welcome to another MedCram COVID-19 update it's been a few days since we did
one and I've been busy in the intensive care unit taking care of kovat 19
patients and one of the things that has struck me in taking care of those
patients is that while there is respiratory issues on the ventilator it
seems as though the biggest issue that we're dealing with is in the
cardiovascular realm it seems as though a lot of the patients that I'm taking
care of are succumbing to cardiovascular complications such as myocardial
infarction or blood clots rather than the inability to ventilate and we'll
talk more about that later but we are at nearly three million total confirmed
cases although the numbers seem as though they're probably much higher than
that based on the epidemiological studies that we're now doing with
antibody testing in the United States were at nearly 1 million cases and it
seems as though the daily new cases in the United States have plateaued and in
terms of daily deaths it's too early to tell whether or not we're having a
decline in Canada forty-six thousand cases and 2,500 deaths also in Canada
daily new cases seemed to have plateaued and again too early to tell whether or
not daily deaths are coming down in the United Kingdom 150,000 coronavirus cases
daily new cases over there seem to have plateaued as well again still too early
to tell whether or not the number of daily deaths are coming down in
Australia almost 7,000 cases and 83 deaths here the daily new cases have
definitely come down and we're watching very carefully to see whether or not the
onset of fall and winter will bring about a recurrence in Australia I know
there were a lot of questions last time about hydroxychloroquine and the review
that we did on a number of the trials and the questions were related to why
zinc was not included in the trials for those of you who are interested in the
intensive care unit that I work in we use hydroxychloroquine and as
from Ison and zinc supplementation and I would add that in the intensive care
unit we are seeing the sickest of patients that are coming in and so far
our outcomes are not very different than those that we presented from the jamb
article a few updates ago but what I really want to get to is this disturbing
article that was put in The Washington Post
young and middle-aged people barely sick with kovat 19 are dying of strokes
doctors sound alarm about patients in their 30s and 40s left debilitated or
dead some didn't even know they were infected and they talked about how this
patient came in to the hospital and had a stroke and they were trying to remove
the clot using the technology that they have and it says here that he observed
something that he had never seen before on the monitors the brain typically
shows up as a tangle of black squiggles like a can of spaghetti he said that
provide a map of blood vessels a clot shows up as a blank spot and he used the
needle device to pull the clot out he saw new clots forming in real time
around it and the question is is why is that happening they mentioned in the
article that many researchers suspect strokes in kovat 19 patients may be
direct consequence of blood problems that are producing clots all over some
people's bodies they're mentioning here that they've taken care of patients in
their 30s with stroke in Kovan and this was extremely surprising he said many
doctors expressed worry that as the New York City Fire Department was picking up
four times as many people who died at home as normal during the peak of
infection that some of the dead had suffered sudden strokes the truth may
never be known because few autopsies were conducted so finally someone is
trying to do some research dr. Chow is hoping to answer such questions through
a view of strokes and other neurological complications in these kovat 19 patients
there was an interesting case study in thrombosis research that was accepted
only a couple of weeks ago and it goes through and talks about an interesting
case a case which is not unusual and one that I have seen many times in the
intensive care unit with Kovan 19 so this is a 72 year old otherwise
healthy male apparently and six days after admission to the hospital the
patient started to decompensate and went into a RDS acute renal
insufficiency and had altered level of consciousness which required the patient
to need to go to the intensive care unit one of the things that they measured was
something called a d-dimer and on that first day the d-dimer was 0.69 which is
just barely elevated but four days later it was 2.55 11 days into it it went to
2.81 21 days later it was twenty point six three and this is pretty high this
is actually what I've been seeing in Mike Ovid 19 patients as well then at
day 24 came back down we'll talk about what happened on day 21 because when
they started to see these numbers rising in a d-dimer what that usually means is
that there's some sort of coagulation occurring so what you have to understand
is that in the blood vessels the blood vessels are coated with tiny cells that
are very flat called endothelium and these tiny cells that are very flat have
on their surface receptors and enzymes and in this case it's a stew and so the
virus can actually attack this h2 we'll talk more about that later
but if there is inflammation that's occurring here in the endothelial cells
just below the endothelial surface is a collection of something called von
Willebrand's factor and von Willebrand's factor can be released when there's
damage to the endothelium and in the lumen of the blood vessel is factor
eight which is one of the active factors that converts factor 10 into the active
form of factor 10a it can get confusing talking about coagulation factors but
the key that I want you understand is that von Willebrand's factor his sub
endothelial and it can get into circulation and it is a pro coagulant so
when they went and measured here on day 21 what the measurement of von
Willebrand's factor was it was actually at five hundred and twenty percent of
what it normally should be and when they measured factor eight it was three
hundred and sixty nine percent of what it should be so what they started at
that point here was unfractionated heparin this is an anticoagulant this is
something that inhibits the body's ability to coagulate and when they did
that the d-dimer levels then dropped by day twenty four to six point two six and
finally by day 29 it dropped down to one point nine four the other thing that
they noticed was here they started noticing positive eye g-m antibodies for
anti cardiolipin antibody and also positive for anti beta 2 glycoprotein
