← Blood, Sweat and Smears - A Machaon Diagnostics Podcast
Blood, Sweat and Smears - A Machaon Diagnostics Podcast
Talking to Dr. Toyosi Onwuemene about TTP and the value of Hematologists
00:37:14
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- [00:06]
A
Hello and welcome to Blood, Sweat and Smears, your Macheon Diagnostics podcast with tag team hosts, including Our medical director, Dr. Brad Lewis, senior director Bjorn Stromses, that's me. And other guest hosts. We hope you find these podcasts interesting and informative. Thank you for listening. And away we go.
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B
Foreign.
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C
So all of you, welcome to another episode in Macheon's Blood, Sweat and Smears, a hematology podcast. I'm Brad Lewis and I'm here today to talk about TTP with Dr. Toyosi from Duke. She's an associate professor. Actually, she's a. More importantly even than that, she's a hematologist, one of a very small number of us around these days. Hopefully we'll talk more about that at the end of this podcast. But she's a hematologist who's an associate professor in the Department of Medicine and also in the Population Health sciences department. And some of that will become clear as we talk about some of the more unusual presentations, unusual aspects of ttp. We're going to talk a bit about ttp. We'll talk about how to approach it up front and then some of the pitfalls that you run into in approaching the diagnosis of ttp. I think you may have a case you wanted to begin with, or we can jump into the diagnosis.
- [01:26]
B
Sounds good, Brad. Thank you for having me.
- [01:29]
C
Oh, thank you so much for doing this. It should be fun.
- [01:31]
B
My pleasure. So the case that I have is a case of a young woman. This is in the midst of the COVID crisis, and she comes into the ED because her primary care doc sends her in. She presented to a primary care doctor that day with a platelet count of 50. She was complaining of bruising. The PCP saw the platelet count and thought, ah, you know, it's not that low. Let's see when we can get her in with hematology and send her home, because she was otherwise well. And then the PCP gets a call from the lab saying, we see schistocytes on the blood film. And so the PCP calls me and says, well, she's well, the platelet count of 50 is low, but not terribly low. What should I do? And because I'm a hematologist and I'm always thinking about ttp, I say, send her to the emergency department. Unfortunately, she proceeds to be in the emergency department for about a day or two, because remember, this is. This is Covid times, and she wasn't that sick. And the ED docs are not impressed by a platelet count of 50. So by the time we figure out that she's in the emergency room and we need to see her, she's already ready to leave ama. And fortunately for her and for, I think, for everyone, she stays long enough to start getting empiric plasma exchange and for her results to come back. And she's diagnosed with ttp. And so I bring up her case because she's a little unusual in that we think about TTP sometimes as an acute diagnosis and people are critically ill. Many times we see patients earlier on in their course where there's some platelet activation. We can tell, but they look well and. And so, yeah, that's the case. I wanted to share, I wonder if you wanted to share any comments about it so far?
- [03:18]
C
I think it's a great case and it may serve as a backbone for a lot of the things we're going to talk about. So when I have residents, I often, on the first day of our attending, I used to attend on medicine. On the first day, I would tell them that, remember, every time you see a sick patient who has anemia and thrombocytopenia, that's ttp, and their jaws drop and you can see their minds start to churn as they think, oh, my God, how many cases of this have I missed? And I said, no, I'm lying. That's why I'm probably wrong 99.9 of the time. The point is that if you don't think about TTP, or at least or TMAs, I try to think about TMAs first. But if you don't think about it, every time you see a patient who could have it, you're going to miss the one who comes through that really does have it. And then my question maybe back to you is sort of, where do you tell people to anchor? I mean, clearly, schistocytes. I mean, my teaching has always been, if you see schistocytes, you've got a tma, you're done. There are a few other things. Leaky cardiac valves and Kasselbach Merit syndrome and a few other things that give you schistocytes. B12 deficiency can fool you. But first pass, you got schistocytes, you've got a tma. You need to be moving forward and making that diagnosis. And it could be simple. It could be a viral related tma. We see that with COVID There were a lot of other possibilities here, but schistocytes make it. But what if you hadn't had schistocytes? You have thrombocytopenia. The thrombocytopenia enough to make you think at all seriously about a tma. When do you.
