Bobbi Pritt, M.D. (00:40):

Hello, I'm Dr. Bobbi Pritt, a clinical microbiologist and laboratory leader at Mayo Clinic and your host for today's episode. I'm excited to be here today with Mayo Clinic Laboratories CEO and president Dr. Bill Morice to get the latest news. And then I will be joined by Dr. Juliana Perez Botero to discuss bleeding disorders during the deep dive. Bill, it's great to have you back.

William Morice II, M.D., Ph.D. (01:03):

It's great to be back, as always.

Bobbi Pritt, M.D. (01:05):

Yes. So few things going on in the news that we could chat about. I thought we could start with just a review of what's going on with PAMA.

William Morice II, M.D., Ph.D. (01:14):

Yeah, it's very timely, right? Because we're right in the middle of the data reporting period for PAMA and so there's hopefully a lot going on already for labs. It's really important that labs report. Remember that we actually are required to report by law. There's no penalty if you don't right now, but we are required by law. And it's the best thing for us and our patients because it is the data that will be used to determine how much the government reimburses us for the very important services that we provide for patients.

Bobbi Pritt, M.D. (01:44):

Yeah. So we'll all have to keep an update on what's going on with that once we get more information. And I understand that you are doing a lot of advocacy work through ACLA.

William Morice II, M.D., Ph.D. (01:53):

Yeah, so just to kind of do the brief review of the PAMA history. PAMA was implemented several years ago, pre-pandemic. The way it was implemented was actually challenged by ACLA, the American Clinical Laboratory Association in the courts, because the way the bill was intended to be used was to determine market rates for lab tests and then set the pricing based on those market rates. Well, the way that the data was collected in the first iteration of the bill, or the first implementation of the bill, really heavily skewed towards independent labs, which tend to have much lower reimbursement compared to hospital labs and other laboratories. And so, the data then really drove down and the way the bill is written, there can be up to a 15% cut in the reimbursement for these tests based on the market data.

So basically, ACLA challenged, and won in court, that the data collection was not done in a way that was consistent with how the bill was intended, but the court didn't have any recourse to actually stop or change anything. And so now, that's what we're facing this year. Now these cuts have been delayed, delayed, delayed because of COVID. This year we are in data collection and the cut will happen based on whatever the data that's reported, unless something changes. What change would be a new bill that would be introduced and passed in Congress, which would change PAMA in a way that made it essentially more actionable and more feasible for labs. Because this data is super hard to get. It's not real easy for labs to go back and for hospitals to go back and collect this data.

Bobbi Pritt, M.D. (03:21):

Well, and that would be a significant cut if up to 10 to 15% cuts I think is what is on the table right now.

William Morice II, M.D., Ph.D. (03:27):

That's the way the law is written. It's up to 15% cuts. So, the good news is that members of Congress on both sides, all agree that something needs to be done to correct this. That's why we've gotten the many delays, you know starting with COVID, from the next round of cuts being implemented. Now the clock is running. There is a bill that's out there called the RESULTS Act, which would have some significant improvements I think to the current PAMA law. And it has, I think, over a hundred co-sponsors. So, there's a lot of support. So the key will be then, the score of the bill. Basically every year at the end –of-year legislation, Congress has to make sure that CMS spending itself is overall flat. Meaning if you're going to spend more in one place, you have to spend less someplace else. And so, the score of the bill is what basically the budgeting office of Congress, every bill that comes through says, estimates, what it'll cost the government so then they can make these reconciliations. And so that'll be the big thing now is what's estimated that this would cost the government. And then based on that number, that will be kind of the headwind that we'll have to get past to get it through Congress.

Bobbi Pritt, M.D. (04:35):

Yeah, there's a lot of history there. Well, you'll have to keep us updated. Definitely an important topic as you mentioned, so that we can get reimbursed for the important services we provide.

William Morice II, M.D., Ph.D. (04:44):

Yeah, and I think as you and I've really said for many years now, the important thing here is to stay engaged, right? We have to remind the members of the government, the members of Congress, how important labs are for the health and safety of our country. And so, that only comes if we continue to speak up and I'm sure we'll have more to follow up.

