Subscribe
Share
Share
Embed
A Mayo Clinic podcast for laboratory professionals, physicians, and students, hosted by Justin Kreuter, M.D., assistant professor of laboratory medicine and pathology at Mayo Clinic, featuring educational topics and insightful takeaways to apply in your practice.
- This is Lab Medicine
Rounds, a curated podcast
for physicians, laboratory
professionals and students.
I'm your host, Justin Kreuter,
a transfusion medicine pathologist
and assistant professor
of laboratory medicine
and pathology at Mayo Clinic.
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
and the clinical practice through
educational conversations.