- [04:48]
B
Yeah, it's a great question. I think I agree with you 100 of the time you have anemia and thrombocytopenia, you should think ttp. I think we're doing a better job thinking about ttp, at least at maybe more tertiary academic medical centers, probably less so where people are in their local community hospitals or EDs. But I agree, because you don't want to miss a patient with ttp. I would say that classically we thought the person who's acutely ill with anemia and thrombocytopenia, but sometimes it's a mild thrombocytopenia, as in this case, A platelet count of 50 is low, but not enough to make maybe an emergency department doctor who's used to seeing maybe people coming with platelet counts of 10, not enough to make them sneeze. But I agree that that's the first thing you should think about, because thinking about it at least allows you to go looking and to be able to clarif. I think you're right. There's so many situations in which we see tma, and so patients come in with pretty bad high blood pressure. You can see schistocytes in the blood film. A patient gets dialysis in the morning, they'll have schistocytes on their blood film. And so having the opportunity to look at the blood film, and I think it's made easier now by access to digital slide technology like television. I think it's important to, to think about TTP so you can start looking and also look at the blood film and do the blood work. But you're right, everyone should look for TTP as soon as possible. And I know we're biased because we're hematologists and sometimes no one's thinking about it, but that's why we're here.
- [06:23]
C
Yeah. And again, I think this case is a great example of it. And I, I try to tell my, my, my fellows, you really want to think about TMAs before you think about TTP, because there's so many others. And what I get is a lot of people who call me and they say, I thought it was TTP, but now you're telling me the Adamts 13 so it's not now what do I do? And their hands go up in the air and they just don't have any idea where to go next. And I said, well, let's take a step back. What you really meant was you had a tma which you still have. And now we know it's not ttp. We have to figure out which TMA it is. As we work our way through this case is interesting because with just thrombocytopenia, unless there was some significant anemia, I'd be hard put to not think about itp. And, and then as well as every other TMA that was possible in there, it was going to be tricky. The schistocytes push obviously drop you over the fence. Although at that point, if they'd gone and gotten a plasmic score, it would have told them that this patient doesn't have TTP.
- [07:20]
B
That's right.
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C
That's right. That 50,000 platelet count. I'm kind of with the ER docs in a well patient, that wouldn't have shaken me up. And then the question is, where do you go from there without any organ damage? Proteinuria would have been something I might have looked for. But it can be tough and these things do stutter. And we'll talk more about that maybe when we talk about congenital ttp. But you know, these, this, these kind of things can stutter up on you a little bit. What if you presented with. Go ahead.
- [07:50]
B
No, I love your perspective. The truth is we should take a step back and ask what is going on. Tma, I think, is the broadest category and we should start from there. I think of the corollary of, of hit, right? People say, is this heparin induced thrombocytopenia? And when we say no, then people are stuck. They're like, well, I don't know what to do now. It's not hit. Similarly, you come in with guns blazing, you start plasma exchange, you say, oh my goodness, this might kill you. And then it turns out not to be ttp. And then we withdraw from the patient because, you know, we withdraw all this active therapy, but now we're stuck because we started with a close ended perspective. So yes, it's important to take a step back and say, okay, there is a thrombotic microangiopathy. Clear. And then now think about what is on the differential. We're ruling out ttp, but we're not going to stop when we find out it's not ttp. We have a plan. And so it's kind of thinking more holistically. I think we've done a better job educating people around needing to look for TTP when they're schistocytes. What we haven't done as a good job of is now helping people understand the bigger spectrum of TMA and how we should be approaching diagnosis in a systematic fashion. To your question, this patient. You know, I will say that earlier I may not have been so worried. It's just that, you know, once you start to see edge cases, then your index of suspicion is a little bit higher. And to your point, I think her plasmic score was 4. You have to have a 5 or 6, at least a 6, 5 or 6, at least to just have a high enough index of suspicion. But she was 4, so she wouldn't have gotten any plasma exchange. Except that about a year or so prior, we met a young woman who had a stroke and had very slight thrombocytopenia following the stroke, and then subsequently was identified to have TTP based on our viewing of her blood film, which had schistocytes. Otherwise healthy young woman, but this was her second stroke. And because I had seen this kind of unusual case at least once or twice, I thought, at the very least, we owe it to her. We owe it to ourselves to evaluate. And to your earlier point, LDH is not significantly elevated. Platelets of 50 are respectable, even though they're a little bit low. And she didn't have significant anemia, which, you know, in a. She was in her 40s, so you're not very impressed by a mild anemia. But my index of suspicion was high. And I think what was fortunate for this patient is the earlier outreach from her primary care provider, because the challenge in hematology is unless somebody introduces us to the patient, we may never have the opportunity to help make the diagnosis.
