 Welcome to Texas Heart Institute educational programs cardiology in the time of COVID-19 featuring today thrombotic and embolic complications. My name is Vanmer Kraser. I'm an international cardiologist at Texas Heart Institute and CHI Health, Baylor St. Luke's Medical Center. Joining me today here is Dr. Stephanie Coulter, who is assistant medical director at Texas Heart Institute and also director for Women's Heart and Vascular Institute and also program director of cardiovascular fellowship at our institution. Welcome Dr. Coulter. Thank you Dr. Kraser. Joining us also today is our special guest Brianna Costello, she's an international cardiology fellow at Texas Heart Institute here in Houston, Texas. Thank you Dr. Kraser and Dr. Coulter for having me. You're welcome Brianna. So Dr. Kraser, please explain to us the potential effects of coronaviruses on the vascular system. Well let's start with the recent publication that was published in March of 2020 by our former fellow Dr. Mohamed Majeed and the title of this manuscript was potential effects of coronaviruses on the cardiovascular system. It was a systematic review and I believe one of the best reviews related to coronaviruses on the cardiovascular system. We can see here from his publication very extensive effect of coronaviruses on cardiovascular system particularly concentrating on the cardiac system per se. One of the most important things from this information and from publications elsewhere is that coronaviruses affect the vascular system directly and produce a significant degree of inflammatory process. We all know that this is done through a spike protein on coronaviruses that attaches itself to ACE2 site and then enters the cell and causes very aggressive cellular destruction. ACE2 sites are very extensively represented throughout the vasculature in the heart and also peripheral vessels as well but also in lung tissue and this is where most of the damages occur. We have also seen from many publications and also related to Majeed's publications that there are certain similarities among coronaviruses such as SARS coronavirus and SARS coronavirus 2 because both of them attack and attach itself to a ACE2 receptor site. They have a very similar incubation period and also re-duplication as far as infectiveness is concerned. Of course there is a significant difference as far as mortality is a concern while SARS co-virus and the MERS have a significantly higher mortality, SARS co-virus 2 has a significantly lower mortality but it certainly causes a lot of cardiovascular problems. The mortality as we can see is for SARS co-virus around 10% and the MERS at 30% while SARS co-virus 2 mortality depends tremendously depending on the comorbid conditions and pre-risk of certain individuals that might be more prone. We know that as far as ACE2 receptors are concerned they are more prevalent in males, they are more prevalent in patients with hypertension, they are somewhat less prevalent in females, somewhat less prevalent in children and we know that that certainly plays a significant role as far as mortality and morbidity of this particular virus is concerned. So as far as SARS co-virus 2 risk of thrombosis in arterial and also venous system is concerned the mechanism is by damaging the endothelium and causing anothelial dysfunction and stimulating formation of inflammatory substances such as interleukin 6 and other ones and that causes reduction in the thrombo-plastin that leads to thrombosis. All of those factors play a significant role not only affecting the endothelial dysfunction but also producing cytokrine in the storm which is more prevalent in a patient that have a very significant elevation of inflammatory substances such as interleukin 6. Brianna can you tell us a little bit about hypercargulability state and how is this caused and manifested on the venous side? So we all know Birkhouse triad of stasis of blood flow endothelial or vessel wall injury and hypercargulability those are the kind of three cornerstones of thrombosis particularly in the venous side. There are some arterial aspect to this too but in these patients especially the patients who already are at risk with say perhaps venous insufficiency or hyper inflammatory states at baseline COVID adding another layer of hypercargulability by disrupting the clotting cascade certainly is like a third strike. So when you have these three aspects of stasis, injury and hypercargulability you're really at risk for a venous event which many of these patients have. Kind of dovetailing off of that again these patients they're not just any healthy patient walking the street most of our patients we're seeing with coronavirus have underlying risk factors many of these are acquired and we've all seen patients with advanced age or you know immobility but we have there's many others that we don't often think of such as diabetes this is you know increases your risk for thrombotic events both arterial and venous. The other less common ones of course are myeloproliferative disorders and HIV and AIDS but again many patients have these other risk factors that they've acquired through their life. Some of the hereditary ones which are again less common and we as cardiologists maybe perhaps we don't see them as frequently so we don't think about them as often but factor 5 lidon is a big it's you know very common hereditary cause for a thrombotic event and these patients I'm certain there's probably not been anything published on this just quite yet correct me if I'm wrong but patients with some factor 5 lidon and coronavirus likely are at higher of course are at higher risk than a patient without factor 5 lidon with coronavirus