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Thrombosis In COVID - 19
8 Plays5 years ago
In this episode of Critical Matters, we will discuss thrombosis in COVID-19. We will discuss the pathophysiology, diagnosis, and management of arterial and venous thrombosis in COVID-19.
Our guest is Dr. Gregory Piazza, a cardiovascular medicine specialist at Brigham and Women’s Hospital in Boston. Dr. Piazza is the Director of the Vascular Medicine Section, in the Division of Cardiovascular Medicine, and Associate Professor of Medicine, at Harvard Medical School.
Additional Resources:
Diagnosis, Management, and Pathophysiology of Arterial and Venous Thrombosis in COVID-19: https://jamanetwork.com/journals/jama/fullarticle/2773516
Registry of Arterial and Venous Thromboembolic Complications in Patients with COVID-19: https://www.jacc.org/doi/full/10.1016/j.jacc.2020.08.070
ACCP Guidelines for Management Thromboembolism in COVID-19: https://journal.chestnet.org/article/S0012-3692(20)31625-1/fulltext
ISTH Guidelines for Management of Thromboembolism in COVID-19: https://onlinelibrary.wiley.com/doi/10.1111/jth.14929
Books Mentioned in this Episode:
Dune by Frank Herbert: https://www.amazon.com/Dune-Frank-Herbert
Recommended
Transcript
Introduction to Critical Matters Podcast
00:00:06
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Welcome to Critical Matters, a sound critical care podcast covering a broad range of topics related to the practice of intensive care medicine.
00:00:14
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Sound Critical Care provides comprehensive critical care programs to hospitals across the country.
00:00:20
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To learn more about our programs and career opportunities, visit www.soundphysicians.com.
00:00:27
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And now your host, Dr. Sergio Zanotti.
COVID-19 and Thrombotic Complications
00:00:33
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COVID-19 has been associated with arterial and venous thrombotic complications.
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The potential role for anticoagulation in COVID-19 patients has been an important consideration during this pandemic and a topic of hot debate.
00:00:47
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In today's episode of the podcast, we will discuss the pathophysiology, diagnosis, and management of arterial and venous thrombosis in COVID-19.
00:00:55
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Our guest is Dr. Gregory Piazza, a cardiovascular medicine specialist at Brigham's and Women's Hospital in Boston.
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Dr. Piazza is the director of the vascular medicine section, the division of cardiovascular medicine, and is associate professor of medicine at Harvard Medical School.
00:01:10
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He has authored over 70 peer review publications.
00:01:13
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His clinical practice and research focuses on the treatment of VTE and prevention of stroke.
Thrombotic Complications in COVID-19 Patients: US vs Global Data
00:01:19
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Dr. Piazza recently published a JAMA Insights article on the topic of COVID-19 related thrombosis.
00:01:25
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Greg, welcome to Critical Matters.
00:01:27
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Thank you so much.
00:01:28
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It's a joy to be with you this morning.
00:01:32
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As we were discussing before we started recording, it seems that we're headed into a heavy winter with surges of COVID patients throughout the country.
00:01:42
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You're in Boston, I'm in Houston, and we're definitely feeling that we're going in that direction.
00:01:47
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And one of the topics that's been very, very hot in terms of therapeutics during the first two waves was the use of antithrombotic therapy or the use of anticoagulation for patients with COVID.
00:02:00
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I would like to start maybe with a general overview of thrombotic complications in COVID patients.
00:02:06
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What have we seen?
00:02:07
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What have we learned just in terms of the presentation and some general epidemiology considerations?
00:02:15
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Sure.
00:02:15
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It's been really one of the big challenges, especially in the critical care and cardiovascular community, because the
00:02:24
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burden of thromboembolic events that seemed to signal out of Asia and Europe was really quite impressive.
00:02:32
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And some of the studies were quoting numbers of 70% thromboembolic events, despite thromboprophylaxis in the ICU setting.
00:02:43
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And one of the big challenges for the US was to quickly during the first surge, figure out whether
00:02:51
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Those were numbers that we could expect to see in our patient cohorts.
00:02:56
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Were we really going to see that high of a frequency of thromboembolic events?
00:03:01
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There were some signals that we might see fewer events than were initially reported out of Asia and Europe.
00:03:09
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First of all, in contrast to, in particular, the practice in China, we provide thromboprophylaxis to most of our ICU and hospitalized patients.
00:03:21
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So that's not standard in the practice in China.
00:03:27
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And so we suspected that we might see a little bit of a decrease in the thromboembolic events.
Pathophysiology and Contributing Factors of Thrombosis in COVID-19
00:03:35
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We'll fast forward to this first surge.
00:03:38
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And many of us were able to get registries and observational cohort studies up and running.
00:03:45
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We had one called Corona VTE, which we published in the Journal of the American College of Cardiology.
00:03:51
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And the numbers in the US were still high, although not as impressive as the ones out of Europe and Asia.
00:03:59
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We saw a high rate of symptomatic venous thromboembolism across the US.
00:04:06
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What are the rates like?
00:04:07
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Well, somewhere more in the 30% range, especially in the intensive care cohort.
00:04:13
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In hospitalized non-intensive care patients, it's more in the 1% to 5% range.
00:04:20
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Outpatients appear to have a lower risk of thrombosis.
00:04:25
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Also important, we saw an uptick in myocardial infarction and stroke, so arterial thromboembolism as well.
00:04:33
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And all of this came in the background of a high rate of thromboprophylaxis.
00:04:39
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And in the U.S. experience, I would say that somewhere between 85 to 90% of patients in the hospital are receiving thromboprophylaxis.
00:04:51
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And that has really been fuel for some hypotheses that a certain proportion of patients, especially the critically ill, may need more aggressive thromboprophylaxis
00:05:03
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than the standard doses that we're used to.
00:05:06
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Another fascinating aspect of COVID and thrombosis was the reporting, especially in around March, April, of strokes in young patients and these very catastrophic thrombotic events in people who would be considered otherwise low risk.
