Hello, everyone, my name is Dr. P. J. Miller. I come from a unique training background. I am residency trained in combined internal medicine and pediatrics. I then subsequently went on to complete a fellowship in hematology and then in a 2nd fellowship in critical care medicine. My academic interests are critical care coagulopathies and thrombotic disorders, as well as dysregulated coagulation, including DIC and COVID-19. I have a large interest in the critical care management of patients with cancer, which is a fascinating complex and emerging niche in critical care medicine as patients with cancer continue to live longer and their treatments become more complex. I'm the medical director of the medical oncology ICU at Atrium Health Wake Forest Baptist, as well as educational roles for medical students and residents as they rotate through the ICU or on consult rotations. Today, I'll be discussing antiphospholipid antibody syndromes, particularly when they're relevant for the intensive care unit. I have no financial or other conflicts of interest that are relevant to the presentation today. So, what are antiphospholipid antibodies? Antiphospholipid antibodies are heterogeneous, meaning there are several different types. They are autoimmune, therefore, there are antibodies that are directed to self, specifically targeting the phospholipid binding proteins. These antibodies have the potential to cause cascading and widespread thrombotic events through the thrombotic events through very complex and interacting pathways within coagulation. They may occur as a primary condition or secondary to an underlying autoimmune disease, and oftentimes these can be set off by a critical care illness that occurs with one of these underlying diseases or that results in one of these underlying diseases or processes occurring. The diagnosis, particularly in an ICU environment, when you have a lot of different things going on and the patients are terribly complex, may be very challenging, although what I hope to discuss today is how that rapid recognition in treatment is imperative for ensuring best outcomes for patients. Now, the prevalence of antiphospholipid syndrome is somewhere around 17 to 50 patients per 100,000, and there is an association with approximately 30,000 DVTs, 50,000 pregnancy losses, and greater than 100,000 strokes and myocardial infarctions per year. Now, I'll be honest, I think that this is probably an underestimate, mostly because I think a lot of this goes unrecognized, I'm trying to think back of the number of patients that I've directly diagnosed with antiphospholipid antibody syndrome in the ICU over the past year, and that's a pretty small number. However, I truly believe that these antibodies do play a role in critical illness and do have higher associations. The main grouping of antiphospholipid antibodies includes anticardiolytin, as well as the lupus anticoagulant, and this is the one that is typically of initial concern, resulting from a prolonged APTT that does not correct with a one-to-one mixing study. There is also the anti-beta-2 glycoprotein 1. It is important to recognize that the presence of antibodies does not equal the development of antiphospholipids. It is possible to have non-pathologic antibodies. In fact, we do identify these on a pretty regular basis, especially in critically ill patients. The thought process behind this is when you are critically ill and your immune system is revved up, that that ability for your body to recognize self is either overwhelmed or diminished, and that you may actually be producing some of these antibodies. But thankfully, a lot of them are not truly pathologic. The process is believed to require second or multiple hits, and this dysregulation needs to overweigh feedback control mechanisms, as I'll discuss a little bit later during this presentation. This is a different representation of what I was just talking about. So, you can have a large number of patients that develop antiphospholipid antibodies, the vast majority of which you or I or the patient would never know. A smaller percentage of this population has an associated or correlated hypercoagulable state, and an even smaller number are those that develop pathologic thrombotic events secondary to this hypercoagulable state in the presence of antiphospholipid antibodies. Now, this red part of the triangle here is really kind of what we'll be focusing on for the rest of the lecture here. Antiphospholipid antibodies, particularly anti-beta-2-glycoprotein-1, activate endothelial cells. They activate monocytes as well as platelets. They're demonstrated to activate neutrophils, which result in the release in NETs or neutrophil extracellular traps. Another way I want you to think about neutrophil extracellular traps, they're a net-like structure composed of proteins, histone, and DNA of the neutrophils, and they set out this web-like structure that has the ability to capture pathogens such as fungi, protozoa, etc. But we're also learning that these NETs have pathologic roles, potentially in cancer metastasis, recruitment of other immune cells that may be playing a role in autoimmune diseases. So