for thrombotic events so maybe these patients are you know being over represented in the coronavirus thrombotic you know group but again just a reminder the hereditary causes factor 5 lidon, prothrombin, 20210A, there's protein C and S deficiency so the factors that generally help you de-clot if you're deficient in those elevated homocysteine and then there's a variation of elevated factors that can also increase your risk for clotting. A couple of the more rare disorders dysfibrinogenemia and antithrombin deficiency again are still risk factors but less common but things that to keep in mind in your patient who might be presenting as a clot with coronavirus. And also recently it was published that in the patients with the coronavirus infection the lupus anticoagulant might be playing a significant role in this particular problem. And again all of these things we're kind of seeing as the pandemic kind of progresses so it'll be interesting to see how that pans out and you know what happens to these patients long term. It's interesting to me how much we've learned since we had our first COVID-19 cardiology session with Muhammad Majid and only six weeks ago and how much more we've experienced because we've taken care of these clinically difficult patients and what we've seen and how much has been added to our knowledge even if it's on Facebook blogs or communication between physicians from New York and New Orleans and how much we're learning. So there's going to be a lot of information to come out later. Hopefully people are storing blood samples on some of these very critically ill patients so they can go back retrospectively and look at those that had pro-thrombotic events to look to see how many of them had factor five lightened because when you're in the heat of the moment caring for these critically ill patients you're just looking to put out the fire you're not looking for what caused the fire and so I'm hopeful that astute clinicians here in the states are going to be more carefully investigating what are the predisposing conditions. Yeah that would be great. All right Dr. Krazier so tell us what are the fat risk factors and hemostatic abnormalities and clinical manifestations of these patients with COVID-19? Well Breanna you already mentioned the acquired factors and the genetic factors that play a significant role and I don't think it's necessary to repeat all of them I would just like to mention that acute illness of any kind is a major risk factor and inactivity which is very common obviously in patients with COVID particularly if they're on a respirator and bedridden and you talked about the genetics which play a significant role. What has not been mentioned to a certain degree in the literature is that there are subset of patients with pelvic obstruction disease such as May Turner and similar other things that could be related to a certain degree to it from trauma that could also lead to a hypercoagulable condition and thrombosis including also dehydration with all those factors and also in patients with chronic venous insufficiency and trauma to the lower extremities and previous history of thromboflabitis. Dehydration is a major factor I think that plays a role in a lot of those patients but also liver failure, chronic renal failure, COPD, congestive heart failure and malignancy as you mentioned before. There are numerous hemodynamic or hemostatic sorry hemostatic abnormalities that occur and one of the common ones that has been found on a pathology evaluation of patients that died is frequent pulmonary microemboly and on occasion intravascular coagulopathy that affects the many organs. Myocardial injury is not rare it's common elevated troponin is very common and myocardial injury could be due to myocardial infarction but also it could be related to myocarditis. There are numerous inflammatory biomarkers that are very frequently present in patients with COVID such as elevated D dimer even without evidence of pulmonary emboli, elevated PT and activated PTT, elevated fibrin degradation products and CRP are very commonly elevated and of course elevated interleukin-6 particularly in cytokine storm is very frequently elevated. Platelet count is frequently low and lymphopenia is low as well as decreased TIFP factor and there are numerous clinical manifestations. We have talked already on our previous webcast on cardiac effects but we are now considering on DVT which is not uncommon and pulmonary emboli whether microemboly or major emboli are not also uncommon myocardial infarction CVA has been described more and more now particularly in younger individuals and peripheral thrombosis for a variety of reasons and the DIC has been described as a relatively common condition in patients with advanced and serious condition particularly those patients that are rapidly deteriorating and also have a cytokine storm. Now I would like to ask Dr. Coulter Stephanie if you can tell us a little bit about incidence of stroke we just mentioned this in this infection and what do you think is the cause of this occurrence? Well large vessel stroke is a presenting feature of COVID-19 in the young and in these young people about with stroke these are people without advanced vascular disease with you know really low cardiovascular risk maybe as in these groups as much as five percent of hospitalized patients so we think it's a direct effect of the infection on the vascular endothelium associated potentially with a hypercoagulable state. We've actually seen a couple of cases here in our institution of large vessel stroke in otherwise very low risk individuals so you have to really assume there's something intrinsic to the way that