00:05:25
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And what I wanted to ask you, Greg, is one of the things that I was pondering at that time was that
00:05:31
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I've seen some body complications with septic shock many times throughout my career.
00:05:37
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What I've never had seen was a number of infections, of severe infections from one pathogen at the same time.
00:05:45
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And I was wondering how much of this is just severity of disease and the burden of disease versus a unique characteristic of COVID-19.
00:05:54
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Any thoughts about that?
00:05:56
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It's a terrific question and it's one that has actually
00:06:00
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kept all of us awake during this pandemic so far.
00:06:06
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There are some data, Sergio, that show that the virus directly infects the endothelium and causes an inflammatory process almost like an endotheliopathy or endothelialitis.
00:06:18
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But by the same token, there have been some studies that have looked at trends in thromboembolic complications pre-COVID and then during COVID
00:06:30
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And interestingly, if you adjust for severity of illness, the rates of thromboembolism aren't that much different.
00:06:37
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There was a very nice study from the UK that actually showed that non-COVID-related infectious illness, when it leads to a similar severity, had a very comparable rate of thromboembolic complications.
00:06:53
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very similar to what the investigators observed this year with COVID-19.
00:06:59
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So I think that we, in some patients, the virus itself might have some intrinsic properties that predispose to thromboembolic complications, but for many patients, it's simply the intense inflammation, the immobility of being in the ICU, super infections, the use of indwelling devices like central venous catheters,
00:07:22
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other types of mechanical circulatory support systems that lead to these thromboembolic complications.
00:07:29
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An additional point that I have noticed when these patients, especially early on, these patients were treated the same way we were treating patients maybe 15, 20 years ago.
00:07:41
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Heavy sedation, heavy paralytics, barely being moved, prolonged mechanical ventilation courses, which all we know would increase the risks of thrombotic complications.
00:07:53
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Yeah, absolutely.
00:07:54
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I think that early on, because of the concern about managing these patients with ARDS, there were a number of different ventilatory strategies applied based on previous or prior data focused on ARDS, but not necessarily specific to COVID.
00:08:13
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And some of the strategies could have led to more immobility
00:08:19
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greater sedation, as you mentioned, and a higher
Complexity of Treating COVID-19 Thrombosis
00:08:22
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risk.
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I think with experience, we've kind of learned to tailor our mechanical ventilatory strategies to each patient and keep in mind the need to check neuro status frequently, to lighten sedation, and to make sure that we're providing all sorts of prophylaxis for thromboembolic complications.
00:08:47
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I would like to just talk a little bit more about pathophysiology before we move on to more clinical considerations.
00:08:54
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The connection of microthrombosis and organ damage is something that we've been discussing in sepsis and severe infections for some time, and it has led to the failed trials with heparin, with antithrombin-3.
00:09:10
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It led to the approval of activated protein C that eventually was withdrawn from the market.
00:09:16
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So clearly this connection of inflammation and coagulation and organ failure is not a new connection, but is one that has come up again to the forefront with COVID based on autopsy reports of microthrombosis throughout different organs, especially in the lungs, obviously.
00:09:37
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Could you comment a little bit about what we know about pathophysiology related to thrombosis and organ failure?
00:09:44
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Sure.
00:09:44
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So really, the pathophysiology is quite complicated and multifactorial.
00:09:50
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As I mentioned, there are some data, especially from histopathology studies, that suggest that there's direct viral infection of the endothelium, an inflammatory response in the endothelium, and the development of in situ thrombosis, which can be
00:10:12
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micro or macrovascular, although typical microvascular.
00:10:17
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There's also an upregulation of the clotting system, we've seen since early in the pandemic, high levels of D-dimer, but there are other clotting factors that are also upregulated that contribute to a prothrombotic milieu.
00:10:37
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There's also in some patients,
00:10:40
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stimulation of immunologic factors that lead to thrombosis, lupus anticoagulants, antiphospholipid antibodies.
00:10:49
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There's hyper reactivity of the platelets.
00:10:53
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That's actually been shown in a number of very nice studies showing increased platelet aggregation, increased activity of platelets.
00:11:04
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And then finally, as you already mentioned,
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There are traditional risk factors that seem to aggregate in patients who are critically ill with COVID-19.
00:11:15
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Many of these patients have immobility, factors like diabetes, heart disease, heart failure, COPD, plus all of the infections that we know increase the risk of thrombosis.
00:11:27
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So really our biggest danger is oversimplifying the pathophysiology.
00:11:34
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It really is complicated.
00:11:36
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There really are a number of pathways, and I think addressing all of the different factors is what's key to preventing this terrible complication of COVID-19.
Antithrombotic Therapy Strategies for COVID-19
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It also seems that a reductionist approach to pathways, which we enjoy as frameworks over the years, has proven probably not to be sufficient to design therapeutics because, like you said, it's a complex system.
00:12:04
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And if you block something on the left, something on the right might be exacerbated and the outcomes might still be worse.
00:12:12
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This probably applies to not only the modulation of the cardiopathy, but also the modulation of inflammation as we've seen with COVID.
00:12:24
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You did mention platelet activation, and that seems to be something that in the world of cardiology, obviously, is very prevalent in the world that you live.
00:12:34
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In a lot of what we see in critical care, people are more focused on other pathways of procoagulation.
00:12:43
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However, a lot of the push has not been around antiplatelet agents.
00:12:48
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Is there a reason for that?
00:12:51
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I think that, as you mentioned, we tend to take a sort of reductionist view on how we can tackle a situation like this COVID-19 pandemic and from all complications.
00:13:04
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and we have a vast experience with antithrombotic therapy for prevention.
00:13:09
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A lot of this comes on the background of the trends in cardiovascular medicine.
00:13:17
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We've actually, as a field, pivoted and moved away from antiplatelet therapy a bit and have focused much more on antithrombotic therapy and combinations of antiplatelet and antithrombotic therapy for,
00:13:33
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different vascular disease processes such as atherosclerosis.
00:13:38
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So I think that plus the fact that we're relying on what we're used to has taken our attention away from the platelet.
