- This is Lab Medicine Rounds, a curated podcast
for physicians, laboratory professionals and students.
I'm your host, Justin Kreuter,
a transfusion medicine pathologist
and assistant professor of laboratory medicine
and pathology at Mayo Clinic.
And today we're rounding with Dr.
Jansen Seheult, Assistant professor of laboratory medicine
and pathology in the division
of Hematopathology at Mayo Clinic in Rochester, Minnesota,
to talk about pre-analytic variables
for coagulation testing.
Thanks for joining us today, Dr. Seheult.
- Thanks for having me, Dr. Kreuter.
- Hey, so why don't we kick off with, you know,
for our podcast audience, why is it important for them
to appreciate kind of the role
of pre-analytical variables in coagulation testing?
- That's a good question. So I think 20 years ago,
laboratory community
and patient facing clinicians
probably did not truly understand the impact
of pre-analytic variables.
It took some seminal papers with the Mario Banani in 1997
and then 2006 to show how prevalent these errors were.
At that time, they were done in stat lab testing,
and I think he, he quoted a figure like
4,000 parts per million.
If you do 1 million in laboratory tests, 4,000
of them could have errors associated
with pre-analytic phase of testing.
And then when he followed that study up,
it decreased slightly, but it never went away.
So what we've learned over the last two decades is
that we can hone in the analytical phase
of testing quite well through standardization
of our practices, advances in
instrumentation and methodologies.
But the pre analytical phase,
and to some extent, the post analytical phase
remain a challenge to tackle.
And it is because it encompasses
so many human factors in the process
that we cannot fully automate.
Some of the more recent literature
and coagulation testing in particular have cited figures
as high as 5% of all coagulation testing being affected
by pre variables.
It is a bit challenging to capture the full scale of this.
We can identify patterns in the lab
that we know are definitely,
or we are confident are associated with pre variables.
My lasting concern has always been
what is the true extent of what we do not detect?
And those are the subtle patterns that might be associated
with a true clinical phenomenon or it might not.
And that is all the more impactful
or problematic in a reference laboratory test setting like
we have at Mayo Clinic, where we do not necessarily get
information on the clinical history, the medications
that the patient is on.
We do not know the provenance
of the specimen from the time it was ordered
through the time that it arrives at us, most likely
as an aliquot that is frozen.
So that's why it, it takes a lot of education collaboration
to, to address or try to begin to address this problem
of pre-analytic variables.
- Well, that's awesome. I think you got my attention
with the prevalence.
And I love, I think I, I really like this idea that,
you know, what is it that we don't know that we don't know?
And your point's very well taken that, you know,
these may be artifacts
or there may be things yet to be discovered in,
in clinical coagulation.
Maybe can we kind of take a little bit
of a dive into maybe a few of those, you know,
are there a few of the common pre-analytic variables
that you're, that you've talked about recently
that are podcast audience might, should be aware of?
- Yeah, I, I like to categorize
or classify pre-analytic variables into five pin buckets.
I call it the PC PST, Penta
patient Collection.
And then the last three, processing storage
and transportation don't necessarily
happen in a single order.
And they can be duplicative process.
We could store a sample multiple times along the chain.
So they're almost like a cycle when it comes
to the most prevalent, I think in the laboratory, we like
to think about things that we can test for.
Hmm. So in the laboratory, if you asked a trainee
what are some pre-analytic variables,
you're probably gonna hear things like hemolysis, ictaurs, lipemia,
those are testable problems.
We have pre an check modules that we can test
for those using different light wavelengths.
In the grand scheme of things,
they probably are not the most prevalent.
I think patient related factors are probably the most
prevalent throughout all laboratory disciplines.
But in coagulation in particular,
when I say patient related, I'm talking about medications.
Many patients who are being tested for a bleeding
or thrombosing disorder might be on an anticoagulant
or a procoagulant drug.
And those drugs can actually influence the results
what we report from the laboratory.
There are also patient diseases
that might have an impact on laboratory assays testing
for a different disease.
So, or, or even the same disorder.
So let's say a patient comes in
with acute venous thromboembolism.
Many professional organizations have said that
that is not the right time to be testing for thrombophilias
or prothrombotic states.
And that is because the clotting cascade is disarrayed at
that point when the patient has an acute clot
and you can have a, a decrease in natural procoagulant
and anticoagulant factors.
So that's one case where if you see a borderline abnormal
result, you don't know if it is related to clot consumption
or if it's a true reflector of,
of the patient's underlying disease state.