- [10:32]
C
I'm just curious. What was the Adam TS13 on this patient?
- [10:37]
B
She was less than 10%. She was. She was the real deal. She was the real deal. Yeah.
- [10:42]
C
And I think less than 10% or less than.
- [10:45]
B
She was less than 5%. She was less than 5%. You know, the assays changed over time, so I don't remember if it was when we were reporting less than 10% versus 5, but she was. She was low. I don't remember.
- [10:57]
C
Earlier on, we had talked about a problem people often have with sick patients who come in like this is they anchor on some other disease and they decide, well, it's ITP or, well, it's Covid or it's sepsis. It's some other thing. And they're so anchored on that diagnosis that they let the TMA percolate off to the side and don't really move over and focus. And I. I'd add in this. The other side works, too. That is, I've I myself, I, I do more ahus than I do TTP probably, but that same thing, it's easy to anchor on one of those diagnoses. I know this is going to be ttp, I know it's going to be hus and I just kind of move along that way. And you get them started on a plasma exchange, you get them started on a C5 block or whatever you're going to do, and then you realize that you've misanchored sometimes much too far down the road. And I've seen people, you know, go on with plasma exchange for a week and I've gone on with eculizumab for quite a while before I finally realized that this just isn't percolating, it's not beginning to add up the way I hoped it was going to. And what I tell myself is that the mistake of treating in these settings is often less than the mistake of not in some of these sick patients. And I'm willing to mistakenly give a plasma exchange or two and I'm willing to mistakenly give a dose of a C5 blocker when I'm reasonably sure. And if I turn out to be wrong, so be it. And then we move on. As long as you don't get too awfully anchored.
- [12:20]
B
Yeah, yeah. I think what's most important is that because it's in your mind and you're thinking about it's on the differential, then at least you can do a comprehensive assessment and feel confident in your evaluation. And brad to the work that you do, it's so important that we have access to ADAMTS13 activity and that the turnaround is super fast so that even if we are going over the top and treating with plasma exchange, we have the answer soon enough to make the diagnosis or at least to change direction. And so I just want to put a plug in for the importance of access to Adam 13 testing as soon as possible.
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C
I wasn't going to throw that plug in, but I'll take that opportunity and obviously that's why we do it. We started doing the ADAMTS 13 when I was a professor at UCSF because it took them five to seven days to get me back my ADAM TS 13. And people died waiting for the ADAMTS 13 to come back so we could decide which of the TMAs we really had there. And that that doesn't play out. And now with, with Matrian, the Adam TS13 is a 24 hour turnaround pretty much everywhere in the country. And we get samples from New York, you know, from New York Coming to us. We can, we can get those samples out. We get, same day we get the sample, we get a result out, which for many, many places is actually faster than they can do internally. And it avoids that two or three day sitting on your hands period, as the patient said. This patient is fairly stable, but some of them are not in the slightest stable as you're sitting in your hands waiting to see which direction you want to move in.