00:13:45
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I think that as we mentioned, some of the mechanistic data that have come out so far suggests that the platelet may play a role and there are a number of studies underway
00:13:57
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that are actually combining antiplatelet and antithrombotic therapy, we're looking at antiplatelet therapy for thromboprophylaxis.
00:14:04
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So I think that while initially in the pandemic, we went to rely on what we typically use, we've been more forward thinking as we've planned out these clinical trials and have indeed some studies focused on the platelet as a prime actor.
Anticoagulation Practices and Further Studies
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Excellent.
00:14:22
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I would like to pivot now more in the clinical direction
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And would like to start, Greg, with some comments on retrospective data.
00:14:31
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Colleagues of yours in New York, the cardiology group at Mount Sinai published one of the first US-based retrospective studies that really suggested that the outcomes in mechanically ventilated patients with COVID-19, the most critically ill, were better or had better survival if they actually received full-dose anticoagulation.
00:14:54
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And that was a license for many people to start developing all sorts of protocols gearing at full dose antipyrolation.
00:15:02
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Could you comment on the merits and the shortcomings or the caveats of a study like that?
00:15:09
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Sure.
00:15:10
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So I think that there's just a lot to unpack in that particular observation.
00:15:17
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So first of all, that thinking is born out of the fact that
00:15:25
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patients seem to develop complications despite prophylaxis doses of anticoagulation.
00:15:33
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And that anecdotally has led clinicians to consider, as you mentioned, full dose anticoagulation in these patients.
00:15:42
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One of the problems is those are not randomized trials.
00:15:48
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So the selection of the full dose anticoagulant strategy
00:15:53
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will typically be considered in patients with a very low bleeding risk.
00:15:58
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And that's not really adjusted for in these analyses.
00:16:02
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So while it may seem like a good idea, there could be an important hazard in the form of bleeding if this was applied routinely.
00:16:10
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And it's for that reason that if you look at the guidelines, guidelines, especially from the American College of Test Physicians, don't recommend routine
00:16:19
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therapeutic anticoagulation as prophylaxis for critically ill patients.
00:16:25
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While the early data on COVID-19 suggests that bleeding's probably less of a concern than thrombosis, we don't know for sure that therapeutic anticoagulation is going to provide our patients with a net clinical benefit.
00:16:43
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There's always the chance that when broadly applied, it could lead to an excess of bleeding.
00:16:49
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So, Sergio, there are a number of great studies underway right now looking at therapeutic dose anticoagulation in the critically ill and randomizing them to that versus more standard doses.
00:17:01
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And I think only when we have those data will we remove some of the biases that are in these retrospective cohort studies.
00:17:12
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And it's interesting how we're seeing a pattern of positive retrospective observations
00:17:18
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than being negative randomized trials prospectively with many of the proposed therapeutics for COVID that are now not part of our considerations anymore.
00:17:28
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But before we dive into more detail on the guidelines and the clinical therapeutic management, I would like to start by asking you, Greg, a little bit about like just a diagnostic evaluation.
00:17:40
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If you're seeing, if you're consulted or patients who get admitted to the ICU or to the hospital with COVID,
00:17:46
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What should be some of the labs that we should be routinely obtaining from the coagulation or hematological perspective, in your opinion?
00:17:54
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So I think that looking at the observational data thus far, there's been a strong suggestion that increased D-dimer, especially when it's above two or three times the upper limit of normal, flags a patient as higher risk for thromboembolic complications.
00:18:13
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Now,
00:18:15
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I'll challenge that a little bit because in our study that we published in the Journal of the American College of Cardiology, you can also use clinical factors to identify patients at very high risk.
00:18:26
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For example, if your patient has ARDS, in our study, that was the most powerful predictor of adverse outcomes.
00:18:35
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rather than D-dimer.
00:18:36
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So you may be able to just clinically look at your patient and say, all right, this is a patient who's got multi-system organ failure, ARDS, mechanically vented on pressers.
00:18:46
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I don't need a D-dimer.
00:18:47
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I know this patient's high risk.
00:18:49
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Other things that are important are to follow treatments over time.
00:18:54
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There is quite a bit in the literature about thrombocytopenia related to COVID-19.
00:19:01
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It doesn't necessarily mean that patients are going to bleed due to the thrombocytopenia, but it can complicate antithrombotic therapy.
00:19:08
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So that's something to keep track of.
00:19:11
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Coagulation testing.
00:19:13
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There is a risk for disseminated intravascular coagulation.
00:19:19
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It's probably not as high as we initially thought.
00:19:22
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but it is something that can happen in our critically ill patients.
00:19:26
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And so being cognizant and aware of trends in laboratory studies that could hint to that are important.
00:19:32
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But by and large, it's a lot of the bread and butter testing that we do in our critically ill, stuff that you've been trained, Sergio, to do for your whole career.
00:19:45
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That's standard in these patients.
00:19:47
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And there's not a whole lot that is going to be different.
00:19:51
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These are
00:19:52
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critically ill patients that need the very best that we bring to the table for intensive care medicine.
00:19:58
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I would like to dive a little bit deeper into D-dimer because it's become such a topic of discussion.
00:20:05
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And you mentioned the study that your group published in the American Journal of Cardiology.
00:20:10
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And it is interesting that perhaps a lot of people have taken an association as almost a causation.
00:20:16
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And like you said, two patients with severe ARDS
00:20:20
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We know they have an increased risk of thrombosis, increased risk of death.
00:20:24
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But we don't know that the D-dimer itself by itself dictates a different therapeutic approach, correct?
00:20:31
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Correct.
00:20:31
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So the D-dimer, even pre-COVID, we knew to be a very nonspecific marker.
00:20:38
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It's a marker of inflammation.
00:20:40
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It's a marker of intrinsic or endogenous fibrinolysis.
00:20:45
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It doesn't necessarily speak to mechanism, at least as far as we know.
00:20:50
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So in these patients, it's probably best used as a litmus test for how sick the patient is rather than a mechanism for thrombosis.
Risks and Recommendations in Anticoagulation
00:21:01
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And like I said,
00:21:03
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there are other factors that we can draw on clinically that probably tell us similar prognostic information.