these antiphospholipid antibodies actually rev this process up. Now, this is in support of a concept of immunothermosis, and this is the critical interplay between coagulation and the immune system. You really can't have one without the other. Now, I always joke around, particularly in the ICU or when I'm on hematology consults, that I'm a hematologist. I'm an intensivist, but I'm also a hematologist. I love hematology. I do not necessarily love immunology or rheumatology. I think that they are fascinating fields. They're just really not what does it for me. But the funny thing is, and what I joke about with my trainees, is that they're really all the same specialty. Immunology, hematology, and rheumatology. You're looking at the same cells, but in a different way, and the different roles that they have in disease. So as we continue to gain more knowledge, we're actually learning how much more similar these fields of medicine are, and not how much more different they are. This is a good graphic from the New England Journal of Medicine with the citation below. It is a summary of the proposed pathogenesis of antiphospholipid antibody-mediated clinical problems. I won't necessarily go through this entire graphic here, but you can see that the production of these antiphospholipid antibodies and how they interact with some of the structures that we were just talking about, and how they are associated then with inflammation, vasculopathy, thrombosis, and also, very importantly, pregnancy complications. Now, unfortunately, I can't show this graphic. This was going to be able to be used during the live presentation, which I had permission to use. However, I did not have permission to use this particular graphic for recording or later for materials that would be distributed, but I still want to go on and at least describe some of the coagulation cascade. Now, we learn that the coagulation cascade is made up of the extrinsic pathway and the intrinsic pathway, and that they come together at factor X, and then you have the common pathway that ultimately results in the production of a thrombus. Now, I joke around with my trainees and tell them very frequently, the coagulation cascade does not exist. Now, how can I say that? It does not exist in the way that we are taught to learn. This extrinsic pathway that is independent from the intrinsic pathway and how they come together into this common pathway is massively oversimplified. It's as complex as thinking about our solar system and thinking about how we just have, whether you believe it's eight or nine planets that we have in our solar system, as opposed to thinking about the entire universe. I want you to think about the coagulation cascade as the entire universe. It is that complex. There are tons, if not hundreds, of different interactions which are probably all occurring at the same time, and these complex interactions are what can go haywire when you don't have a regulated feedback in place. So again, the coagulation cascade, the way that we learn it, is almost a disservice. Yes, we have to teach it in such a way that it is relatively simple to learn so that the concept is there, but it is much, much, much more complex than we truly give it credit for. Now, what are the typical clinical manifestations of antiphospholipid antibody syndrome? Well, these antibodies typically result in a pro- or hypercoagulable state. Why do I say typically? It is actually possible to have an antiphospholipid antibody that is targeted specifically to factor II or thrombin, where a patient could actually have a bleeding disorder secondary to this, but that is exceedingly, exceedingly, exceedingly rare and not what we are discussing here today. So typically, these antibodies result in a pro- or hypercoagulable state. Venous thromboses are much more common than arterial thromboses, and typically higher titers of antiphospholipid antibodies, when they are pathologic, equals a higher thrombotic risk. Now, people tend to ask me, when should I suspect antiphospholipid antibody syndrome? And I tell people, you know, when you have things that are occurring that seem out of proportion or out of the norm or out of expectation for their illness that you're treating them for. So if somebody has unexplained venous or arterial thromboses, now, if you have somebody who has a very easily explainable inciting event, this is not the person who I would necessarily chase antiphospholipid antibody syndrome in. That's the person who you're probably going to identify a non-pathologic antiphospholipid antibody in that patient, if they have it at all, and it could be very complex to tease it out at that point. So again, if you're having unexplained events or recurrent events, or you're having pregnancy-related complications in your patient, so fetal death after 10 weeks or the patient with multiple gestation losses, this is the population who I would be thinking of antiphospholipid antibody syndrome in. And I tell people, even though this is a lecture about antiphospholipid antibody syndrome, however, when I have a patient who is having unexplained complications, that's when I typically take a step back and