Podcast: Coagulopathy, thrombosis and COVID-19
Transcript
Kirsten Patrick: Our knowledge of SARS-CoV-2 and COVID-19 is evolving rapidly. We now know that many patients have symptoms and injuries related to damaged blood vessels and blood clots throughout the body. There are still many unanswered questions but endothelial injury and hypercoagulability must be anticipated when COVID-19 is suspected in a patient. I'm Dr. Kirsten Patrick, Executive Editor for the Canadian Medical Association Journal (CMAJ). Today, I'm talking to Dr. Patrick Lawler and Dr. Lucas Godoy, who have co-authored an article on coagulopathy and thrombotic manifestations of severe COVID-19. The article is published in CMAJ. Dr. Lawler is a cardiologist at the Peter Munk Cardiac Center in Toronto, and a clinician scientist at the Toronto General Hospital Research Institute. Dr. Lucas Godoy is a cardiologist and research fellow at the Peter Munk Cardiac Center in Toronto. I've reached them today in Toronto. Welcome.
Patrick Lawler: Hi, Kirsten. Thanks for having us. Pleasure to be here.
Kirsten Patrick: Lucas, let's begin with you. Can you tell us how common are thrombotic manifestations or endothelial injury in patients with COVID-19?
Lucas Godoy: Yeah, sure. That's an important question. So the rate actually varies according to the different reports in the literature. So we can say that it's somewhere between 5-30% of the patients with COVID that are hospitalized that end up developing a thrombotic event. And the reason for this variation might be the severity of the patients that are included in each one of these reports. So the first reports we have from China, and then from Europe, they tend to include more patients in the critical care unit, they were more severe patients and those patients that are at a higher risk of developing a thrombotic event. Now the most recent reports, they also included patients from the wards with not as severe COVID disease, and you know, the rates then are a bit lower. So that's the reason for this variation. But anyway, it's important to realize that COVID seems to be related to thrombotic events in a more important way than other similar conditions like influenza, even you know, when you are dealing with less severe patients. So that's the importance of this topic.
Kirsten Patrick: Can I clarify with you, you're not able to say from the evidence that we have, what my likelihood of having a thrombotic event would be if I were to get COVID, you can only say within hospitalized patients that it's this common?
Lucas Godoy: Yes, that's correct. So, you know with COVID, only around 10% max of the patients end up going to the hospital. And the evidence that we have for the thrombotic rates are really for these patients. We don't have right now a lot of data for outpatients with COVID most of the evidence that we have are for patients that at least needed to be hospitalized. So as I said, in the beginning, it was only for ICU patients. Now, we also know a bit about patients that are not that critical, not that sick. But for outpatients it's more difficult to know exactly what would be that rate. Probably lower than hospitalized patients, but it's really hard to say,
Kirsten Patrick: Patrick, can we anticipate or predict which patients are more likely to be susceptible to coagulopathies?
Patrick Lawler: It's a rapidly moving target and I think the evidence is accumulating very quickly. You know, some of the biomarkers that people have looked at to try to ascertain risk are things like D-dimer. D-dimer, obviously is a marker in general of intravascular coagulation, but there may be imprecision to using it as such in patients with COVID. For example, there's a sense that augmented bradykinin activity leads to extra vascular tissue factor binding, which then causes extra vascular clotting pathways to be activated, D-dimer seeps back into the bloodstream, but isn't actually associated with intravascular clot in that setting. And something similar to that is seen in hereditary angioedema attacks where bradykinin is particularly active. So there's a sense that that's a marker of interest, and many have indeed shown that is associated with outcomes, but the exact way by which we should ascertain that risk is definitely a moving target. And I think it's a great question. As Lucas says, we increasingly appreciate that across the spectrum of illness severity those that have really quite a high burden of disease are much more likely to have one of these thrombotic events. And it's important to mention and conceptualize that these events likely do cluster together, as you started out by saying the endothelial injury of course is a systemic injury. And the manifestations of such could be a macro vascular event such as myocardial infarction or stroke, on the arterial side, or thromboembolic event such as a deep vein thrombosis (DVT) or pulmonary embolism, on the venous side. But that may also track with other microvascular thrombotic processes causing things like renal failure or secondary demand-type myocardial infarction (MI) and respiratory failure, of course. So, all that to say, I think certainly the sick patients are those in whom to think about it more, although it certainly is a problem across the illness severity spectrum. And I do think at least at the moment that D-dimer is a reasonable place to start, accepting that there is imprecision and the quest to find more accurate markers is certainly underway.