00:21:12
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I have seen multiple institutions and groups, including academic groups throughout the country, utilize D-dimer levels to trigger antipyrelation and to back off of it on the way down as well.
00:21:28
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It seems that based on what we're discussing right now,
00:21:31
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even though there might be some theoretical merits to that, we don't really have data to say that's what we should be doing in all patients.
00:21:38
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Absolutely.
00:21:38
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We do not have rigorous trial data to tell us how best to use D-dimer.
00:21:44
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All of this is very speculative.
00:21:47
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It's based on prior experience.
00:21:50
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We're all trying to
00:21:52
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find the best path forward to taking care of these severely ill patients.
00:21:57
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But acknowledging where we have gaps in the data is also important.
00:22:00
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And that's D-dimer is one of the areas where we have a gap.
00:22:05
Speaker
And one of the interesting contrasts that we can make with this discussion with other similar discussions in COVID is that many people have argued that, let's say something like hydroxychloroquine has very little side effects, which is always dangerous when you're
00:22:20
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using a different population, right?
00:22:22
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But the risk of full dose anticoagulation is well documented and it's real.
00:22:29
Speaker
And I think that's something that a lot of times people are not including in their thought process.
00:22:35
Speaker
And it seems like they're almost forgetting in the frenzy of all these patients.
00:22:39
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Absolutely.
00:22:40
Speaker
So I think you make an excellent parallel between hydroxychloroquine and some of the other therapeutics.
00:22:48
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When we say they have a low risk of adverse events, that's in chronic management of disease, right?
00:22:56
Speaker
Hydroxychloroquine is something that has been used in autoimmune disease, patients with chronic autoimmune illness, not in critically ill patients.
00:23:07
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The safety profile has to be reassessed in those settings.
00:23:11
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And we can't assume that a drug that's safe in a relatively
00:23:16
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healthy but otherwise chronically ill patient is going to be safe for someone who's holding on by a thread on mechanical ventilation.
00:23:27
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And so I think that's been some of the challenges that we've seen in some of these immunosuppressive approaches to COVID-19.
00:23:35
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You're trying to call the inflammation
00:23:39
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but they're also super infected and you may be crippling their immune response to the super infection.
00:23:45
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So I think we just have to be very careful.
00:23:47
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We can't assume that things like therapeutic anticoagulation that even in healthy patients have a certain bleeding risk is going to be really well tolerated in these critically ill patients.
00:24:01
Speaker
Regarding diagnosis of thrombotic complications, Greg,
00:24:05
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Can you give us any recommendations?
00:24:08
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Are there any guidelines, anything that we should do differently?
00:24:11
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Or should we just be very in tune into potential from body complications and early a rule out if possible?
00:24:18
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Because also moving these patients around is not always as easy and there's other considerations.
00:24:24
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So your point right there is probably the most important one, which is being attuned to the risk of thrombobotic complications.
00:24:32
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I think the literature has armed us
00:24:34
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with enough of a sense that thromboembolism is an important source of morbidity and mortality in these patients.
00:24:40
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So I think that it's on our radar and it needs to be high up on our list of considerations in the differential diagnosis of patients that are showing some signs of deterioration or symptoms or signs of thrombosis.
00:24:55
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So that's key.
00:24:57
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Recognizing the patient's risk, that's important.
00:25:01
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I think that the
00:25:02
Speaker
approach to diagnosing is very similar to the way we would diagnose thromboembolic complications in all critical ill critically ill patients high index of suspicion and use the tests that are going to definitively answer your question you raised another important question or concern about sending patients for tests when they're critically ill obviously if we're if we have a patient that's
00:25:30
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prone and ventilated and on pressers, that's not the patient that we're going to want to move without careful consideration of the risk of deterioration.
00:25:40
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So if you're going to send a patient for a test, send them for the test that answers the question.
00:25:45
Speaker
You're worried about PE, do the CT angiogram, answer that question.
00:25:49
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Don't do tests necessarily that maybe have the perception of being less cumbersome to order, but will only provide you
00:26:00
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with a fraction of the certainty.
00:26:02
Speaker
Get your answers and then move on, I think is the key thing.
00:26:05
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And if you look at guidelines, they'll tell you, you're evaluating for thromboembolic disease, use the test that your center is comfortable with and has experience reading, and get your answers and move on.
00:26:21
Speaker
And there seems to be no recommendations that I'm aware of, of doing serial testing for venous thromboembolic disease.
00:26:29
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routine testing in these patients.
00:26:30
Speaker
Is that correct?
00:26:31
Speaker
Correct.
00:26:32
Speaker
So it's a great question.
00:26:34
Speaker
If you look at the test guidelines or the guidelines from ISTH or other organizations, they don't recommend serial ultrasound to diagnose asymptomatic DVT.
00:26:46
Speaker
The reason is we don't know the prognostic implications of that.
00:26:50
Speaker
It's
00:26:51
Speaker
It's not always a DVT that we're going to treat, especially if it's a calf DVT and the patient has contraindications to anticoagulation.
00:27:00
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And we don't necessarily have data that shows that it corresponds with a higher risk of adverse outcomes that would merit aggressive therapy.
00:27:10
Speaker
So currently the way things stand is serial ultrasound for DVT is not endorsed by the guidelines.
00:27:20
Speaker
And you mentioned two important guidelines that we'll attach to the show notes, which are the guidelines from the American College of Chest Physicians and the International Society of Thrombosis and Hemostasis guidelines, both of which are based really on a lot of data in non-COVID patients because... Correct.
00:27:39
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Right, which is important to mention.
00:27:40
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But as you did say earlier, we're also... There's multiple trials ongoing, and we've seen that the amount of
00:27:48
Speaker
of publications that is coming out is really impressive.
00:27:51
Speaker
So we'll probably have better and more defined answers in the future.
00:27:55
Speaker
But let's talk about what we can do today and the present.
