Decoding the VTE enigma: Learnings from COVID 19: Episode 1

This edition of the podcast will focus upon:

• Incidence and pathophysiology of COVID-19 associated coagulopathy

• Thromboprophylaxis protocol for VTE in COVID-19 patients

• Recommendation on dosing for VTE thromboprophylaxis in hospitalized patients with COVID-19

Time stamp



00:07 - 00:25

Male Speaker

Welcome to VTE Unplugged, a brand new podcast series curated by Sanofi. The aim of VTE Unplugged is to bring latest in the field of Venous Thromboembolism management delivered by renowned experts in this field. Today, let's listen to Professor Roopen Arya in conversation with Dr. Abhay Bhave.

00:30 - 01:25

Dr. Abhay Bhave

Hello, friends. I am Dr. Abhay Bhave. I am a hematologist practicing in Mumbai. It is my absolute pleasure to welcome you for a series of podcast sessions, which we have titled as VTE Unplugged. VTE Unplugged is an educational initiative by Sanofi, which will bring together experts in the field of Venous thromboembolism to talk on several interesting and at times, controversial aspects, but which will make a difference to us in the day-to-day management of our patients. Today I am delighted to have Professor Rupan Arya with us who is the professor of thrombosis and hemostasis at the King's College Hospital in London. He is the Director of King's Thrombosis Center and Clinical Lead for VTE Exemplar Centers Network as on the NICE guidelines for thrombosis. So welcome Professor Roopen Arya.

01:27 - 01:35

Prof. Roopen Arya

Thanks, Dr. Bhave. It's a pleasure to be with you all today, and I look forward to interesting discussions. Thank you.

01:36 - 02:24

Dr. Abhay Bhave

Thank you, Dr. Arya. Thank you. Let's start with the question on the pathophysiology and the associated coagulopathy. So the current wave of COVID has been rather scary, in fact, disastrous in a way, and the number of cases are soaring, especially in our country. So for us it's a difficult situation to be in. And we are losing many of these patients to COVID, with one of the main causes being Venous thromboembolism. And that has led to a significant morbidity and even mortality. So our audience would like to hear from you that what's the incidence of COVID-associated coagulopathy? And what is the current understanding on this pathophysiology of this COVID-associated coagulopathy?

02:26 - 06:43

Prof. Roopen Arya

Thanks, Dr. Bhave. Indeed, the effects of the SARS Coronavirus-2 on the clotting are remarkable. And we have seen an extraordinary burden of thrombosis related to COVID-19 disease. Up to half of the patients have changes in the blood clotting associated with the inflammation caused by the virus. Very typically, these can be a prolongation in the clotting times, both the VTT and the fulfillment time, often a moderate lowering of the platelets, and very high D-dimers, and an increase in the acute phase reactants, which have been shown to correlate with an increase in the inflammatory markers like CRP and IL-6. So it is a remarkable association with Coronavirus and with COVID-19, certainly more than we are accustomed to seeing with other viral infections. And there seems to be an increased risk of thrombosis in these patients, particularly in patients who are severely affected, and in hospitalized patients. In our experience, in our institution, about 5, 6% of patients with moderate and severe COVID had evidence of Venous thromboembolism. In critical care, about 16, 17% of our patients had evidence of pulmonary embolism despite the use of standard prophylaxis. And in our ward patients, it was mere about 4%. So what we are seeing is two or three times what we are accustomed to seeing either in medical patients on the ward with infection or in critical care patient with infection. And the thrombosis seems to be affecting both the large and the small vessels. About 80 to 85% of the thrombosis is venous. The rest is arterial, whether it's stroke or myocardial infarction or peripheral arterial disease. And we have also been seeing increased incidence of Lyme related clots, as well as block renal circuits in patients hospitalized with COVID. Now the pathophysiology of this thrombosis is very interesting. The activation of the host defense results in a marked inflammatory surge, which leads to a phenomenon called thromboinflammation or immunothrombosis, which is a combination of COVID-associated coagulopathy, as well as vascular damage. The polyphosphates in the virus activate the contact pathway. In addition, there's activation of the complement pathway, as well as the NETs or the Neutrophil extracellular traps along with a huge release of cytokines, all of which results in both an activation of the clotting, as well as endothelial damage. In addition, the ACE2 receptor, which is the receptor for viral adhesion both in the epithelial cells and the endothelial cells activates a process of endothelial damage, as well as microvascular thrombosis, which is widely seen in these patients, the growth in the lungs and the other organs. This is the multi-organ disorder, and in our findings and neurotoxins. So in summary of COVID-associated coagulopathy of SARS Coronavirus-2 infection, and it's associated with an extraordinary burden of thrombosis.

06:45 - 07:35

Dr. Abhay Bhave

Thank you, Prof. Arya. You have beautifully established the pathophysiology of VTE and the worrying data that's about two to three times higher incidence of venous thromboembolism in patients with COVID and associated coagulopathy. Now this is significantly high. And you've also told us that its association with morbidity is significant. So this will bring us to a very important question as to how to then prevent this clot from forming if a patient has COVID-19. So what's your current recommendation for prevention of VTE in COVID-19 patients? What's the thromboprophylaxis protocol?

