February 7, 2022 • 42 mins
Gerald Maloney, DO, CPPS, CHCQM, FACEP
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Gerald Maloney (00:00):
Hi, my name is Jerry Maloney and I'm here to
talk to you today aboutmanagement of bleeding in the
anti coagulated patient. Okay,hi two o'clock. I'm the
Associate Medical Director forthe year the Cleveland VA and
I'm also Associate Professoremergency medicine at Case
Western. I am also a lieutenantcurrently Army Reserve and an
oaf veteran.
(00:21):
I have no disclosures to make.
So our objectives for thistopic, were listed different
anticoagulant drugs and theirindications review the lab
testing and tech regulatedpatient. Define what constitutes
major bleeding anticoagulantpatient discuss reversal agents
use and their supportingevidence. So we're going to
(00:42):
start things off with a casepresentation. 63 year old male
with a history of AFib anokhobbies presents for dissident
Jaws swelling for the past fewdays. So five milligrams of
Warfarin a day is a sign ourcheck a month ago was 1.8. He's
not any new medications, nohistory of trauma, the sun
desert board they held miss somedose and devil up to catch up on
his warfarin. So this is the oneI walk in the room. What do I
(01:06):
see picture. And in this case,what I saw was something that
made me very, very nervous rightoff the bat. In terms of file
size is a furrowed brow slightlytachycardic and hypertensive to
kip Nick and satting. And kindof borderline low 92% of the
Roman era. He's alert looks alittle bit anxious, you can open
the show a couple of fingerbreaths. As for the picture, you
(01:28):
can see there's pretty muchnothing but tongue in there. The
floor, his mouth, his hardtongues elevated. His
submandibular areas fall infirm, and he actually has a
little bit of ecchymosis thatmandibular area. As long as he's
slightly diminished bilaterallyis tacky and irregular isn't a
fib on the telemetry monitor.
(01:50):
He's not having any mob justiceor coughing up any blood right
now. So for labs, he's got anormal white blood cell count.
His hemoglobin is a little bitlower than baseline baseline is
around 14.3. Today is plateletcounts normal to 40, his BMP and
LFTs are grossly normal, is INRcomes back greater than 10. So
(02:13):
management, what's the bestreversal agent given his
elevated INR? And are there anyother therapies we should give.
And similar vein to our othercase presentation this gentleman
is somebody who had a recentbiopsy of a soft palate mass.
It's not a pixel band for a fibhad the pixel man held the day
(02:35):
before the procedure had theprocedure at the Pixabay and
restarted that night and wasfine and for a day or so and
then post op day. Number two, hecame in coughing up large clots
of blood. So in terms of classesof commonly used anticoagulants,
when I was a resident, we reallyhad three vitamin K antagonists,
(02:56):
heparin and platelet inhibitors.
Now we also add in directthrombin inhibitors and factor
10 A inhibitors. The vitamin Kantagonist category, there's
really only one that you setbeautifully, which is warfarin.
Direct thrombin inhibitors arekind of the first of the what
used to call noacs novel oralanticoagulants and doacs Direct
oral anticoagulation agents. Thebigger trend was the first in
(03:21):
that class. The have had someintravenous ones that have Allah
Rudan and our gastro ban. Thenext class of oral
anticoagulants under the doacslash noec category was the
factor 10 inhibitors and riverrocks a ban was the first
category followed by pixel banadoxa ban and kind of the newest
(03:43):
kid on the block is vetrix haveand they've had injectable
factor 10 inhibitors and loggingthey've had oral ones find a
paradox, which for a while isused at our place for cancer
related thrombosis heparinsunfractionated Heparin, which we
don't see uses commonly anymore.
(04:04):
The out of hospital raises we'relooking most of these
medications that people are onat home and come into the Edie
with low molecular weightheparin enoxaparin. The most
commonly used one is really whatwe see used for this category.
And then platelet inhibitors,the most common which are
aspirin and clopidogrel. Sosince we're talking about
(04:26):
anticoagulants, we do need to gointo the coagulation cascade
briefly. Warfarin causes themost widespread effects of this
calculation cascade it knocksout what they call the vitamin K
dependent clotting factorschoose seven nine and 10. The
end result of all this is thatit prevents the activation of 10
A which is the common link inboth the intrinsic and extrinsic
(04:50):
pathways. 10 A is the factorthat converts prothrombin to
thrombin and activate thrombinnecessary to convert fibrinogen
into fibrin.
Without conversion of fibrinogeninto fibrin, we can't form that
plug to create the clot. The 10inhibitors don't affect the rest
(05:14):
of the Cascade the way Warfarindoes, but they do hit right at
10. A itself. heparin alsoprints the actuation 10 A and
also blocks thrombin to preventit from activating fibrinogen
into fibrin, so do the directthrombin inhibitors. So we
really get down to it. There'sreally two points where all
(05:34):
these anticoagulants seem towork 10 A or thrombin. Since we
do strapped people onanticoagulation from the Ed does
help to quickly review theindications for these things.
Vitamin K antagonists have thebroadest indications, mainly
because we're using the longestright so a fair both alveolar
nerve alveolar fib DVT or PE,both cancer and non cancer
(05:57):
related primary clottingdisorders. Things like factor
five light and protein CNSdeficiencies, and also they've
been used as prophylaxis, afterthings like joint replacements.
The direct thrombin inhibitorshave indication for DVT and PE
treatment cancer associated in afib nonvalvular. The 10 A
(06:20):
inhibitors pretty similar theyhaven't added indication for DVT
prophylaxis. The other thingthat the 10 inhibitors are used
for CBT and PE it can be used incertain cancer related ones as
well. Because of increasedbleeding rates with GI Gu
cancers, they do not recommendusing them for those particular
(06:44):
indications. heparin obviouslyis the preferred one
particularly low molecularweight heparin for cancer
related thrombosis, and forprophylaxis as well. And
platelet inhibitors usedprimarily in stroke and ACS PCI,
although they've been used forother things like DVT
prophylaxis may be used inpatients with afib, who are
(07:06):
considered higher risk of beingon the stronger anticoagulants.
They don't have a primaryindication for anticoagulation
for any of these otherindications per se. So just to
go a little bit more into thecancer related indications. They
compare two pics Amanda docsbetter for Oxman Alta Dalta
paren, which is another onewalkaway heparin for cancer
(07:26):
associated venousthromboembolism. And
interestingly, although theywere rated at a superior or non
inferior to Delta parent interms of treatment of cancer
associated VT II, they hadhigher bleed rates, especially
the GI cancers. They arepreparing comparing them to the
(07:47):
vitamin K antagonists theseindications as well. Currently
the recommended is no GI or Gumalignancy. I bring that up
because for those of you workingin the VA, like me, obviously I
get probably a couple ofpatients a week that I sent down
from CT because they had theirstaging CT down and they found
(08:07):
multiple asymptomatic PE. Sothey had some other study down
and found that they had a DVT.
So they got filtered to the ERso starting them on
anticoagulation is something wefrequently have to do. I'm a
medical toxicologist by trainingas well. So I do like to talk
about things like kinetics. I'mnot going to go into this in
(08:27):
great detail, but looking at thebigger trends and the most
commonly used 10 inhibitors.
Looking at the tannic IP plasmaconcentration is pretty similar
with all the right summarize.
And the minimum one hour andusually about three hours. There
half lives are relativelysimilar to redox events somewhat
(08:51):
shorter half life, but the restof them, I summarized at least
nine and assigned to biggertrans cases 17 hours and the
frequency with most use once ortwice daily. Some of this
depends on renal function. Andthey are all renally excreted to
a significant degree,particularly the biggest fan
which is majority renallyexcreted. They have antidotes
(09:12):
which we'll go into a little bitlater, but there's n DEXA and
Daris ism AB, or prac spined andthey all take at least 48 hours
after the last dose for completecessation of all pharmacologic
(09:34):
activities. So although theylike to say you can hold it for
a day, if you really want tocomplete washout of all their
anti Quagga activity, you reallygot to give it 48 hours. So in
terms of laboratory testing, sothe INR is primarily for vitamin
K antagonists and typicallywe're looking at a range between
two and three occasion up to 3.5for prosthetic valves
(09:59):
on occasion There will be peoplewho are on higher Target INR
hours based on something thatthey've worked out with a
hematologist. But rarely is anINR greater than 3.5. So
consider the therapeutic range.
