neurological symptoms, when you worry about CNS ischemic changes, severely ill patients, I would certainly think in a patient who previously had a stroke related to TTP and now they have a relapse, that's certainly caplacizumab, this drug would be used upfront.
And also there is an ongoing clinical study also looking at it instead of plasma exchange. There is certainly case reports from Europe, even large case series, in patients that did not want plasma phareses, patients that could not have plasma exchange due to religious beliefs, where just using caplacizumab to prevent the binding of von Willebrand factor and platelets, while there's that in the background, rituximab is used and steroids to eradicate the antibody, that is actually fairly effective and these patients have done well. So a large study is now ongoing multi-center, where caplacizumab can be used up front instead of as a backup with plasma exchange for patients with TTP. So a lot of exciting developments with these new options.
Yeah, it sounds like there's a number of tools coming out. And it also sounds like, because classically it's just basically been plasma exchange for patients, if there was any delay starting plasma exchange, the classic teaching was you would do a plasma transfusion until somebody could get exchanged, but it sounds like with these new tools, and what I'm hearing you saying is that in the coming years we're going to get a fair amount of sophistication of, I guess maybe that's my to wrap this up question. It sounds like we'll be getting more sophisticated. Do you think at some point we might be realizing maybe there's subtypes of TTP and why this patient maybe would be treated well with caplacizumab or that case report, this patient is going to be doing well with the recombinant ADAMTS13?
Yeah, I think that's a great point. Yes. I mean, it's a relatively rare disorder still. So it's great that we have these multi-center studies and I think they're looking at a lot of parameters exactly to better refine which patients would best benefit from each approach. So yes, and I do think that now we're refining the treatment upfront based on the PLASMIC score, but also based on the ADAMTS13 level, based on the clinical presentation, so I definitely can see in the future, because we're going to have these, so to speak, the abundance of different options and different approaches, where there would be a role for very individualized management. I think actually that's going to be very exciting.
We've been rounding with Dr. Wysokinska to talk about clinical updates on TTP. This has been a wonderful reunion for me. Thanks for joining us today.
Likewise.
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