A Year of mHam 2.0 - Three Observations with host Dr. Brad Lewis

A retrospective look at the Modified Ham (mHam 2.0) Complement-Dependent Cell Killing Assay, one year after its release.

Don't forget, this test has a STAT TAT of < 24 hours (M-F).

Visit ➡️ https://mham.machaondiagnostics.com/ to learn more. 

Transcript

SPEAKER_00: 0:05

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 Stromsis, that's me, and other guest hosts. We hope you find these podcasts interesting and informative. Thank you for listening, and away we go.

SPEAKER_01: 0:26

Welcome to another sort of episode in the Blood, Sweat, and Smears series of podcasts, but this one is obviously a webinar, so it's a little bit different. Wanted to talk a little bit about a new test we're offering called the Modified Ham test. And in particular, I want to talk about the test itself, but I also want to talk about some observations we've had now that we've had this test going for about eight months, nine months or so. So it's a bit of an over of a look back to see what have we learned about this really very novel test. So I want to, before I talk about the M Ham, I wanted to take a step back just a little bit and talk about why you care about the modified ham test. And the reason you care is because there is a group of disorders called thrombotic microangiopathies. This is really a pathologic diagnosis. It's swelling of the lining of small blood vessels that causes platelets to stick and then fibrin formation and shredding of red cells as they go through that. But hematologists have a hubris that allows us to believe that we can make pathologic diagnoses just by looking at the blood. Am I always right? No, not quite, but close enough for hematology purposes. So what I used to say to my residents is every time you see a case of anemia and thrombocytopenia in a sick patient, that is a thrombotic microangiopathy. Is that true? No, that is not true. Most of the time it's not, but this is uncommon enough and it's important enough to recognize thrombotic microangiopathies, that I think every time you see a case of anemia and thrombocytopenia, you ought to at least stop for a split second and ask, could this be my chance to see a thrombotic microangiopathy? Then what you want to know is does it meet the criteria? Does it have thrombocytopenia? Need not be severe. In fact, the thrombocytopenia, depending on which thrombotic microangiopathy it is, may or may not even track with the severity of the thrombotic microangiopathy, which I'm going to call a TMA from here on. There should be an anemia, but not any old anemia. It should be a microangiopathic hemolytic anemia. Red cells that are being shredded in the microvasculature in that process I described earlier on. Ideally, there would be schistocytes. That's what you see here. Red cells which have been shredded. They're not there maybe 25% of the time overall in TMAs, and it's worse in some particular kinds. Post-bone marrow transplant TMAs, for example, in pediatrics, 50% of the kids may not have schistocytes, at least not initially. Other signs that you have a maha when you don't see schistocytes are that the LDH, which is being released from these cells, is very high because the destruction is happening intravascularly, unlike so many other hemolytic anemias, where the destruction happens in the spleen, in the liver, in the bone marrow, someplace where your body is able to handle the detritus better. So the LDH and stuff doesn't cope as much. Similarly, the haptoglobin is typically low because hemoglobin is being released and it's being mopped up by the haptoglobin, then that complex is being excreted. Be aware, though, that haptoglobin is an acute phase reactant. So sick patient with a TMA, often the story, the sick patient part may elevate their haptoglobin, and then the TMA lowers their haptoglobin and they end up being normal or low normal. And then for research studies, certainly, you want to see some organ damage. You know, we kind of hope that sometimes we can make this diagnosis even before there's a lot of organ damage and try to head that off. And kidneys tend to be the canary in the mind. So you've made the diagnosis of TMA. The next step is to begin to go through the differential. And for those of you who are newer to medicine, this is not something you need to copy down. This is in every resource you could choose to look at. You can find a differential. Typically, we worry about TTP and atypical HUS because they're both rare, very severe, often fatal, and they both have great therapies when they are treated. So we worry about these. Although I don't mean to belittle the severity of any of the rest of these things I'm about to talk about. If the patient has diarrhea, then we worry about toxin-induced HUS, which sounds like it's related to AHUS, but is not really. And this is induced by toxigenic bacteria, typically E. coli, but Chigella and pneumococcide do it occasionally. Very, very unlikely if the patient doesn't have diarrhea. Although I've had a few cases where they kind of ran out of diarrhea, but that's another story. There are some rare congenital causes of TMAs. Typically, these are diagnosed because patients look like they have atypical HUS. They didn't get better the way they were supposed to. So you get genetics trying to sort things out, and then you find DGKE deficiency, cobalamin C deficiency, occasionally severe G6PD deficiency, congenital TTP can