So in terms of INR with doac,typically the INR is all very
the direct but it's not linearrelation, it's not like
(10:21):
Warframe, where you can kind ofdetermine if they're
therapeutically anticoagulated.
Based on what their INR is.
Frequently it is elevated, notalways. So you can also have
patient who is taking a doac whohas a normal INR but will still
have therapeutic anticoagulationactivity. So bottom line is that
(10:43):
the INR is somewhat helpful ifit's elevated, at least confirm
the patient's taking a doac. Anormal INR does not exclude that
the taking of doac and there'sno real correlation between the
INR level and level ofanticoagulation. This has come
up because I've occasionallypeople say, Well, you know, if
we get somebody who comes in andtheir stroke syndrome, and
(11:05):
they're not really response, wedon't have medical history on
them, we can check a quick INRand if it's normal, that
unfortunately doesn't exclude adoe x, so it makes it a lot
harder to conclusively excludetheir anticoagulant in that
case. The anti 10 is best forthe oxidants low molecular
weight heparin but again, shortof some facilities that do a lot
(11:25):
of research protocols and stuff.
With the 10 inhibitors, it'sreally hard to get a rapid turn
around 10 A, the PTT is good fora fraction heparin. It can also
be elevated with a directthrombin inhibitors, but again,
similar to INR and the doacs.
It's the elevation that you getin PTT with a direct thrombin
(11:48):
inhibitor is not correlative ofthe degree of anticoagulation,
same wages for infraction,heparin. So how do we define
major bleeding? This is going tobe critical site right in the
airway, intracranial pulmonarypericardial active GI bleeding
not and I had a little bit ofmelon, but I seem to be having
severe like medic ease yeahhematemesis or an uncontrolled
(12:14):
extremity bleed. If theyhemodynamically unstable if
they've lost more than two gramsof hemoglobin from their
baseline, or if they've beentransfused at least treants have
packed red blood cells throughthe bleeding. So if you're
looking for the soundbite sideof this presentation, this is
it. The journal sets majorbleeding Control Stop
(12:36):
resuscitate reverse, so you wantto strap your anticoagulant
agent, resuscitate the patientfluids blood, etc and reverse
the anticoagulant. This is amodule we get to employ
frequently at my shop we have ona given month about 10,000
patients through our facilitythat are on some type of
anticoagulation, typicallyeither vitamin K antagonists or
(12:59):
doac. There's if there's ahandful heparins and find a
paradox is thrown in there.
These patients have a higher eduse rate than the rest of the
population typically. And it'snot uncommon at all to see one
that come in some type ofleading complication. So going
(13:19):
on to the agent specificmanagement. Um, each class seems
to have a specific reversalagent or therapy. This journal
therapies we look at I'll talkabout those briefly. Things like
FFP tranexamic acid DDAVP,estrogen and platelet
transfusion. But the crux is isgoing to be looking at what
specific reversal agents we usefor this specific type of
(13:40):
anticoagulant. So I'm atoxicologist as I mentioned
earlier, so I love antidotes. Solooking at our anticoagulants,
several of them do haveantidotes. The bigger Tran has a
darest ism AB or the slightlyless tongue twisting prac spined
(14:01):
river rocks of n and Pixabay isindex alpha or and DEXA.
Warfarin the actual antidote forit is actually vitamin K. And
heparin uses Protamine someother journal verse legends we
talked about again FFP forfactor PCC. So vitamin K
(14:21):
antagonists, right? So theyinhibit vitamin K dependent
clotting factors, which are 279and 10. And they were playing
him in st called V K O RC, whichactivates vitamin K vitamin K
isn't activated, then it cannothelp with the formulation of the
vitamin K dependent clottingfactors. And the vitamin K that
we give intravenously forphytanic die own is actually UK
(14:44):
wide or activated vitamin K. Sobypass is a blockade of
warfarin.
Warfarin interestingly enoughcame from moldy hay. It was
described in cows first whodying from hemorrhage And it was
the Wisconsin area ResearchFoundation that discover this
(15:05):
industry thought it was aheparin oId type of thing. Hence
the Aeron. So that's where thewharf in the warfarin came from.
They also use it for rat poisonand they have short and long
acting Coumarins. The longacting ones are not used ever
for human treatment. Although,as a fellow we certainly
(15:25):
followed many people whooverdosed and rat poison. I
remember one case of a Johndeclining acting coumarin and
was still anticoagulants. Sodetectable levels in his blood.
45 days after it's overdoses,some of these long acting ones
really stick around for a while.
The advantages to warfarin,we've been using it forever, we
know how to monitor it, we havea test that very accurately
(15:46):
reflects level anticoagulationwith the INR. And because we've
used so much for everything,it's something everybody's
familiar with his vastexperience with their
management, disadvantages gothigher rate of bleeding than
pretty much all the otheranticoagulants there's a ton of
drug food and drug druginteractions is also widely
variable metabolism. So youknow, one patient may get
(16:08):
therapeutic with a milligram ofwarfarin, somebody else may take
10 milligrams, so there's a lotof kind of trial and error with
Warfarin dose and get somebodytherapeutic with their INR. Now
for treatment, again, there isan antidote for iron
antagonists, and the antidote isvitamin K. The guy says get
(16:29):
super therapeutic INR, butthey're not bleeding, it's less
than five, just hold it no giveanything between five and 10 can
hold it and give us a small doseof vitamin K, usually, anywhere
from one to two and a halfmilligrams pure IV, it's greater
than 10, the checkout holding itand then giving a dose of
(16:50):
vitamin K again, depending onsituations two and a half to
five milligrams, they do notrecommend subcutaneous vitamin
K, because it's poorly absorbedoral is preferred IV if the
patient can't take oral there'sa small risk of anaphylaxis with
IV vitamin K, the ever majorbleeding issue then they
recommend kind of hitting themhard 10 milligrams of vitamin K
(17:11):
IV and then either FFP or fourfactor a PCC. So FFP this has
been kind of long standingtreatment for this, you need to
get to at least him about 10% ofclotting factors restored to be
able to reverse anticoagulation. So if you look at
FFP, each unit gives you about2.5% of clotting factors. Since
(17:33):
diagnosis, always four units.
And the higher the INR, the moreyou may need to use a universal
donor plasma ab. And typically,if you give a full dose of FFP,
for their INR, typically aboutthe best you can graduate to is
(17:54):
1.6. And that gives you about 30to 50% clotting factor activity
that INR. So typically Tigerwould give you at least a leader
of a hypertonic solution, if notmore than that. So the issue has
always been a lot of people whoare on warfarin and
cardiomyopathy or a fib they'vegot poor UFC can't tolerate a
(18:17):
lot of fluids. So there's beenconcerns about limitations with
FFP. And you can't exactlypressure bag this stuff in so it
takes hours to go in. So you'realso not talking about rapidly
reversing somebody how you doingover several hours if you need
to reverse them more quicklythan that FFP doesn't provide a
(18:38):
great option. So now we'relooking at four factor PCC this
is kind of new on the block,they came up with a three factor
prothrombin complex concentrate.
The three factor has been usedfor hemophilia, but the three
factor because it's missingfactor seven doesn't seem to be
as good for reversing warfarin.
(18:58):
Same with the four factor caseSentra. The four factors
indication is for warfarinreversal. Although it's been
used with other bleeding issues,it's only real FDA approved
indications for warfarinreversal. It contains factor 279
and 10. It also contains proteinCNS, and it contains some
heparin in it as well. The doseis based on the weight in the
(19:20):
INR it's capped at a weight of100 kilograms. And to give you
kind of a conversion, one vial aPCC equals about two units of
FFP. With the case Sentra, youcan reverse the INR as low as
1.3 within 30 minutes andusually get about 24 hours of
human stasis. What that means isyour bleeding should be
completely stopped by four hoursand no further reversal agents
(19:43):
needed in the next 24 hoursafter giving case, Sandra.