I run through my head and I said okay, quickly, what criteria could this patient meet for diagnoses such as TTP or thrombotic thrombocytopenic perfora, or HLH, hemophagocytic lymphohistiocytosis, or antiphospholipid antibody syndrome. Those are diagnoses that come to my head when I'm having these unexplained events in a patient. This is a fantastic review slide with the citation below. For the most common manifestations in antiphospholipid antibody syndrome, according to the Urophospholipid Project. Now, I'm not going to go through all of these, obviously, but what I want you to recognize here is look at how many different manifestations that can be presenting in your patient and the percentages at which these may be presenting in your patient as the pathologic event. So there are so many different types and that's why I say if there's one thing that I could push hard on today for everybody listening to this lecture is when to take a step back, when to say I need to hit the brakes and I need to think about what's going on and potentially identify the underlying cause of these unexpected or unanticipated complications. I will feel like I'm a failure in this lecture if I get everybody to memorize diagnostic criteria, but not that ability to take a step back and say, whoa, something unexpected, unanticipated is happening. So that's the big goal of my lecture today because, again, look at all the different potential thrombotic complications and where they are and how they're occurring in the frequency that they could be occurring in these patients. So let's go through some of the diagnostic criteria for antiphospholipid antibody syndrome. You need to have one or more of the following. So some type of vascular thrombosis, whether this is arterial, venous, small vessel, or a pregnancy morbidity, including greater than or equal to one unexplained death of a morphologically normal fetus that is greater than 10 weeks of gestation, greater or equal to one premature birth of a morphologically normal fetus before 34 weeks of gestation, which is due to either eclampsia, severe preeclampsia, or some type of placental insufficiency, or greater than or equal to three unexplained consecutive spontaneous abortions before the 10th week of gestation. And this does exclude maternal, anatomic, or hormonal abnormalities or parental chromosomal abnormalities. Now, again, it's not necessarily that I want you to memorize these, but, again, at least have some recognition so you could go back and look up exactly what these criteria are. You need to have one or more of the following detected twice 12 weeks apart, and I'll give you a little bit of a memory tool to help with this. So one or more of the following, lupus anticoagulant, your anti-cardiolipin IgG or IgM in a medium or a high titer, or your anti-beta-2 glycoprotein IgG or IgM in a high titer as well. Now, if all three of these are present, that's referred to as triple positive, and there are believed to be increased risks of pathologic events associated with this. Now, how do I get people to try to remember? How do I teach this? Because these criteria are pretty complex, and let's be honest, you'll remember them for a while, but unless you're doing this every day, they're going to slip your mind. So for antiphospholipid antibody syndrome, I teach this as one, two, three. You need to have one test that is positive twice over three months. One, two, three. Now, avoid committing to the diagnosis if the labs are less than 12 weeks or if they're separated by five years between the positive antiphospholipid test and the clinical manifestations that you are observing in the patient. And this is where diagnosing antiphospholipid antibody syndrome, particularly in an ICU, will be challenging. And it makes it very difficult from the consult side as well when I'm called to consult on these patients, because oftentimes I can say, you know, I have a very high clinical suspicion that this is what it is, and this is the diagnosis until we know otherwise. But realistically, until I come through with all of these different criteria over the one, two, three that I was just talking about, you know, it may not be that diagnosis. So it does take expert opinion as well as having experience in treating these patients and also having a strong background in treating and recognizing these disorders. Now, what is the initial management for patients with antiphospholipid antibody syndrome? So if there are other pilots in the audience or listening today, when I was doing my flight training, my instructor would tell me, fly the plane. In an emergency situation, never forget that you have to fly the plane. So what do I mean by that? What does that mean for what I'm talking about here? Take care of your patients. Managing, assessing, and treating complications or organ dysfunctions is far more important than walking away from your patient to try to calculate a bunch of diagnostic criteria. Manage your patient first. Fly the plane first. Assess for other conditions. Does your patient have levator reticularis? Are there diseases of your cardiac valves? Do you need an echocardiogram? Look specifically at your