Kirsten Patrick: And how exactly does SARS-CoV-2 lead to disordered coagulation? I mean, what do we know about the cellular mechanism?
Patrick Lawler: Increasingly, I think it's clear that the virus uses the angiotensin-converting enzyme 2 (ACE-2) receptor as its host receptor, which allows it to be uptaken into the vascular endothelium and that causes a diffuse endotheliitis. It causes direct endothelial damage both from the viral infection, and then also from the secondary host response that is triggered in response to that endothelial injury. So the body's own system then proceeds to attack the endothelium. All that endothelial damage, as it always does in other settings, leads to upregulation of coagulation pathways, and those in turn cause in situ thrombosis. That seems to be particularly a problem with SARS-CoV-2. In general in things like influenza there is a sense that heightened inflammation does cause direct activation of thrombotic pathways, and there certainly is an immuno thrombotic kind of activation pathway that is present really in all infections, but it's particularly a problem in COVID, because of this diffuse endotheliopathy that develops as a result of the infection.
Kirsten Patrick:
So expanding on that thought of diffuse endotheliopathy and that tissues all over the body are supplied by arteries and veins, what are some of the thrombotic events that patients with COVID-19 might have? Give us an idea.
Lucas Godoy: Well, Patrick touched a bit on that. And if you get the whole spectrum of coagulopathy you can have thrombotic, or bleeding, events. And from what we know right now COVID is more related to thrombotic events rather than bleeding. Bleeding might happen as well but it doesn't seem to be that common and when it happens, it may be more related to consumptive coagulopathy, rather than a primary bleeding disorder caused by COVID. So it's more thrombotic. And amongst thrombotic events, we can have venous or arterial thrombotic events and COVID may cause both. We have more reports in the literature of the venous thrombotic events, so they seem to be more important right now. And for venous thrombotic events, we're talking basically about pulmonary embolism and deep venous thrombosis. It's important to highlight there is a big discussion right now in the literature if what we see in the lungs in patients with COVID, the thrombi that we see there, if the origin of that is from the venous thrombosis or rather a primary formation of thrombus in the lungs. So it's not clear yet it might be the case that since the virus causes so much inflammation in the lungs, it might be triggering thrombosis to happen directly and primarily in the lungs rather than an embolus from the lower limbs. Regarding arterial events, there have been lots of them reported. So cardiac injury seems to be common in patients of COVID. Up to 20% of hospitalized patients with COVID develop cardiac injury that could be only a troponin leak but can also be myocardial infarction caused by a thrombotic event in the coronary arteries. So that seems to be the most important of the arterial thrombosis events. We can also have stroke and others such as acute limb ischemia and even mesenteric ischemia have been reported in patients with COVID.
Kirsten Patrick: So we can get some indication of coagulopathy and what's happening in that regard from biomarkers. What are some of the abnormalities that we may identify in patients with COVID who are at risk of coagulopathy?
