Activity Transcript

Florian Lordick, MD, PhD: Welcome to the Medscape program, “Thrombosis, Inflammation, and COVID-19: From Evidence to Practice.” I welcome today our 3 experts who will discuss the topic with me: Dr Anna Falanga -- she's a professor in Bergamo, Italy; Dr James O'Donnell -- he's a professor at the St James's Hospital in Dublin, Ireland; and Dr David Smadja -- he's based in the University Descartes in Paris in the Georges Pompidou Hospital in France.

I am Florian Lordick. I am a medical oncologist based in the University of Leipzig in Germany. This session will be about the COVID-19 pandemic, also known as the coronavirus pandemic, an ongoing global pandemic, which leads to severe acute respiratory syndrome.

As we know, this is not only a disease of the lung. This is an inflammatory systemic disease that also involves the vasculature, which may lead to hypercoagulability. Therefore, thrombosis is an important topic that we need to discuss today.

The outbreak of this pandemic was identified in December 2019 in Wuhan, in China. The World Health Organization declared the outbreak a public health emergency of international concern on 30 January 2020, and a pandemic on 11 March 2020.

As of 15 September 2020, more than 29 million cases of COVID-19 have been reported in more than 188 countries and territories, resulting in more than 925,000 deaths.

Unfortunately, meanwhile, we are seeing a second wave, especially in the European countries, while in the Americas we still speak about a first wave.

As an example, in Spain, we saw a decrease in cases by the end of April, and there was a relatively controlled period until mid-July, and now cases are taking up. The same is observed in many other countries, for instance, in France.

We had hope, and still have hope, that the morbidity and mortality of the patients is not increasing that much. But we need to see, when older patients are affected again, we need to see if the morbidity and mortality will increase.

Meanwhile, we know that vascular events are part of the morbidity and mortality that we see. Therefore, it will be important to discuss how do we treat hypercoagulability, and how do we treat or prevent thrombosis and arterial thrombotic events.

I give the word first to Dr Falanga, who has so much experience, from Bergamo. Maybe you can report to us a bit about your experience. How did these patients occur in your clinical practice, what were their clinical presentations, typical clinical course, and risk factors?

Anna Falanga, MD: Thank you. I think we were just overwhelmed by a sort of tsunami, because, in Bergamo, everything started very early compared to other countries and regions. The majority of people that arrived at that time, since we did not have much knowledge about the disease and the course of the disease, were in terrible condition.

However, we must say that, in general, this viral infection can have a different presentation, and, fortunately, the majority of cases exhibit mild to moderate symptoms. Only 15% overall progress to severe interstitial pneumonia, and eventually 5% have the really bad disease, the very, very severe disease. There are different degrees or presentations.

Hopefully, now, things will be managed much better than it was in the months of February and March, because now, the situation is completely different. There are many asymptomatic patients or patients with mild disease. The severe disease starts with after a median incubation of five days, and then goes to a more severe - but not requiring hospitalization - situation in the first week or so. Then it can become, in a minor proportion of patients, very, very severe with acute respiratory distress syndrome and the need for oxygen support.

Also, I would like to anticipate here that there are some predictors of mortality that have been identified in several studies, including the age of the patients, the presence of chronic comorbidities, and so on;, also the male gender can be associated with [increased mortality].

Dr Lordick: It's very interesting, your experience. You said that now you see less severely ill patients. Do you think this is due to a different population that is affected, maybe younger people, or do you have the impression that the character of the disease has changed?

Dr Falanga: I think that several things have changed. First is what you say is that the younger population that is affected, just because in the recent months, the social distance was less restricted than it was in the beginning of the pandemic. The young people are starting to get very much together and there is the diffusion of the infection.

Because there is an important tracking system now, we can also detect that infection very soon and also track many asymptomatic patients and their contact. Everything starts earlier. Also where we have patients, because we have patients in hospital now, but the situation is not so dramatic as it was in the beginning. Although there are some patients that are in ICU and in severe condition because this is the situation.

The majority are kept beforehand, so for us in the hospital, it's a much more handling, but not because the virus is changed. It's just the overall management has improved.