the virus interacts with the vascular endothelium. You know it's it would be interesting to see I don't know and maybe a neurologist would know or you know interventional neurologist what the ACE2 receptor concentration is in the brain if it's higher in the brain like it is in the lungs I don't know if they would know that answer maybe that's causing more localized inflammation in those large vessels. But the other interesting thing about these young patients that present with stroke is that they're not presenting with acute severe COVID-19 related systemic illness they're just presenting formfruce with stroke which takes out a lot of the other co-founding factors that Dr. Crazier just went through because certainly hypoxia in patients on ventilators with COVID-19 in the hospital have are well demonstrated to have elevation in their RV systolic pressures which early on in the pandemic we assumed was related to ARDS but certainly you know vascular endothelial dysfunction in a patient with hypoxia related vasoconstriction you could see where you've set up a perfect storm for micro thrombi in the pulmonary vascular bed we're seeing this on echocardiograms that are being obtained in these corona patients and as well as on the portable what do we call it pokus what do we call that oh I know what it's called point of care ultrasound where in fact some of the pre-terminal events for these patients really are when the right ventricle begins to fail which is often associated with marked elevation of the RV systolic pressures. All right thank you Dr. Coulter. So Dr. Crazier what have we learned from the early reports on COVID-19 effects on thrombosis and thrombotic risk? Well we have learned a lot in the last few months as far as thrombosis is concerned not only as far as the incidence is concerned but also different sites and causes and treatment what works what doesn't work. As Dr. Coulter has mentioned pulmonary thrombotic complications occur relatively frequently particularly in patients that have respiratory manifestations as a primary feature of this particular disease. There is obviously increased risk of clotting related to many different things that we have already discussed but for instance like patients that are on CVV HD they have high incidence of clotting patients that have indwelling caters they frequently have clotting caters and exercise for that particular reason. We have also learned that in early experiences VT prophylaxis was not routinely used because we didn't realize the importance of this particular treatment and we also learned in early experiences that VTE occurred in spite of a prophylaxis and that kind of alerted us that maybe we were not addressing it properly and maybe we were not using adequate treatment modalities and doses of those drugs and since then we have certainly learned quite a bit and adjusted the use of endosis of anticoagulants and noticed some improvements. What we have also learned that there is a relatively low incidence of bleeding which indicates that we maybe should be more aggressively treating patients with COVID because we can avoid major complications such as bleeding. On the right hand side you can actually see that over a period of time as far as infection is concerned this pro thrombotic effect goes up progressively which is understandable because as the virus continues to circulate it affects more and more endothelium and causes more and more pro thrombotic type of occurrences and it can be somewhere in the range of 33 to 35 percent of all the hospitalized patients with COVID conditions. Well clearly that incidence Dr. Crazier exceeds what we know about the incidence of hypercoagulable states that are genetic or predestined in this in this clinical syndrome so certainly you know we might think there's a background of risk that may be six percent of the population but certainly 33 percent is an exorbitant risk of pro thrombotic complications that seems to plateau you know on that on that slide that you presented suggesting that the virus itself which goes along with viral infections in the past where certain viruses could induce a hemorrhagic um milieu and in other viruses obviously we're seeing a pro thrombotic complication right all right Dr. Coulter so tell us about critical illness and VTE risk with VT prophylaxis versus no VT prophylaxis thank you Brianna we can see here on this slide that in those that have no VTE prophylaxis the risk of developing venous or thrombosis event ranges from 13 to 31 percent but in those that are on some sort of VTE prophylaxis the incidence is reduced to between five and 24 percent but in those with COVID-19 if they're not on prophylaxis you can see that the risk is about 25 percent or greater and on those with prophylaxis um and this is just prophylaxis doses the rates are not that much reduced suggesting that whatever the occurrence in the cell or the endothelial cell we're going to have to overcome a serious resistance um within the system and develop a better technique to prevent thrombosis yeah and this probably you know helped um you know develop as we're going to talk about um soon the guidelines because I'm sure that most of these patients if they were critically in the ICU as per a normal ICU you know protocols were on prophylaxis um but this was a stark and shocking um you know event when many of these patients still developed thrombosis so it's very you know interesting and unique to the coronavirus uh 19 COVID-19 um so I mean it in this Brianna this slide clearly shows that even with the background of like intravenous heparin the rates of thrombosis are still quite high and certainly there's some benefit to full dose therapeutic