sometimes get in there and fool you a little bit. And then there's another story really about immunologic heperinduced thrombocytopenia. That leaves us with this other group of other possibilities. These are all interesting because everything here causes a TMA. Everything here also can trigger atypical HUS. So it can be confusing sometimes. And patients often present with one from column A and one from column B simultaneously. But DIC, mechanical destruction of the cells, which typically does not trigger AHUS, by the way. Malignant hypertension, which is a triple threat. It triggers AHUS, it looks like AHUS, and refractory hypertension is one of the more common manifestations of AHUS. Lupus, scleroderma, other similar autoimmune disorders can also cause TMAs. We'll get come to that a little bit when we look at some of our data. Catastrophic or thrombotic lupusanoagulant disorders, catastrophic antiphospholipid syndrome, that too, which may also be complement mediated, but that too can cause a TMA. Pregnancy-related TMAs, HELP syndrome, pre-eclampsia, those may also be somewhat complement triggered. That's a work in progress, I think, right now. Infections of every sort. Bacterial infections, obviously, if they're overwhelming bacterial infections, the kind that give you DIC, we expect to see a TMA, but milder infections can do it sometimes. Protozoal infections, acid-fast bacteria, TB can do it. You name it, malaria does it, lots of infections can do it, viral infections, COVID, HIV, CMV, for example. Malignancies can do it. Usually these are advanced malignancies. Occasionally it can be the first manifestation of a malignancy. Gastric cancer is notorious for that. Graft rejection and drugs, calcinurin inhibitors, gemcitabine, and a number of other drugs can also cause TMAs. So you've got a differential to work through. Most of the time, this is a very straightforward differential. So before I talk more about our data, just real quickly to look at this cartoonized version of the complement cascade, a couple of points I wanted to make. One is that at the bottom of the complement cascade, you cleave C5, C5B attaches itself to the cell membrane, it then assembles C6, C7, C8, and C9, forming a complex that destroys or punches holes through the cell membrane. That creates the C5B through 9 complex, most commonly by me at least, called the membrane attack complex. The way that comes to be a problem in atypical HUS is that this cascade is very efficient. And to keep it in check, you have a number of inhibitors. Atypical HUS is typically a functional defect in one of the inhibiting factors of the complement cascade, allowing the cascade, when it's stimulated, to sometimes get overstimulated and out of control. Similarly, it can be a gain of function mutation in one of the stimulators of the complement cascade. So that when the cascade is triggered by something, it then takes off. Now that may not take a lot of trigger. The alternative pathway is always on, for example, but antibodies can trigger the pathway with the autoimmune diseases we talked about, infections and malignancies. The antibodies can trigger it via the classical pathway. Infections, malignancies can trigger it via the lectin pathway. Also, anything triggers the complement cascade, you then require the inhibitors to keep it in check. If you don't keep it in check, then you begin to cleave too much C5 and you begin to have attacks on the on various membranes with kidneys being a particularly sensitive substrate. So what is this MHAM test we talked about? Let me just, because I get so many calls, asking me the question why is it called MHAM? This is not a ham test. The ham test was actually a test developed years ago as a way of diagnosing the very rare disorder, paroxysmal nocturnal hemoglobin urea. And you took the patient's red cells, which were very sensitive to complement destruction, and you added in serum with complement in it in a situation that was very conducive to activation of the complement and looked for destruction of the red cells. That's not what we're really looking at. We are not trying to diagnose PNH here. The original MHAM test, however, was a red cell that was modified to make it very sensitive to complement. So we took our red cells, not the patient's red cells, added the patient's serum on top of that, and looked to see if the patient's serum was able to lysensitized red cells. That turned out to be a difficult test to scale up, but a version of that, a next generation version of it, if you will, was to develop a bioluminescent immortal renal cell. So these are no longer red cells, they're now renal cells. They're bioluminescent when they're alive. It's an energy requiring process. When they die, they stop luminescence. So it lets us follow their activity, if you will. And then these are modifiable, and these renal cells have been modified to remove one or another or many surface proteins which protect the cells against complement. For our purposes, removing CD46, CD46 knockouts, if you will, makes the cells appropriately sensitive to complement destruction to give us sensitivity and specificity of this test for atypical HUS. We then take these immortalized bioluminescent cells and we add heat-treated plasma. Heat treatment destroys the complement, so very few are destroyed. You can add in normal plasma. And when you do, there's a little bit of destruction, but not a lot. There's complement activity in normal