Dr Lordick: I think in all our countries, we did a lot also to protect cancer patients, because many studies from China, but later also from Europe and North America, showed that having cancer is a risk factor for a severe course. Especially when it comes to hematological cancers, these patients are high-risk. Also, lung cancer is associated with adverse outcomes.

Also, the disease stage is of importance. We have seen that patients in metastatic stages are at much higher risk to go to the ICU, or to have a severe course, or even to die from the disease than patients with a localized cancer. Also, one has to say that the postoperative period for major visceral surgery, for instance, is also really a very risky period.

In some areas, in some regions, cancer operations were even stopped. Maybe we will exchange our experience. It was not really necessary in my country, but in other countries, hospitals decided that because it was feared that the resources for ICU are not enough, and also, if a patient in the postoperative period acquires a COVID infection, he's at high risk.

I think there is still some uncertainty about treatment. We have seen associations between chemotherapy and a higher risk of getting a severe course of the COVID infection. And it is much less clear for other treatments, like molecularly-targeted treatments or immunostimulants like immune checkpoint inhibitors. I think this is still an open field...if they are protective, if in certain phases of the disease they might even aggravate things. Maybe also something that we will discuss later, if this interferes with the management of these patients.

Maybe I ask now David Smadja, who has a lot of experience in hematology, from Paris, which was and still is also a hotspot of infections. How did these patients present in your department? What are the factors we could look at to foresee if this is a severe course that we need to expect, or if it's less severe? Maybe you share your experience and knowledge with us.

David Smadja, MD, PhD: Yes, thank you. Definitely this COVID-19 for us really now can be defined like a vascular disorder and more than a vascular disorder, we have a very strong abnormalities in hemostasis. These hemostasis abnormalities are really frequent. In the hospital, as Dr Falanga told, we had some severe form, some people who were in the ICU, but even if most of the people are moderate form.

In hospital, we had the more important cases, and we had, at entrance in to the hospital, patients with high level of immunogen, high level of D-dimers, with no clear to significant modification of the classic PT ratio and aPTT. Clearly, we didn't have any DIC in contrast to what probably we thought at the beginning of the disease. We just had this huge increase of D-dimers.

The big point, in terms of biomarker, is to understand if we can have interpretation of the D-dimers level. The first step was to try to understand if D-dimers can help to decide if it's a COVID-19 patient or not a COVID-19 patient.

Clearly, at the start of the outbreak, at a period where we did not have PCR very quickly or it was the starting of the outbreak, we tried to have D-dimers in terms of diagnosis. When we check, I don't have a number at all, there is a lot of men with COVID-19 is the risk factor, and when we combined D-dimers with the sex enzyme of thrombopathy, we clearly can't have a screening of patient better. D-dimers below 500 mg/mL, combined with a woman and no sign of thrombopathy, clearly we can exclude COVID-19 with a very high sensitivity.

D-dimers can be very important for ICU orientation. When a patient arrives in the emergency department, clearly we observe that with a high level of D-dimers, we have a very huge percentage of patients that go directly in to the ICU or in the ICU in the first days of hospitalization.

This D-dimers level for us was really correlated to a microvascular thrombotic process inside the lung, but probably inside other tissue like the kidneys. We try to check if the D-dimers was the best biomarker usable in clinical practice to orientate people in the ICU.

D-dimers were great, but probably the best markers than D-dimers are the troponin level at entrance. If you check the troponin level, we can have a very high sensitivity and specificity to address the patient in the ICU.

The interpretation of this combined D-dimers and troponin level is clearly, for us, a microvascular thrombosis disorder inside the lung that induces right ventricular dysfunction and we had some result in terms of analysis of cardiac function. This right heart ventricular defect makes this increase of troponin. Clearly a combination of D-dimers and troponin, for us, is a good sign to see if the patient needs to go in to the ICU directly or not.

Finally, D-dimers are clearly linked to high mortality process. There is a lot of studies now that concern these data. Clearly, if you have a patient that enters into emergency department with high level of D-dimers, clearly you need to expect that the patient is in a bad condition. We confirmed this in a multicentric study analysis in the whole country, and, clearly, we find that D-dimers over 1000 mg/mL is clearly linked to a high level of mortality in the hospital.