heparin but certainly it doesn't completely squash the risk in these high-risk patients and it's so interesting you know as the biomarkers go up you know the de dimer goes up um it's almost linear how much the mortality increases in those heparin non-users now for you guys I want to hear um as an attending how has coronavirus 19 affected the way you care for your patients in your practice in the office well Brianna thank you very much for asking us this very very important question and of course we're still learning and the criteria are still evolving but uh the international society of thrombosis uh has established guidelines and this has been published recently in the american journal of cardiology uh 2020 and uh I personally follow those guidelines what is very important and is pertinent as far as all the information we have just discussed first you talk to the patient if the patient has any history of a hypercoagulable state such as a genetic or a quiet hypercoagulable state you have to address the patient differently and those patients have only mild or minimal symptoms also the approach and treatment is different if the patient has a serious condition and has to be hospitalized versus patient that can be managed on outpatient basis but the ISTH guidelines as far as VT prophylaxis and monitoring concern uses the following criteria at a time of presentation of course you should obtain routinely PT APTT D dimer uh fibrinogen levels uh platelet count CRP ferritin of course CBC with differential CMP those would be routinely obtained uh when you see the patient regardless of the patient's condition and severity of the disease now once you have elevated fibrinogen and particularly if you have significantly elevated D dimer more than thousand this would indicate worse outcomes uh and very poor prognosis and this particular patient would require admission and very close observation and then the question is what is the testing frequency how often should you repeat those tests to make sure the patient condition is not deteriorating it depends on the severity of disease first we start on daily basis for hospitalized patients and if we see that any of the parameters are rapidly deteriorating particularly as far as D dimer level or fibrinogen level then we do it almost on daily basis but if the condition is relatively stable or the patient is being evaluated and treated on our patient basis we might do it once or twice a week very good doctor culture what do you think about the thrombosis prophylaxis and treatment recommendations i think they have finally come out with some thoughts on this so for patients that have COVID-19 or that are admitted with COVID-19 the recommendations now are that all hospitalized patients should receive some pharmacologic prophylaxis according to risk stratification so we look at the creatinine clearance and um note that if the creatinine clearance is greater than 30 mils per minute then we recommend um weight adjusted low molecular weight heparin at full dose and if the creatinine clearance is less than 30 then we do weight adjusted and renally adjusted um unfractionated heparin um to better able to watch the creatinine clearance we recommend monitoring of the PT the D dimer the fibrinogen the platelet count the LDH the creatinine and obviously the liver function tests over time but in patients that have elevation of the D dimer with multi organ failure we're recommending full dose low molecular weight heparin or unfractionated heparin yeah i agree stefan with all of your comments and suggestions as far as treatment is concerned the most frustrating scenario occurs when you have a multi organ failure and when you have a patient with renal functional impairment which typically seen in very advanced covid cases and also liver failure as well and some of those might also have problems with risk of bleeding gastritis and and so on and then it becomes really really complicated scenario how to treat it and what it what is the best option as far as treatment is concerned from the literature there is in general consensus that thrombolytics probably should not be used in this type of a scenario because of the high risk of bleeding because of all the organ so that are affected with this particular condition so dr crazier what are our current unanswered questions on covid 19 and that's a tough question for you because i'm pretty sure there's a lot of questions we still have unanswered it's a tough question for all of us definitely as a matter of fact we have learned so much in the last few months as far as covid pandemic and all the problems that are this particular infection is causing and i think that there are a lot of unanswered unanswered questions that we are struggling with one of the particularly frustrating one is for how long are patients with covid 19 infection pro thrombotic of course we can get certain ideas by doing those tests on a regular basis but there is unknown factor particularly in those scenarios where we see a patient has mild symptoms and then it gets better and then in a week or two gets significantly worse symptoms and develops one of the features such as myocardial infarction or cva or thromboflavitis or pulmonary emboli so those are challenging scenarios and we still don't understand why this happens and why those patients have recurrence of symptoms and rapid deterioration another scenario is what treatment offers the best outcomes not only related to treatment with anticoagulants but with any other drugs that are currently being used we're still experimenting with a lot of drugs there might be 20 or 30 clinical trials ongoing and we still don't have all of the answers and