plasma, normal serum, really, but not an enormous amount. And then we add in, or if we add in AHUS, then the activation of the complement will destroy a lot. Our cutoff is if you destroy more than about 60% of the of the cells, getting less than 40% viability, you clearly have a typical H2S, or clearly have an abnormal complement mediated disorder. So this complement biosensor test, or more and more we call it the biosensor MHAM test, measures the ability of patient serum to destroy target renal cells. So you're looking, it's a functional test looking at the ability of the patient's serum to destroy cells. We can adjust the sensitivity, and we've done that with our CD46 knockout. It's similar conceptually in that it looks at complement activation to the soluble C5B through 9 or soluble MAC test, which many of you may be more familiar with, but it's quite different. This test, the M HAM, is a functional assay. It's looking at the ability of the patient's serum to destroy renal cells. It's looking at exactly what you're interested in. The soluble MAC, soluble C5B through 9, is a byproduct. You're measuring C5B through 9, which was bound by vitrinectin and some other stuff, inactivated and solubilized, stabilized, making it easier for us to measure it, but it's a byproduct. It doesn't measure the ability of the serum and with all the things that are involved in that to destroy renal cells. I believe that this complement biosensor test we offer is the first commercially available functional assay. I believe there are some others that have also come on. It's very similar to the functional testing that you might read about in Italy, in Chapel Hill out in Iowa, out of the University of Iowa, but our test is reliable and scalable. There are others are reliable. I'm not so sure about the scalable, and ours is quickly available with a 24-hour turnaround. This is from an article written by Michael Cole and his group out of Johns Hopkins. They developed the modified ham test as well as the bioluminescent modified ham test. And this is just two graphs that show the same thing. This makes the point that we can follow the activity of the cells over time. We don't do that as part of our routine testing. This looks at it in a static way, but notice here if you add normal human serum, there's some cell killing, but it doesn't cross the abnormal threshold. If you look at patients with atypical HUS, there's a lot of cell killing that's caused. If you add Eculismab back into the in vitro, you then abrogate the cell killing. So we can prove in vitro, and we do with every assay, we we show not only that there's been destruction, but that we can abrogate the destruction by adding in Eculismab. If you look at patients who have AHUS who are on therapy receiving a C5 blocker, Eculismab or Aulismab, then indeed you you do normalize that the cell killing in those patients also. So what's the utility of this MHAM testing? Obviously, it appears to have a tremendous utility for the diagnosis of AHUS. It's still a fairly new test, but it appears to be both a bit more sensitive than the soluble MAC or soluble C5B through 9 at diagnosing AHUS and simultaneously more specific for AHUS, although it's also positive with thrombotic lupus anticoagulants and maybe some other disorders like Help syndrome, but it does appear to be more specific for AHUS and AHUS-like disorders. Appears to separate pretty well from other complement-mediated disorders that might have TMAs, things like lupus and scleroderma, sepsis, and malignancy that I mentioned earlier on. Similarly, if the test comes back negative, it makes the diagnosis of AHUS much less likely. And as I'll mention in one of the cases that we have, it makes you go back to the drawing board and ask whether we might have missed something else that's causing this TMA. It also is useful because in many patients it's positive in remission. So, for example, in assessing a patient before a renal transplant, they're genetically positive, that makes it easy. But 60% of people with seemingly genetic AHUS who respond to therapy will have negative genetics. Another way to evaluate those patients, even when they're in remission, is with the modified AM test, which is often abnormal. We're not using this a lot, but it also would be potentially useful in evaluating variants of unknown significance. It's positive in many asymptomatic carriers of genes that cause atypical HUS, and it allows you to do trio testing, looking at the proband as well as the proband's parents, even with genetically negative disease, looking to see which parent is carrying the defect and to track genes to perhaps be able to show that some of these VUSs are actually disease-causing variants. And we didn't talk about it, but you can within the modified ham test also isolate individual complement pathways, the classical pathway, the lectin pathway, as well as the alternative pathway, to look at which pathway is really carrying a defect, again, allowing us to hone in on variants in pathways other than the alternative pathway. So this were our results from the first eight months or so. I think you have about 170 samples in here. The first thing that jumps out at me, at least, is it was an interesting social phenomena going on. So on the y-axis here, you have viability of the cells. So this is normal to have 100% viability. And when you have less than 60% viability, it becomes interesting. When it's less than 46% viability, you