SCCM Resource Library-COVID-19 Hypercoagulability: Pathophysiology

Video Transcription

Hi, my name is Mark-Corey Scheibel, I'm an intensivist at Emory University in Atlanta. I have no disclosures.  Today, I'm going to talk a little bit about some of the likely mechanisms of COVID coagulopathy.  I'm going to talk a little bit about how this maybe is not new to COVID, and then appreciate some of the complexities of the evolving understanding of the coagulation cascade and  why modulating it can be so difficult. So I was reminded repeatedly throughout putting this together about the parable of the blind  man and the elephant, which appears repeatedly throughout history in several East Asian and South Asian cultures.  And basically it's a parable that a group of blind men can't agree on what an elephant is because they can only see what the small part that they're grasping.  And I feel like COVID, as often in medicine, really exemplifies this problem as we kind  of desperately reach for any hint of a cause and effect that could be a target for intervention.  Probably within about a month, I think, we really grasped some of the elephant parts, but the identifiable arrangements, the derangements were surrounded by a black box.  For the most part, all we could really do was treat the symptoms around the edges. I think over the ensuing year or so, there was accumulating evidence for some of the  details of the coagulopathic state in COVID. Most notably, we characterized the micro and the macro thromboses, and not only in, I think,  in consuming patients, but we were able to quantify that in autopsies and also found that it correlated with the disease severity.  Some of the other findings that accumulated were that elevated serum viscosities that were likely a result of von Willebrand factor monomers and hyperfibrinogenemia and a phenomenon  known as a fibrinolytic shutdown that was likely induced from PI-1 inhibition, and this is something we've seen in other processes, which we'll talk about in a bit.  Also characterized by neutrophil extracellular traps or nets, these are structures composed  of intentionally dying neutrophils that eject DNA and histone complexes, and these essentially  trap pathogen particles that, as a consequence, are also extremely pro-coagulant, but these are also prevalent in the areas of active infection.  As I alluded to, we've seen very similar presentations with other viral illnesses, but also other inflammatory illnesses, such as a trauma or ARDS.  For all the novelty of the virus, a lot of these specific derangements and the end products of the black box have been studied before.  There's actually a fair amount of investigational research around a lot of these pieces that most of the providers, including myself, were probably unaware of when we first started  dealing with COVID. As an example, as early as 1988, ARDS was known to be characterized by mycoplot, and  ensuiting research elucidated that there was damage to the vascular endothelium with neutrophil activation, cytokine release, and platelet activation.  The endothelial damage was known to be multifactorial and involved a variety of molecular and mechanical pathways.  Similarly, in sepsis, it has been known for a while that immune activation reduces cytokines  that activate platelets, damage the glycocalyx, and expose activating factors in damaged endothelium  to procoagulants, in a process we all recognize as disseminated intravascular coagulation.  So a lot of these underlying processes are very, very similar, and it's clear that endothelial disruption is a kind of common unifying factor in all of this.  And so in COVID, it really does help to explain not just the coagulopathy, but some of the other circulatory and pulmonary symptoms.  You know, the normal mechanism of inflammation meant to generalize local related responses  propagates systemically through cytokine release and activated immune cells, or as the virus itself propagates systematically.  And I'm not sure we understand yet which of these mechanisms is the most contributory  in COVID pathophysiology, but certainly we've identified viral particles at the sites of most common organ involvement.  So it really could be that primary viral invasion of endothelial cells ultimately what is triggering this off at multiple sites.  You know, similarly, cytokines are known to play a role in activating other sets of procoagulant pathways.  Interestingly, with hepatocytes reacting to IL-6, which upregulates fibrinogen production and PI-1 release, and intuitively having identified these insults in the various pathways,  you should be able to, you would think at least you should be able to derive interventions by targeting points along those pathways, as is suggested here along the right side  of the diagram. This is from, you know, an article in 2020. You know, the problem is over the ensuing year, as we tested a lot of these, that the problem, they didn't seem to work.  And, you know, in point of fact, with the exception of tocilizumab, which unfortunately was not in itself a major game changer either, none of these interventions really seem to  have any effect. You know, similar lack of benefit was seen with other therapies targeted to the inflammatory  coagulation cascades, such as antiplatelet therapy, plasma exchange, or TPA infusions. You know, the exception to all this is, you know, regular old corticosteroid, although  even here, the benefit is largely early in the disease course before much damage has been done, or these pathways have gone out of control.  So and, you know, that said, I think there's a separate role for higher dose steroids in the later organizing pneumonia, but that's a different topic.  And, you know, sadly, this is not the first time we've experienced failure to interrupt these pathways with a hope to halt, or at least mitigate, endothelial and coagulation  damage from the immune response. And, you know, unfortunately, I think we've forgotten a lot of this, but, you know, the  desire for a very targeted brake pedal to interrupt what seemed to be a linear pathway, you know, particularly with the drug Zygris was so great that, you know, a healthy skepticism  was suspended. And, you know, it wasn't realized until it was realized that harm was being done.  So you know, I think the lesson was that there are clearly unappreciated effects on unanticipated parts of the immune and coagulation responses that were further damaging.  Similarly, efforts to identify single target cytokines in ARDS have also been unfruitful. So what went wrong?  You know, there's a lot of easily imagined reasons why these attempts in COVID and other diseases failed. You know, was the targeted pathway just a side effect?  Do you have to block multiple pathways at once to make one part better, but another worse by blocking any particular agent? So you know, why is this so difficult?  You know, I think the short answer is really because the pathways are so complex and interdependent,  it's hard for us to predict anything past that small piece of the elephant that we're still holding on to.  But we can begin to appreciate the process and where we are in our understanding, I think.  And I'm just going to kind of review as best I can in five slides, a hundred years of molecular biological research.  So you know, I think, you know, we understand the basics of clot formation as a result of endothelial damage, that endothelial damage exposes von Willebrand's factor, it causes  platelet aggregation, the release of tissue factor and triggering of coagulation cascade, and which we'll demonstrate in a minute, and fibrin deposition, and that this is balanced  out later by, you know, various anticoagulant pathways and eventually fibrinolysis once the underlying damage has been repaired.  You know, we all painfully memorized this clotting cascade and thought, well, this was the end of it.  But I think we, you know, we really thought that it gave us a pretty good understanding  of, you know, just by understanding the intrinsic, the extrinsically common pathway, everything you needed to know about clotting.  You know, if you're really a gunner for the boards, you threw in some basic inhibitory pathways and most, but you know, for most of us, it stopped there, at least until COVID  hit and we had to think a little harder. And it turns out, as, you know, serious coagulation researchers could have told you for years  and years and years, that there's a lot more to it, and that it, particularly for COVID, the details really matter.  You know, in particular to COVID, the fibrinolytic pathway, in its full complexity, as you can  see here, is a little, is important to understand, but, you know, there are also other intersections  with the cytokine and complement systems that end up being important as well and may not be as fully understood.  On that note, you know, just to kind of show some of the pathways involved, there's a,  you know, the kininkel-krien system, you know, tantalizingly, and it involves this ACE2 receptor  that COVID also uses as a cellular entry point, you know, so there's probably a lot of dysregulation there.  The system is also responsible for PI1 release, again, that gets back to the fibrinolytic  pathway in the prior piece, which is probably, and, you know, also discussing from hepatocellular  cells previously, you know, you begin to see some of the interties for propagating the coagulopathy in COVID.  Similarly, you can throw in direct intersections with the immune system, so, you know, that the coagulopathy also induces complement activation that then amplifies the inflammatory  process and likely, again, feeds back into the coagulopathy, you know, the point being that while we can trace out, you know, a part of these pathways from, you know, a trigger  to a clot that, you know, we expose my immunodeficiency factor and it makes a clot, that, you know,  we just don't know enough about all the interactions as a whole to reverse the process once it's begun.  So they're likely not sufficiently linear that a single intervention or therapeutic is going to optimally modulate the entire system, which I think we've all been keenly  aware of with COVID. So you know, in summary, the inflammatory immune and coagulation pathways are incredibly complex and unfortunately very intimately linked.  COVID activates and deranges coagulation pathways similar to other inflammatory processes and  organisms through direct endothelial damage, fibrinolytic shutdown, complement activation and net formation, and no one part really explains or is completely determinant of the  range of COVID pathology, and no single target is likely to interrupt the multiple cascades. So for the moment, really the only way to modulate this big black box that ties together  all the inflammatory responses with the hypercoagulable state and the endothelial damage and all the  other ravages of this disease is to prevent initiation of these cascades to begin with, and that's with vaccination, which I'm alluding to here.  But optimistically, I think someday we really will have good enough understanding of the whole system such that we can finally control it, but it will take some years of effort  at the bench and the same number of years that was required to understand the subtleties of immunization at the molecular level that, you know, to understand it sufficiently enough  to develop the mRNA vaccine. If anything, you know, I hope COVID has really provided us with the incentive to invest in a lot more basic research into these mechanisms. Thank you.