Although it seems to be somewhathelpful and small stays with
doacs were particularly beforethey had other antidotal agents
where they kind of gave itseemed to help some. It doesn't
necessarily make sense that itwould be a great reversal agent
(20:07):
for doacs with Jo xe issuesinhibition of 10 a deficiency of
10 a. So replacing factor 10isn't necessarily going to be
particularly helpful because youstill have blackk to the
activation that factor 10Because it's got heparin is
contra indicated people withheparin induced
(20:27):
thrombocytopenia. And in termsof causing clotting issues
similar to FFP. So althoughthere's been concern at our
place, we actually have arestriction where I have to talk
to a hematologist. If I want touse this. Hematology, his big
concern has been that they thinkthere's gonna be higher rates of
venous thromboembolism becauseit's more rapid reversal. But
(20:47):
looking at the literature, theredoes not seem to be that risk
compared to giving FFP alone.
jacket with a bigger trend abit. Again, it was the first
doac highly renally excreted,which has been an issue limiting
its use in people with advancedCKD. The dosing is 150
milligrams once or twice daily.
(21:09):
If the GFR is greater than 3075milligrams, it's 15 to 30
minutes below 15. They don'trecommend it. They may place it
ceiling dialyze double doacbecause before they came out
with an actual antidote for it,their argument was well if
you're having severe bleedingcan dialyze it and remove it,
which is possible but again todialyze patients frequently have
(21:33):
to use heparin as well. I mean,you can do a saline. Okay,
anticoagulation as well for thedialysis but science effective.
So dialysis is not a greatresponse when somebody who's
acutely bleeding out, whichpressured them to come up with
an antidote. syndications again,nonvalvular a fib DVT PE. The
(21:59):
thing with this one though, iscompared to looking at the other
doacs It was studied for DVT PEafter they had five days
apparently oral anticoagulationso basically I'd have them on a
heparin drip for five days orLovenox, or five days and then
you could switch them over withdoes have DVT prophylaxis and
occasion for one thing, which ispost hip surgery. So now on to
(22:22):
the antidote, right? So a Darrisism AB, or prac spine, it's a
monoclonal antibody and some ABand binds both free and thrombin
bound to bigger trans when yougive it it doesn't just find the
stuff that's floating aroundloose, it actually pulls it off
thrombin as well. It is renallyexcreted somewhere to the bigger
(22:43):
fan itself, and the halfway isabout 10.8 hours. So practice by
itself is also dialyze of allthat's part of the reason why.
Again, for people who are havingsevere bleeding things, they
still recommend dialyze them topoint you can remove the prac
spine with dialysis, the dose isfive grams, which is to 2.5 gram
(23:06):
vials when I talked to the rep afew years ago. each vial was
$2,500 roughly. So it's about abuck a milligram so that makes
it fairly expensive. Again, it'sa monoclonal antibodies, it's
not surprising. The prac spineddoes not seem to have an aging
(23:28):
thing to it, it doesn'teventually unbind after a while,
like some things we worriedabout, like digibytes. So the
practice by and seems to formkind of an irreversible ionic
bond with the bigger Tran so youdon't have to worry about the
practice behind eventuallyunbinding the patient becoming
(23:51):
re anticoagulated. As with allof these things, there is a risk
of rebound thrombosis after youuse it because these patients
obviously had indication behindit in the first place. So now
we're taking the rest of doacsCall the Oxy bands. So there was
river rocks van Kai the firstone picks a ban, which is the
(24:16):
other most widely used oxy banedocs a ban and Bitrex have an
ID. So all of these areactivated 10 A inhibitors. So
they bind to activate 10 A andprevent it from activating
thrombin engine into thrombin.
So it makes it impossible foryou to then activate fibrin
(24:43):
inform that clot.
Their arrival is really kind ofchanged the face of
anticoagulation single dose andthey started the anticoagulant
activity right away. There's noramping up and waiting a few
days, like you have withWarfarin They've been shown to
be as effective as Warfarin formost indications, and their
(25:08):
overall bleeding or seems to belower than Warfarin as well. So
they've absolutely changed theworld of managing thrombotic
disorders. I've because of theavailability of the Oxy bands,
the VA, I've rarely had to admitpeople with uncomplicate DVTs
(25:29):
anymore. It's a next step,talking about the Oxy bands. As
I said they're all anti tenniesriver rocks a ban in a pixel ban
have indications a lot of theedocs a ban for DVT PE
management except for patient giGu cancers for non valve a for
(25:49):
prophylaxis and rivaroxaban andPIXMA. Also for DVT prophylaxis
in hospital Bitrix abandonedTristan has a DVT prophylaxis
indication but that's focusednot just in hospital but up to
42 days post discharge. Sothey're really the only one that
looked at doing DVT prophylaxisin the outpatient setting.
(26:09):
Additionally, although this isnot anything they've gotten an
FDA indication for somefacilities of like to to use
river ox ban or pics of and forVT e prophylaxis in people with
severe COVID infections thatpeople are hospitalized for
while severe level of diseaseelevated D dimers. And they've
(26:30):
been usually using four to sixweeks of either river oxidant or
a PIXIV and post discharge. Nowit was in some places I my
facility is actually usingLovenox. But there are several
that are using a doac. Again,this is an off label indication.
So bleeding issues withoxymorons, right? Gi is the most
(26:51):
common CNS is rare and a lot ofthese other abnormal bleeding
sites like retroperitonealhemorrhage airway, hemorrhage
haemoptysis, are also very rarewith the Oxy bands. And we
actually reviewed all theserious bleeding issues in our
anticoagulated population over ayear. And it came out to be you
know, probably about 60 to 70%of the bleeds that we saw with
(27:14):
the Oxy bands were GI bleeding.
More from was kind of all overthe place. It was mostly GI
bleed or some CNS bleeds thatseem to happen more commonly
with trauma patients. But Trixhave an interest of does have a
warning for spinal epiduralhematoma. That is in the study
of people who have had some typeof procedure and lumbar
puncture, spinal anesthesia,epidural catheter, etc. Looking
(27:37):
specifically at trauma patients,at least the largest
retrospective analysis and sofar, they have a much lower
symptomatic intracranialhemorrhage than vitamin K
antagonists. Again, looking atisolated head trauma, the
vitamin K antagonists are in17%. And that was going to have
24 hours post injury. The dogsabout 5%. And the delay bleeding
(28:02):
rate was a little bit lower aswell interest if not zero. This
protocol kept everybody for 24hours and did a initial head CT
and then repeat head CT 24 hoursand then compared it to a non
anticoagulated cohort. Lookingat the overall bleed rate for
the doacs posttraumatic ich intolabeling, he actually seems
(28:26):
similar to the controls. So ifyou read it that way it is the
doacs not appear to have anysignificantly increased risk of
me immediate or delayed headbleed compared to a control
population. That said, there'sstill ongoing data with this, so
I wouldn't hang my hat on thatjust yet. But it does appear at
(28:49):
least like our local traumacenters are not considering doac
use alone as an indication formeeting people for 23 hour odds
and repeat head imaging. Ifthere's no other indication to
admit them, and there otherwiseare logically intact. So now one
of my favorite subject theantidotes and DEXA alpha or n
(29:10):
DEXA is the intro for the Oxybands. It was designed for picks
a band and river rocks a bandbut certainly a factor for all
of them. Because they're allfairly chemically similar. It's
a call a decoy 10 A proteins soit's designed to look like 10 A
and preferentially bind to theOxy ban so it will actually pull
(29:34):
them off the real 10 A and getthem to bind to it. So Kevin,
interesting our concept. Thedosing is based on the molar
concentration of the ox of n. Sofortunately, that doesn't
require us to sit there and pulloff a guidroz number and figure
that out for each individualmedication out It does depend on
(29:59):
the specific medication the doseof the medication the time from
the last dose. So it's not assimple to doses say two vials
like crack spine. They've hadmultiple trials, several of them
were looking at, you know, doesit seemed to reverse anti
correlation, healthy volunteers,the biggest one looking at
(30:23):
actual people, the bleedingissue was a Nexus four. And that
demonstrated efficacy reversalof anti coagulation hemostasis
by lab parameters, right. Sothey looked at different lab
parameters, they looked atthings like hematoma size. So
this was not a patient orientedoutcomes rather, but disease
oriented outcomes or laboriented outcomes. They did not
(30:45):
value death or morbidity. Sothey did look to see if this
improved clinical outcomes,though, to see if it improved
laboratory outcomes. There'sabout 10% risk for venous
thromboembolism in this study,post reversal. And they also did
a single arm study this go outcriticism because they didn't
compare it to something else.