actually have a clear-cut positive. So the majority of the samples we got during our first eight months, as you can see, came up with normal modified ham tests. We simultaneously were running the non-functional assay, the soluble C5B through 9 or soluble MAC levels. And you can see that many of these patients had positive soluble MACs. So why are we not seeing positive M HAMS? I think what you're seeing here in some large extent was a social phenomena. We've gone back and talked to as many of these physicians as we could to find out about who these patients were. And so far, no one with atypical HUS had come in with a negative modified hand test, except for a few where they were already on therapy. And indeed, the modified hand test normalizes, as does the soluble MAC, once you go on therapy and those patients show up in the space. But I think what was happening was the calls I was getting was look, I've got this patient. If I really thought it was AHAS, I'd just have him on therapy. But I I don't really think it's AHUS, but I'm just concerned about that possibility. Could we get a modified ham test? And the vast majority of those cases where they didn't really think that it was it was AHAS, it wasn't AHAS, it was something else. And I'll show you a little smattering at least of what some of those other things were. So one of the patients who had a very high soluble MAC had had lupus. And they were concerned because there was more hemolysis than you generally expect with the TMA that's often seen in association with lupus. But this patient did not have atypical HUS. Similarly, this other green dot was another patient who had known HLH, again with more hemolysis than you generally expect. Obviously, you can see hemolysis, but you know, that's why they have us. That's why you have physicians taking care of these people, is that your clinical judgment sometimes steps in, and this seemed like more hemolysis than you might really expect. But indeed, this patient also did not have atypical HUS. And this case was actually very, very interesting. In that little green dot was a patient who'd come in with a TMA as well as some renal disease, got a biopsy of his kidney, and on that biopsy had clear-cut TMA. So now it really looked like this was atypical HUS. We ordered our testing, and as you can see, both the soluble MAC and the MAM are normal in this patient, which caused us to go back to the drawing board and look for other possibilities. And on scan, this patient was found to have a very large prostate abscess, and process, the pathologic process, went away when this abscess was drained and the patient was treated. So, what about the soluble MAC? Has it been kicked to the side of the road? No, not yet. It's a cheaper test than the modified ham test is. It's the the only test which has been shown that when it's negative at the echulysomab trough, the risk of relapse if you stop therapy is very low. In a study from Furkuri and his group from a few years back. So it may be useful at trying to decide if the patient can stop therapy. The modified hand test may also turn out to be useful for that, but not yet been clearly shown. If a patient is on echulysmab, one of the questions that comes up is is this dose effective? Can I decrease the dose? And if the patient is starting to have some symptoms or some signs, is it possible that the dose needs to be increased over the usual dose? Um, using the cyboMAC allows for dose adjustment. It's fully suppressed when you have an effective dose of aculismab on board. And then interestingly, it is elevated in cases of non-AHUS complement activation, lupus maligncy, sepsis. What that means in terms of therapy downstream, especially as we get more targeted therapies for different complement pathways, that's up in the air at this point. What's the value of a positive M HAM test? I think the value is, like you see here, this patient was positive on everything, positive genetics, positive soluble MAC, positive M HAM test. This patient has AHUS, and he had a positive biopsy, too, if I remember correctly. This just confirms what we probably could have guessed in other ways. Um, this patient had a soluble MAC that was a little bit more equivocal, but a very positive modified ham test, allowing to start therapy right away. This case and a number of other cases also raised another thing I just wanted to comment on. Obviously, we do stat genetics here at Maycheon, and I'm a fan of genetics. I think they have a role in AHUS, but that role is not usually the role of diagnosis. Occasionally we do lean on it when we're really, really confused. But only 40%, maybe less, of patients who have AHAS will have positive genetics. So if they're positive, that's incredibly useful in a confusing case. But negative genetics do not change my mind. If I think somebody has AHUS, they still have AHUS. So once I've decided somebody has AHUS, I don't wait for genetics ever. Once I've decided, I go ahead and treat. If I'm really confused, my go-to would be the modified ham test as a way of sorting that out. And obviously that's what happened here. But waiting for genetics is almost always a mistake in these cases. This was a patient who I believe was going to be going to transplant, if I remember correctly now, who had negative genetics and had come off therapy, because that's quite safe when your genetics is negative, but it's not completely safe. And indeed, he had relapsed. And the modified