Endotheliopathy in COVID-19- associated Coagulopathy

Transcript

• 00:00Uhm, I know a lot of you guys already,
• 00:03but I'm one of the clinical
• 00:05hematologist here at the Cancer Center,
• 00:07and for the last nine years my main
• 00:09interest have been medical education
• 00:10and thrombosis or blood clotting.
• 00:12And then in mid March of this year
• 00:15Is everybody knows kovid hit and so
• 00:17early on when the first kovid patient
• 00:19arrived at Yale New Haven Hospital.
• 00:21A few of us in the hematology
• 00:23section were asked to join a multi
• 00:25disciplinary effort designed to try
• 00:27to understand in combat the disease,
• 00:29an one of the more interesting and kind of.
• 00:32Unexpected features of COVID-19
• 00:33infection was that there's actually
• 00:35a huge component of blood clotting,
• 00:37and this is something that's term
• 00:39COVID-19 associated Coagulopathy.
• 00:40So we became interested in the hematology
• 00:43section and trying to not just manage
• 00:45this but also understand this,
• 00:47and so that's what I'm going to be
• 00:50talking with you all about today.
• 00:53So again,
• 00:54this this whole feature of blood
• 00:55clotting in Kobe 19 infection is
• 00:58something that's called COVID-19
• 00:59associated Coagulopathy.
• 01:00Its abbreviated CAC and at the laboratory
• 01:03level it's defined by 4 basic things.
• 01:05So one is that these patients
• 01:07have an elevated D dimer.
• 01:09That's often very, very high.
• 01:10The second is that they have
• 01:13a high fibrinogen level.
• 01:14Again, that's often very high.
• 01:16The third is that many of these patients
• 01:18have a normal prothrombin time,
• 01:20or very slightly elevated prothrombin time,
• 01:22and the 4th.
• 01:23Is that most of them have normal
• 01:26platelet counts,
• 01:27although some of them do have a
• 01:29slightly reduced platelet count.
• 01:31And again, as I mentioned before,
• 01:33clinically the main feature
• 01:35associated with code 19 associated
• 01:36Coagulopathy is thrombosis.
• 01:38So these patients have a very high
• 01:40risk of developing blood clots,
• 01:42predominantly venous thromboembolism or VTE,
• 01:44and in particular pulmonary embolism.
• 01:46There are some single institution
• 01:48studies that suggest that up to 37
• 01:51to even 40% of COVID-19 patients
• 01:52in an intensive care unit.
• 01:54Who are ready on prophylactic
• 01:56anticoagulation will develop a pulmonary
• 01:59embolism or a deep vein thrombosis.
• 02:01And In addition Artur thrombosis an
• 02:04then microvascular thrombosis on
• 02:06autopsies has also been described.
• 02:08So because of this very high rate
• 02:10of thrombosis are hospital system,
• 02:12our institution was actually one
• 02:14of the first in the country to
• 02:16develop what we call an escalated
• 02:19intensity anticoagulation regiment.
• 02:20So what I mean by this is that as
• 02:23most of you who are clinicians know,
• 02:26whenever patients in general get
• 02:27admitted to the hospital already there,
• 02:30blood clotting risk goes up and
• 02:32so most patients admitted to a
• 02:34hospital center including Smilow
• 02:35would be on what we call a low dose
• 02:39of prophylactic anticoagulation.
• 02:40Typically,
• 02:40enoxaparin had a dose of 40
• 02:42milligrams once a day.
• 02:43But in kovid patients,
• 02:45because of this increase risk of
• 02:47Trumbo Sis we adopted this escalated
• 02:50intensity anticoagulation regiment
• 02:51so that patients with Cove in
• 02:53infection who had a D dimer level
• 02:55that was above a certain cut off
• 02:57which we ended up choosing us 5
• 03:00milligram per liter would
• 03:01automatically get a higher
• 03:03dose of anticoagulation.
• 03:04We would call this intermediate
• 03:06enoxaparin typically,
• 03:07which is at a dose of 0.5 milligrams
• 03:10per kilogram twice a day and then
• 03:12again because of this super high.