(31:08):
And the author's main argument,well, we can't compare it
against placebo because youwouldn't treat bleeding patients
with nothing. And they said thismedication array guide an FDA
indication for reversal of anti10 A inhibitors it did not have
any other medications with thisspecific indications as well.
(31:31):
You know, we didn't compare itagainst a four factor PCC
because four factor PCC doesn'thave an indication. So this was
a single arm trial. So there wasno blinding so there was
obviously concern that therecould be some bias in the
results. Alright, so now ournext group the heparin so low
(31:52):
molecular weight heparinenoxaparin. So it's commonly
used one, anti 10 A is the besttest again, as we said before,
that's not the easiest test toget. Half Life is four and a
half to seven hours or 12 hoursfor anti coagulation effects,
which kind of goes on the factthat we usually doses big unless
use a higher dose to try and geta longer duration at coagulation
effects. The treatment forsevere bleeding with this is
(32:15):
Protamine Protamine, is fairlywell so choosing with
unfractionated heparin with lowmolecular weight heparin, it
seems to have some efficacy butnot as much. That's largely
because interestingly enough,there seem to be a different
size of molecular fragments inlow molecular weight heparin. As
(32:41):
a result of this, the Protaminebinds better It seems to larger
ones and smaller ones, and youcan wind up having issues where
some of the inactive parentsbowel and some of it isn't
compared to unfractionatedheparin and where it binds much
(33:01):
better to the molecule. Andagain, as a result, you get
variable reversal. So theProtamine is not quite a magic
bullet. When you look at thedosing the Protamine, it really
depends on time from lastheparin dose. And chi breaks
(33:22):
down to how many minutes? Thisis one that you're perfectly
honest, I've rarely given backwhen I was a resident and
Lovenox had first became kind ofa big thing. We had
cardiologists, progestins toopen ox, every single person was
admitted with chest pain. Andthen we started finding people
getting hypotensive and shockyafterwards on the floor, and we
(33:43):
find out that a lot of againretroperitoneal hematomas. So
then we had to familiarizeourselves with Protamine dosing,
although, again, the Protaminedidn't seem quite as effective
for this as for regularunfractionated heparin. That
said, I've rarely had to reverseLovenox. Aspirin, clopidogrel,
Plavix, aka DAPT, both withplatelet adhesion aggregation.
(34:08):
This is gonna die quick there isno real strategy beyond
supportive care.
If you transfuse platelets, youseem to have an increased
mortality actually. So despitethe fact that you think while
the platelets that we havearen't working, let's give
working platelets that justdoesn't seem to help recommend
strategies Yeah, they have mildbleeding issues they actually
(34:28):
recommend just not changinganything, keep them under adapt.
If they got moderate bleeding,they're kind of holding one
agent prefer the aspirin andthen try and restart the adapt
in three days when some bleedingcenter control this severe
bleeding stock gappednecessitate source control so
they got bleeding also go in andtry and score a See also etc.
And then reevaluate the agentswhen bleeding is controlled. Now
(34:50):
obviously certain indicationssomebody recently a drug eluting
stent place where their risk ofincendiary thrombosis is high
without particularly Plavix. Butthere's still times when the
bleeding issues are significantenough that you're not going to
be able to do that.
Occasionally, students still putin bare metal stents and
patients who have other bleedingissues, because they know that
(35:11):
they're just not going to beable to safely keep them on
Plavix. Just some brief wordsabout the other direct thrombin
inhibitors bivalirudin is reallyused anymore. less bleeding and
heparin are the glycoproteinembryos but higher rates of
thrombosis. That's really CathLab drug argatroban soon was
kinda cath lab or impatient drugthrombosis associated with
(35:34):
hepatitis thrombocytopenia. Butit's also got higher mortality
rates because when it bleeds isreally nothing to give to
reverse it. There's no There'sno really discreet reversal
agent for either of these to getfor limited indications find a
parent x. Similarly, with theadvent of dough accessing that
(35:55):
use very rarely, that saucerinjectable 10, a inhibitor. The
indexer has not been studied andfind a paradox. So there's no
real reversal agent 40 of thetreatment, like with these other
ones is supportive care. So justlike it's my therapeutics, we
(36:15):
use it leading patient rightplatelet transfusion. Most
cases, it's increased mortality.
You can get temporary boosts ifsomebody has thrombocytopenic
from severe liver disease orsplenic sequestration. But for
most everything else, it doesn'treally seem to help a whole heck
of a lot. DDAVP is helpful theygot von Willebrand disease but
(36:39):
doesn't seem helpful andmedication induced bleeding
disorders and conjugatedestrogens simulation work well
for your remit plateletdysfunction, but they don't
really seem to do a whole heckof a lot for medication induced
platelet dysfunction. And so thenext one is T XA. This is kind
of like the magnesium ofprocoagulant in something that
(37:01):
we try to keep using to findindications for it's a synthetic
license that amino acid thatprevents the conversion of
plasminogen to plasmin. Itstabilizes clots by preventing
the degradation of fibrin.
Interestingly, although thisisn't the first thing that we
think of for it's only FDAapproved uses for severe
mineralia. It does reduce deathsdue to trauma induced
(37:22):
coagulopathy particularly ifit's given the first three
hours. That's why it's been alot pre hospital protocols
utilizing it now. Several yearsago, my previous job was I love
one trauma said had tone airmedical service. And we'd
started giving tranexamic acidto select the trauma patients on
the helicopter. It's been steadyfor head injury doesn't seem to
(37:43):
improve mortality and isolatedhead injury. They've looked at
it for a bunch of other stuff,dental end bleeding, postpartum
bleeding, post surgical,bleeding and multiple areas. And
probably the coolest one wasnebulized. For haemoptysis, most
of these have not been ananticoagulant patients, except
(38:05):
for some dentals and epistaxisstudies. They did take a big
look at for GI bleeding, but itdoesn't seem to really help too
much. And people with GIbleeding especially here big
virus co lead is that can ithappen medication is quite low
apathy. So not too many studieshave actually looked at this. So
most the anticoagulants actuallyprevent clot formation. Remember
10 A thrombin. You can't convertfibrinogen to fibrin, so you
(38:29):
can't make that clot. So sinceTSA can't reverse any of that
stuff, its role is primarily inpreventing climate breakdown. If
you can't find the cloud tobegin with and so clots then TX
is trying to do a whole heck ofa lot.
So I'd seen some benefit withdental extractions and
(38:49):
anticoagulant patients or selectinto procedures you know people
who have had for example, atonsillectomy or biopsy done
people with severe epistaxis aview looked at using topical TX
A for that. And as I said theyhad that one case that somebody
got nebulised TX say forhaemoptysis but overall it's
used in medication acoagulopathy seems to be very
(39:11):
limited. So to go into our caseresolutions that facias was
given for factor PCC and VitaminK went to the O R guide
tracheostomy evacuation hematomais discharged on post update for
and then he was ultimatelyswitched back to aspirin only as
Chad's VAs score was one. Hiscompliance was an issue so they
thought he was too high risk toput back on warfarin, he entered
(39:34):
alcohol treatment programs whichhopefully is going to help a lot
of his compliance issues andother medical issues both short
and long term. So to summarizethe most common anticoagulant
type things going into yourvitamin K antagonists, 10 A
inhibitors and plateletinhibitors. We do see direct
thrombin inhibitors a long walkaway heparins used less
frequently on the outpatientnow, for factor PCC produces
(39:57):
more rapid reverse of vitamin Kantagonists. dependent
coagulopathy you've seen vitaminK though because four factor PCC
action is relatively short livedactivity, it seems to clear out
within a few hours. So if youdon't get the vitamin K, there's
a chance that they will becomere anticoagulated. And x is a
(40:17):
trigger for the Oxy bands ismethodologic issues with trials
and they've looked primarily atlab parameters, clinical
parameters, but that said rightnow it's the only FDA approved
game in town for thesemedications. And if you're
looking at trying to start ananti Cragun Joe oxymorphone,
comparable effectiveness formost indications, any questions
(40:40):
or comments, please feel free tocontact me gerald.maloney@va.gov
Thank you very much.