Bobbi Pritt, M.D. (05:03):

Yeah, that would be great, Bill. Advocacy is so important. Well, best of luck.

William Morice II, M.D., Ph.D. (05:07):

Thanks.

Bobbi Pritt, M.D. (05:08):

You know, also in the news, something that's been hitting my lab very hard and been in the media quite a bit is our big Cyclospora outbreak. For those who are listening who don't know, Cyclospora is a parasite that usually comes in through imported produce into the United States. And if you eat the small microscopic parasites that you can't see, you could end up with this really terrible, what's described as explosive diarrhea. So clearly, something that nobody wants. And you get it usually by eating imported fresh produce, which obviously we want people to be eating fresh produce, it's very healthy. But a small percentage is probably contaminated with a parasite. Right now, the main guidance is to thoroughly wash your fruits and vegetables. And if you start feeling sick and having explosive diarrhea, go to your physicians. There is a treatment. It's actually trimethoprim-sulfamethoxazole, Bactrim, as we call it. So, an antibiotic that can be given for treatment.

William Morice II, M.D., Ph.D. (06:08):

Well, that's good news. And I guess also to be mindful, right? Because I think of someone like me that travels a lot. There's certain fruits, like raspberries and things, you know, you're going to be exposed. Whereas if it's a peeled fruit, like a cantaloupe or something like that, right? That's the other choice you can make, I think.

Bobbi Pritt, M.D. (06:24):

Yeah, they always say cook it, peel it, or forget it. So if you're traveling, that's kind of a whole different story because there's all sorts of different parasites and pathogens you could be exposed to. Best to get the fruit that you could peel, or completely cook it before eating it.

William Morice II, M.D., Ph.D. (06:40):

Good. Yes.

Bobbi Pritt, M.D. (06:41):

I have to say the Cyclospora outbreak has really just brought home the importance of laboratory testing. Our laboratory volumes have gone through the roof. Over the weekend, they increased 400%, and we had a 50% positivity rate.

William Morice II, M.D., Ph.D. (06:56):

Wow.

Bobbi Pritt, M.D. (06:56):

It shows the importance of laboratory testing though, because diarrhea is a pretty broad symptom. You could have a lot of diverse causes of diarrhea. It's not specific to any one organism.

William Morice II, M.D., Ph.D. (07:09):

Truly, these topics are related, right? Because it is the getting adequately reimbursed for the services we provide that allow laboratories like yours to be ready for these different things that pop up.

Bobbi Pritt, M.D. (07:21):

All ties together.

William Morice II, M.D., Ph.D. (07:22):

Peel it, cook it, or forget it. I guess that's the message for today.

Bobbi Pritt, M.D. (07:25):

Well said. Thank you, Bill, and thanks for joining, as always.

William Morice II, M.D., Ph.D. (07:29):

Oh, it's always a pleasure.

Bobbi Pritt, M.D. (07:35):

Welcome to the deep dive. We're going beyond the headlines today with Dr. Juliana Perez Botero, a hematologist in the Department of Laboratory Medicine and Pathology at Mayo Clinic, to explore bleeding disorders. Specifically, we'll talk about the role of laboratory medicine in supporting care for patients with these disorders. Dr. Perez Botero, thank you for joining us today.

Juliana Perez Botero, M.D. (07:57):

Thank you so much for having me. I'm a very big fan of the show.

Bobbi Pritt, M.D. (08:00):

Oh, wonderful. That's great to hear. Well, we're talking about something that we have not really covered much in the past, which is bleeding disorders. So, I wonder if you could start with the basics and tell our listeners some of the symptoms that patients experience and how these disorders occur.

Juliana Perez Botero, M.D. (08:17):

Of course. So, our blood and our blood vessels do an amazing job every day keeping the blood flowing, but also making sure that when we encounter any injuries, a clot forms and we don't have inappropriate bleeding. And there's a very fine balance between the forces that favor clotting and the forces that favor bleeding. And when that balance is broken, we end up with pathologic clotting or pathologic bleeding. And so, the symptoms that people can present with when they have either an inherited bleeding disorder or an acquired bleeding disorder is bleeding that is spontaneous in what we call inappropriate, let's say spontaneous bruising, nosebleeds that last a long time, you can't get them to stop, and even bleeding in the joints, muscles, and other organs. And it is a little bit tricky because if you think about it, we all to some extent have some appropriate bleeding. So, what defines pathology ends up being a little bit harder than one would think.