- [13:53]
B
Absolutely. And what we don't talk about is the consequences of being wrong and over treating. Right. Because it's not, it's not a small thing to give people 15 units of plasma at one time. There are many reactions that come up. And so to be able to stop treatment as soon as you need to is also critical as well. So. Yes, absolutely.
- [14:13]
C
Yeah, yeah, yeah. One of the cases I, that I had when I was attending was a young woman who came in with what looked for all the world like bad ttp. And over the course of the five days, she got up to twice a day plasma exchange, along with some chemotherapy and immunosuppression and high dose steroids. She got infected from the catheter that she had placed. She's going down the tubes and they're just becoming more and more aggressive. Finally, on day five, shortly before she died, the Adam TS13 came back at 50%. So she never did have TTP. There was a, you know, it was something else. So, yeah, you know, I couldn't agree more. I think there's, there's some downsides to being stuck in a treatment, although I think the worst downside is being stuck with the wrong treatment. And you need to make an answer. I feel real strongly about getting however you get it. And there are lots of places besides Matrion Mayo can often turn it around in 24 hours for people. I think you need to get that Adam TS13 back really in 24 hours. I think there's just, there's nothing else that's acceptable, despite personal bias about that sort of thing. So this case was interesting because things were so mild and you had some interesting lab abnormalities. What about the other side, when people don't have a lot of lab abnormalities? You alluded to a case like that, but patients come in with, you know, unexplained, slowly progressive renal insufficiency and then failure or strokes. You, you had mentioned the patient with strokes. I've actually seen several of those myself where young, young people have recurrent strokes and you don't really have a good, good answer. And often it takes a while before people come to thinking about TMA as a possible cause of that, of that stroke, cardiac disease. We've actually seen several people develop heart failure or cardiac arrhythmias, looking like some of them, they had myocardial infarctions without a good reason for this young person to be doing that sort of thing. We've actually had a couple people who went to heart transplant for cardiomyopathies. And it wasn't until after the transplant that somebody took a step back and said maybe that TMA that was going on was actually the reason. And in fact, in all the four I think that we've seen, it's always been atypical hus, but they had a TMA that was presenting with organ damage. So how about organ damage stuff? When. When do you tell people to get excited about, can we all see a million strokes, cardiac problems, heart failure, um, obviously renal insufficiency? When do you tell people to think about a TMA in those settings?
- [16:38]
B
Yeah, I think that we should always be thinking about TMA whenever there's anemia and thrombocytopenia. What is challenging, right, is when you're concerned that it's sepsis, and there's so many things that mimic sepsis. I remember, as you were talking, the case of a young man who came in with. With an mi. It was an acute mi. Cardiac troponins were very high, and. And they assumed that he had an MI and sepsis, and that's why the platelets were low and there was an and. So finally we made the diagnosis of ttp, but that was the primary presenting factor. It was the acute mi. Now, those patients typically don't go to hematology because you expect to have thrombocytopenia and anemia. They go straight to the cardiac cath lab, and hopefully they do well, but not always. And so I think maybe the bigger opportunity is how often do you involve hematology in making these diagnoses? Because I think we do think a little bit more holistically about the TMAs and trying to make sure that we are not just anchored on one diagnosis. But if you think about it, we need a gatekeeper to let us in. Someone's got to say, this is important enough for me to engage hematology. We have patients in the icu, so TTP can present with sepsis. Right. So infection can be a trigger at the time of diagnosis. And so you come into the hospital, you go to the icu, you're getting all the treatment. We're not surprised by the anemia and thrombocytopenia, we're not surprised by the schistocytes because it's maybe dic, but it's not. And so I think, you know, I'm not necessarily advocating everyone consult hematology every time you see a patient with thrombocytopenia, but I think it is important, especially when the patient is not responding to whatever course of treatment you've prescribed, to step back and ask the question, well, could this be something different? And we have a couple of cases like that where, you know, a patient was in the hospital for up to. Up to a week or two with sepsis that wasn't responding to antibiotics and subsequently was diagnosed because somebody thought, let's look at the blood film and try to understand this better.