Hi, my name is Jerry Maloney and I'm here to
talk to you today aboutmanagement of bleeding in the
anti coagulated patient. Okay,hi two o'clock. I'm the
Associate Medical Director forthe year the Cleveland VA and
I'm also Associate Professoremergency medicine at Case
Western. I am also a lieutenantcurrently Army Reserve and an
oaf veteran.
(00:21):
I have no disclosures to make.
So our objectives for thistopic, were listed different
anticoagulant drugs and theirindications review the lab
testing and tech regulatedpatient. Define what constitutes
major bleeding anticoagulantpatient discuss reversal agents
use and their supportingevidence. So we're going to
(00:42):
start things off with a casepresentation. 63 year old male
with a history of AFib anokhobbies presents for dissident
Jaws swelling for the past fewdays. So five milligrams of
Warfarin a day is a sign ourcheck a month ago was 1.8. He's
not any new medications, nohistory of trauma, the sun
desert board they held miss somedose and devil up to catch up on
his warfarin. So this is the oneI walk in the room. What do I
(01:06):
see picture. And in this case,what I saw was something that
made me very, very nervous rightoff the bat. In terms of file
size is a furrowed brow slightlytachycardic and hypertensive to
kip Nick and satting. And kindof borderline low 92% of the
Roman era. He's alert looks alittle bit anxious, you can open
the show a couple of fingerbreaths. As for the picture, you
(01:28):
can see there's pretty muchnothing but tongue in there. The
floor, his mouth, his hardtongues elevated. His
submandibular areas fall infirm, and he actually has a
little bit of ecchymosis thatmandibular area. As long as he's
slightly diminished bilaterallyis tacky and irregular isn't a
fib on the telemetry monitor.
(01:50):
He's not having any mob justiceor coughing up any blood right
now. So for labs, he's got anormal white blood cell count.
His hemoglobin is a little bitlower than baseline baseline is
around 14.3. Today is plateletcounts normal to 40, his BMP and
LFTs are grossly normal, is INRcomes back greater than 10. So
(02:13):
management, what's the bestreversal agent given his
elevated INR? And are there anyother therapies we should give.
And similar vein to our othercase presentation this gentleman
is somebody who had a recentbiopsy of a soft palate mass.
It's not a pixel band for a fibhad the pixel man held the day
(02:35):
before the procedure had theprocedure at the Pixabay and
restarted that night and wasfine and for a day or so and
then post op day. Number two, hecame in coughing up large clots
of blood. So in terms of classesof commonly used anticoagulants,
when I was a resident, we reallyhad three vitamin K antagonists,
(02:56):
heparin and platelet inhibitors.
Now we also add in directthrombin inhibitors and factor
10 A inhibitors. The vitamin Kantagonist category, there's
really only one that you setbeautifully, which is warfarin.
Direct thrombin inhibitors arekind of the first of the what
used to call noacs novel oralanticoagulants and doacs Direct
oral anticoagulation agents. Thebigger trend was the first in
(03:21):
that class. The have had someintravenous ones that have Allah
Rudan and our gastro ban. Thenext class of oral
anticoagulants under the doacslash noec category was the
factor 10 inhibitors and riverrocks a ban was the first
category followed by pixel banadoxa ban and kind of the newest
(03:43):
kid on the block is vetrix haveand they've had injectable
factor 10 inhibitors and loggingthey've had oral ones find a
paradox, which for a while isused at our place for cancer
related thrombosis heparinsunfractionated Heparin, which we
don't see uses commonly anymore.
(04:04):
The out of hospital raises we'relooking most of these
medications that people are onat home and come into the Edie
with low molecular weightheparin enoxaparin. The most
commonly used one is really whatwe see used for this category.
And then platelet inhibitors,the most common which are
aspirin and clopidogrel. Sosince we're talking about
(04:26):
anticoagulants, we do need to gointo the coagulation cascade
briefly. Warfarin causes themost widespread effects of this
calculation cascade it knocksout what they call the vitamin K
dependent clotting factorschoose seven nine and 10. The
end result of all this is thatit prevents the activation of 10
A which is the common link inboth the intrinsic and extrinsic
(04:50):
pathways. 10 A is the factorthat converts prothrombin to
thrombin and activate thrombinnecessary to convert fibrinogen
into fibrin.
Without conversion of fibrinogeninto fibrin, we can't form that
plug to create the clot. The 10inhibitors don't affect the rest
(05:14):
of the Cascade the way Warfarindoes, but they do hit right at
10. A itself. heparin alsoprints the actuation 10 A and
also blocks thrombin to preventit from activating fibrinogen
into fibrin, so do the directthrombin inhibitors. So we
really get down to it. There'sreally two points where all
(05:34):
these anticoagulants seem towork 10 A or thrombin. Since we
do strapped people onanticoagulation from the Ed does
help to quickly review theindications for these things.
Vitamin K antagonists have thebroadest indications, mainly
because we're using the longestright so a fair both alveolar
nerve alveolar fib DVT or PE,both cancer and non cancer
(05:57):
related primary clottingdisorders. Things like factor
five light and protein CNSdeficiencies, and also they've
been used as prophylaxis, afterthings like joint replacements.
The direct thrombin inhibitorshave indication for DVT and PE
treatment cancer associated in afib nonvalvular. The 10 A
(06:20):
inhibitors pretty similar theyhaven't added indication for DVT
prophylaxis. The other thingthat the 10 inhibitors are used
for CBT and PE it can be used incertain cancer related ones as
well. Because of increasedbleeding rates with GI Gu
cancers, they do not recommendusing them for those particular
(06:44):
indications. heparin obviouslyis the preferred one
particularly low molecularweight heparin for cancer
related thrombosis, and forprophylaxis as well. And
platelet inhibitors usedprimarily in stroke and ACS PCI,
although they've been used forother things like DVT
prophylaxis may be used inpatients with afib, who are
(07:06):
considered higher risk of beingon the stronger anticoagulants.
They don't have a primaryindication for anticoagulation
for any of these otherindications per se. So just to
go a little bit more into thecancer related indications. They
compare two pics Amanda docsbetter for Oxman Alta Dalta
paren, which is another onewalkaway heparin for cancer
(07:26):
associated venousthromboembolism. And
interestingly, although theywere rated at a superior or non
inferior to Delta parent interms of treatment of cancer
associated VT II, they hadhigher bleed rates, especially
the GI cancers. They arepreparing comparing them to the
(07:47):
vitamin K antagonists theseindications as well. Currently
the recommended is no GI or Gumalignancy. I bring that up
because for those of you workingin the VA, like me, obviously I
get probably a couple ofpatients a week that I sent down
from CT because they had theirstaging CT down and they found
(08:07):
multiple asymptomatic PE. Sothey had some other study down
and found that they had a DVT.
So they got filtered to the ERso starting them on
anticoagulation is something wefrequently have to do. I'm a
medical toxicologist by trainingas well. So I do like to talk
about things like kinetics. I'mnot going to go into this in
(08:27):
great detail, but looking at thebigger trends and the most
commonly used 10 inhibitors.
Looking at the tannic IP plasmaconcentration is pretty similar
with all the right summarize.
And the minimum one hour andusually about three hours. There
half lives are relativelysimilar to redox events somewhat
(08:51):
shorter half life, but the restof them, I summarized at least
nine and assigned to biggertrans cases 17 hours and the
frequency with most use once ortwice daily. Some of this
depends on renal function. Andthey are all renally excreted to
a significant degree,particularly the biggest fan
which is majority renallyexcreted. They have antidotes
(09:12):
which we'll go into a little bitlater, but there's n DEXA and
Daris ism AB, or prac spined andthey all take at least 48 hours
after the last dose for completecessation of all pharmacologic
(09:34):
activities. So although theylike to say you can hold it for
a day, if you really want tocomplete washout of all their
anti Quagga activity, you reallygot to give it 48 hours. So in
terms of laboratory testing, sothe INR is primarily for vitamin
K antagonists and typicallywe're looking at a range between
two and three occasion up to 3.5for prosthetic valves
(09:59):
on occasion There will be peoplewho are on higher Target INR
hours based on something thatthey've worked out with a
hematologist. But rarely is anINR greater than 3.5. So
consider the therapeutic range.