• 03:14Risk of thrombosis in any covert
• 03:16patient in whom there is a suspicion for
• 03:19venous thrombotic event or confirmed
• 03:21Venus Don Bolic event we would
• 03:23recommend full dose anticoagulation
• 03:24typically again with enoxaparin
• 03:26editors of 1 milligram per kilogram
• 03:28twice daily so as I mentioned we
• 03:30were one of the first hospital
• 03:32centers in the country to develop.
• 03:35One of these escalated escalated
• 03:37anticoagulation dosing guidelines
• 03:38and many other hospitals if not most
• 03:40around the country have followed suit.
• 03:42One of the challenges that
• 03:44we've all had his clinicians.
• 03:45Is that even though most of us
• 03:47in the country are doing these
• 03:49escalated anticoagulation regiments,
• 03:50we don't actually know if they're safe
• 03:52or if there even affective and so at
• 03:54yell our group is in the process of
• 03:56analyzing this now as are many others
• 03:58and there are some clinical trials
• 04:00around different institutions in the
• 04:01country that are looking at this issue.
• 04:03This question as well.
• 04:06So one of the early studies that
• 04:07came out from China on covert
• 04:09associated Coagulopathy reported that
• 04:11it was essentially a variation of
• 04:14disseminated intravascular coagulations,
• 04:16or DIC,
• 04:16which as most of you all know as sort
• 04:19of an end point of a coagulopathic
• 04:21picture that's characterized by
• 04:23pretty high rates of thrombosis
• 04:26and terminal disease.
• 04:27But DIC itself again as a
• 04:29lot of other clinicians know,
• 04:31has a very characteristic laboratory pattern,
• 04:34and to us it really didn't seem.
• 04:36White covered associated Coagulopathy
• 04:38was similar to DIC at all.
• 04:41So early on when we start first started
• 04:44seeing kovid patients in our hospital,
• 04:46we decided to do a couple of studies
• 04:48to try to understand what the
• 04:50code associated Coagulopathy is.
• 04:52And so this first study that we did
• 04:54was led by one of our star first
• 04:57Hematology Fellows George Joshua,
• 04:58and what we did here was to look at
• 05:01the 1st 200 plus patients with Kobe,
• 05:04who are admitted to our hospital and
• 05:06we calculated what's called a dic
• 05:08score at specified by the International
• 05:10Society of thrombosis and hemostasis,
• 05:12or IST age.
• 05:12And so the way this works is that
• 05:14the ice TH score essentially looks
• 05:17at different laboratory features of
• 05:19patients suspected of having DIC,
• 05:21and then it spits out a score.
• 05:23And if your score is in the range
• 05:25of five and up,
• 05:26then that's considered overt DIC
• 05:28in anything less than five is
• 05:30not consistent with over DSD.
• 05:31And so in our first couple 100 patients
• 05:34with Cobain infection admitted to Yale,
• 05:36New Haven Hospital when we
• 05:37calculated the IST FDIC scores,
• 05:39whether we were looking at patients who
• 05:41survived or patients who did not survive.
• 05:43As you can see,
• 05:44almost all patients had a very low
• 05:47IST HDC score in this entire group.
• 05:49There was only one patient who
• 05:50had an IST HD
• 05:52score of six consistent with over DIC,
• 05:54but this is a patient who had
• 05:56helped syndrome after pregnancy,
• 05:57and we didn't think that this is
• 06:00related at all to COVID-19 infection.
• 06:02So based on this,
• 06:03we really started to feel that
• 06:05kovid associated Coagulopathy
• 06:06was not consistent with DIC,
• 06:09and so the next thing that we did
• 06:11was to perform a somewhat large
• 06:13study of a number of ICU and
• 06:16non ICU patients with Cove it,
• 06:19in which we measured lots and lots of
• 06:21different coagulations factors trying
• 06:23to see what exactly the mechanism of
• 06:25covert Coagulopathy might be an weather.
• 06:28Again this was distinct from DC.
• 06:31So this work here was carried
• 06:32out by four people who are shown
• 06:34at the bottom of the page.