If patients get thrombolytic therapy, a clot buster drug,
you can see influences on
procoagulant factors like fibrinogen factor
five and factor viii.
This is not an artifact, this is a natural phenomenon
that is a consequence or sequela of giving a treatment.
But we have to be cognizant
that if we request laboratory assays
for procoagulant factors, they might be influenced by some
of these therapies or medications.
So I, I think the patient related factors
are probably the most prevalent.
And those are related to the patient condition
or the, the medication.
One area that is, is kind
of pervasive throughout laboratory testing is
did you order the right test
and also patient misidentification problems.
I think those are big, no-no from the point of view
of blood bankers and transfusion medicine staff,
but it's, it's also a problem from our point of view,
we don't have direct knowledge
of when those occur in coagulation testing.
It's not like it's a reportable event to the FDA
as the analogy with blood banking or transfusion medicine,
but I, I presume that it happens just as frequently.
So I think we need to have robust systems
deployed at the point of collection
to make sure those errors aren't happening as well.
- Wow. I I really like how you're, you know, one
of the things for our audience to appreciate the perspective
that you're adding to us, right?
This idea of there's a lot of the things
that are maybe top of mind.
You're talking about lipemia, hemolysis, these things
that are testable as you, as you put it, right.
You know, these things that we're aware of it
and that's why they're top of mind.
But highlighting that they're probably
not the most prevalent.
And then highlighting that there's several
talking about diseases, medications,
I certainly appreciate this challenge
of when somebody has an acute DVT, right?
That's when somebody wants to do coag testing,
and I'm totally on board with,
that's probably not the ideal time.
That kind of maybe leads me into my next question, which is,
you know, as you're saying, these are things
that are a challenge to automate.
How do you, how could you envision our medical community
kind of better coming together to together to collaborate
to kind of mitigate some of these
patient related issues?
- Yeah, the, the medical community probably needs
to be very, an expansive view of
what the medical community is from allied health staff that
do phlebotomy
or specimen collection all the way through laboratory staff
that can identify errors as they happen.
But I, I would premise
that the medical community probably includes
industry partners as well.
So I, I think if we were to tackle Pre-analytical variables, we have
to tackle it at each step of process along the way
where an error can happen if you look at the failure modes
of what a pre variable can cause.
So we, we are developing better systems
for patient positive patient identification.
I think we have trained our collection staff very well.
And, and, and that's a testament to decades of efforts
and initiatives that went into education
and making sure people are aware
that positive patient identification is critical
to providing an accurate laboratory
test result for a patient.
We also have to facilitate some of that.
So making sure that phlebotomy stations are set up in a way
that, that are compatible
or commensurate with the
safety critical tests that they're performing.
Sometimes we don't think of phlebotomy as safety critical,
but if you're gonna act on a laboratory test result, I,
I think that it is a safety critical
task that they're performing.
One shortcoming, I believe is that,
and this gets into physician burnout slightly and,
and allied health staff burnout,
we would like more information about the patient
when we receive a specimen to perform testing.
There is always a trade off between the physician
or allied health staff effort that goes into populating
what our requirements might be
because they're dealing with such a high volume practice,
they're collecting multiple specimens.
The person that is collecting the specimen may not have
knowledge of the condition that is important
to the laboratory and when interpreting the results.
So that is a gap.
I don't think it is an easy gap to address.
Maybe computerized physician order entry has gotten us one
step further along the way to, to addressing that.
But that has created more administrative overhead, I think,
for physicians and allied health staff as well.
So I think it probably is contingent on pathologists
and laboratorians to identify maybe the assays
or collection practices that where pre
variables may be most critical
and ask for key pieces of information only for those,
or for a small set of assays.
I think you get buy in a couple ways from that.
You, you are providing education
by telling people these are things
that might influence the result that and,
and the interpretation of those results that we provide.
But you probably also encourage people
to start thinking about how these might
affect other assays as well.
And then I, I talked about industry partnerships.
So I think some of that is, is creating
technology instrumentation assays that are less susceptible
to pre-analytic variables.
We have some examples of that in coagulation testing.
There have been a lot of efforts
to make ddi er assays less susceptible
to heterophile antibody interferences.
The, the, one of the challenges in coagulation testing is a
lot of, of what we do are functional assays
and they rely on a complex interaction of multiple proteins
and enzymes along with the methodology
that we use to detect an endpoint.
So it is, it will remain a challenge
to address all the pre-analytic variables, primarily
by optimizing or advancing the science of coagulation assays
or instrumentation itself without addressing all
of the steps that go before.