So in terms of INR with doac,typically the INR is all very
the direct but it's not linearrelation, it's not like
(10:21):
Warframe, where you can kind ofdetermine if they're
therapeutically anticoagulated.
Based on what their INR is.
Frequently it is elevated, notalways. So you can also have
patient who is taking a doac whohas a normal INR but will still
have therapeutic anticoagulationactivity. So bottom line is that
(10:43):
the INR is somewhat helpful ifit's elevated, at least confirm
the patient's taking a doac. Anormal INR does not exclude that
the taking of doac and there'sno real correlation between the
INR level and level ofanticoagulation. This has come
up because I've occasionallypeople say, Well, you know, if
we get somebody who comes in andtheir stroke syndrome, and
(11:05):
they're not really response, wedon't have medical history on
them, we can check a quick INRand if it's normal, that
unfortunately doesn't exclude adoe x, so it makes it a lot
harder to conclusively excludetheir anticoagulant in that
case. The anti 10 is best forthe oxidants low molecular
weight heparin but again, shortof some facilities that do a lot
(11:25):
of research protocols and stuff.
With the 10 inhibitors, it'sreally hard to get a rapid turn
around 10 A, the PTT is good fora fraction heparin. It can also
be elevated with a directthrombin inhibitors, but again,
similar to INR and the doacs.
It's the elevation that you getin PTT with a direct thrombin
(11:48):
inhibitor is not correlative ofthe degree of anticoagulation,
same wages for infraction,heparin. So how do we define
major bleeding? This is going tobe critical site right in the
airway, intracranial pulmonarypericardial active GI bleeding
not and I had a little bit ofmelon, but I seem to be having
severe like medic ease yeahhematemesis or an uncontrolled
(12:14):
extremity bleed. If theyhemodynamically unstable if
they've lost more than two gramsof hemoglobin from their
baseline, or if they've beentransfused at least treants have
packed red blood cells throughthe bleeding. So if you're
looking for the soundbite sideof this presentation, this is
it. The journal sets majorbleeding Control Stop
(12:36):
resuscitate reverse, so you wantto strap your anticoagulant
agent, resuscitate the patientfluids blood, etc and reverse
the anticoagulant. This is amodule we get to employ
frequently at my shop we have ona given month about 10,000
patients through our facilitythat are on some type of
anticoagulation, typicallyeither vitamin K antagonists or
(12:59):
doac. There's if there's ahandful heparins and find a
paradox is thrown in there.
These patients have a higher eduse rate than the rest of the
population typically. And it'snot uncommon at all to see one
that come in some type ofleading complication. So going
(13:19):
on to the agent specificmanagement. Um, each class seems
to have a specific reversalagent or therapy. This journal
therapies we look at I'll talkabout those briefly. Things like
FFP tranexamic acid DDAVP,estrogen and platelet
transfusion. But the crux is isgoing to be looking at what
specific reversal agents we usefor this specific type of
(13:40):
anticoagulant. So I'm atoxicologist as I mentioned
earlier, so I love antidotes. Solooking at our anticoagulants,
several of them do haveantidotes. The bigger Tran has a
darest ism AB or the slightlyless tongue twisting prac spined
(14:01):
river rocks of n and Pixabay isindex alpha or and DEXA.
Warfarin the actual antidote forit is actually vitamin K. And
heparin uses Protamine someother journal verse legends we
talked about again FFP forfactor PCC. So vitamin K
(14:21):
antagonists, right? So theyinhibit vitamin K dependent
clotting factors, which are 279and 10. And they were playing
him in st called V K O RC, whichactivates vitamin K vitamin K
isn't activated, then it cannothelp with the formulation of the
vitamin K dependent clottingfactors. And the vitamin K that
we give intravenously forphytanic die own is actually UK
(14:44):
wide or activated vitamin K. Sobypass is a blockade of
warfarin.
Warfarin interestingly enoughcame from moldy hay. It was
described in cows first whodying from hemorrhage And it was
the Wisconsin area ResearchFoundation that discover this
(15:05):
industry thought it was aheparin oId type of thing. Hence
the Aeron. So that's where thewharf in the warfarin came from.
They also use it for rat poisonand they have short and long
acting Coumarins. The longacting ones are not used ever
for human treatment. Although,as a fellow we certainly
(15:25):
followed many people whooverdosed and rat poison. I
remember one case of a Johndeclining acting coumarin and
was still anticoagulants. Sodetectable levels in his blood.
45 days after it's overdoses,some of these long acting ones
really stick around for a while.
The advantages to warfarin,we've been using it forever, we
know how to monitor it, we havea test that very accurately
(15:46):
reflects level anticoagulationwith the INR. And because we've
used so much for everything,it's something everybody's
familiar with his vastexperience with their
management, disadvantages gothigher rate of bleeding than
pretty much all the otheranticoagulants there's a ton of
drug food and drug druginteractions is also widely
variable metabolism. So youknow, one patient may get
(16:08):
therapeutic with a milligram ofwarfarin, somebody else may take
10 milligrams, so there's a lotof kind of trial and error with
Warfarin dose and get somebodytherapeutic with their INR. Now
for treatment, again, there isan antidote for iron
antagonists, and the antidote isvitamin K. The guy says get
(16:29):
super therapeutic INR, butthey're not bleeding, it's less
than five, just hold it no giveanything between five and 10 can
hold it and give us a small doseof vitamin K, usually, anywhere
from one to two and a halfmilligrams pure IV, it's greater
than 10, the checkout holding itand then giving a dose of
(16:50):
vitamin K again, depending onsituations two and a half to
five milligrams, they do notrecommend subcutaneous vitamin
K, because it's poorly absorbedoral is preferred IV if the
patient can't take oral there'sa small risk of anaphylaxis with
IV vitamin K, the ever majorbleeding issue then they
recommend kind of hitting themhard 10 milligrams of vitamin K
(17:11):
IV and then either FFP or fourfactor a PCC. So FFP this has
been kind of long standingtreatment for this, you need to
get to at least him about 10% ofclotting factors restored to be
able to reverse anticoagulation. So if you look at
FFP, each unit gives you about2.5% of clotting factors. Since
(17:33):
diagnosis, always four units.
And the higher the INR, the moreyou may need to use a universal
donor plasma ab. And typically,if you give a full dose of FFP,
for their INR, typically aboutthe best you can graduate to is
(17:54):
1.6. And that gives you about 30to 50% clotting factor activity
that INR. So typically Tigerwould give you at least a leader
of a hypertonic solution, if notmore than that. So the issue has
always been a lot of people whoare on warfarin and
cardiomyopathy or a fib they'vegot poor UFC can't tolerate a
(18:17):
lot of fluids. So there's beenconcerns about limitations with
FFP. And you can't exactlypressure bag this stuff in so it
takes hours to go in. So you'realso not talking about rapidly
reversing somebody how you doingover several hours if you need
to reverse them more quicklythan that FFP doesn't provide a
(18:38):
great option. So now we'relooking at four factor PCC this
is kind of new on the block,they came up with a three factor
prothrombin complex concentrate.
The three factor has been usedfor hemophilia, but the three
factor because it's missingfactor seven doesn't seem to be
as good for reversing warfarin.
(18:58):
Same with the four factor caseSentra. The four factors
indication is for warfarinreversal. Although it's been
used with other bleeding issues,it's only real FDA approved
indications for warfarinreversal. It contains factor 279
and 10. It also contains proteinCNS, and it contains some
heparin in it as well. The doseis based on the weight in the
(19:20):
INR it's capped at a weight of100 kilograms. And to give you
kind of a conversion, one vial aPCC equals about two units of
FFP. With the case Sentra, youcan reverse the INR as low as
1.3 within 30 minutes andusually get about 24 hours of
human stasis. What that means isyour bleeding should be
completely stopped by four hoursand no further reversal agents
(19:43):
needed in the next 24 hoursafter giving case, Sandra.