Clearly, what I would say for the basic clinical orientation marker, it's important to take these D-dimers at entrance. Probably we need to have this troponin evaluation, also, when a patient enters into the hospital. For these D-dimers and biological progression at admission, now things are quite clear.

What is not quite clear is what we can do with this biomarker during hospitalization. Clearly, we need to know, now, if D-dimers can be usable during ICU to probably increase dose of anticoagulation or not. For now, today, we do not have this research. We do not know if we can use D-dimers level to increase doses of anticoagulation.

Why is this so important I seem to use this anticoagulation? Probably because we all observe that we have a lot of thrombotic event in this COVID-19 patient. We have this microvascular thrombosis that I previously described, and now we know that we have also macrothrombosis and probably pulmonary embolism. And this pulmonary embolism clearly could be linked to inflammation, to male gender, and also probably time-to-symptom-onset at hospitalization.

This pulmonary embolism--and I don't know if I can say pulmonary embolism clearly because it's probably more local thrombotic process more than embolic disease--it's something we really need to figure out and it can be difficult with all the lung symptom to detect this pulmonary embolism. There are tons of studies now with pulmonary embolism. There is a high level in ICU. We also observe pulmonary embolism in patients hospitalized in classic ward. For pulmonary embolism, everything is quite clear.

For other venous thrombosis, clinical studies are quite different, and we really don't know if we have such a high level of venous thrombosis other than pulmonary embolism in COVID-19. There is also some description of arterial thrombotic process. In contrast with pulmonary embolism, it's also less clear what kind of arterial thrombotic event we can have with COVID-19.

Dr Lordick: Maybe we should go now even a bit deeper into the pathophysiology, and then I would love to hear now some comments from Dr O'Donnell, who is a vascular biology specialist and will give us certainly some insights in this field.

James S. O'Donnell, MB, PhD, FRCPI, FRCPath: Well, thank you, Florian. As everyone listening to this will be aware, cancer is associated with an increased risk of venous thrombosis. This venous thrombosis in cancer patients results in significant morbidity and mortality.

From meta-analysis, we know that the risk of thrombosis has increased somewhere between 5- and 7-fold in cancer patients compared to controls. Something like 20% of all cancer patients will develop clinical VTE during their journey. If we look more closely, in fact, almost 50% of cancer patients will have evidence of asymptomatic DVT and almost all cancer patients will have evidence of coagulation activation.

We also know that specific types of cancer are associated with an increased risk of thrombosis, for example, pancreatic, gastric cancer; and that patients with metastatic disease have been higher risk than patients who have got localized disease only. Of course, we also know that different types of cancer therapy further increased the risk of thrombosis, particularly chemotherapy, with some drugs such as doxorubicin or cisplatin have been particularly associated.

When it comes to understanding the pathogenesis of cancer-associated thrombosis, there's very good evidence that cancer and cancer therapies impact on all aspects of Virchow's triad. That's to say stasis of blood flow, damage to blood vessel wall, and hypercoagulability of the plasma.

Over the last 10 or 15 years, we've gained significant insights into the biological mechanisms underpinning those associations. For example, one important mechanism is that many tumor cells actually express tissue factor on their cell surface, and this tissue factor glycoprotein is able to initiate the coagulation cascade.

There are a whole bunch of different ways through which tumor cells can directly activate coagulation in vivo. They can activate platelets, they can impact upon endothelial cell biology, and they can inhabit fibrinolysis.

Importantly, in addition to those direct effects of tumor cells initiating a procoagulant effect, we know that tumor cells are also associated with a proinflammatory state. So that there's expression of a bunch of proinflammatory cytokines and chemokines, and these mediators can further increase the risk of coagulation by activating monocytes, by activating platelets, and again, by having effects on endothelial cells.

In essence, we know that cancer can increase risk of coagulation, activation, and risk of venous thrombosis, and that the proinflammatory state associated with cancer is important in modulating that interaction.

If we go back to COVID-19, what is striking, and as David has already pointed out, is that, of course, in COVID-19 or severe COVID-19, we also see this conjunction of a proinflammatory state and a procoagulant state, both of which appear to be present at a relatively early stage during severe COVID-19 pathogenesis.

Going back to Virchow's triad, not only does cancer impact upon all 3 aspects of the triad, but so also does severe COVID-19. There are a whole multiplicity of mechanisms through which COVID-19 can affect the balance between procoagulant and anticoagulant pathways in vivo. I don't plan to talk through all of these, but you can see them on the associated slide.