ham test confirmed that this patient had AHUS now in relapse and is no longer a candidate really for coming off therapy. So a positive test clearly is useful. We've had so far no false positive tests. One other thing I wanted to talk about before I close here. One of the things we had noticed is that triglycerides appeared to be interfering. So we did a in vitro study, we had some normal samples and we had some known abnormals. If you look at these samples straight out, the normal obviously has normal viability at 98%. And our AHUS patient had only a 15% viability. If you add in hemoglobin, nothing really happens. So we have a falsely normal sample with these high triglycerides. Then the question is, is that only going to happen with four plus triglycerides, or is it going to happen with lower levels of triglycerides? So we looked at lower levels. Our one plus triglycerides are still visible to us, but it's a very modest treatment of triglycerides. And that moves an abnormal sample from, in this case, a clearly abnormal 22% to a barely abnormal 42%. So it's a substantial and clinically meaningful change in the result that we got. With two plus spiking of the tube, the normals remained normal, but our abnormal sample became an equivocal sample bordering on being a normal sample. So it's made a huge difference. And it's a dose-related difference. Obviously, the more triglycerides there are, the more normal the sample becomes. That's the bad news. The good news is we've so far only seen two patients with visible triglycerides out of the 185 or 190 samples that we've done so far. So this is not a common problem. But if you send us a sample and we see triglycerides, you will get back a report, noting that we don't trust this sample, particularly if it's equivocal or borderline normal. We'll be wondering about the possibility of it being an abnormal sample. We are looking right now at ways to abrogate this phenomena. We have not developed one yet, but we're working on that. So again, a great new test. Looks as though the modified ham test is going to offer us both sensitivity and specificity in diagnosing atypical HUS. Um, this triglyceride problem so far has not been a clinically bothersome problem for very many patients. But again, an interesting new test. So thank you very much for coming along. I do have some questions. First question: how confident would I be in a patient with transplant associated TMA to not treat with Eculismab in the setting of a negative MHAM? I think we don't have enough data so that if I really thought that someone had a transplant-associated TMA with an elevated, you know, soluble MAC and meeting the other criteria that Jodell has has published on. And it looks like they have a transplant-associated complement mediated TMA, I would probably treat that patient at this point in time. I just don't have a lot of data in that setting on the possible false, false negativity of MHAMS. Hopefully, I will get to that point at some point. Why is 60% used as a cutoff? That just turns out to work. We see virtually no one who's abnormal with a viability above 60%. In the 60% to 46.5% range, it's a little bit equivocal. We've had some people go each both ways. Below 46.5% viability of the cells, everybody so far has had atypical HUS and appears to be very sensitive using those cutoffs. That's just empirically picked from the results that we've been getting. So I actually don't know how our spiking correlates with biological levels of triglyceride, embarrassingly. The levels were picked to correlate roughly with the kinds of triglyceride levels you see. What I can say is that we see some but very modest interference at a level of triglyceride one plus that we are able to see visually. So we can for now easily screen for meaningful elevation in triglycerides. Hopefully, we'll find a way to remove that. But again, has not been a problem much. So you know, half a percent or so of patients have had significant triglycerides. Someone else asked the a very appropriate question that has modified ham test been validated with renal limited TMA? No, it has not. There's nothing that's been well looked at yet for the renal-limited TMA. That whole field is a bit of a work in progress. So someone notes, hi Rita, it's nice to hear from you. Someone notes that they're having trouble getting this test done as an outpatient. It is a problem. Talk to us when that comes up. I believe we do have some resources for I'm getting a yes, I'm looking out of the corner of my eye here. We do have some resources for getting those tests paid for when insurance won't in in outpatients. It's obviously much easier, and most of our testing, because of the nature of this testing, has been on inpatients. But call us, talk to us if you have a patient. We do pretty darn well at finding resources most of the time. What do I think of the Prismax score? I'm now I'm really embarrassed. I don't know the Prismax score. Is that like the plasma score for TTP, which I don't find particularly useful? They've just codified the seat of my pants, basically. They said the things that we would all normally look for, and then they put them into a scale, but it's easy enough to just look at it and say this patient does or does not meet the criteria for TTP. And there are enough, there's enough slop in that that personally I get an ADM TS-13 on everybody uh in that setting. And it's quick and easy. We have a 24-hour turnaround for that