- [18:47]
C
Yeah. Yeah. Do you have any tips? What do you do to get yourself in sooner? And I might even disagree and say, I wouldn't mind being called for every thrombocytopenia. That isn't an obvious thrombocytopenia. Yeah, if you're giving them chemo, that's. That's fine. But I've had cases of thrombocytopenia with renal failure. And they say, well, it's from the renal failure. And I say, no, it's the anemia that's from the renal failure, not the thrombocytopenia. And I've really gotten to where if you see thrombocytopenia, you probably want me to at least run my hand over the surface of the chart and say, you know, it's not pseudo thrombocytopenia. It's not, you know, if. If it's itp, you know, is it a congenital ITP where I have to worry about secondary malignancies? There are so many little pearls that a hematologist can bring in. Maybe it's another argument we can get to that at the end. But another reason why we ought to have more hematologists is so that.
- [19:33]
B
Absolutely. Yeah. Yes. Sitting here with you, Brad, I want everybody calling me all the time when I'm in the hospital on consults. I would prefer that the calls, because we are so busy and it's the reason we do need more hematologists. We. And I mean, it's just such a. It's a great work that we do, if I may say so myself. But I think one thing that we do help is help interpret. Right. How serious is this. To what extent is this sepsis related? To what extent is this renal failure the cause or the. The subsequent response to the, to the tma. And I think at the very least we can have a conversation that's thoughtful in helping people think through the diagnosis. So I think that's something that's we're easily able to do and amenable to doing. And you do it, Brad, a lot. Just talking to the primary clinician and having a conversation that steers you one way or the other. So I agree. I think, I think the more hematologists you have in your life, the better. And, and, and definitely involving hematology early on is, is critical.
- [20:40]
C
Yeah. Still don't know quite how to sell us to gatekeepers. We've tried going to the intensive care docs, we've gone to some of the hospitalist groups because they're well organized enough that you can kind of grab them all at one time if you're, if you're lucky. But you know, so many other possibilities. We, I mean, one of the young women I had who had a stroke due to a tma, she was seeing neurologist after neurologist and several of them had written at the bottom of their notes, once we get this figured out, she's young, 20ish year old woman having recurrent strokes. They said once we figure this out, we should probably send her to see a hematologist to figure out why she's anemic and thrombocytopenic. But you know, it was finally an ER doc who gave me a call and said this is just really weird, but it's hard. There ought to be, you know, there's sort of an outreach that I think hematologists need to do within their hospital system to let people know that they're, they're available for everybody. And I think the guys I mentioned, those specialties tend to see a lot of these patients early on. Maybe nephrologists and rheumatologists too, Although they tend to think about calling hematologists in my experience.
- [21:40]
B
Yeah. When we've looked back at our cases, we've seen that patients have been to orthopedic surgery with osteonecrosis. We've seen people go to ophthalmology, we've seen people go to ob. I mean people are accessing, talking to specialists about different manifestations of TNA without talking to hematology. And so I agree, I think there's the importance of outreach but also recognizing the value of hematology to a system. Right. It's not the individual diagnoses as much as how can we get involved early enough so we save you those 10 days in the hospital without clarity, how do we get involved early enough in thinking about other disease entities where we save you the additional seven or eight units of FFP that you didn't need? And so I think maybe it's an opportunity to think differently about how complex hematology is, is used in a hospital system so that we are accessible to answer those complex questions sooner and not after two weeks in the hospital. And, you know, so there's just opportunity to think differently about how do you use your specialists when there's a shortage and the value is really in cost savings more than in accumulating patients.
- [22:57]
C
Yeah, yeah. Kaiser in Northern California realized back in around must have been about 2016, that they needed to have hematologists there to prevent mistakes from happening, to prevent patients from sitting around in the hospital when they didn't need to. And they created their own fairly substantial sized hematology program. And even with a big hematology program, they found they didn't have enough and they began to very actively use. I always think of as curbside consulting, but a computer based consulting program where you could send a message to a hematologist, get a quick message back, and one hematologist can deal with a lot of those little curbside consults. And you know, half the time, two thirds of the time, you can solve it right there. Oh, yeah, this anemia is clearly going to be this, you know, give them some iron and then call me back if that doesn't take care of the problem or this anemia and thrombocytopenia in a patient who's a little bit confused, that gets me excited. Why don't you, you know, tell me where they are and I'll go see them right now. But that kind of curbside consulting, formally or informally. Yeah. Can make a big difference too, in these things.