mitral and aortic valves, whether you're getting a formal echo or you're skilled to do this bedside yourself. Assess for thrombotic microangiopathies. Look, does the patient have thrombocytopenia? Is there a known or unknown component of a hemolytic anemia? And if there's evidence of end organ damage, as I was commenting on, treat, if you can, those end organ damages. Limit end organ damage. Reassess what medications or interventions that you are doing to try to prevent worsening of these end organ damage. And once you are successfully managing your patient or flying the plane, then do your laboratory testing. But consider the timing of the testing, particularly if the patient is on an anticoagulant or something that could interfere with these lab tests. Now the lupus anticoagulant and the APTT are technically more challenging to assess while anticoagulation, but a lab with experienced consultants or providers or physicians that have experience working these diseases up in that setting could be of significant value. Consider thrombophilia testing. Know your institutional tests. An acute thrombosis should not interfere with genetic testing, but they do or they can affect certain functional panels. I would not rush to send functional panels for thrombophilia in the setting of an acute thrombosis, in the setting of severe critical illness, or if the patient is on certain types of anticoagulation medication. Now can you still make these diagnoses? You can raise your level of concern for these diagnoses, but it does make it exceptionally more challenging. And if you have a patient that you start working up for antiphosphate antibody syndrome, consider working the patient up for systemic lupus erythematosus. Anticoagulate your patient. Heparin over low molecular weight heparin over direct thrombin inhibitors. Once you have your patient stable on anticoagulation and they meet whatever institutional guidelines that you may have or following, bridge the patient to warfarin when clinically ready. Now can you use a DOAC? This is a question I get all the time. It's so much more convenient. Can I use a DOAC in this patient? There is a lot of controversy with this, and there are three separate studies that I won't necessarily get into all the details in particularly in this, but we don't have strong solid evidence that DOACs are necessarily better than warfarin. And some of this may just be how DOACs function. So if you have something that is directly inhibiting factor 10, but you have a revved up immune system, you may need more than just blocking that specific component of the coagulation cascade or the entire coagulation event. You may need something along the lines of warfarin or coumadin where you are causing a regulated dysfunction in multiple parts of the coagulation event. Now can I say that I've never used the DOAC in these patients? Absolutely not. I've definitely used DOACs in incorrect patients, but this is coming from a level of experience. This is coming from discussing with the patient, having an honest and open discussion with the patient of saying, hey, this is what we're dealing with. This is FDA approved treatment. This is an alternative option. This is why I think you are a good candidate for alternative therapy, or this is why you are not a good candidate for alternative therapy. I've had some patients who absolutely refuse warfarin under any circumstance. They've had a family member who's been on it, or they've been on it in the past, or for whatever reason, absolutely refuse. Well, I'm not going to not treat that patient. But typically in patients, I will recommend at least initially warfarin. And then, like I said, after having some degree of shared decision making with my patient, I will come up with the treatment plan that I will send them out on. And I may also, if they already have a hematologist or a rheumatologist or an immunologist, discussing that with them as well to determine what the comfort level is of multiple different physicians or providers. Sometimes, despite the best management that you could be providing for your patient, a patient develops a complication that is far more extensive, or they have multiple events occurring within a very short period of time, if not simultaneously. And in antiphospholipid antibody syndrome, when you have multiple catastrophic events occurring around the same time, if not together, this is termed catastrophic antiphospholipid antibody syndrome. Now, the criteria for this, evidence of three or more organ system dysfunctions. They develop simultaneously or within a week, and you have a histopathologic confirmation of small vessel occlusion, as well as laboratory confirmation of antiphospholipid antibody syndromes. Now, definite requires all four. Suspected, you have less than four, but your patient continues to worsen or have these complications. It is very important that you exclude other causes of multi-system organ failure in these patients. This could be exceptionally challenging, for example, if you have a patient that you're working up for antiphospholipid antibody syndrome, or you have a high clinical suspicion, and then suddenly a blood