• 06:36Parveen,
• 06:36but hell is one of the lab
• 06:38technicians in the Park Street Lab
• 06:40who did all of the quag elation
• 06:42testing and then George Joshua
• 06:43refers to your fellow Alex Pine,
• 06:45one of our star senior 30 or
• 06:47Fellows in he monk and then a
• 06:49super MD PhD student at my slash
• 06:52also together did this analysis.
• 06:53So first I'll starting at the
• 06:55top of the page.
• 06:57The first thing we measured were D dimer
• 06:59levels and something else called a thrombin,
• 07:01antithrombin complex or TI-80.
• 07:02So as most of you know,
• 07:04the D dimer level is something that tends
• 07:07to go up on patients form blood clots,
• 07:09and it can often be a very
• 07:11useful measure of blood clotting,
• 07:13and one of the significant features of
• 07:15the D dimer is that encoded infection.
• 07:17the D dimer level seems to be
• 07:19one of the very very prominent
• 07:21markers of mortality and overall
• 07:23course clinical cores and so.
• 07:25It's a very useful and important
• 07:27marker in covert patients,
• 07:28both for thrombosis and also
• 07:30for their overall disease cores,
• 07:31and then thrombin,
• 07:33antithrombin complexes you can
• 07:34think of those as sort of a fancy
• 07:37and more specific D dimer that
• 07:38really looks at whether AD dimer
• 07:40elevation comes from activation
• 07:42of the Quag Elation Cascade.
• 07:44So when we measured D dimer
• 07:45levels an from an anti thrombin
• 07:47complex is both in ICU and non ICU
• 07:50patients with colon infection.
• 07:52We found that both of these were elevated,
• 07:54particularly in patients.
• 07:55We were in the ICU and on a separate
• 07:58analysis we found that the D dimer
• 08:00levels and from an anti thrombin
• 08:02complex is correlated together.
• 08:03So this let us know that the source
• 08:06of the high D dimer encoded associated
• 08:09Coagulopathy is indeed activation
• 08:10of the Quag Elation Cascade.
• 08:13The next thing we did was to measure a
• 08:15number of endogenous anticoagulants,
• 08:17antithrombin, protein C, and protein S,
• 08:19as well as a fire analytic enzyme
• 08:22called A2 Antiplasmin.
• 08:23So what are all of these?
• 08:25Whenever you form,
• 08:26activate coagulations through
• 08:27the coagulation cascade,
• 08:28the body has a natural mechanism to
• 08:30shut off Coagulations and therefore
• 08:32prevent from boces from getting
• 08:34out of control and so that natural
• 08:36mechanism happens through two sources.
• 08:38One is through endogenous
• 08:39anticoagulants that are designed to turn
• 08:41off the Coagulations Cascade,
• 08:43and those are these first three up.
• 08:45Top antithrombin protein protein S
• 08:47and then the 2nd way that the body
• 08:50regulates the Quag elation cascade
• 08:52is to turn on fiber analysis or the
• 08:54process of digesting blood clots that
• 08:56are formed and the principal enzyme that
• 08:59does this is called A2 Antiplasmin.
• 09:01So as you can see here,
• 09:03when we measured in documents anticoagulants,
• 09:05antithrombin protein protein S in ICU and
• 09:07non ICU patients with colon infection,
• 09:10we found that they were basically on normal.
• 09:12Normal is usually anything about
• 09:1480% and as you can see.
• 09:16All of these patients had essentially
• 09:18antis arm approaching CN Protein
• 09:20S levels around 100%,
• 09:22indicating that there was not excessive
• 09:24consumption of anticoagulants.
• 09:25Endogenous Lee and then we also
• 09:27looked at A2 Antiplasmin.
• 09:29The main fibrinolytic enzyme
• 09:30that I just mentioned,
• 09:32and again here you can
• 09:34see the levels in both.
• 09:35I see you in an ICU patients with
• 09:38colon infection were normal,
• 09:40so this let us know that when we
• 09:42looked at endogenous anticoagulant
• 09:43San fibrinolytic enzymes,
• 09:45we were not seeing consumption.
• 09:47Of any of these,
• 09:48and the important feature here
• 09:50is that in most patients with
• 09:52DIC you should see consumption
• 09:54of endogenous anticoagulant.
