The use of oral anticoagulation at the time of acute COVID-19 infection and subsequent development of [long-COVID], 2025, Frost+

[SNT Gatchaman]

The use of oral anticoagulation at the time of acute COVID-19 infection and subsequent development of long-COVID/post-acute sequelae of SARS-CoV-2 infection
Frost, Freddy; Rivera-Caravaca, José Miguel; Lip, Gregory Y. H.

Long COVID (LC) or post-acute sequelae of SARS-CoV-2 infection (PASC) is defined as ongoing, relapsing or new symptoms/conditions persisting after an acute COVID-19 infection. Given the potential role of oral anticoagulants (OAC) in treating thrombotic sequelae of LC/PASC, we investigated whether prevalent OAC use at the time of acute COVID-19 infection was associated with reduced development of LC/PASC.

Retrospective cohort study within the TriNetx network. The primary cohort was defined as adults with a confirmed diagnosis of COVID-19. We defined OAC users as those who had received OACs (either direct-acting OACs [DOACs] or vitamin K antagonists [VKA]) in the preceding 3-months and non-users as those without OAC use within the previous 12-months. The primary outcome was a composite of 9 features associated with LC/PASC.

We identified 38,409 DOAC users, 19,243 VKA users, and 2,329,771 non-OAC users with acute COVID-19 infection. After successful propensity score matching (PSM), we found an increased risk of LC/PASC features in those receiving DOAC compared to non-OAC (HR [95% CI] 1.50 [1.35 to 1.68], p < 0.0001), and in VKA users compared to non-OACs (HR [95% CI] 1.98 [1.78 to 2.20], p < 0.0001), while DOAC users were at reduced risk compared to VKA users (HR [95% CI] 0.71 [0.62 to 0.81], p < 0.0001).

We found no evidence that prevalent OAC at the time of acute COVID-19 infection was associated with reduced risk of LC/PASC. Further work is needed to understand whether there is a role for OAC therapy in the management of LC/PASC.

Link | PDF (Journal of Thrombosis and Thrombolysis) [Open Access]

 

[boolybooly]

There is stuff to unpick here.

we found an increased risk of LC/PASC features in those receiving DOAC (direct oral anticoagulant) compared to non-OAC ... We found no evidence that prevalent OAC at the time of acute COVID-19 infection was associated with reduced risk of LC/PASC.

We undertook a retrospective cohort study within the TriNetX network, a global federated health research network with access to electronic medical records (EMRs) from academic and community hospitals mainly located in the United States (U.S.).

This study is based on recorded clinical symptoms, presumably diagnosed by attending clinicians and reported by patients. Not laboratory level empiricism but nevertheless potentially informative.

Primary outcome of interest was a composite of 9 features associated with LC/PASC as previously described [1]. The constituent clinical features were as follows: ● Cognitive dysfunction. ● Myalgia. ● Headache. ● Pain. ● Anxiety/depression. ● Abdominal symptoms. ● Abnormal breathing. ● Chest/throat pain.

Our main finding is that OAC use does not appear to be associated with any reduction in LC/PASC symptom development and, in general, OAC users were associated with increased risk of LC/PASC.
...
Our findings of no benefit for prevalent OAC use on PASC should not be interpreted as evidence for a lack of effect of OAC for PASC. For example, a mechanistic clotting study found extremely high resistance of LC/PASC microclots to fibrinolysis
...
Another unresolved question, not covered by our study, is the potential role of OAC when a diagnosis of LC/PASC is already made. Following COVID-19, chronic inflammation may persist and contribute to endothelial cell activation, platelet stimulation, and increased inflammatory responses. This process can upregulate procoagulant factors and impair the protective function of the vascular endothelium, leading to abnormal coagulation [7]. Under such conditions, starting OAC -or maintaining this therapy if already prescribed- may lead to lower risk of worse clinical outcomes

What strikes me about this is people already taking OAC are likely to be more vulnerable to microthrombotic effects of LC/PASC since they are already having trouble with thrombosis risk requiring blood thinners. They may even already have a similar problem, undiagnosed, in relation to an immune response, possibly to another infection indicating a host generated predisposition to the kind of immune response causing LC/PASC.

By a mechanical analysis I would not really expect there to be an advantage reducing incidence rate of LC/PASC from taking OAC during infection. If anything I would expect potential increase in viral infectivity in those taking blood thinners and thereby initial severity simply due to easier diffusion of virus particles in thinner blood plasma increasing the rate at which they find their target receptor and infect host cells. However I have read of papers stating initial severity is not correlated with likelihood of developing LC/PASC.