- Hmm. And with,
in your practice in this kind of building,
this collaboration, I really like that you're kind
of broadening this out to who is in the medical community
and really highlighting that.
'cause I think that probably accurately ref reflects our
listenership, you know, are there ways
or things that you have worked on doing
and, you know, is there a, a story that you can kind
of share about in an intervention
or something that was tried and how that worked out?
- Specifically addressing a pre-analytic variable? Yeah.
- Yeah. - I, I can think of a couple,
I'll follow on the example I just
gave about d dimer testing.
So a lot of those new methodologies are not available yet
for use in the United States because they're not FD approved
or cleared, but they are in use in, in Europe.
We have had to come up with workarounds
to addressing this d dimer,
heterophile antibody interference issue.
And it was a laboratory partnership
between our special coagulation lab
and the core clinical chemistry lab
because the chemists have a long history of dealing
with heterophile antibodies.
They are the experts in this area.
I, I think it starts with
identifying that there might be a problem.
And many times in DDI er testing that is a patient
who has had hundreds of thousands
of dollars spent on complex radiographic workups
to explain a significantly elevated DDI er
without an explanation.
And then it takes an astute clinician to identify, well,
could this be a pre analytical variable
that is in interfering with the D dimer assay?
And that triggers, now we have a, a, a stepwise algorithm
that we follow that includes things like dilution studies,
testing with a second method, try to test with
hetero vial blocking reagents.
So we've created a process now for doing that,
but it starts with the astute clinician
identifying that there's a problem here
and that that process we, we can't replace.
I, I think we, we need to train more clinicians to try
to identify these issues when they come up.
But that's where I think partnership
with patient facing clinicians and laboratorians
and even within the Department of Pathology
and lab medicine collaborations among work units
or sections can, can provide a lot of value.
- Yeah, I I love that you're showing that example, you know,
that there are experts within our community
and how we can go to the clinical chemist
and they can really inform
and help the coagulation laboratory out.
Right. The answers can sometimes come within from within
- And you would be surprised.
Well, we were surprised to know that they had very detailed
standard operating procedures to deal with these issues,
but we sometimes live in a silo where we don't know
what exists outside of that silo.
- Exactly. Wow.
So what do you think the, the future
of coagulation testing looks like?
You've kind of preempted a little bit of this,
but maybe to kind of wrap up this interview,
what do you think the future looks like?
- I think hemostasis testing
is heading towards genomic testing
and also proteomic mass spectrometric based testing.
Whether the assays that we use today will become antiquated.
I cannot predict that it is likely that for the next 10
to 15 years, we will add to the activity menu of assays
that we perform, but they would supplement one another.
So you would start screening
with the functional coagulation tests that we used today
and then reflex on to more esoteric,
potentially more costly assays.
Eventually, when the cost
of doing genomic testing is less than the cost
of doing a panel of coagulation assays,
the calculus might change.
I don't know if that will happen in my field.
It potentially could,
but one of the challenges to recognize is that as we broaden
that activity menu, we are now dealing with
a even more di diverse array
of pre-analytic variables that we have to think about.
We work actively on developing mass spectrometric assays
for antigen levels or coagulation factors,
or even for activity assays.
And we're learning every day
that the same pre-analytic variables
that might influence our conventional coagulation assays
are not what you consider when you think
about a mass spec assay.
But there, there are unique considerations
for a mass spectrometric method.
And the same can be said of genomic testing.
I think there are additional issues
that you have to think about.
Patient identification I think is gonna be critical for all
of this and ordering the right test.
Those are two commonalities
that apply across all of laboratory testing.
And when it comes to things like,
does a medication interfere
with a functional coagulation test,
that may not be an issue anymore.
If we are doing a mass spec asay that's using a substrate
and the coagulation enzyme is cleaving that substrate,
so the field is gonna change.
I don't know what adoption will look like,
and I don't know what the rate of
that change will look like,
but it's, it's actually an exciting time
to be in coagulation right now.
And, and we're trying to implement procedures
and perform the correct validation verification activity so
that we fully understand upfront I priori
what these pre-analytic variant might be
before we implement these assays.
- We're rounding with Dr.
Seheult talking about pre-analytical variables
for coagulation testing.
I, I always appreciate your insights and,
and the perspective you bring to this topic.
Thank you so much, Dr. Seheult. Thanks
- Very much for the opportunity.
- And to all of our listeners,
thank you for joining us today.
We invite you to share your thoughts
and suggestions via email to MCL education@mayo.edu.
If you've enjoyed this podcast, please subscribe
and until our next rounds together, we encourage you
to continue to connect lab medicine
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