test. It's quick and easy, and it solves the problem. Experience with MHAM in delayed hemolytic transfusion reaction in sickle cell patients. No, this is actually something we're very interested in. We have not, and no one I know yet has been looking at the MHAM in a one is published, looking at the MAM in various sorts of sickle cell crises, although we do have more and more data coming in, including some functional testing of the complement cascade, suggesting that complement is involved in sickle cell crises, particularly in the hemolytic crises. Does the threshold for positive or negative help us? Not yet. For now, when they're positive, they're positive, and when they're not, they're not. And I don't know what very positive means in this setting. It makes me think that the patient has more complement activity, but I don't have, and I think no one has enough data right now to say what that really tells me in terms of what I'm going to be doing. And then I do expect the MHAM to fully normalize with therapy. So one of the things it tells me is that the patient is not on therapy, or at least not on clinically effective therapy. Rita, I'm embarrassed. I don't know that score. I think that may be the end of the questions that are coming in. The result is reported as a positive or negative, and you will be given the percent viability. Someone asks. I have a question that just came in. Oh, sensitive. So again, I think these tests are new enough. You've seen the data that we have. There's also the experience out of Johns Hopkins. The test appears to be very sensitive. 90%, 95% is a number that's been thrown around. I think we don't have any good big Big studies yet to really begin to look at this. I can only tell you that of the patients that I showed you, we had no positives that we are aware of in patients who had negative M HAM tests, unless they were already on therapy, which has happened. And it should have been obvious from what I was saying already, but an MAM test in a patient on therapy, unless you're looking to assess the efficacy of therapy, is not a useful test. It needs to be done off therapy. If you're thinking, especially about using one of the long-acting C5 blockers, it's worth getting that MHAM test, even if it's only as a baseline to know what's going on with this patient in case you need something to compare to down the road. Once you put them on a long-acting C5 blocker, it's very hard really to get a good result on this at this point in time. We're working on ways to get rid of C5 blockers in the assay, but don't have anything currently available. So someone asks about the handling of the sample with pre-analytic variables that are such a bugaboo in our business. We asked that the sample be processed within a couple hours of being drawn and then the serum sample removed and frozen. When we've looked, it really between you and me, despite what it says, it looks as though these samples are quite stable at room temperature and relatively resistant to mishandling in terms of changing the values. It would appear that if you mishandle the samples, the MMA might become more normal, while the soluble MAC becomes more abnormal with the same kind of mishandling. But again, the MHAM appears to be quite a robust test. Someone asked if I can share the reference for the cyuble MAC's utility in assessing the risk of relapse when stopping therapy in patients with AHS on therapy. I am not sitting here with my references. The author is Fakuri. It was published right around 2023. And the title is something like the utility of genetic testing for stopping treatment of AHS. It's something like that. If you want to send me an email, as soon as I get off here, I can pull up my end note and get you that specific reference. And there's a lot of references, a lot of articles by Fer Curry, but Fer Curry is the first author on this one. But if you send me an email, I'm happy to send you the reference. And it's really about genetics, but it also notes that if they checked the cyboMAC at TROF, these were patients on Echulysimab at their Trough, a positive test had the same significance as positive genetics, and a negative test had the same significance in terms of risk of relapse as negative genetics. And this was done in a subset of patients in what was really meant to be a genetic study. All right. You guys have one more moment to send in some questions. Right. If you get more questions, I'm very happy. Most of you on here have my phone number, my cell phone number. Um it's on the Machion website, I believe. And you're welcome to call me. You're also welcome to send me an email, also on the Macheon website, but Brad.lewis at Macheon Diagnostics.com. I'm always happy to hear from people. I'm happy to talk about patients before you order tests as well as after you've ordered our tests. If you want to talk about what sort of testing might be useful in a given patient. And as some of you know, I'm happy to talk about patients, period. I'm always happy to talk. Okay. With that, thank you all very much. I look forward to doing another one of these very soon. Thank you.

SPEAKER_00: 33:28

That's it for us here at Blood Sweat and Smears, a podcast produced by Machion 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 BloodSweat and Smears at Machion Diagnostics.com. That's M-A-C-H-A-O-N diagnostics.com. You can follow Macheon at Twitter at Macheon DX. 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.