- [24:00]
B
Yeah. I think our, one of our great values just to piggyback off of that, is our ability to interpret. Right. That's what we do well. And so the, the opportunities is not necessarily to see the patient always as much as it is to say, okay, well, I'm looking at this set of labs. Here are the results. Is this, is this PTT prolonged? Is it, is it correcting? Those are the kinds of things that we easily do and I think would be very valuable.
- [24:27]
C
I agree, obviously. Right. Any other pearls that you wanted to throw out there before we. I was going to talk a little bit about congenital TTP if you want to, but any pearls you have about diagnosing TTP that we haven't talked about.
- [24:39]
B
I think that, I think the plasmic score is helpful. I think that we shouldn't necessarily anchor on the plasmic score if we have high clinical suspicion. And I. So it's most helpful if you don't have kind of a history, a rich history of having managed a lot of patients with ttp. And so everyone should know how to calculate one and also think a little bit more deeply beyond the plasmic score. But I think the positive score is an excellent tool just because of its predictability.
- [25:09]
C
One of the things I often throw out there is people sort of anchor on the, on the haptoglobin. They want to see that there as a marker for hemolysis, but it's an acute phase reactant. And you talk about these patients who often are septic and then they move on into a tma. And with those patients, I'll see the haptoglobin shoot through the roof and then drop back down to normal as they begin consuming. And that normal haptoglobin throws people off. And you know, the other thing that kind of alluded to earlier on, but a fair number of people with, with TMAs, including TTP, don't have schizocytes up front. I mean, most of the ttps get it in my experience, within a few days. But that can be a big few days sometimes. And making that, being willing to make that leap sometimes before you have the clearly diagnostic schistocyte just because all the rest of the pieces fall into place and then it's that uncertainty problem of how many pieces does it take? You know, the LDH is up, the platelets are down, but the hemoglobin's normal or the, you know, and then the haptoglobin is normal. When, when is it enough? And I think you already said it, but. And the other pros you have, but some of it is just experience. That's why you need a hematologist. Somebody who's seen 10 or 20 cases of this before feels pretty comfortable saying it sure might be. And I can't think of anything else for it to be and let's just go for it.
- [26:26]
B
Yeah, I think one thing you mentioned that's worth talking about is the renal dysfunction. Similar to the case you mentioned. I've seen a patient who over time had progressive renal dysfunction, ultimately recognized to be TTP related, but who by the time he came to, had enough chronic kidney disease, acute on chronic, that people thought, oh no, it can't be TTP because of the creatinine is high and it's to your point about taking a step back and looking at the whole patient and their history and their trajectory and making sure we're not dismissive. So yeah, it doesn't look like your classic case, but let's go back and do the workup. Let's make sure we send the Adam TS13, let's do all the things that help us clarify the diagnosis. And then when we get to thinking about, okay, so it's not TTP, the NTS 13 has come back normal. How do we think about treating a complement mediated tma? And I'm curious to say at what point you say, okay, well, let's activate use of a complement inhibitor.