Video Summary

The speaker, Mark-Corey Scheibel, talks about the likely mechanisms of COVID-19 coagulopathy. He explains that the understanding of the coagulation cascade is complex and interconnected. He highlights that COVID-19 activates and deranges coagulation pathways through direct endothelial damage, fibrinolytic shutdown, complement activation, and neutrophil extracellular traps. The speaker emphasizes that no single target or intervention has proven effective in modulating these pathways and that prevention via vaccination is currently the best approach. He concludes by highlighting the need for more basic research to better understand these mechanisms and develop effective interventions.

Asset Subtitle

Infection, Hematology, 2022

Asset Caption

COVID-19 has been shown to infect endothelial cells, which, along with inflammation, can lead to a hypercoagulable state. This session will review the pathophysiology of endotheliopathy and perturbation of coagulation in COVID-19, screening strategies for deep vein thrombosis and pulmonary embolism, evidence about timing and dosing of prophylactic and therapeutic anticoagulation, evidence for hyperviscosity, and the role of cytokine release in altered coagulation. Lessons learned from the COVID-19 pandemic may be applicable to other critically ill patients.

Meta Tag

Content Type Presentation

Knowledge Area Infection

Knowledge Area Hematology

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Coagulation

Tag COVID-19

Year 2022

Keywords

COVID-19 coagulopathy

coagulation cascade

endothelial damage

fibrinolytic shutdown

complement activation

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