culture, for example, comes back positive for something. So you really need to exclude other causes of organ system dysfunction before labeling and committing the patient to that diagnosis. You can certainly have it in the back of your head as a high level of concern, but just be cautious about truly committing to that before you can exclude these other causes. Continuing your ICU management, organ system support. Again, manage your patient, fly the plane, start them on anticoagulation when you can and are able. Systemic glucocorticoids, or IVIG, may be of additional benefit, as well as therapeutic plasma exchange. Now, I think discussing and going in depth of all of these different treatments is going to exceed the limits of this particular presentation, because realistically you can talk for an hour about each of these things. But these are different types of treatments, where if you have your patient and you're suspecting antiphospholipid antibody syndrome, or catastrophic antiphospholipid antibody syndrome, these would be different treatments to consider. In refractory cases, your consultant may be recommending rituximab or ecolizumab as additional therapies to try and abate this process. Now, I have absolutely recommended rituximab or ecolizumab in some of these cases, and that is exceptionally challenging, because you are, especially with ecolizumab, because you are talking about potentially immunosuppressing your patient. And if this person that you're treating has septic shock, or concerns for septic shock, or sepsis, or even bacteremia, by giving some of these additional agents, you may be further immunosuppressing them. And if you're incorrect, you could actually cause mortality, or at least, at a minimum, additional morbidity in this patient. Now, one last thing that I just wanted to touch on very briefly is SARS-CoV-2, or COVID-19, and what is the association of antiphospholipid syndrome, or antiphospholipid antibodies, in patients with COVID-19? And the data for this has kind of been all over the place. And the way that I would think about this is, think of your critically ill patients. We know that critically ill patients, through a revved up immune response, are going to have increased numbers of antiphospholipid antibodies. Again, we don't know, are all of these pathologic, or are only a small percentage of these pathologic. And the same for COVID-19. In COVID-19, certain patients we know have a very revved up immune system. They are very pro-inflammatory. Their pro-inflammatory markers are increased. And in these patients, certain studies have identified antiphospholipid antibodies at higher titers in some patients with these macrovascular thrombotic events. And I will be the first to tell you, I don't know. I don't know if this is a red herring. I don't know if this is just an association or a correlation. Now, do I think that some of these patients with COVID-19 have some degree of antiphospholipid antibody syndrome that was set off by COVID-19 because they had an undiagnosed or unknown underlying autoimmune or rheumatologic disorder? Yes, absolutely. But do I think that every single patient that is having a thrombotic event in the ICU is secondary solely to antiphospholipid antibodies that they develop because of their COVID-19? No, I do not. However, in these patients, most commonly it is the lupus anticoagulant, which again, you could be alerted to that based on a prolonged APTT, especially when it does not correct with a one-to-one mixing study. And as I was just talking about, it's uncertain if these are transient or if they are truly pathologic antibodies. Is this just representation of a revved up immune system in a pro-inflammatory response? Or are a certain percentage of these antibodies truly pathologic? A lot still is unknown about this. And this is an area that actually I find absolutely fascinating because not only could this potentially identify reasons for why patients have these thrombotic events, but it could also potentially lead to new and exciting treatments in preventing some of these complications from occurring at all. Thank you everyone again for listening to my lecture. Again, my name is Dr. PJ Miller. My contact information is available here for you on the slide. I encourage you, please feel free to reach out if you have a patient or you need to run something by me with the different experiences that I have. I'm always happy to help colleagues out when I'm able. I hope that I was able to educate you as well as entertain you a little bit during this lecture. I know that this is some uncommon diagnoses that we may be seeing in the ICU. And again, I hope that the biggest thing that you took away from this lecture is when to take a step back, how to take a step back, and how to identify when you may need to call for some additional help from clinicians or physicians that have differing experiences than what you may be providing for the care of your patients. Again, thank you very much and I hope you enjoy the rest of the Congress.

antiphospholipid antibody syndromes

thrombotic events

diagnosis

organ dysfunctions

anticoagulation

COVID-19

high-titer antibodies