May 1, 2020

expert reaction to study looking at COVID-19, ischaemic stroke and blood clots

A study, as published in the Journal of Neurology, Neurosurgery, and Psychiatry, reports on COVID-19, ischaemic stroke and blood clots.

Prof Paul Evans, Professor of Cardiovascular Science, University of Sheffield, said:

“Stroke has previously been reported in patients with COVID-19 and this paper provides detailed clinical characteristics of six such patients. Blood tests suggested that all 6 patients were more prone to form blood clots. The authors therefore suggest that patients with COVID-19 that are at risk of clotting may benefit from anti-coagulation drugs at an early stage, however further studies including clinical trials are required to assess this further. It should be noted that this study does not prove that COVID-19 is a cause of stroke, because patients had several risk factors for stroke that may be independent of viral infection including high blood pressure and abnormal heart rhythm. The study emphasises that more research is required to understand how SARS-CoV-2, the virus that causes COVID-19, alters the behaviour of arteries and the blood components that are involved in clotting.”

Prof Philip Bath, Stroke Association Professor of Stroke Medicine, Chair & Head Division of Clinical Neuroscience, NIHR Senior Investigator, University of Nottingham, said:

“Werring and colleagues report a small case series of 6 patients with ischaemic (blood clot) type stroke and COVID-19 infection.  Although the range of ages was broad most patients were male.  In 5 of the cases, COVID-19 preceded the stroke and this suggests the possibility of causality.  However, it is a relatively common finding that patients with acute stroke have had a recent infection (often related to the chest or urinary tract).  Infections in general will lead to bone marrow stimulation producing not just more white cells to fight the infection but also more-sticky platelets (cell fragments that cause clots to form in blood vessels).  Infections also lead to increased clotting and inflammation factors in the blood.  The combined presence of inflammation and clot formation, as seen in this case report, will typically lead to large strokes with poor outcomes.  So the relationship between the SARS-CoV-2 virus and subsequent stroke may be no different from that of any virus (or bacterium).

“The presence of increased clot formation is not a reason for anticoagulation, at least outside of clinical trials.  A majority of patients with an ischaemic stroke have a tendency to increased clot formation.  Much of this is related to increased platelet activity and we know from two very large clinical trials that anti-platelet drugs (such aspirin) are effective in preventing a further stroke and mildly reducing disability.  In contrast, anticoagulants have been widely studied in the same types of patients and found to have no overall benefit – any tendency to reduce further stroke is offset by increased bleeding, including into the brain.  So antiplatelet drugs should remain the mainstay of prevention treatment in acute stroke.

“It is interesting that stroke rates have reduced worldwide during the peak of the pandemic.  So the virus may have different effects in different people.  In a majority of potential stroke patients, the virus may reduce inflammation and clot-formation and so the stroke does not happen (or maybe is delayed).  In contrast, in a minority of patients, it may cause or at least worsens the developing stroke.”

Dr Richard Francis, Head of Research Awards at the Stroke Association said:

“This article reports that six adult stroke patients with coronavirus in London had signs of abnormal blood clotting.  This suggests that for some people, the coronavirus may increase the chance of blood clots forming, that can lead to stroke.  However, this is a small early study and the majority of patients also had conditions that are known to increase the risk of stroke including high blood pressure, atrial fibrillation (irregular heartbeat) and diabetes.  Therefore, it can’t tell us that the coronavirus caused stroke in these people.

“The researchers also suggest that medications that stop blood clots forming could be an interesting avenue for further investigation to test whether they could help some coronavirus patients avoid a stroke.  Larger studies would need to test if there is a benefit and who they would be suitable for.

“We welcome more research to understand any possible association between stroke and coronavirus.  Right now, it’s most important that if you, or someone you’re in contact with, whether that be at home, on the phone or video call, is showing signs of stroke you act FAST and call 999.”

Prof Edwin van Beek, SINAPSE Chair of Clinical Radiology, University of Edinburgh, said:

Is this a large study or early findings?

“This is a small study, but fits with observations in other locations.  The absolute number of these types of complications are small, but they have significant impact and given their urgency, are important.

Does it show COVID-19 caused ischaemic stroke or is it an association?

“We think that COVID-19 causes a generalised thrombo-inflammatory process in many hospitalised patients.  This can be determined by monitoring a blood test (D-dimer), which has proven of prognostic significance in large studies from China.  More recently, people have started to assess patients with raised D-dimer levels more closely, and it turns out that up to half of those hospitalised suffer from thromboembolism and about 1 in 10 of these are cerebral strokes.  We have seen a few cases like this in Edinburgh as well.

Are there confounding factors?

“This is likely a systemic response, whereby the blood shows abnormal clotting in response to the virus.  The mechanisms are more clearly explained in this article: https://press.rsna.org/timssnet/media/pressreleases/14_pr_target.cfm?ID=2173

Is this study alone enough to suggest the use of anticoagulant drugs in hospitalised COVID-19 patients or is it too early?

“There is much to say for earlier use of anticoagulant drugs in those hospitalised with COVID-19.  This is due to the high level of abnormal blood clotting in the system, in combination with “normal” risk factors such as immobilisation in patients on respirators.  This study shows an algorithm based on the level of D-dimer as a potential way forward: https://pubs.rsna.org/doi/10.1148/radiol.2020201629  There is no role for anticoagulants at home in the context of COVID-19.