- [27:24]
C
So I sort of feel about the complement mediated TMAs the way you do about TTP. That's, that's probably most of what I see these days is complimediated TMAs. That's kind of an everyday, you know, several times occurrence for me. So it's, it's tough, it's probably the real answer and it's, that's why I'm so, so focused on thinking about everything as a TMA first, because you have a differential, but it's a fairly finite differential and you just work your way through it. And you know, eight times out of ten you can, in about 15 minutes, I can, with a good history and physical, I can work my way through the differential for, for TMAs. And once the Adam TS13 comes back and tells me it's not TTP, I'm done. I don't have anything else on my list except atypical hus. A complimented tma. And am I always right? No. I mean, I've been fooled by gastric cancer where they didn't have any symptoms, they didn't have a known history, but they had a tma. Well, give me a TMA without an etiology. I call it atypical hus. And then a week later when they get stomach problems and you scope them again, this time you actually see the gastric cancer that was probably there the first time, but we missed it. So I'm wrong sometimes. And that question we talked about earlier on most of the time I feel pretty comfortable treating once I'm reasonably certain rather than waiting to see how bad things are going to get before I treat. But yeah, it's really ruling out all the other possibilities. I'd love to say that we have a test that diagnoses it and I think, you know, the Johns Hopkins test, the modified Ham test they call it, is really Intriguing. I don't think it's quite ready to. I'm not ready to say that it's perfect, but, you know, the vast majority of the time if you have atypical hus, that test is positive. And the vast majority of the time, if you don't have atypical HUS or catastrophic antiphospholipid syndrome, the test is negative. And we've had quite a few cases where to all of us, it looked like it was going to be a case of hus. And then the mm, the modified HAM test, came back normal. And we went back and took a second look, and one of them, that pops to my mind, on second look, they found a big bacterial abscess in the prostate. And when they drained that abscess, the TMA disappeared. Until then, you know, we would have sworn it. We didn't do an MHAM on the gastric cancers that I've seen. But my guess would be that in those cases too, the MM would be negative and maybe send you back to relook to search again for some underlying malignancy or some other sort of thing you might have missed, you know, a more subtle case of lupus, which is. Which is one of the other things we've seen when that. So, you know, I think functional complement testing, like the M hand test and some other tests like that, Muzi has a similar assay. Those are coming. And I think a time will come when we'll be able to get one of those maybe at the same time as you get your ADAMTS 13 and then in the morning when they both come back, you know, which direction to move in. Are we talking complement or are we talking TTP or, you know, do I need to go back and do my homework again and look through all the other more subtle TMAs that maybe I missed on my first go round.
- [30:21]
B
Yeah. I think one thing that you highlight that's so important is the importance of the clinical diagnosis. We are focused on testing, and testing is only really complimentary to our thinking and the importance of having a plan so that when, as results come back, you're thinking, okay, well, this leads me to the next thing. And, you know, it's hard to. It takes time and experience to be able to develop that. But, you know, sometimes I worry that we're very focused on testing as the be all, end all, and testing really supports our clinical thought and the importance of continuing to hone that clinical acumen.
- [30:59]
C
Yeah. Although, again, one of the hallmarks, for me, one of the hallmarks of the practice of Hematology is. We have a huge amount of uncertainty in our business. I used to tell young docs who were thinking about being hematologists that you need to first ask yourself what your tolerance is for uncertainty. And if that makes you uneasy, you're probably in the wrong field. You need to go somewhere where they have more clear cut diagnostic tests.
- [31:22]
B
True. It's the most exhilarating. I mean, it's just what I love is to be able to walk in the room and calmly have a plan. And I think that's the, that's the biggest thing, because you're right, we don't know there is uncertainty, but what we do know is how to establish the hypothesis and test the hypothesis. And that's what they're testing and to be confident as we're moving forward that we're moving in the right direction. And I think that's a really cool skill that I appreciate having as a hematologist.
- [31:50]
C
Couldn't agree more. So let's get back to the TTP stuff. So I just had a case recently where a pregnant woman came in with a TMA. They got an Adamts 13 appropriately, and it came back at 12% with a low titer positive inhibitor. And they called me and they said, we've got a case of really weird ttp. And we talked about that for a while. And I don't think that was just really weird ttp. I think actually I know now that she had congenital ttp, which would be, this would sort of be a classic presentation. So, you know, it's one of those things where if you talked to me a few years back, I'd have told you you don't have to worry about it. That's really my pediatrician's problem. And I just stay away from kids so I don't have to think about things like DGK deficiency or congenital ttp. It's just nice that way I can skip all those disorders. And now we know that it's much more common than we ever used to think. The reason we thought it was so rare is we never looked. We didn't really have the tools for looking. Well, but now that we have easy, quick gene sequencing available to us, it makes it much, much easier to pick these guys up. So any thoughts about when do you tell people to think about congenital TTP instead of a regular case of ttp?