• 09:55An fibrinolytic enzymes.
• 09:57So the fact that we were not seeing that.
• 10:00Let us know that CAC is probably
• 10:04mechanistically distinct from DC.
• 10:05The next thing we did was to
• 10:07measure an enzyme called plasminogen
• 10:09activator inhibitor or Pai one.
• 10:11This is the main negative regulator
• 10:14of fiber analysis and what we
• 10:16found was that this was elevated
• 10:18both in ICU and non ICU patients.
• 10:20The significance of this is that
• 10:22whenever we see this elevated it
• 10:24sometimes will suggest that fiber
• 10:27analysis is inhibited and so it
• 10:29makes us wonder when we see this
• 10:31weather perhaps encoded associated
• 10:32Coagulopathy there may be an inhibition
• 10:35of Clock breakdown which might
• 10:37contribute to overall thrombosis risk.
• 10:39And then the last thing we
• 10:41did was at the very bottom.
• 10:44Here we measured three tests,
• 10:46von Willebrands Factor,
• 10:47Antigen von Willebrands factor activity
• 10:49and factor 8 coagulations level.
• 10:51So what are these fun Willebrand factor?
• 10:53Is a hemostatic factor that's
• 10:55released by endothelial cells and
• 10:57the purpose in coagulations of fun.
• 10:59Willebrand factor is basically to
• 11:01help platelets bind to sites of
• 11:03damaged endothelium and initiate
• 11:05primary hemostat stasis,
• 11:06which is important for blood
• 11:08clotting factor 8.
• 11:09Separately is a coagulations factor that.
• 11:12Wines to von Willebrand factor in
• 11:14the circulation and So what we
• 11:17notice when we measured levels of
• 11:19an willebrand factor in factor 8
• 11:21both in ICU and in ICU patients,
• 11:23we saw that the levels were quite high,
• 11:26and in particular the levels were
• 11:28super elevated in ICU patients,
• 11:30and I just want to show you another
• 11:33curve here.
• 11:34This right here are DOT plots
• 11:36showing Refactor Antigen one factor
• 11:38activity and factor 8 in ICU versus
• 11:40non ICU patients with the green.
• 11:43Rose indicating what the
• 11:44normal ranges should be,
• 11:45so again based on this,
• 11:47as you can see, one will benefactor in
• 11:49factor 8 levels are elevated both in
• 11:52ICU and non ICU patients with Cove it,
• 11:54but there are through the roof high,
• 11:56particularly for von Willebrands
• 11:58factor in the ICU patients.
• 11:59The significance here is that the major
• 12:01source of on lower end factor in the
• 12:04body as it circulates through the blood
• 12:06is endothelial cells and so whenever
• 12:08we see this sort of pattern where
• 12:10we have very very high levels of fun
• 12:12willebrand factor circulating in the blood.
• 12:15It tends to point towards a
• 12:17pattern of endothelial injury.
• 12:18In addition, von Willebrands factor
• 12:20can also be stored in platelets,
• 12:22and so looking at this pattern,
• 12:25it made us wonder if perhaps both
• 12:27endothelial cells and platelets
• 12:28were being hyper activated in
• 12:30the setting of coded infection.
• 12:32Particularly as patients
• 12:34progressed to critical illness.
• 12:36So in order to test this,
• 12:38we were interested in looking at specific
• 12:41markers of endothelial function and
• 12:43platelet activation and so for this,
• 12:45we collaborated with Doctor
• 12:46Hengchun who's an investigator
• 12:48in the Cardiology Section who,
• 12:50along with his two postdocs,
• 12:51doctor home Chang and doctor,
• 12:53honey and Zhang performed a series
• 12:55of experiments on all of our ICU and
• 12:58non ICU patients looking at different
• 13:00endothelial and platelet activation
• 13:02markers and the specific ones we
• 13:04looked at were soluble key selecting.
• 13:06Which is shown up in the top left,
• 13:08which is a marker of both
• 13:10endothelial cells and platelets.
• 13:11And then we also looked
• 13:13at soluble CD 40 ligand,
• 13:14which is seen which is released
• 13:16by platelets and lymphocytes.