00:27:59
Speaker
In terms of what I understand, and correct me if I'm wrong and just give some color to this in more detail, we should be focusing on making sure that every patient that's admitted to the hospital and every patient that is in the ICU gets appropriate antithrombotic chemical prophylaxis unless they have active bleeding.
00:28:18
Speaker
Absolutely.
00:28:18
Speaker
If you look at the guidelines, the statements are very strong that the language like universal prophylaxis or routine prophylaxis, those are the terms that are used.
00:28:31
Speaker
So very powerful messaging in those terms that hospitalized patients should receive, as you put it, chemical thromboprophylaxis to prevent thromboembolic complications.
00:28:45
Speaker
Is there a preference in what drugs to use?
00:28:48
Speaker
Yes, so really we want to make sure that we're giving effective thromboprophylaxis.
00:28:56
Speaker
So in some patients where there's a question of their GI absorption, we want to focus on parenteral anticoagulation, and usually that means injectables, such as low molecular weight operins or fondoparinox.
00:29:12
Speaker
The other thing is we have to keep our colleagues, our nursing staff in mind when we prescribe prophylaxis.
00:29:20
Speaker
We really want our colleagues minimizing the number of times they go into the room of a critically ill patient with COVID-19 for their own health and for making sure that we're not spreading COVID throughout the hospital.
00:29:34
Speaker
So once daily thromboprophylaxis is recommended by the guidelines.
00:29:41
Speaker
What
Dosing Adjustments for Thromboprophylaxis in COVID-19 Patients
00:29:42
Speaker
is the role of intermediate dose anticoagulation or where should we consider maybe increasing the dose of the prophylaxis?
00:29:51
Speaker
So it's a terrific question.
00:29:53
Speaker
It's currently a matter of debate.
00:29:55
Speaker
If you look at the American College of Chest Physician guidelines, they're somewhat reluctant to recommend anything higher than standard anticoagulation for prophylaxis.
00:30:09
Speaker
you look at the ISTH guidelines, they're more open to this idea of intermediate or therapeutic dosing for thromboprophylaxis.
00:30:18
Speaker
I would say in patients that are critically ill that have other markers, and what those markers are varies.
00:30:27
Speaker
It could be a D-dimer being very high.
00:30:29
Speaker
It could be ARDS.
00:30:31
Speaker
It could be other prothrombotic risk factors.
00:30:33
Speaker
But
00:30:34
Speaker
If the feeling is that the risk of thrombosis is particularly high and the risk of bleeding is low, consideration could be given to intermediate dose thromboprophylaxis.
00:30:47
Speaker
What about morbid obesity?
00:30:49
Speaker
We've heard a lot about obesity being a risk factor for COVID.
00:30:53
Speaker
And certainly in my practice, when we had the surgery in Houston, I've seen an important number of morbidly obese, high BMI patients with severe ARDS.
00:31:05
Speaker
Absolutely.
00:31:06
Speaker
I think obesity is an important risk factor.
00:31:09
Speaker
It's on a number of the risk scores for patients, even with and without COVID-19 to signal the need for thromboprophylaxis.
00:31:18
Speaker
I would say that for parenteral anticoagulation, for the low molecular weight heparins, there are dose adjustments that are recommended for obesity, and those should be applied here in COVID-19.
00:31:34
Speaker
So as the BMI exceeds 40, typically there'll be a higher level of thromboprophylaxis provided to adjust for that level of obesity.
00:31:47
Speaker
As the BMI exceeds 50, there are even higher levels of antithrombotic prophylaxis given.
00:31:56
Speaker
And there are a number of documents that can be followed to look for those dose changes
00:32:01
Speaker
We do use those, and I think that that's an important consideration.
00:32:06
Speaker
An important measure of quality is to adjust up thromboprophylaxis for obesity.
00:32:13
Speaker
Excellent.
00:32:14
Speaker
So as we move forward in kind of the different scales, let's talk a little bit about full-dose anticoagulation.
00:32:20
Speaker
And there are clear indications for full-dose anticoagulation in these patients, and they're probably not different than the ones in non-COVID patients, but can we maybe just review those
00:32:30
Speaker
examples of when you would have no doubts, let's put this COVID-19 patient on full dose anticoagulation?
00:32:37
Speaker
Sure.
00:32:37
Speaker
I mean, outside of treating acute thromboembolism, there are other situations where you would consider full level antithrombotic therapy.
00:32:52
Speaker
I think that for patients who develop
00:32:56
Speaker
complications like heparin-induced thrombocytopenia even without thrombosis.
00:33:02
Speaker
You could make a rationale in the critical care setting to provide full anticoagulation using a direct thrombin inhibitor.
00:33:14
Speaker
I think for patients where you're worried about microvascular thrombosis, you're not able to see a macrovascular PE on the CT scan,
00:33:24
Speaker
but the patient's behaving like they have small vessel in situ thrombosis, that's a situation where we consider therapeutic anticoagulation.
00:33:36
Speaker
And then there are some patients where they're so high risk, maybe multi-system organ failure, mechanical ventilation for ARDS, many risk factors for venous thrombosis, and you feel like,
00:33:52
Speaker
some prophylactic dosing is not going to be adequate.
00:33:57
Speaker
I would encourage enrolling patient into a study in that setting, but that's the type of situation where we might consider full dose anticoagulation for prevention.
00:34:10
Speaker
We noticed in our study on cardiovascular disease and COVID-19 that atrial fibrillation develops somewhat frequently in these patients, and that would be another situation where we might consider
00:34:23
Speaker
full-dose anticoagulation and no contraindication to prevent stroke.
00:34:29
Speaker
What about patients who are on ECMO or continuous renal replacement therapy?
00:34:34
Speaker
Those seem to be also patients who probably for other reasons benefit from full-dose anticoagulation and would probably be standard or best practice at this point.
00:34:43
Speaker
Is that correct?
00:34:44
Speaker
Yes, yes.
00:34:46
Speaker
Excellent.
00:34:47
Speaker
Now, talk to me a little bit, Greg, about suspicion for
00:34:52
Speaker
either macro or worsening microthrombosis at the bedside.