However, what is clear from the data that we already have, and as David has mentioned already, is that COVID-19 seems to have a particular effect on endothelial cells. That's maybe because the ACE-2 receptor that COVID-19 uses to access cells is actually expressed directly on endothelial cells.

In autopsy studies, we are seeing severe endothelial cell injury, swelling, apoptosis, and death. Endothelial cell activation directly or indirectly, because of severe hypoxia and complement activation, as well as the cytokine storm, is undoubtedly at the heart of the pathogenesis of the COVID coagulopathy.

We are seeing DVT and pulmonary embolism commonly in these patients, particularly in the patients who are admitted to intensive care. Undoubtedly, development of pulmonary embolism explains some of the sudden deteriorations that we're observing in these patients.

I think what is really important is the postmortem studies have shown evidence of disseminated microthrombi through the lungs of these patients, so not only are we seeing macrovascular thrombosis, DVT, and pulmonary embolism, which we would expect to see in patients who have severe sepsis, but we're also seeing this novel pulmonary intravascular coagulopathy, so a PIC, if you like, rather than a DIC.

In simplistic terms, what we think is happening is that the alveolar is becoming filled up with an inflammatory infiltrate and an exudate, as well as cell debris, which is impacting upon ventilation. But at the same time, the microvasculature of the lungs is being occluded by the formation of these microvascular clots. Not only are we getting a ventilation problem, we're also getting a profusion problem, and so the patients are getting markedly hypoxic because we have a double whammy effect.

Dr Lordick: I see. You mentioned already the role of low-molecular-weight heparin. This is certainly something we need to discuss now in a bit more detail and depth and also from a clinical practice viewpoint.

Maybe Dr Falanga, you start first and give us some insights, in which patients in the ambulatory setting, but also in the inpatient setting, you would recommend to give low-molecular-weight heparin, if you give prophylactic dose or even higher doses in some settings, and if this interferes also with cancer, which can be an additional risk factor, as Dr O'Donnell just alluded to us?

Dr Falanga: As we said before, there are different steps in the development of this infectious disease from a clinical point of view. But I think that from mild to severe symptoms, prophylactic dose low-molecular-weight heparin, or in other cases also fractionated heparin, needs to be started in all patients.

This is something that the majority of guidance, guidelines from institutions or from scientific societies, agree on. I think that all of them agree that a prophylactic dose has to be started in all patients, even those who are not in a severe condition.

The point is that for the critically ill patients who are hospitalized or who are in the ICU, the scenario was a bit different because they started to have complications. For the thromboprophylaxis in these patients, the approach was very valuable. Particularly, the anesthesiologist started with higher doses of anticoagulant thromboprophylaxis.

This is still under discussion. Probably it can be useful or not, but I think this is something that must be proved by means of clinical trials, because there is no supported evidence for that. Also, it is very important to consider that every anticoagulant drug brings also the possibility of bleeding complication. A very accurate evaluation of the risk of thrombosis, but also of bleeding, must be performed in the individual patient.

This is particularly true also for the patients with cancer who also have an increased risk of bleeding together with an increased risk of thrombosis. I think that the approach now for thromboprophylaxis, in general, is that the majority of guidance settled on giving that information and the recommendation with low or the classical doses given for prophylaxis for prevention, not for treatment. Whereas the treatment dose of low-molecular-weight heparin, or fractionated heparin, or other approaches must be considered when there is a clear evidence of thrombosis or a strong suspicion of it.

If it is not possible to perform adequate testing for the diagnosis of pulmonary embolism or thrombosis, it is reasonable to start with a therapeutic dose if the clinical suspicion is very high. This is also something that is widely accepted in the available guidance.

Dr Lordick: It was very clear, Dr Falanga, what you told us. I have the specific question because we are talking today about cancer and COVID and thrombosis, and we also have some uncertainty for outpatients diagnosed with cancer, with cancers like pancreas, stomach, lung cancer, who have a Khorana score maybe of 2 or more. There is a question of anticoagulation in the outpatient setting.