It stands to reason, if LC/PASC involves microthrombosis you would expect less severe microthrombotic symptoms in patients taking OACs.


I am interested in this personally because I am having a long drawn out struggle with a migraine causing condition for which I am taking fibrinolytics bromelain and nattokinase because they do appear to reduce symptom severity.

 

[jnmaciuch]

However I have read of papers stating initial severity is not correlated with likelihood of developing LC/PASC

I believe the main study showing that severity and LC risk are correlated is one of the Al-Aly veteran's center studies. Several others since then have shown that there's no strong correlation. There might be others I'm not remembering right now. As it stands, it seems like severity of illness is not a strong predictor of LC on its own. It also depends on how disease severity is defined--higher viral titres often do correlate with more respiratory stress, reduced oxygenation, use of ventilator, etc. but it's not a perfect correlation.

I am interested in this personally because I am having a long drawn out struggle with a migraine causing condition for which I am taking fibrinolytics bromelain and nattokinase because they do appear to reduce symptom severity.

I also noticed a benefit from nattokinase. Small benefit for me but it did seem to help with lessening intensity of post-activity muscle pain, stiffness, and feverish feelings. My hairdresser also noted that I had much more growth in baby hairs at the first appointment after I started the supplement, which tends to be a sign of improved circulation.

Interestingly enough, I don't think I've ever had COVID. It's possible I've had a completely asymptomatic infection, but I was limited in how much I could be out of the house anyways since the pandemic started and always am very cautious about masks, avoiding crowded unventilated places, etc.

I actually had blood clotting issues before the pandemic ever started in 2019 when I got my wisdom teeth taken out. My ME/CFS did not start from a clear viral trigger, though I can't completely rule out another non-COVID asymptomatic infection. It makes me wonder whether differences in coagulation are generally related to ME/CFS pathology, and whether COVID is just one way of potentially triggering a long-term coagulation issue.

 

[forestglip]

I believe the main study showing that severity and LC risk are correlated is one of the Al-Aly veteran's center studies. Several others since then have shown that there's no strong correlation. There might be others I'm not remembering right now. As it stands, it seems like severity of illness is not a strong predictor of LC on its own.

When I went searching for recent reviews, they all seemed to agree that acute severity increases LC risk. I didn't read them in detail, though.

 

[jnmaciuch]

When I went searching for recent reviews, they all seemed to agree that acute severity increases LC risk. I didn't read them in detail, though.

It's very much up for debate--I did a deep dive on it about a month ago when I was searching for citations on that claim for a LC publication. There's evidence on both sides to some extent, the main issue is extreme inconsistency in how it's assessed.

For example, the studies I looked at varied on whether or not age was accounted for as a covariate (since age was strongly associated with severe disease to begin with), whether LC was defined by long-term physical and cognitive deficit or simply the persistence of one or more symptoms after infection, and whether there was enough data from non-hospitalized LC cases to accurately judge prevalence from mild infection.

As one example, the research team I was part of put out this study showing no correlation with severity amongst hospitalized patients. Granted, all were hospitalized, so it is skewed in that way. Though we did have a good number of mild cases that didn't exhibit high respiratory distress and were discharged after just a few days with no or minimal treatments.

 

[forestglip]

It's very much up for debate--I did a deep dive on it about a month ago when I was searching for citations on that claim for a LC publication. There's evidence on both sides to some extent, the main issue is extreme inconsistency in how it's assessed.

For example, the studies I looked at varied on whether or not age was accounted for as a covariate (since age was strongly associated with severe disease to begin with), whether LC was defined by long-term physical and cognitive deficit or simply the persistence of one or more symptoms after infection, and whether there was enough data from non-hospitalized LC cases to accurately judge prevalence from mild infection.

As one example, the research team I was part of put out this study showing no correlation with severity amongst hospitalized patients. Granted, all were hospitalized, so it is skewed in that way. Though we did have a good number of mild cases that didn't exhibit high respiratory distress and were discharged after just a few days with no or minimal treatments.

Interesting, thanks. That link isn't working for me though, but I think it's supposed to be this study:

Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study (2024, Nature Communications)

 

[jnmaciuch]

Interesting, thanks. That link isn't working for me though, but I think it's supposed to be this study:

Features of acute COVID-19 associated with post-acute sequelae of SARS-CoV-2 phenotypes: results from the IMPACC study (2024, Nature Communications)

Yes it is! Sorry, I must have copied it wrong trying to do it in my phone.