Although it seems to be somewhathelpful and small stays with
doacs were particularly beforethey had other antidotal agents
where they kind of gave itseemed to help some. It doesn't
necessarily make sense that itwould be a great reversal agent
(20:07):
for doacs with Jo xe issuesinhibition of 10 a deficiency of
10 a. So replacing factor 10isn't necessarily going to be
particularly helpful because youstill have blackk to the
activation that factor 10Because it's got heparin is
contra indicated people withheparin induced
(20:27):
thrombocytopenia. And in termsof causing clotting issues
similar to FFP. So althoughthere's been concern at our
place, we actually have arestriction where I have to talk
to a hematologist. If I want touse this. Hematology, his big
concern has been that they thinkthere's gonna be higher rates of
venous thromboembolism becauseit's more rapid reversal. But
(20:47):
looking at the literature, theredoes not seem to be that risk
compared to giving FFP alone.
jacket with a bigger trend abit. Again, it was the first
doac highly renally excreted,which has been an issue limiting
its use in people with advancedCKD. The dosing is 150
milligrams once or twice daily.
(21:09):
If the GFR is greater than 3075milligrams, it's 15 to 30
minutes below 15. They don'trecommend it. They may place it
ceiling dialyze double doacbecause before they came out
with an actual antidote for it,their argument was well if
you're having severe bleedingcan dialyze it and remove it,
which is possible but again todialyze patients frequently have
(21:33):
to use heparin as well. I mean,you can do a saline. Okay,
anticoagulation as well for thedialysis but science effective.
So dialysis is not a greatresponse when somebody who's
acutely bleeding out, whichpressured them to come up with
an antidote. syndications again,nonvalvular a fib DVT PE. The
(21:59):
thing with this one though, iscompared to looking at the other
doacs It was studied for DVT PEafter they had five days
apparently oral anticoagulationso basically I'd have them on a
heparin drip for five days orLovenox, or five days and then
you could switch them over withdoes have DVT prophylaxis and
occasion for one thing, which ispost hip surgery. So now on to
(22:22):
the antidote, right? So a Darrisism AB, or prac spine, it's a
monoclonal antibody and some ABand binds both free and thrombin
bound to bigger trans when yougive it it doesn't just find the
stuff that's floating aroundloose, it actually pulls it off
thrombin as well. It is renallyexcreted somewhere to the bigger
(22:43):
fan itself, and the halfway isabout 10.8 hours. So practice by
itself is also dialyze of allthat's part of the reason why.
Again, for people who are havingsevere bleeding things, they
still recommend dialyze them topoint you can remove the prac
spine with dialysis, the dose isfive grams, which is to 2.5 gram
(23:06):
vials when I talked to the rep afew years ago. each vial was
$2,500 roughly. So it's about abuck a milligram so that makes
it fairly expensive. Again, it'sa monoclonal antibodies, it's
not surprising. The prac spineddoes not seem to have an aging
(23:28):
thing to it, it doesn'teventually unbind after a while,
like some things we worriedabout, like digibytes. So the
practice by and seems to formkind of an irreversible ionic
bond with the bigger Tran so youdon't have to worry about the
practice behind eventuallyunbinding the patient becoming
(23:51):
re anticoagulated. As with allof these things, there is a risk
of rebound thrombosis after youuse it because these patients
obviously had indication behindit in the first place. So now
we're taking the rest of doacsCall the Oxy bands. So there was
river rocks van Kai the firstone picks a ban, which is the
(24:16):
other most widely used oxy banedocs a ban and Bitrex have an
ID. So all of these areactivated 10 A inhibitors. So
they bind to activate 10 A andprevent it from activating
thrombin engine into thrombin.
So it makes it impossible foryou to then activate fibrin
(24:43):
inform that clot.
Their arrival is really kind ofchanged the face of
anticoagulation single dose andthey started the anticoagulant
activity right away. There's noramping up and waiting a few
days, like you have withWarfarin They've been shown to
be as effective as Warfarin formost indications, and their
(25:08):
overall bleeding or seems to belower than Warfarin as well. So
they've absolutely changed theworld of managing thrombotic
disorders. I've because of theavailability of the Oxy bands,
the VA, I've rarely had to admitpeople with uncomplicate DVTs
(25:29):
anymore. It's a next step,talking about the Oxy bands. As
I said they're all anti tenniesriver rocks a ban in a pixel ban
have indications a lot of theedocs a ban for DVT PE
management except for patient giGu cancers for non valve a for
(25:49):
prophylaxis and rivaroxaban andPIXMA. Also for DVT prophylaxis
in hospital Bitrix abandonedTristan has a DVT prophylaxis
indication but that's focusednot just in hospital but up to
42 days post discharge. Sothey're really the only one that
looked at doing DVT prophylaxisin the outpatient setting.
(26:09):
Additionally, although this isnot anything they've gotten an
FDA indication for somefacilities of like to to use
river ox ban or pics of and forVT e prophylaxis in people with
severe COVID infections thatpeople are hospitalized for
while severe level of diseaseelevated D dimers. And they've
(26:30):
been usually using four to sixweeks of either river oxidant or
a PIXIV and post discharge. Nowit was in some places I my
facility is actually usingLovenox. But there are several
that are using a doac. Again,this is an off label indication.
So bleeding issues withoxymorons, right? Gi is the most
(26:51):
common CNS is rare and a lot ofthese other abnormal bleeding
sites like retroperitonealhemorrhage airway, hemorrhage
haemoptysis, are also very rarewith the Oxy bands. And we
actually reviewed all theserious bleeding issues in our
anticoagulated population over ayear. And it came out to be you
know, probably about 60 to 70%of the bleeds that we saw with
(27:14):
the Oxy bands were GI bleeding.
More from was kind of all overthe place. It was mostly GI
bleed or some CNS bleeds thatseem to happen more commonly
with trauma patients. But Trixhave an interest of does have a
warning for spinal epiduralhematoma. That is in the study
of people who have had some typeof procedure and lumbar
puncture, spinal anesthesia,epidural catheter, etc. Looking
(27:37):
specifically at trauma patients,at least the largest
retrospective analysis and sofar, they have a much lower
symptomatic intracranialhemorrhage than vitamin K
antagonists. Again, looking atisolated head trauma, the
vitamin K antagonists are in17%. And that was going to have
24 hours post injury. The dogsabout 5%. And the delay bleeding
(28:02):
rate was a little bit lower aswell interest if not zero. This
protocol kept everybody for 24hours and did a initial head CT
and then repeat head CT 24 hoursand then compared it to a non
anticoagulated cohort. Lookingat the overall bleed rate for
the doacs posttraumatic ich intolabeling, he actually seems
(28:26):
similar to the controls. So ifyou read it that way it is the
doacs not appear to have anysignificantly increased risk of
me immediate or delayed headbleed compared to a control
population. That said, there'sstill ongoing data with this, so
I wouldn't hang my hat on thatjust yet. But it does appear at
(28:49):
least like our local traumacenters are not considering doac
use alone as an indication formeeting people for 23 hour odds
and repeat head imaging. Ifthere's no other indication to
admit them, and there otherwiseare logically intact. So now one
of my favorite subject theantidotes and DEXA alpha or n
(29:10):
DEXA is the intro for the Oxybands. It was designed for picks
a band and river rocks a bandbut certainly a factor for all
of them. Because they're allfairly chemically similar. It's
a call a decoy 10 A proteins soit's designed to look like 10 A
and preferentially bind to theOxy ban so it will actually pull
(29:34):
them off the real 10 A and getthem to bind to it. So Kevin,
interesting our concept. Thedosing is based on the molar
concentration of the ox of n. Sofortunately, that doesn't
require us to sit there and pulloff a guidroz number and figure
that out for each individualmedication out It does depend on
(29:59):
the specific medication the doseof the medication the time from
the last dose. So it's not assimple to doses say two vials
like crack spine. They've hadmultiple trials, several of them
were looking at, you know, doesit seemed to reverse anti
correlation, healthy volunteers,the biggest one looking at
(30:23):
actual people, the bleedingissue was a Nexus four. And that
demonstrated efficacy reversalof anti coagulation hemostasis
by lab parameters, right. Sothey looked at different lab
parameters, they looked atthings like hematoma size. So
this was not a patient orientedoutcomes rather, but disease
oriented outcomes or laboriented outcomes. They did not
(30:45):
value death or morbidity. Sothey did look to see if this
improved clinical outcomes,though, to see if it improved
laboratory outcomes. There'sabout 10% risk for venous
thromboembolism in this study,post reversal. And they also did
a single arm study this go outcriticism because they didn't
compare it to something else.