00:34:56
Speaker
Would it be fair to say that in these patients, maybe having a little bit of a lower threshold when we suspect something's going on is granted, but that we have to follow that up with trying to figure out what really is going on once we initiate the therapy?
00:35:14
Speaker
I think that's exactly right.
00:35:16
Speaker
I think that in the critically ill population where there's a decompensation that feels like it's pulmonary embolism, but there's not evidence of pulmonary embolism, we do need to have a low threshold to consider microvascular thrombosis and to consider full therapeutic anticoagulation.
00:35:40
Speaker
There are actually even some studies looking at fibroanalytic therapy for those patients.
00:35:46
Speaker
I don't know of any positive results from those studies, and it's not something I would encourage in the absence of definitive studies, but I think that it's reasonable, given how tentuous these patients are, to think about microvascular thrombosis, to even consider treating
00:36:09
Speaker
as we would from suspected microvascular thrombosis, and then doing the workup to make sure we're not missing something else that could produce a similar presentation.
00:36:21
Speaker
And you did mention antifrombinolytic or thrombolytics.
00:36:25
Speaker
So as of now, really, there is no specific data that supports a use out of what we would normally consider it specific to COVID-19, right?
00:36:36
Speaker
Exactly.
00:36:37
Speaker
I think that there's a lot of interest in that based on the observation that these patients are so ill and we want to do anything we can to improve their oxygenation and gas exchange, but we do not know that it's going to be worth the risk of bleeding with systemic fibrinolytic therapy at any dose.
00:37:00
Speaker
We need to study that.
00:37:02
Speaker
That's
00:37:02
Speaker
obviously a much different risk-benefit ratio.
00:37:08
Speaker
And a point I want to reemphasize, because I do believe it's very important and very prevalent, is the idea of utilizing a test such as a DG-dimer to dictate therapy.
00:37:21
Speaker
So clearly it sounds like from what you're sharing with us, Greg, there is no data to support that.
00:37:27
Speaker
It is associated with worse outcomes as many other factors,
00:37:31
Speaker
and could be part of a decision analysis, but really to say the D-dimers X, I'm going to start full dose anticoagulation, and when the D-dimers Y, I'm going to go to intermediate, currently is not based on any hard evidence that we can say it will definitely improve outcomes.
00:37:47
Speaker
That's exactly right, and that is worth emphasizing that really, at best right now, it's part of a clinical picture about the patient's risk, but it shouldn't really
00:38:00
Speaker
And it's not recommended by the guidelines to be used as a sort of one-off factor that would lead you to change your therapy.
Post-ICU Thromboprophylaxis Considerations
00:38:10
Speaker
Excellent.
00:38:11
Speaker
I have a question.
00:38:12
Speaker
As we transition patients out of the ICU, any recommendations?
00:38:18
Speaker
And you obviously see patients in all sorts of settings in your practice.
00:38:22
Speaker
But one of the things that I always fear is that we start all these therapies in the ICU,
00:38:27
Speaker
whether they're merited or not, like let's say full dose anticoagulation in a suspected case or intermediate dose anticoagulation, and we send them out and there's no plan to how do we wean that down or what is the stop date.
00:38:41
Speaker
Could you comment on some just recommendations based on what we know so far, understanding that the data is not right now extremely clear on this?
00:38:51
Speaker
Yeah, I think it's a really good question.
00:38:54
Speaker
When the patients leave the ICU,
00:38:56
Speaker
there needs to be a recognition that although they're improved, their risk for thromboembolic disease may not be that much different than when they were in the intensive care unit.
00:39:08
Speaker
And so the prophylactic measures that were provided in the intensive care unit should likely be continued until we have a better sense of what the overall risk is and whether it's really changed.
00:39:23
Speaker
When these patients are transitioned to home, there's always the question of should they continue some level of thromboprophylaxis past discharge?
00:39:34
Speaker
And that's the focus of a number of clinical studies.
00:39:36
Speaker
But I think it's important to remember that these patients, when they leave the hospital, they're not necessarily 100% recovered.
00:39:45
Speaker
And there still can be infection, inflammation, immobility,
00:39:50
Speaker
a pro-thrombotic sort of environment that warrants extension of anticoagulation of thromboprophylaxis.
00:40:01
Speaker
We need to keep that in mind and not just sort of assume that patients are out of the woods.
00:40:08
Speaker
And in terms of patients who are being discharged home, that's not something that we commonly do from the ICU unless they're going, obviously, to some sort of long-term acute care center.
00:40:18
Speaker
But this has also been heavily debated, and I'm sure that you get involved with a lot of these patients.
00:40:24
Speaker
And my understanding is that the American College of Chest Physicians and the International Society of Thrombozian Hemostasis have a little bit of a different take on this.
00:40:32
Speaker
Could you comment on that?
00:40:34
Speaker
Sure.
00:40:35
Speaker
So the American College of Chest Physicians really advise against extended duration thromboprophylaxis when patients are discharged.
00:40:45
Speaker
And they do so largely based on
00:40:49
Speaker
their own guidelines for the medically ill patient, the non-COVID patient, that those patients not receive thromboprophylaxis after discharge based on limited data in the literature.
00:41:03
Speaker
There have been some studies since that recommendation that suggests that a subpopulation of medically ill patients may benefit from extended duration thromboprophylaxis.
00:41:13
Speaker
but in the absence of really knowing what to do in COVID-19, the CHESS guidelines argue against that.
00:41:20
Speaker
Similarly, the ASH guidelines have argued against extended duration thromboprophylaxis for medically ill patients, including those with COVID.
00:41:30
Speaker
Now, if you look at the ISTH guidelines, that's very different.
00:41:34
Speaker
There they provide a little bit more of a tempered view on extended duration thromboprophylaxis
00:41:41
Speaker
They allow it and even suggest it if patients at discharge have significant markers of ongoing risk of thrombosis.
00:41:53
Speaker
So they recommend the use of something like a improved score.
00:42:00
Speaker
I don't know, Sergio, if you use that in your practice, but it's a...
00:42:04
Speaker
It's a bedside scoring system that you can use to assess risk of thrombosis.