• 13:17And then Lastly we looked at soluble
• 13:19from a module in which is specific
• 13:21mostly to endothelial cells.
• 13:23Come here because these are
• 13:24all research tests.
• 13:25They don't have normal reference
• 13:27range is so as a result we also got
• 13:30blood from 13 different control
• 13:32patients or control individuals,
• 13:33many of whom are listening
• 13:35to this talk right now.
• 13:37So the significance of this is that
• 13:39when we looked at all these three
• 13:41different markers of endothelial cell
• 13:43plus or minus platelet activation,
• 13:45we saw in pretty much every single case
• 13:48that the levels were higher in ICU
• 13:51patients with kovid than they were.
• 13:53Then controls in the case of
• 13:55soluble thrombomodulin.
• 13:56We did not see a significant change in
• 13:58the level of soluble thermal modeling.
• 14:01ICU versus control patients.
• 14:02But what we did notice was that
• 14:05there were several patients in the
• 14:07ICU group who had a quite high level
• 14:09of soluble thermal module in that
• 14:11made us think that perhaps there
• 14:13was something going on with soluble
• 14:16thermal modeling and therefore
• 14:17endothelial cells that might be
• 14:19specific to ICU patients.
• 14:21And so when we did a series of
• 14:23tests looking at all these different
• 14:25markers and comparing to mortality,
• 14:27we found that interesting Lee soluble
• 14:29thrombomodulin level segregated
• 14:30with mortality.
• 14:31Whether we looked at the entire
• 14:34population in our cohort or
• 14:36whether we looked at ICU patients.
• 14:38Alright, so putting this altogether,
• 14:40what did we learn from from these studies?
• 14:44First in measuring different
• 14:45levels of endogenous anticoagulant
• 14:47sand fibrinolytic enzymes,
• 14:48we found that antithrombin protein to
• 14:50protein S and A2 anti plasm overall
• 14:53preserved which is distinct from DIC
• 14:55indicating that indeed code associated
• 14:57Coagulopathy is not the same as DIC.
• 15:00We also learned that Pai one is elevated,
• 15:03encoded associated Coagulopathy suggesting
• 15:05that fiber analysis might be inhibited.
• 15:07Although we haven't
• 15:09completely confirmed that.
• 15:10In addition,
• 15:11we saw that on Willebrand factor,
• 15:13in factory levels, which are markers,
• 15:15particularly endothelial cells and platelets,
• 15:17are elevated in both non
• 15:18ICU and ICU patients,
• 15:20and in particular are through
• 15:21the roof high in ICU patients,
• 15:24suggesting that there is a significant
• 15:25component of any Philly Opathy and
• 15:28platelet activation encoding infection,
• 15:29particularly as patients
• 15:31become critically ill.
• 15:32And then Lastly,
• 15:33we saw that when we measured
• 15:35specific markers of endothelial
• 15:36cell and platelet activation,
• 15:38we found that these were elevated in ICU
• 15:40patients with soluble thrombomodulin,
• 15:42which is quite specific for endothelial
• 15:45function segregating with mortality.
• 15:47So In conclusion,
• 15:48what we believe our data shows is
• 15:50that code associated Coagulopathy is
• 15:52actually an Endo Philly Opathy where
• 15:54you see augmented von Willebrands
• 15:57factor release platelet activation an
• 15:59hypercoagulability all coming together
• 16:00causing an increased risk of thrombosis,
• 16:03including Venus thromboembolism,
• 16:04Artur thrombosis and also
• 16:06microvascular thrombus.
• 16:06In addition,
• 16:07we think that endothelial
• 16:09dysfunction or injury is a marker
• 16:11of progression of critical illness,
• 16:13encoded 19 infection and we find
• 16:15that soluble from a modeling as
• 16:17a specific endothelial marker
• 16:19seems to segregate with mortality.
• 16:22Um,
• 16:22the importance of all of this is that
• 16:24it's made us wonder if there might
• 16:26be a role for adding antiplatelet
• 16:29or even endothelial cell modifying
• 16:31therapy to our anticoagulation algorithm.