Do you think, James or David, that we should be more generous in prescribing prophylactic anticoagulation in these times when patients might be at risk to get COVID, or if there is an infection in a cancer patient who still is an outpatient, should we be more generous to prescribe LMWH?

Dr Falanga: I agree on considering the thromboprophylaxis with standard doses or the classical doses more widely in this situation, particularly because in some situation like the epidemics in general or the situation where people are staying more at home, are not immobilized but less active, and they may have some fever or other complication and have cancer or other active treatment, I think in those cases one must consider thromboprophylaxis.

Dr Lordick: David, would you concur with the statement? Because I think that's very important from a clinical management viewpoint. What is your comment to that, David Smadja?

Dr Smadja: I think I have the same feeling as Prof Falanga. I think probably we could have a more wide use of low-molecular-weight heparin. Unfortunately, it's just a clinical feeling, but we need to have a clinical study. I think we have the same question now for outpatient, but also for inpatient because we have some study, some retrospective study, about anticoagulation. We all have the feeling, and we have some tiny result now, that probably prophylaxis decreases mortalities, that anticoagulation could be good in particular for patients in the ICU, but we don't have a clear randomized study.

I think widely, everybody agrees that we need to have anticoagulation in this patient, but what would be the regimen? What kind of patient do we need to anticoagulate? There is now some clinical trial ongoing. I hope that we have soon very strong result of randomized study, but we need to do it correctly because if we don't do it correctly now, we will have forever this feeling that we need to anticoagulate, but we don't know the regimen. Clearly, we need clear clinical study. And I have exactly the same feeling, probably we need to use low-molecular-weight heparin. But it's not evidence-based medicine. It's just a feeling.

Dr Lordick: When we are talking about anticoagulation with heparins, is there any role in this setting at the time being for direct oral anticoagulants or DOAC?

Dr Falanga: I think there can be room for DOACs because we have clinical trials and also different guidelines that have started to give the recommendation for those drugs, which have the specific randomized trial available.

The problem is if we are talking about COVID and cancer, the situation can be different, because in this situation, we need also to consider the interference of drugs, because there are many drugs that are used for COVID-19 that interfere with DOACs.

Our policy, for instance, was to switch from, if we had the patients already on oral anticoagulant therapy, we switch to low-molecular-weight heparin in the hospital because we didn't want to have a problem with the antiviral drugs. This was our policy.

Dr Lordick: Thank you very much. We all see this is a very dynamic field and we are learning from week to week and from month to month. I will try to summarize our nice discussion from a best clinical practice viewpoint.

It is clear, and all of you have made clear, that we have here an overlapping problem. We have cancer as a risk factor for thrombosis and for vascular events. We also have the situation of COVID-19, which is an inflammatory disease which can become a vasculopathy, which can become a coagulopathy. We certainly need to put these things together, but evidence is still very limited.

In an outpatient setting, we came to the conclusion, which is not fully evidence-based, that the risk for cancer patient if he or she acquires COVID-19 is probably higher to acquire thrombosis. It is already high in some diseases, like stomach cancer, pancreas cancer, lung cancer, but we have a certain agreement that we should really be aware and that probably we should consider prophylactic anticoagulation with standard doses in those patients who become symptomatic, who have to stay at home, lie in bed, that we should consider to be prescribe low-molecular-weight heparins in routine doses.

Then when it comes to hospitalization, all of you, and also the guidelines, seem very clear to me, as soon as the patient enters the hospital and has symptoms, which are mild to severe, anticoagulation in a prophylactic standard dose is absolutely needed. If more is needed, higher doses, additional treatments, etc, is a matter of clinical studies.

The risk evaluation is very important. We heard that a good clinical assessment, together with D-dimers, troponin, and maybe some other factors which still need to be defined are an important tool to estimate the prognosis of these patients, high-risk patients for becoming critically ill for undergoing an even more vasculopathy.

We also need to be generous in augmenting the dose even if there is no proof of pulmonary embolism or thrombosis. If there is high clinical suspicion of that, we should go to full doses of low-molecular-weight heparin.

Thank you very much for the faculty. It was very interesting discussing with you. Thank you also very much to the audience. Please fill in the questions. It was a great pleasure for all of us to be with you in this Medscape program.

This is a verbatim transcript and has not been copyedited.

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