even though the IgG s were negative indicating an acute antibody now it's
interesting to note that they switched to unfractionated heparin when the
patient was first admitted the patient was started on a prophylactic dose of
Delta Perrin at around five thousand units
sub-q daily so it seems as though these blood clots may be mediated by very high
levels of von Willebrand's factor and even factor eight in the coagulation
cascade and why is this happening it may be related to endothelial activation
from inflammation that's going on and release of this von Willebrand's factor
which binds factor eight in the lumen of the blood vessel so why is all of this
happening it may be happening because the virus is taking out a stew number
one because it's binding to a stew but number
to it maybe taking it out because as it binds to a stew it's now rendering that
enzyme completely inactive now remember what we talked about back in update 37
where we talked about what happens with a stew in relation to angiotensinogen
and angiotensin 1 and angiotensin 2 let's review that real quickly remember
we said that angiotensinogen is converted by renin into angiotensin one
and then angiotensin 1 is converted into angiotensin 2 by the enzyme ace just
regular ace this is where ace inhibitors are used so if you have angiotensin 2 in
low levels remember that ace 2 will take these angiotensin 2 levels that are low
and converted into angiotensin 1 7 angiotensin 1 7 is actually a
vasodilator and it reduces inflammation however when the virus this pink thing
comes in and binds to a stew it now no longer can convert angiotensin 2 into
angiotensin 1 7 and instead what you get is vasoconstriction because you have
high levels of angiotensin 2 and you have vasoconstriction increased blood
pressure increased vascular permeability pulmonary edema and a RDS in other words
in order to keep your angiotensin 2 levels under good control and prevents
vasoconstriction you need a stew when the virus binds a stew and degrades it
it takes it out of circulation and what you're left with is a bunch of
vasoconstricting angiotensin ii levels that can cause oxidative stress now here
was a very interesting study that was published in 2008 looking at angiotensin
converting enzyme 2 or ace 2 looking at the endothelial protection and what it
does with atherosclerosis so in this situation they used mice and they
knocked out the ACE 2 gene to see what would happen in this case the ACE two
knockouts would be as if the mice had been infected with the corona virus
and taken out there ace two enzymes and in this situation they showed here that
a student mice exhibited impaired endothelium dependent relaxation in
other words they were constricting it also talks about how they know that ace
2 has been identified as a critical negative modulator of angiotensin 2
bioactivity counterbalancing the effects of ace here is however I think the most
important statement of all and that's the enzyme ace 2 which is the target of
SARS cub 2 kovat 19 attenuated angiotensin Stu induced reactive oxygen
species production in part through decreasing the expression of P 22 fox
what they're saying here is that when a Stu is down regulated it can no longer
mitigate the effects of angiotensin 2 and specifically oxidative stress on the
endothelium so in other words when the virus binds the endothelium it takes out
a stew and now ace 2 cannot prevent angiotensin 2 which is now reigning
unrestrained cannot prevent it from causing oxidative stress and more
inflammation that would have normally been the case would just the infected
cell to begin with finally they conclude these data indicate that ace 2 in an
angiotensin 1-7 dependent fashion in other words through angiotensin 1:7
functions to improve endothelial homeostasis via a mechanism that may
involve attenuation of NADPH ox induced reactive oxygen species production now
let's just unpack that NADPH oxidase is an enzyme that takes oxygen and adds an
electron to it to make superoxide superoxide can damage cells very quickly
and it's used by neutrophils to kill bacteria but there is also another
version of NADPH oxidase which is found in vascular cells so in
an infection with the SARS cuff to virus where you do not have the ACE 2 enzyme
you're going to have NADPH oxidase reigning unrestrained because there is
no angiotensin 1 7 with that inflammation you may have release of von
Willebrand's factor which will couple with factor 8 and form intra-arterial
thrombosis and they state here that ace 2 based treatment approaches may be a
novel approach to limit aberrant vascular responses and a thorough
thrombosis so let's summarize what's going on here we have SARS cub 2 and
what happens is when you breathe it in its gonna go first to your lungs and
specifically it's going to go to the ACE 2 receptor in your lungs and what we all
thought and imagined was that we were going to get a RDS and that's why we
started treating patients with hypoxia secondary to a RDS because this is what
we all were expecting for months and months but the virus gets worse and
spreads and then it starts to go into the blood vessels and the blood vessels
inside of them also have a stew and what happens is when it goes to a stew now we
have unopposed angiotensin 2 we have release of von willebrand factor and
factor 8 and so we get thrombosis and with this happening these things happen
so quickly that before this a RDS has a chance to get bad enough to cause the H
type of lung problem we have thrombosis which is causing the ground glass
opacification and we get the L type of lung problem and the final common
denominator in this process over here which seems to be taking most of the
patients in the intensive care unit is a process known as oxidative
stress and as will show in the upcoming lectures and updates the people with the
worst oxidative stress from a baseline standpoint are those
people with cardiovascular diseases diabetes and overweight and these are
exactly the same people who we see as having the largest risk of dying in Cova
19 what we have over here are the happy hypoxic these are the patients that look
like they're at high altitude according to some emergency room physicians these
are the people who are having cardiovascular collapse and blood clots
in their vessels these are the ones that are put on ventilators but to little
avail and so I think that an understanding of oxidative stress and
how it might be involved with kovat 19 is going to be instructive and it may
give us some avenues for therapeutics so if you like this video click like if you
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