00:42:10
Speaker
They mentioned consideration of that.
00:42:14
Speaker
And there are a number of other metrics for illness that you can use.
00:42:20
Speaker
So I have not used the improve score.
00:42:23
Speaker
I am familiar with it, but I'll definitely attach it to the show notes for the listeners to look at it if they're not familiar with it.
00:42:29
Speaker
But what I'm hearing is that we still don't have like
00:42:32
Speaker
COVID-specific randomized trials, but that it probably is at least worth doing an individual risk assessment for patients and then making an individual decision based on risk-benefit ratios and based on a discussion with that patient, I presume.
Future Research and Clinical Trials on COVID-19 Thrombosis
00:42:51
Speaker
Yes, absolutely.
00:42:54
Speaker
You mentioned, Greg, that there's a lot of ongoing trials.
00:42:57
Speaker
There's a lot of unanswered questions.
00:42:59
Speaker
I'm just curious from your perspective as someone who not only, I mean, has a great interest, but obviously a great expertise in these topics, what excites you or what are you really eager to see come out in the upcoming months?
00:43:13
Speaker
I think the first few studies looking at intermediate or higher dose thromboprophylaxis in inpatients, we should have a sense of that in the next few months.
00:43:25
Speaker
hopefully six months or so, which will help to guide us through subsequent surges.
00:43:31
Speaker
And I do think, unfortunately, there will be more than just the surge we're going through, even though vaccines will help.
00:43:39
Speaker
Those will be more of a long-term help than short-term help.
00:43:43
Speaker
I think that one big question for us is what to do with
00:43:47
Speaker
high-risk patients that are never hospitalized and have a risk for thromboembolic disease.
00:43:53
Speaker
So there are patients right now, the vast majority of patients, that don't actually need to come into the hospital but have obesity, prior VTE, malignancy, diabetes, other markers for a risk of thrombosis.
00:44:12
Speaker
And we don't know what to do with those patients.
00:44:14
Speaker
And I think we may have answers on that also within the next several months that could help us to protect a very vulnerable group that don't see the inside of our hospital.
00:44:24
Speaker
So that's very exciting.
00:44:26
Speaker
I hope to see more information on how to detect and how to manage microvascular disease, because I think that that's probably at the root of a lot of decompensations in the critical care setting.
00:44:40
Speaker
I've been really impressed, Sergio, by the ability of clinical research and basic science to really dive in and try to figure out this pandemic.
00:44:51
Speaker
I've been also really impressed by patients' willingness to participate in clinical trials to help us fight the virus.
00:44:59
Speaker
And so although I find these surges discouraging, I'm encouraged by everything that we've been able to do research-wise in our centers.
00:45:10
Speaker
And that's a great point that is worth reemphasizing just from the perspective of some positive light, right, on a difficult year.
00:45:21
Speaker
It seems that we become so accustomed to immediate returns, even with COVID and the pace of information, it feels like if you don't release, if you update a talk and it's like two months old, it's probably outdated, right?
00:45:37
Speaker
And you feel like the pace is something that I've never seen in our career.
00:45:43
Speaker
But the amount of information, of good information that has been published in 2020 is really breathtaking.
00:45:51
Speaker
We're learning a lot.
00:45:52
Speaker
It's been very difficult.
00:45:53
Speaker
But I do agree that the ability that people have had to set up trials, the willingness of patients is something like we've never seen before.
00:46:03
Speaker
And going back to what you mentioned, this is not going to go away.
00:46:07
Speaker
So instead of doing things that are unproven that might eventually prove to be harmful for certain things, we should really be trying when possible to encourage patients to be enrolled in the proper clinical trials so that we can find the proper answers and have better treatments for our patients.
Summary of Best Practices and Concluding Thoughts
00:46:25
Speaker
Absolutely.
00:46:28
Speaker
We could talk about this for a long time, and I want to be very respectful of your time.
00:46:32
Speaker
Like you mentioned, Greg, there's a lot coming.
00:46:35
Speaker
There's a lot we've learned.
00:46:36
Speaker
But
00:46:36
Speaker
like everything in medicine, still a lot of unanswered questions.
00:46:39
Speaker
But I do believe that there's a lot of basic things that we can assure in anticoagulation, like making sure people get the proper prophylaxis, evaluating people aggressively, being very thoughtful about how we would escalate to intermediate if necessary, or to full-on anticoagulation, and not just saying everybody should get this when we don't have the data, but clearly being very cognizant of the potential risk
00:47:07
Speaker
which is real, of bleeding complications, and I'm sure a lot of our listeners have seen those.
00:47:13
Speaker
Is there any other comment regarding antithrombotic therapy that you want to make kind of on the closing of this part before we go to the closing questions?
00:47:22
Speaker
I think that the most important thing really is to remember the risk of thrombotic complications.
00:47:30
Speaker
This idea of universal thromboprophylaxis is really not a bad idea.
00:47:37
Speaker
I know we try to avoid really algorithmic care when possible.
00:47:42
Speaker
We try to individualize care, but I really think that keeping thromboprophylaxis at the top of our to-do list for all of our patients with COVID in the hospital is really important.
00:47:54
Speaker
Until we know whether we should tailor the intensity of the thromboprophylaxis to higher or lower, at least we should provide some thromboprophylaxis.
00:48:06
Speaker
Excellent.
00:48:07
Speaker
So we have a custom at Critical Matters that we close the podcast by tapping into the wisdom of our guests with some questions that are unrelated to the clinical topic.
00:48:18
Speaker
Would that be okay?
00:48:19
Speaker
Yes, of course.
00:48:21
Speaker
The first question, Greg, is related to books.
00:48:24
Speaker
Is there a book or books that have influenced you the most or a book that you have gifted most often to others?
00:48:31
Speaker
Yeah, I would say it's funny.
00:48:33
Speaker
I haven't thought about this in a while, but I'm
00:48:37
Speaker
it's probably gonna be Frank Herbert's dune, mainly because I think, you know, we all are sort of struggling to find our place in our careers and especially in medicine, how we're trying to, you know,
00:48:58
Speaker
contribute to the care of the patients in front of us and the patients around us.