Bobbi Pritt, M.D. (09:17):

That's so interesting. I remember learning all about this. I have a little bit maybe of existing anxiety from learning the coagulation cascade, but I also thought it was fascinating back in the day when I had to memorize all that. So obviously, laboratory testing is going to play a large and important role in caring for these patients. Can you give a little bit of an overview on the role of testing for patients with bleeding disorders?

Juliana Perez Botero, M.D. (09:42):

Of course. So, because bleeding is very similar and pretty much the same no matter what the cause is, and if you get to the specifics, yes, there's patterns of bleeding that suggest that maybe one component of the blood, platelets, versus another component like clotting factors, are compromised. But as clinicians, we can't really tell where the problem is without laboratory testing. So, the lab plays an essential role in being able to identify the cause of bleeding and then, in turn, identifying that cause will help select the safest and more effective treatment. Because we don't want to go too much in the other way on the clotting risk. We want to maintain that balance, so specificity matters. And beyond establishing the specific diagnosis, we call them laboratory diagnostic tests. So, the word diagnosis is there, but even when you know the diagnosis already, it helps you determine the expected severity of bleeding.

For example, for coagulation factor deficiencies like hemophilia A or B, the degree to which a person's clotting factor is decreased will correlate very well with how much bleeding they're expected to have. We can also anticipate complications. So, inhibitor antibody formation to coagulation proteins when we treat patients, which is very important. We can also, with our laboratory testing, for example, figure out who is at risk of developing antibodies against platelets, developing extra hematologic features, so damages of other organs, risk of cancer. And then we can also monitor therapy, because when we are replacing specific factors, we want to make sure that patients are not undertreated or overtreated. So, our laboratory plays a role in all aspects of the care of these patients, from the diagnosis to their day-to-day life.

Bobbi Pritt, M.D. (11:35):

Oh, you've explained that so well, and you've really covered some of the things that we've talked about multiple times on this podcast. So of course, we're diagnostic testing, but it's also predictive. It's good for prognosis, it's good for following treatment. So, laboratory testing can be very broad and nuanced, and that's why we need experts like you. Now, it's my understanding that genotype assays are becoming more widely available. Maybe we could talk about those a little bit more, more of the innovative, cutting-edge diagnostics. Can you tell us about the science behind these advances and what they mean for patient care?

Juliana Perez Botero, M.D. (12:11):

Genetic sequencing has revolutionized medicine in all areas, and it's the ability to sequence a large number of genes quickly and at a cost that makes it more accessible to most people. Of course, hematology is not an exception. And in the process of reaching that diagnostic specificity and doing more prognostication, genetic testing is very important for the inherited disorders of people. Now, from a technical perspective, genetic testing has filled a lot of gaps that we had with our assays, either because there are parts of the coagulation system that are very difficult to test. So, think about platelet function, for example, where we have to test a fresh sample, do this in a very specialized way that's not accessible to most people. Only large academic labs will do this testing.

Also, disorders of fibrinolysis, these are the ones that happen kind of at the tail end when the clot forms, and we're trying to prevent the body from degrading it too quickly. So, when we don't have functional, we call them functional or plasma studies, genetic testing fills that gap. And it also covers some of the blind spots, right? One of the things that we are very aware with in coagulation testing is that the way that we're measuring clotting and kind of our bleeding tendency is artificial. We are taking the blood out of the body, we're putting it in a tube, we're separating components, and we're testing each component separately. So, it's really hard to get a sense of what the whole is doing. And we also have limitations, by the way, that we've designed our assays. So, genetic testing has definitely helped. It's a very big complement to what we do in patients with platelet disorders specifically, for example. It has led to a lot of prompt and more specific diagnoses, but it is not the one magic solution. It is still a complement to the clinical evaluation, to the plasma studies. And it requires integration to what we know about how the patient is presenting, their family history, and then their coagulation studies.