07:36 - 10:32

Prof. Roopen Arya

Thanks, Dr. Bhave. I would completely agree that prevention of venous thromboembolism is a very, very important part of their care when they're admitted to hospital, and the guidance on VTE prophylaxis mainly pertains to patients severe enough to be hospitalized and usually invariably on supplemental oxygen or advanced respiratory support. We can see this hospitalized population in two main groups of cohorts where the patients with COVID pneumonia who are being cared for on the wards with the supplemental oxygen, and then they have the patients severe enough to need a high flow oxygen and CPAP and then transfer to critical care where they are often on a ventilator. So I think what is beyond dispute is that all of these patients severe enough to be hospitalized due to COVID-19 disease are at a high thrombotic risk and should be considered as such. So I think, you know, in a departure from our usual practice where we need to work through the thrombotic risk factors and then the risk factors for bleeding, I think it's safe to assume that all of these patients have a high thrombotic risk. And then it is down to us to assess the bleeding risks, and if the bleeding risk is low, then to administer pharmacological thromboprophylaxis to all the hospitalized patients. And currently, low molecular weight heparin at the standard prophylactic dose is the mainstay of thromboprophylaxis. Now this is based on the fact that all the supporting evidence for the use of anticoagulants and thromboprophylaxis supports the efficacy and safety of low molecular weight heparin. Equally, it is well absorbed. It's got a short half-life. So it's convenient to use in patients. And also very importantly, because patients admitted to hospital with COVID-19 usually are on multiple drugs. I think it is the anticoagulant with the fewest drug-to-drug interactions. So my recommendation which is really according all the guidance is to use low molecular weight heparin at a standard prophylactic dose, usually adjusted, of course, for weight, as well as for renal function.

10:33 - 10:56

Dr. Abhay Bhave

Right. Thank you, Prof. Arya. It's now established that immunothrombosis occurs as a coagulopathy in COVID-19, and that its prevention can be done with the help of low molecular weight heparin. So that brings us to another question. Can you please share with our audience what would be the dose that you would recommend for this thromboprophylaxis for such patients?

10:57 - 16:44

Prof. Roopen Arya

Thank you, Dr. Bhave. I think my starting positional statement would be to use standard dose Venous thromboembolism prophylaxis adjusted as I said both for body weight, as well as renal function for all hospitalized patients with COVID-19 disease. But the early evidence from the first wave last year indicated that this one-size-fits-all approach was slightly inadequate for the most severely affected patients, particularly those on critical care who are having two or three times as much VTE as we are used to seeing in critical care patients. And as a result of this clinical observation, many centers have been using intermediate dose low molecular weight heparin in clinical practice. Now what this means, for example, if the standard dose of enoxaparin is 40 milligrams once a day? We have been using 40 milligrams twice a day in this patient cohort. There is quite a lot of discussion around the ideal approach to the dosing of the prophylaxis and the timing of the prophylaxis. And now there is more data available that helps to inform the discussion. There are multi-platform RCTs, REMAP-CAP, ACTIV, and ATTACC, the results of which have been released in the past three or four months. And the preprints have been published in recent weeks and days that suggested that there might be a benefit from therapeutic dose of low molecular weight heparin early on in the patient pathway in the moderately affected patients. Now the extent of the benefit is small, and it seems to be not on Venous thromboembolism as such, but on the number of organs support-free days. This study was just published earlier this week which showed a nearly 5% reduction in the organ support-free days outcome and some improvements in the survival to discharge. Now this information is fairly new, and it's under scrutiny. But it indicates a potential benefit from using larger doses early on in the patient remission, but there has been also published this week a study from the coalition action group which did not show the benefits from full dose anticoagulation using direct oral coagulants or low molecular weight heparin in moderately ill patients with COVID with high D-dimer. So I think we need to understand better what is the optimal approach in moderately affected patients with COVID. And my current recommendation would be to continue to use standard dose low molecular weight heparin in these patients. And then there's the other group of patients which are the patients on critical care in which the results from the multi-platform RCTs indicate that therapeutic low molecular weight heparin might cause harm in these patients and might also be related to more bleeding. And again, the conclusion from these studies question against the use of therapeutic dose anticoagulation in patients on critical care. So what is apparent to me is that the dose of the anticoagulant matters, the type of anticoagulant matters, the timing matters proportionate to both the degree of inflammation, as well as the bleeding risk in the course of the patient pathway. And I think the safest approach is to at the very least make sure that all the patients have this standard dose thromboprophylaxis. I don't think we have enough information at the moment to address the issue of intermediate dose low molecular weight heparin in the critically ill patients. There has been a recent publication from Iran which is the INSPIRATION study which looks at intermediate dose low-molecular-weight heparin versus standard dose low molecular weight heparin in critical care, and they fail to show a benefit from the use of intermediate dose low molecular weight heparin, though some people argue that this study is underpowered to answer that question, and indeed had much lower event rates for VTE than we are accustomed to seeing in the critical care population. I think in my perspective we await the results of the further RCTs like REMAP-CAP to inform us about the value of the use of intermediate dose low molecular weight heparin in critical care patients.

16:46 - 17:21

Dr. Abhay Bhave

Right. Thank you very much, Prof. Arya for that clarity. And it appears from your discussion that thromboprophylaxis in COVID-19 patients might be a moving target, and we may have to adjust the thromboprophylaxis as per the clinical situation of the patient where a moderately sick patient might need a weighty dose of the standard prophylaxis. But it's quite possible that the therapeutic dose may not be beneficial to all the patients, especially the severely affected ones, but the risk of bleeding might be more. So thank you for that clarity.

17:27 - 17:36

Male Speaker

Thank you for joining us today. Watch out this space as we bring to you second part of the ongoing discussion between Prof. Roopen Arya and Dr. Abhay Bhave.