00:49:02
Speaker
And much like the main character of Dune, we have a lot of responsibility and we have a lot of destiny in front of us.
00:49:09
Speaker
And we've got an everyday kind of rise to meet them.
00:49:12
Speaker
I think that's true in COVID.
00:49:14
Speaker
We've been sort of charged with protecting our communities through this difficult time and
00:49:20
Speaker
it's easy to get fatigued and to feel like we've been spinning our wheels, but you know, the journey, the work is part of our duty and we've just got to keep doing it.
00:49:35
Speaker
I think that that was very similar to the main character in that book.
00:49:40
Speaker
And that was actually a surprise, a welcome surprise.
00:49:44
Speaker
I never thought about doing like that.
00:49:46
Speaker
Very timely as I think they're preparing to
00:49:49
Speaker
to launch a movie soon on Dune, but clearly a classic in science fiction and a truly an amazing, an amazing story.
00:49:57
Speaker
And really at the end, they always say that fiction is the only truth in reality, right?
00:50:03
Speaker
It's just a real powerful study in human and human character.
00:50:08
Speaker
So I will definitely link that to the show notes.
00:50:11
Speaker
And I've been, I've been kind of saying maybe I should reread Dune.
00:50:14
Speaker
I mean, I haven't read it in many, many years.
00:50:16
Speaker
So maybe you'll be the incentive for that.
00:50:18
Speaker
And it holds up well to multiple readings.
00:50:22
Speaker
I'll tell you that.
00:50:24
Speaker
Excellent.
00:50:25
Speaker
The second question, Greg, is what do you believe to be true in medicine or in life that most other people don't believe or at least don't behave like they believe it?
00:50:35
Speaker
I think that the sense that.
00:50:41
Speaker
And I don't think I'm completely alone in this.
00:50:44
Speaker
I think that there are those who believe it, but I think too often we underestimate the ability that we have to provide comfort to our patients and to provide healing outside of devices and medications.
00:51:00
Speaker
And we talk a lot about randomized control trials and the effect of net clinical benefit of this medication or that therapy
00:51:11
Speaker
But I think even in this COVID-19 pandemic, our ability to communicate with patients virtually through telehealth and in-person when we can helps to calm some of the anxieties and uncertainties that those in our community have about the future.
00:51:32
Speaker
And as physicians and healthcare providers,
00:51:38
Speaker
We've seen either historically or in our own personal experience, tough times.
00:51:45
Speaker
And this is another tough time.
00:51:47
Speaker
And we need to provide our patients with a little bit of hope that our research is working and that we're finding a pathway forward and that to hang in there
00:52:02
Speaker
And I think if we can do that, if we can inspire our patients to keep pushing on and to follow the guidance for social distancing and wearing masks and doing the right things, that's also as important as any medication we might prescribe.
00:52:21
Speaker
And to expand on that very important concept to the ICU, I think it goes to families, right?
00:52:28
Speaker
Because a lot of our patients obviously are sedated, intubated,
00:52:32
Speaker
But sometimes I wonder if instead of debating for hours where we should give a IL-6 inhibitor without any data, should a phone call to the family or a Zoom to the family be much more valuable from a human perspective?
00:52:45
Speaker
Absolutely.
00:52:47
Speaker
Absolutely.
00:52:47
Speaker
Especially since this disease kind of keeps us from some of the human aspects of our care, our ability to touch patients and family, our ability to
00:52:59
Speaker
you know, in some ways even embrace patients, you know, especially as they get towards the end of life.
00:53:06
Speaker
We have to work extra hard to provide that human contact.
00:53:10
Speaker
It's been brutal, and we just have to keep up the effort.
00:53:16
Speaker
Excellent.
00:53:16
Speaker
The last question, Greg, is what would you want every intensivist who's listening to us to know?
00:53:21
Speaker
Could be a quote or a fact or just a thought.
00:53:25
Speaker
Well, I will tell you that I've never respected my intensive care colleagues more.
00:53:34
Speaker
And I've always, I've considered, you know, I consider it as a resident, a career in intensive care medicine.
00:53:41
Speaker
So I've always, and I love those rotations.
00:53:44
Speaker
I've always loved that aspect of medicine, but I've been so proud of the selfless patient first
00:53:55
Speaker
efforts that my critical care colleagues have put forth during this pandemic, putting themselves in danger to help patients.
00:54:04
Speaker
Just know that those of us who may be consultants for you are here for you.
00:54:11
Speaker
Your cardiovascular colleagues are here to help in any way we can.
00:54:16
Speaker
And we're very thankful and very proud of the job you're doing.
00:54:19
Speaker
And I mean that.
00:54:20
Speaker
It's not just a nice concluding thought for this hour.
00:54:25
Speaker
It's something that I felt continuously because I know what goes on in those ICUs.
00:54:31
Speaker
And that's a great place to stop.
00:54:33
Speaker
I do believe that a lot of our critical care colleagues are tired.
00:54:38
Speaker
It's been a rough year.
00:54:40
Speaker
And feeling the gratitude and support, obviously, from our peers and our cardiology,
00:54:46
Speaker
colleagues and many others in the hospital has really helped and made a difference.
00:54:51
Speaker
And I think will also be very important as we navigate through this winter.
00:54:56
Speaker
Greg, thank you so much for sharing your expertise with us.
00:54:59
Speaker
Thank you so much for the papers you've published on this topic.
00:55:03
Speaker
We'll definitely link those in the show notes.
00:55:06
Speaker
It was a pleasure talking with you.
00:55:08
Speaker
Please take care.
00:55:08
Speaker
And I look forward to having you back on the podcast.
00:55:11
Speaker
You too.
00:55:11
Speaker
Absolutely.
00:55:12
Speaker
I'd love that.
00:55:15
Speaker
Thank you for listening to Critical Matters, a Sound Critical Care podcast.
00:55:20
Speaker
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00:55:26
Speaker
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00:55:31
Speaker
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