Patrick Lawler: So we touched on D-dimer earlier, and I think that's probably where most of this spotlight has focused. It is probably, you know, in my opinion is probably the marker which has the most validated kind of evidence base behind it. Again, with all the caveats mentioned all the imprecision, it does seem to probably be the best one that we've got. There certainly are other markers of coagulopathy. As Lucas says, you know, with the coagulopathy in COVID, as well as with DIC [disseminated intravascular coagulopathy] in general. Of course, there's an intravascular coagulation pathway which are upregulated but then that can progress to a consumptive picture that kind of turns the tables and increases the risk of bleeding as clotting factors are degraded. So certainly monitoring that the clotting factor is in concert throughout the process is really, really important, I think. It does seem that the DIC and COVID is different than the DIC conventionally. So we're still getting a sense of what the, the targets and the goals should be. But certainly watching the whole spectrum of biomarkers, I think, could have coagulation biomarkers that is, of course couldn't improve an understanding of an individual patients, you know, trajectory on that coagulopathy pathway. You know, as Lucas says, we certainly do think that a lot of the end organ injury is because of likely small in situ thrombosis. And so markers of organ injury in general are likely to be correlated with the risk of developing a macroscopic thrombotic event that would require treatment. So there are some institutions, for example, that have protocolized following things like troponin and other markers of organ injury that could, in theory, herald that this process is going on. And there are even some institutions that have advocated for empirically fully anticoagulating patients with D-dimers above a certain cutoff. It's certainly not standard of care but it is a practice that many institutions have started to think about, and some have started to do. So great question. In summary, we don't have great markers. I think D-dimer is probably the best we have. It's important to track all of them in concert and other markers of organ injury would probably be helpful to follow in those patients at risk.
Kirsten Patrick: So you spoke about institutions protocolizing certain investigations, and I wondered what your institution has done in that regard.
Patrick Lawler: It's a good question. I'm in University Health Network in Toronto. We've certainly a lot of discussions and it's been a little bit of a moving target. We have a number of diverse practice settings, which have taken care of these patients. Of course, we're fortunate in that our caseload is very low at this particular day in which we're talking. But there has been a sense, at least, the cardiology community has, for example, recommended sort of an active cardiac surveillance program. There, the checking of D dimers, has certainly at some points been part of the baseline admission order set type thing. But again, it sort of has varied as the process has gone. So I think it may be better for me to speak to my own thoughts, I think my own thoughts would be that D-dimer probably does have prognostic significance and in somebody that, you know, has an equivocal or uncertain prognosis, such as someone coming into hospital and whom you're not sure if they're going to be, what direction they're going to go in, and I think those kinds of prognostic biomarkers can certainly to be helpful. In someone who's already in the ICU and receiving organ failure support, you know, perhaps those markers are less useful, they already know that something bad is happening clinically. So, you know, my thought would probably be that I would check those markers at baseline. I do think that surveying some things like troponin and things can herald the potential clinical deterioration, which can occur abruptly, unfortunately, in these patients. So I think those types of surveillance approaches I, I tend to think are probably worthwhile. I tend to be someone in general, in my practice, who likes a lot of objective data. But I think in the absence of really understanding the problem, questions about what clinical trajectories may unfold for a given patient, I think gathering as much evidence as possible, it makes sense to think those markers can be useful.
Lucas Godoy: Even the clinical society guidelines, they are not uniform, their recommendations regarding the best approach, if you should order in on D-dimer, I think most would say yes, it's important to order D-dimer because of those things that Patrick just mentioned. But you can find in the literature different opinions as well. So it's really hard to come up with a you know, a very standardized protocol or recommendation that would feed every scenario in every kind of practice.
Kirsten Patrick: That makes sense. So moving on from diagnosis and clinical appraisal, once you've realized that there are clinical manifestations of coagulopathy, how are these best managed?
Patrick Lawler: So we generally, I think many are taking the approach that they should be managed as they conventionally are. So, you know, DVT should prompt full-dose anticoagulation, per embolism as such. And the duration of that it's really not known in COVID. But there's a sense that we would just follow the usual clinical practice guidelines for those types of events. You know, the management of myocardial infarction and the provision of catheter based approaches is something that varies from institution to institution. But I would say broadly the sense is we'd managed these conditions and complications as we would managed it inside and outside of COVID.