• 16:33And so early on while we were
• 16:35developing this story,
• 16:36we met with a number of the ICU directores,
• 16:39FDA only Haven Hospital Ann through
• 16:41a lot of discussion just I think
• 16:44last week or the week before aspirin
• 16:46was finally added to our treatment
• 16:48algorithm and now every patient
• 16:50who gets admitted to the hospital.
• 16:52In the ICU with colon infection,
• 16:54get started on aspirin empirically.
• 16:58So I just want to acknowledge a lot of
• 17:00people who contributed to this work.
• 17:02We have this gigantic,
• 17:04an amazing hematology team,
• 17:05both on the research side.
• 17:06In the clinical side,
• 17:07on the left are all the trainees
• 17:09who are working with this.
• 17:11George and Alex are start fellows in
• 17:13a particular alot of our discussions.
• 17:15In fact pretty much every experiment
• 17:17that we've done really started with
• 17:19conversations at George and I had many
• 17:21months ago leading to what we have now.
• 17:23Matt, my salati as I mentioned,
• 17:25is a superb PhD student Eric Chang
• 17:26and Yu Shen Lu are both third year
• 17:29senior medical residents who are going
• 17:31to be our fellows this coming July.
• 17:33And then Rebecca fine is an intern
• 17:35who expressed some interest in doing
• 17:38immunology Hematology Research.
• 17:39Down at the bottom are the members of
• 17:42Doctor Chung's lab who contributed this
• 17:44worth hung Chang and honey Jang where
• 17:46both postdocs as I mentioned in the middle.
• 17:49We have a number of pharmacists,
• 17:51some of them are familiar to you
• 17:52guys who are part of our greater team
• 17:55looking at anticoagulation outcomes.
• 17:57Cajun mean Nick Difilippo,
• 17:58Dana McManus, Cantou Enedina frozen.
• 18:00Uhm and then over on the right.
• 18:03Here we have our amazing, outpatient,
• 18:06benign hematology clinical team.
• 18:07Audrey Gina, Andrea,
• 18:09Joy, Ann and hope.
• 18:11Uhm, and then finally the bottom.
• 18:12I just want to acknowledge Bob Bono,
• 18:14who's our new chief of benign
• 18:15team and then Stephanie Helene's,
• 18:16our section chief as both of them have been
• 18:18incredibly supportive of these efforts.
• 18:20So thank you guys and thank you
• 18:23Charlie. Thank you and congratulations
• 18:25to you and really the entire
• 18:27team on working through this.
• 18:29Uh, in a very short amount of time
• 18:32and frankly making a difference
• 18:34for our patients in the process.
• 18:36and I know we have some
• 18:38questions coming through,
• 18:40but let me start by asking you.
• 18:42Your research seems certainly indicates that
• 18:44this is a process of interfere with damage.
• 18:48And do we? What do we know about the
• 18:51virus itself that lends support that?
• 18:53This would be a primary incident
• 18:56to the endothelium.
• 18:58Yeah, that's a great question,
• 19:00so there does seem to be in autopsy studies.
• 19:03A certain component of endothelial leitis,
• 19:06which some people have shown might be
• 19:08related to direct viral infection.
• 19:10So there have been autopsy studies
• 19:12that have demonstrated viral
• 19:14particles within endothelial cells.
• 19:16Not every study has demonstrated that,
• 19:18but some people do believe that that is
• 19:21part of the incipient process that begins
• 19:24the end of filial pattern of injury.
• 19:27One of the challenges is that.
• 19:29A lot of people tend to think
• 19:31of thrombosis as somewhat later
• 19:32event occuring clinically,
• 19:34so it's not clear if there may be a
• 19:37second sort of hit to the end of Filium,
• 19:39particularly,
• 19:40patients become critically ill that
• 19:41might be independent of viral infection.
• 19:43It might instead involve inflammation
• 19:45and other things like compliment that
• 19:47might trigger and a filial activation.
• 19:50Thank you other questions
• 19:52that have come through.
• 19:53Do you have any information about
• 19:56the specificity of these changes
• 19:58for chobit relative to other
• 20:00respiratory viral infections?
• 20:01For instance, are microvascular thrombi
• 20:03a finding in in other respiratory
• 20:05viral infections beyond coated?