Do we know from other evidence whether we’ve seen an increase in strokes during the epidemic?

“Yes, a recent report in the Netherlands showed 3% strokes in hospitalised COVID-19 patients and a case series from New York was published in the New England Journal of Medicine this week as well.  There is further anecdotal evidence that strokes occur more frequently in COVID-19 patients compared to the normal population or to other viral infections.

“This article describes a potential mechanism for thrombo-inflammation, and was produced by a multidisciplinary team of experts for the Dutch Department of Public Health: https://pubs.rsna.org/doi/10.1148/radiol.2020201629  The impact of D-dimer testing, in combination with advice on anticoagulant prophylaxis, additional imaging requirements and potential upscaling of anticoagulant therapy are described.

“The manuscript/report has led to changes in management of intensive care patients in the Netherlands, where patients have responded well.  Additional reports have shown that thrombosis in the lungs as well as in periphery are much more common (reports from Italy, France, the Netherlands and also from New York City recently), and this includes pulmonary embolism and stroke in up to 50% of patients in intensive care. Thus, the UCL report is in line with the reports coming in from elsewhere.  Although this is a worrying development, it should be pointed out that the absolute numbers of stroke remains small.  However, I recognise the significant impact on resources and the patient as many will suffer long-term consequences from these complications.”

Prof Robert Storey, Professor of Cardiology, Department of Infection, Immunity & Cardiovascular Disease, University of Sheffield, said:

“Some small studies as well as observations by clinical teams suggest that COVID-19 might increase the risk of strokes and heart attacks.  This is not surprising because the coronavirus infection can cause a lot of inflammation in the body in some people and it is well recognised that inflammation is linked to increased risk of blood clots forming in blood vessels, which is the most common cause of heart attacks and strokes.  Inflammation can also accelerate the build-up of fatty deposits in blood vessels supplying the heart and brain, which can eventually lead to blood clot forming and blocking the blood vessels.

“It is usual to give regular small doses of injected anti-clotting medication to people who are hospitalised with serious medical conditions in order to prevent blood clots forming in the leg veins but it is too early to say whether anti-clotting medications should be used either more widely or in higher doses in people with COVID-19 – this needs more clinical trials to look at the benefits and risks of this type of medication.

“However, it emphasises the importance of people continuing medications that they have been prescribed for reducing the risk of heart attack or stroke.  Most importantly, it highlights the importance of people calling for help without delay, via 999 if appropriate, if they have symptoms suggestive of stroke or heart attack – stroke and heart doctors are ready and waiting to provide effective treatment for these conditions and don’t want people to leave it too late to call for help.”

Prof Tim Chico, Professor of Cardiovascular Medicine and Honorary Consultant Cardiologist, University of Sheffield, said:

“This study is consistent with the growing evidence that people hospitalised with COVID-19 are at risk from blood clots in multiple locations; the lungs (causing pulmonary embolus), the brain (causing stroke) and the veins (causing DVT).

“Because otherwise healthy people, or people sick with diseases other than COVID-19 often suffer blood clots, it is impossible to say in any individual person that their blood clot was “caused” by COVID-19.  However, the growing numbers of publications, and the experience of doctors treating COVID-19 patients including myself and my colleagues, strongly suggest COVID-19 substantially increases the risk of blood clots in hospitalised patients.  The risk of blood clots with COVID-19 appears to be even more than the increased risk of blood clots seen in other severe illnesses.

“As well as clinical trials on vaccines and anti-viral drug studies, there are a number of clinical trials examining what level of blood thinning treatment should be used in people hospitalised with COVID-19.  Current practise is to give all admitted patients a low dose injection of a drug called low-molecular weight heparin which is a standard treatment to reduce DVTs.  However, we urgently need to know whether higher doses or more powerful agents should be used, and if so in which patients (because these drugs themselves have risks).

“This study cannot tell us what proportion of patients with COVID-19 suffer blood clots, or whether the risk of this is related to the severity of the disease or can occur even in people with mild or no symptoms.  This requires a comprehensive study including thousands of patients.

“We have not yet seen any overall increase in strokes during the pandemic; in fact there have been very worrying reductions in non-COVID19 admissions for diseases such as stroke and heart attack, which suggests people are not coming to hospital for these life-threatening conditions.  However, it may yet emerge that some of the complications of COVID-19 relate directly to blood clots that might be treated or prevented using existing blood thinning medication.

“People who already take blood thinning medication such as aspirin should continue to take these if they develop COVID-19 like symptoms unless otherwise advised by their medical team.”

‘Characteristics of ischaemic stroke associated with COVID-19’ by Rahma Beyrouti et al. was published in the Journal of Neurology, Neurosurgery, and Psychiatry on Friday 1 May 2020.

DOI: 10.1136/jnnp-2020-323586

https://jnnp.bmj.com/content/early/2020/04/30/jnnp-2020-323586

All our previous output on this subject can be seen at this weblink:

www.sciencemediacentre.org/tag/covid-19

Declared interests

Dr Richard Francis: “The Stroke Association fund a separate research programme that David Werring is conducting, which is not related to COVID-19.”

Prof Edwin van Beek: “I have no conflicts of interest to declare in the context of this work.”

Prof Tim Chico: “No conflicts.”

None others received.