Kirsten Patrick: So nothing special for COVID patients, not earlier intervention?
Patrick Lawler: Well, it's a good question about whether a pre emptive strategy is worth considering. So there are a number of planned and actually a number of ongoing clinical trials looking at whether a strategy of initial empiric full-dose anticoagulation is superior to a strategy of more reactive, usual thrombo prophylactic low doses that then get escalated in the presence of DVT or pulmonary embolism (PE) or other clinical indication. A couple of those trials being led in Canada. One of them that Lucas and I are a part of is called the ATTACK trial. It's an adaptive Bayesian trial that is looking at the concept of doing full dose heparin right out of the gate when a patient is admitted to the hospital versus as they say a kind of watchful waiting with thromboprophylaxis and then an escalation to one of these higher intensity strategies in the event that the patient develops a clinical, conventional clinical indication. The thought is that the clinical manifestations of thrombosis that we have mentioned, such as DVT, PE, MI and stroke, and systemic arterial embolization, are the kind of clinically detectable and conventional consequences of that. As Lucas says, we do think that other mechanisms of organ failure are likely to be underlined by this thrombotic cascade as well. And so the thought in this case is that some of those antithrombotics could have an effect actually prevent organ failure and prevent patients from needing ICU-level therapy and possibly dying. So a lot of those it's very, very exciting sort of landscape. I think a lot of those trials are actively enrolling, as I say, some of them led out of Canada, and it's really very exciting. I think we, you know, hope to have answers in the next six months or so from using these emerging partnerships to try to get answers as quickly as possible through collaboration, which I think are unprecedented and really exciting. But it's still very much an open question. And I think at this stage, as Lucas has highlighted, the guidelines are very much, you know, conventional, low dose thromboprophylaxis, and see how patients do. I think these are opportunities for us to test whether something more proactive might be the right approach. I would say the trial is active in a number of centers throughout Canada and if there is interest, of course, I don't mean to promote it, but I'm sure that there will be an opportunity to collaborate if any listeners would like to learn more.
Kirsten Patrick: We've talked about that this is a rapidly evolving area moving target in terms of evidence, and you've in your article highlighted a number of resources that clinicians can look to. What are some of these main resources that they might want to use?
Lucas Godoy: Yeah, so you know, we have combined some of these resources in the article, it's in Box 2, as we put it there. So there are some society guidelines as the European Society of Cardiology, they put together a document with guidance for the diagnosis, and management of cardiovascular disease during COVID. And they also talk a lot about thrombotic events in that document. The International Society for Thrombosis and Haemostasis also have guidance document on how to diagnose it to do the diagnosis and the management of coagulopathy patients with COVID. I think those would be for clinicians the some of the most important guidelines that you have available right now. There are other recommendations from other entities such as the National Institutes of Health in the US, Thrombosis Canada also has their recommendation, we also put together a list of places to find ongoing clinical trials in patients with COVID. So you know, people might be interested to know what trials are going on where they live, or where they can reference patients to so you have some references there where people can search for current clinical trials in patients with COVID and coagulopathy, or testing coagulopathy interventions, and generally patients with COVID.
Kirsten Patrick: Thanks for writing this brilliant, comprehensive article for CMAJ. I guess the take home messages is for clinicians to be aware that patients with COVID-19 may well develop coagulopathy and be prepared to manage it if necessary.
Patrick Lawler: That's very well summarized. And thanks for the privilege to contribute. It's really been really a great opportunity for us too
Lucas Godoy: Thank you for your invitation.
Kirsten Patrick: I've been speaking with doctors Patrick Lawler and Lucas Godoy, cardiologists at the Peter Munk Cardiac Center in Toronto. To read the article they co-authored visit CMAJ.ca. Also, don't forget to subscribe to CMAJ podcasts on Soundcloud or a podcast app and let us know how we're doing by leaving a rating. I'm Dr. Kirsten Patrick, executive editor for CMAJ. Thanks for listening.