• 20:07Yeah, that's
• 20:08a good question to my knowledge I I'm
• 20:11not aware of a lot of other viruses
• 20:15that show microvascular thrown by.
• 20:17There are certain cases of influenza
• 20:19that can be characterized by
• 20:21massive inflammatory responses.
• 20:23Um dangi infection is also often
• 20:25brought up as an example of a
• 20:27virus that can cause a pretty
• 20:29awful coagulopathic picture,
• 20:31so I'm not sure if any of either of those
• 20:33in particular are classically associated.
• 20:36Microvascular phone by or not,
• 20:38but I'm not aware of a lot
• 20:40of other viruses that are.
• 20:43And then another question do that?
• 20:46Does the Coagulopathy correlate
• 20:48with the static on storm? Yeah,
• 20:51so that's a great question Stewart.
• 20:54So one of the interesting experiments
• 20:56that that Young Chun started to
• 20:59do with our patient samples is to
• 21:01examine different proteomic profiles,
• 21:04and so we're starting to
• 21:06get that data back now,
• 21:08and the hope is to see mechanistically,
• 21:12if any of the changes inside a current
• 21:15profiles that that are shown do correlate
• 21:18with robotic risk or endothelial dysfunction.
• 21:21One of the challenges we have in
• 21:23trying to interpret our data fully
• 21:25is that as most of you guys know,
• 21:27pretty much every critically ill patient
• 21:29in the hospital with kovid receives
• 21:31totalism AB before they reach the ICU,
• 21:33which is an interleukin six receptor blocker,
• 21:36and so there may be some effects of
• 21:38Totalism app not only on Coagulopathy
• 21:40but also on the sideline profile,
• 21:42and so we're trying to figure
• 21:44out how to interpret that.
• 21:47Another question for patients on on a
• 21:49ventilator for other causes of a RDS,
• 21:51do they have elevated levels
• 21:53of one willebrand factor? Yeah,
• 21:55even that's a fantastic question,
• 21:57and so the answer is yes, sort of,
• 21:59but not not quite to the same level.
• 22:02So in the literature there's a lot of other.
• 22:05There's a few other diseases that are known
• 22:08to have very bad end of Philly Opathy,
• 22:10one of them being severe DIC
• 22:13with septic shock and VOD or SOS
• 22:15in transplant is another one.
• 22:17Um, and in fact a RDS is known
• 22:19to also be characterized by NFL
• 22:21dysfunction as somewhat of a control.
• 22:23We separately worked with the ICU to
• 22:26measure von Willebrand factor levels
• 22:28in non kovid ICU patients who are into
• 22:30baited and in those patients we did
• 22:33see elevated von Willebrands levels,
• 22:34but we did not see a consistently
• 22:37super high level of unrelated factor
• 22:39like we do in code and so we do
• 22:42think there's some specificity to
• 22:43this particular Cove in response.
• 22:46Makes sense since the last question
• 22:48from Stuart is you compared ICU
• 22:51versus non ICU versus controls?
• 22:53What about these values in comparing
• 22:56patients with thrombotic complications?
• 22:57For those without cloths,
• 22:59yes Sir, that's a fantastic question.
• 23:01You know, one of the challenges
• 23:03that we have at our hospital,
• 23:05and this is not unique to us,
• 23:08is that because of concerns about
• 23:10excess health care worker exposure,
• 23:12it's not been routine for
• 23:14covert patients at Yale.
• 23:16New Haven Hospital to get
• 23:17imaging to confirm thrombosis.
• 23:19If you guys recall in the Cove
• 23:22at anticoagulation algorithm,
• 23:23we said anybody.
• 23:23Any patient in whom one suspects a Venus
• 23:26Roman Bolic event should automatically
• 23:28start photos anticoagulation.
• 23:29The reason we added that in there is
• 23:31because most patients are not getting
• 23:33imaging to tell whether they really
• 23:35have a Venus thromboembolic event.
• 23:36Therefore we don't really have a
• 23:38good idea of how many patients in
• 23:40our own hospital system and which
• 23:42ones actually have a thrombotic
• 23:43complication and which ones don't,
• 23:45so I can't answer that based on our data.