(31:08):
And the author's main argument,well, we can't compare it
against placebo because youwouldn't treat bleeding patients
with nothing. And they said thismedication array guide an FDA
indication for reversal of anti10 A inhibitors it did not have
any other medications with thisspecific indications as well.
(31:31):
You know, we didn't compare itagainst a four factor PCC
because four factor PCC doesn'thave an indication. So this was
a single arm trial. So there wasno blinding so there was
obviously concern that therecould be some bias in the
results. Alright, so now ournext group the heparin so low
(31:52):
molecular weight heparinenoxaparin. So it's commonly
used one, anti 10 A is the besttest again, as we said before,
that's not the easiest test toget. Half Life is four and a
half to seven hours or 12 hoursfor anti coagulation effects,
which kind of goes on the factthat we usually doses big unless
use a higher dose to try and geta longer duration at coagulation
effects. The treatment forsevere bleeding with this is
(32:15):
Protamine Protamine, is fairlywell so choosing with
unfractionated heparin with lowmolecular weight heparin, it
seems to have some efficacy butnot as much. That's largely
because interestingly enough,there seem to be a different
size of molecular fragments inlow molecular weight heparin. As
(32:41):
a result of this, the Protaminebinds better It seems to larger
ones and smaller ones, and youcan wind up having issues where
some of the inactive parentsbowel and some of it isn't
compared to unfractionatedheparin and where it binds much
(33:01):
better to the molecule. Andagain, as a result, you get
variable reversal. So theProtamine is not quite a magic
bullet. When you look at thedosing the Protamine, it really
depends on time from lastheparin dose. And chi breaks
(33:22):
down to how many minutes? Thisis one that you're perfectly
honest, I've rarely given backwhen I was a resident and
Lovenox had first became kind ofa big thing. We had
cardiologists, progestins toopen ox, every single person was
admitted with chest pain. Andthen we started finding people
getting hypotensive and shockyafterwards on the floor, and we
(33:43):
find out that a lot of againretroperitoneal hematomas. So
then we had to familiarizeourselves with Protamine dosing,
although, again, the Protaminedidn't seem quite as effective
for this as for regularunfractionated heparin. That
said, I've rarely had to reverseLovenox. Aspirin, clopidogrel,
Plavix, aka DAPT, both withplatelet adhesion aggregation.
(34:08):
This is gonna die quick there isno real strategy beyond
supportive care.
If you transfuse platelets, youseem to have an increased
mortality actually. So despitethe fact that you think while
the platelets that we havearen't working, let's give
working platelets that justdoesn't seem to help recommend
strategies Yeah, they have mildbleeding issues they actually
(34:28):
recommend just not changinganything, keep them under adapt.
If they got moderate bleeding,they're kind of holding one
agent prefer the aspirin andthen try and restart the adapt
in three days when some bleedingcenter control this severe
bleeding stock gappednecessitate source control so
they got bleeding also go in andtry and score a See also etc.
And then reevaluate the agentswhen bleeding is controlled. Now
(34:50):
obviously certain indicationssomebody recently a drug eluting
stent place where their risk ofincendiary thrombosis is high
without particularly Plavix. Butthere's still times when the
bleeding issues are significantenough that you're not going to
be able to do that.
Occasionally, students still putin bare metal stents and
patients who have other bleedingissues, because they know that
(35:11):
they're just not going to beable to safely keep them on
Plavix. Just some brief wordsabout the other direct thrombin
inhibitors bivalirudin is reallyused anymore. less bleeding and
heparin are the glycoproteinembryos but higher rates of
thrombosis. That's really CathLab drug argatroban soon was
kinda cath lab or impatient drugthrombosis associated with
(35:34):
hepatitis thrombocytopenia. Butit's also got higher mortality
rates because when it bleeds isreally nothing to give to
reverse it. There's no There'sno really discreet reversal
agent for either of these to getfor limited indications find a
parent x. Similarly, with theadvent of dough accessing that
(35:55):
use very rarely, that saucerinjectable 10, a inhibitor. The
indexer has not been studied andfind a paradox. So there's no
real reversal agent 40 of thetreatment, like with these other
ones is supportive care. So justlike it's my therapeutics, we
(36:15):
use it leading patient rightplatelet transfusion. Most
cases, it's increased mortality.
You can get temporary boosts ifsomebody has thrombocytopenic
from severe liver disease orsplenic sequestration. But for
most everything else, it doesn'treally seem to help a whole heck
of a lot. DDAVP is helpful theygot von Willebrand disease but
(36:39):
doesn't seem helpful andmedication induced bleeding
disorders and conjugatedestrogens simulation work well
for your remit plateletdysfunction, but they don't
really seem to do a whole heckof a lot for medication induced
platelet dysfunction. And so thenext one is T XA. This is kind
of like the magnesium ofprocoagulant in something that
(37:01):
we try to keep using to findindications for it's a synthetic
license that amino acid thatprevents the conversion of
plasminogen to plasmin. Itstabilizes clots by preventing
the degradation of fibrin.
Interestingly, although thisisn't the first thing that we
think of for it's only FDAapproved uses for severe
mineralia. It does reduce deathsdue to trauma induced
(37:22):
coagulopathy particularly ifit's given the first three
hours. That's why it's been alot pre hospital protocols
utilizing it now. Several yearsago, my previous job was I love
one trauma said had tone airmedical service. And we'd
started giving tranexamic acidto select the trauma patients on
the helicopter. It's been steadyfor head injury doesn't seem to
(37:43):
improve mortality and isolatedhead injury. They've looked at
it for a bunch of other stuff,dental end bleeding, postpartum
bleeding, post surgical,bleeding and multiple areas. And
probably the coolest one wasnebulized. For haemoptysis, most
of these have not been ananticoagulant patients, except
(38:05):
for some dentals and epistaxisstudies. They did take a big
look at for GI bleeding, but itdoesn't seem to really help too
much. And people with GIbleeding especially here big
virus co lead is that can ithappen medication is quite low
apathy. So not too many studieshave actually looked at this. So
most the anticoagulants actuallyprevent clot formation. Remember
10 A thrombin. You can't convertfibrinogen to fibrin, so you
(38:29):
can't make that clot. So sinceTSA can't reverse any of that
stuff, its role is primarily inpreventing climate breakdown. If
you can't find the cloud tobegin with and so clots then TX
is trying to do a whole heck ofa lot.
So I'd seen some benefit withdental extractions and
(38:49):
anticoagulant patients or selectinto procedures you know people
who have had for example, atonsillectomy or biopsy done
people with severe epistaxis aview looked at using topical TX
A for that. And as I said theyhad that one case that somebody
got nebulised TX say forhaemoptysis but overall it's
used in medication acoagulopathy seems to be very
(39:11):
limited. So to go into our caseresolutions that facias was
given for factor PCC and VitaminK went to the O R guide
tracheostomy evacuation hematomais discharged on post update for
and then he was ultimatelyswitched back to aspirin only as
Chad's VAs score was one. Hiscompliance was an issue so they
thought he was too high risk toput back on warfarin, he entered
(39:34):
alcohol treatment programs whichhopefully is going to help a lot
of his compliance issues andother medical issues both short
and long term. So to summarizethe most common anticoagulant
type things going into yourvitamin K antagonists, 10 A
inhibitors and plateletinhibitors. We do see direct
thrombin inhibitors a long walkaway heparins used less
frequently on the outpatientnow, for factor PCC produces
(39:57):
more rapid reverse of vitamin Kantagonists. dependent
coagulopathy you've seen vitaminK though because four factor PCC
action is relatively short livedactivity, it seems to clear out
within a few hours. So if youdon't get the vitamin K, there's
a chance that they will becomere anticoagulated. And x is a
(40:17):
trigger for the Oxy bands ismethodologic issues with trials
and they've looked primarily atlab parameters, clinical
parameters, but that said rightnow it's the only FDA approved
game in town for thesemedications. And if you're
looking at trying to start ananti Cragun Joe oxymorphone,
comparable effectiveness formost indications, any questions
(40:40):
or comments, please feel free tocontact me gerald.maloney@va.gov
Thank you very much.
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