Bobbi Pritt, M.D. (14:23):

Well, that's one thing I love about laboratory medicine is we really are part of the clinical care team. We're part of this team that's looking at the whole picture for the patient. So, how do they present, what's their family history, and then how do we best use this array of laboratory tests we have to understand what's going on with the patient? So, that was a great overview of genotypic assays and maybe some of their strengths, but weaknesses as well. Now, I'm interested in what's next. What's on  the next frontier that you're excited about for bleeding disorders?

Juliana Perez Botero, M.D. (14:55):

Well, I mean there is so much, and this is of course a hard question. I would say two things. One is continuing to improve the things that we're already doing, but we need to do at a larger scale. So, things like collaboration, what you were saying. This is an area where we need the expertise of so many different people along the process. And getting these people together to analyze the same data and come up with results and conclusions that are clinically actionable and meaningful is very important. And we recognize here in our lab that most clinicians around the world and most laboratories do not have all those parts of the expertise that are required to put the pieces together. So, scaling up data sharing initiatives, having highly curated data that people can use to care for their patients, to develop research studies. So this is a little bit of maybe what you've heard of sharing variant classifications and things like ClinVar or the ClinGen initiative, where expertly curated data for genotype-phenotype correlations and ways of looking at genetic variants that are specific for some disorders, so, we have a group for coagulation disorders, is available to everyone else. I try to be mindful that when I'm excited about the future, we're not just shifting to what seems new and shiny and exciting, but we're also working on being better at what we do. But from a technology standpoint, I would say, you know, nanotechnology to me is very interesting. We've seen this being incorporated in hematology from the treatment perspective, things like gene therapy. But from the diagnostic perspective, there is a lot of room to have a more physiologic view of how coagulation works. So, imagine putting a very small chip in a tiny needle, making a tiny poke, and then measuring how the body responds to the injury and being able to translate that into, how are the components of clotting working in real life, in real time, inside the patient? And I could envision too, maybe there is a time where we can have a tiny device that actually circulates in the blood and gives you that sort of information. So, there are some groups that are starting to look into this, and I'm looking forward to hopefully seeing this become a reality.

Bobbi Pritt, M.D. (17:19):

Yeah, that's really fascinating, and I never really thought about that. You're right. Once we take the blood out of the patient, we're removing it from the endothelial cells, the other ongoing mediators that are in the blood. It's a little bit of an artificial system. So, I really like your thought about how maybe we could measure more in vivo instead of in vitro. So, that's fascinating. Well, we will look forward to what the future brings and perhaps have you back on a future show to tell us more as we move forward.

Juliana Perez Botero, M.D. (17:49):

Thank you so much. Absolutely. And if anybody wants to learn more about these disorders, we have our Mayo Clinic Laboratories Classical Hematology Conference that we host every year in October. It will be in Florida. It's geared towards a broad audience, so anybody, independent of their level of training or expertise, will find something there to benefit from. So, we're looking forward to meeting any and all of you that want to attend.

Bobbi Pritt, M.D. (18:13):

Oh, that's wonderful. And it's a great time to be in Florida if you happen to live in Minnesota, where October gets a little cold. Well, thank you, Dr. Perez Botero, it's been such a pleasure speaking with you, and I hope we have a chance to talk about this more in the future.

Juliana Perez Botero, M.D. (18:28):

Thank you so much. The pleasure is all mine. I appreciate it.

Bobbi Pritt, M.D. (18:35):

Let's wrap up with the top takeaways and how to learn even more on the topics we've discussed. During today's news segment, Dr. Morice and I discussed the latest on PAMA and the Cyclospora outbreak that you've been hearing about in the news. Next, Dr. Perez Botero joined us to talk about testing advances for bleeding disorders. To learn more, we've included links in the show notes to the upcoming Classical Hematology Conference, where Dr. Perez Botero serves as a course director, as well as some additional information on testing for bleeding disorders. Thank you for joining us today. If you haven't already, make sure to subscribe so you never miss an episode. For our next episode, Dr. Morice and I will dive into what it takes to create an effective innovation strategy. I hope you'll join us.