- [33:01]
B
Yeah. So the case you present is interesting because this was during pregnancy, which would be the time that we would trigger the thought about congenital. But also there was an antibody present and that's interesting because the presence of anybody does not necessarily confirm that you have immune ttp. And so it's important to think about the bigger picture. And that's where the thorough history and the physical is important, to really get a sense of what's happening in family, what happened when you were a child, and to get some of that history to help you make the diagnosis or at least think beyond immune ttp. I think another thing that's been helpful is also looking at their response to therapy, right? I mean, whose platelet count recovers within just one plasma exchange? You know, those are the kinds of things that give you a sense of, okay, maybe this is not your. Your run of the mill ttp. So again, it's. It's really about the pattern recognition and then thinking beyond, okay, well, if this doesn't act like immune ttp, could it be congenital ttp?
- [34:02]
C
Yeah, exactly. Like you, I look a lot at the response because not only do they sometimes respond too quickly, but if they don't normalize their ADAMTS 13 or at least come pretty close to normalizing it down the road, I start being suspicious. Because a lot of these congenitals, you know, they're 15% today, and then you treat them and they get better and they're doing great. They're 15% in a week and in a month and in six months, and it's just not going anyplace. And that makes me think about it. And as you mentioned, pregnancy. I mean, 20% of pregnant women presenting with TTP have, have congenital TTP. And the other side of that same coin, when I hear that, that somebody, you know, they think they have congenital ttp, but they had a pregnancy a while ago and didn't have any problems. I don't believe them is my first pass. If it's really congenital ttp, they didn't make it through a pregnancy without exacerbating. It's just reasons that I have to say I don't understand, but that, that just doesn't seem to happen very much. And like you said, the inhibitor, you know, that's how we differentiate immune from congenital. But it's not perfect, right? 20%, thereabouts of the immunes will have a negative inhibitor, and 10, 15% of the congenitals will have a positive inhibitor of a low titer, but still a positive inhibitor. And I think for a lot of people who don't do this much, like the one I just got called about, they don't really understand what the titers mean anyways. So getting back a low titer inhibitor doesn't set off bells for those guys. It's been fun talking about some of these different presentations of ttp. We still have more to talk about some other day. We need to get together and talk about some of the weird presentations that are stroke like that you've seen. But for now, I think we're going to have to pass. When we talk the next time, I really do want to have you give you a stool to stand on to talk about how important it is for really everybody to think about going into hematology. Just like thinking about TMAs, everybody ought to think about hematology at some point in their medical career. And those who are, you know, talented enough, clever enough, able to tolerate uncertainty enough, they ought to think about moving into it.
- [36:00]
B
Absolutely.
- [36:01]
C
Anyways, thank you very much. And for the rest of you, this, this was Blood, Sweat and Smears. Go ahead. I'm sorry, I didn't mean to cut you off to.
- [36:08]
B
No, I'm just saying it, it's the best kept secret.
- [36:11]
C
It really is. It's. It's easily the most fun of all the, of all the fields. I'm happier, I think, than anybody I know practicing medicine. This is just always a fun thing to be doing. All right. The end.
- [36:26]
A
That's it for us here at Blood, Sweat and Smears, a podcast produced by Matrion Diagnostics, your reference lab and CRO specializing in thrombosis, hemostasis and rare disease. Thank you for listening and if you have a question or comment or there's a topic you'd like Dr. Lewis to speak to, please send us an email to blood sweatandsmeersatrion.com that's M A C H A O N diagnostics.com youm can follow Macheon at Twitter at matriiondx. Be sure to subscribe to stay in the know. Share this podcast with clinicians you think might appreciate it. And we hope you'll join us next time here at Blood, Sweat and Smears.