some of the drugs that are currently being used that show promises to a certain degree we have an issue as far as availability is concerned because we are not they're not being produced in adequate numbers to be able to treat huge populations of patients with these conditions also another question is for how long should we use anticoagulant therapy typically when we have either thromboflavitis we'll do it for a relatively short period of time if there is no evidence of propagation or pulmonary emboli but we don't know what is the optimal time to use this type of treatment in patients with the COVID-19 another issue is what is the effectiveness of unfraction in it happening in acute inflammation and many other scenarios particularly like hit how often does it occur in patients that are on unfraction and it happening in this type of scenario are they more prone to hit because not infrequently in patients with serious COVID infection we will get a DIC and we are not always able to differentiate is it partially related to hit or it's not related to hit and also there are other questions what is the most effective therapy when the patient is discharged and for how long should we treat the patient with this particular therapy and what is certainly not known well what is the role of DOAC post discharge I personally treat patients after discharge with DOAC but I am not sure if they're as effective as other anticoagulants like anti-vitamin K type of anticoagulants for patients with COVID particularly if they still have active condition and another question is also what are the long-term sequelae in these patients and we have seen now scenarios where patients recover physically to a great degree but they have some of the CNS symptoms and even some cognitive deterioration of their function and we don't know whether this is related to microambuli or to some other effects of COVID-19 on the CNS I don't know Stephanie if you have some other comments or suggestions or Brianna that you might think that is also troublesome or unanswered at the present time related to COVID-19 well for sure for patients that have known clotting with DVT or PE we still have to follow the guidelines for long-term anti-coagulation which should give them plenty of time to recover and gives us some background mitigation of risk and we should see what that what those patients look like over time I'm worried honestly for those that are hospitalized for quite a long time and have recurrent events as we see that these people really should be discharged with really therapeutic doses of anti-coagulants I'm a little bit more as an echocardiographer in the use of vitamin K antagonists particularly for the reduction in thrombus burden and I think the efficacy of these vitamin K dependent or warfarin type agents are preferable to the DOAX but I know that may be a little bit more controversial there was an article actually recently looking at clot breakdown in apical thrombi in patients with you know cardiomyopathy and showed that vitamin K dependent inhibition was superior to DOAX in that situation so yeah I agree with you on that comment and particularly in patients that have a genetic hypercoagulant state I'm not sure the DOAX are as effective me too especially since we don't know what the underlying etiology and because you know lupus anticoagulant has been associated with this virus certainly we know that in patients with lupus anticoagulant warfarin is the preferred agent so I think I would be more conservative in use the coagulant the anticoagulant that hits the coagulation cascade at multiple points and not just the targeted sharpshooter at the end of the coagulation cascade targeting thrombin Brianna what do you think you've seen some of these cases yeah so I guess my one of my biggest questions is where when are we going to start seeing all the patients who had their end stemmy or their stemmy's at home because we've certainly seen a downtrend a downtick massively in the ACS cases especially the stemmy and I know there are reports of this happening in major centers across the country in the world so I'm wondering if you know we went back to using TPA are we going to go back to seeing some VSDs or some you know freewall ruptures in these patients that we've not taken to the lab or that have had their MIs at home and then you know furthermore is in the lung in the pulmonary side of things these patients who recover from COVID who had pulmonary symptoms what is this going to mean on you know pulmonary hip for a cardiologist perspective on pulmonary hypertension after they recover so I think we just have a lot more learning as much as we've done but there's going to be a lot more for us to see when this starts to get better the pandemic so it's going to be a lot of learning for all of us all of our you know specialists and internists well Dr. Coulter and Dr. Costello I think this has been an excellent presentation and discussion and I think our conclusion as far as COVID-19 and robotic events are concerned is think about hypercoagulable states in patients with COVID-19 they are very common they could be either caused by acquired conditions which is very common in those patients particularly if they're bedridden and they have inflammatory process and other organ involvement but also think about genetic factors that play a role look for them and address the problem early and effectively if there are no any other questions or comments we greatly appreciate your participation in this program and thank you very much and we'll reconvene very soon another COVID-19 program at Texas Heart Institute thank you very much thank you Dr. Frazier and Dr. Coulter for having me