A Critical Look at the “COVID Causes Blood Clots” Paper

Here’s the biggest problem: They never measured how much Mpro actually exists in COVID-19 patients’ blood.

The authors argue that the virus’s main protease (Mpro) – essentially molecular scissors that help the virus replicate – can also cut up our blood clotting proteins and trigger dangerous clots.

https://www.nature.com/articles/s42003-025-08570-2

The Big Claim That Caught My Eye

A recent paper in Communications Biology claims to have discovered how SARS-CoV-2 directly causes blood clots. The authors argue that the virus’s main protease (Mpro) – essentially molecular scissors that help the virus replicate – can also cut up our blood clotting proteins and trigger dangerous clots.

Sounds important, right? But as I dug deeper, I found some serious logical gaps that should make us pause before accepting these conclusions.

The Setup: What They Did

The researchers took purified Mpro protein and mixed it with:

Human blood plasma
Individual clotting factors

They found that Mpro could activate two specific clotting factors (FVII and FXII) and make plasma clot in test tubes. Case closed? Not quite.

Red Flag #1: The Missing Numbers

Here’s the biggest problem: They never measured how much Mpro actually exists in COVID-19 patients’ blood.

Imagine I told you that table salt can dissolve steel – but only when you use a concentration of salt that you’d never encounter in real life. That’s essentially what’s happening here. The researchers used Mpro concentrations between 50 nM and 7,000 nM in their experiments, but we have no idea if these levels ever occur in actual patients.

Without this crucial data, it’s like proving a gun can fire bullets without checking if it’s loaded.

Red Flag #2: The Specificity Paradox

Mpro is famously picky about what it cuts – it strongly prefers a specific sequence (Leu-Gln). But the clotting factors it supposedly activates have a completely different sequence (Arg-X).

The authors claim Mpro can cut at these Arg sites too, but their own data shows:

This only happens after 30+ minutes
It’s 4x less efficient than the preferred sequence
It only appears after all the preferred targets are gone

It’s like a vegetarian restaurant claiming they serve steak because technically, after all the vegetable dishes are sold out, they might grudgingly grill a burger.

Red Flag #3: The Efficiency Problem

Even under ideal laboratory conditions:

Only 14% of FVII was activated after 3 hours
The “key” cleavage site was detected in only 1 out of 3 experiments

If this mechanism is supposed to cause the rapid, severe clotting seen in COVID-19, these numbers don’t add up. It’s like claiming a leaky faucet caused a flood.

Red Flag #4: The Test Tube vs. Reality Gap

All experiments were done in pristine laboratory conditions with purified proteins. But in real life:

Mpro is primarily inside infected cells, not floating in blood
Blood contains numerous protease inhibitors
Multiple competing processes would interfere

The paper mentions that Mpro “retains 70% activity in blood serum” as if this supports their case. But 70% of an unknown concentration is still… unknown.

Red Flag #5: Cherry-Picked Results?

The researchers tested many clotting factors but only two showed any activation. If Mpro really has this newfound ability to cut at Arg sites, why doesn’t it activate other clotting factors with similar sequences?

They offer no explanation for this selective activity, which suggests the mechanism might be more artifact than reality.

The Statistical Shuffle

The paper reports a “statistically significant” 3-fold increase in clotting probability (p=0.003) based on just 21 blood donors. While technically significant, this is a small sample for such a complex biological phenomenon. Moreover, the clotting time oddly didn’t change with Mpro concentration – a red flag for any enzyme-driven process.

What This Means for COVID Research

Don’t get me wrong – COVID-19 absolutely causes clotting problems. That’s well-established. But this paper doesn’t convincingly prove that Mpro is the direct culprit.

The inflammatory response to infection, damage to blood vessel walls, and immune system overreaction remain the most likely mechanisms. Adding a weak, inefficient, hypothetical mechanism that requires unproven concentrations doesn’t advance our understanding.

The Peer Review Problem

How did this get published in a reputable journal? This case highlights a broader issue in scientific publishing: reviewers often focus on technical methodology while missing fundamental logical gaps. The experiments were performed correctly, but they’re answering the wrong questions.

The Bottom Line

Good science requires more than just running experiments – it requires logical connections between laboratory findings and real-world claims. This paper shows that Mpro can affect clotting factors under artificial conditions, but fails to demonstrate that it does cause clotting in COVID-19 patients.

Before accepting dramatic claims about disease mechanisms, we should always ask:

Do the experimental conditions reflect reality?
Are the effects strong enough to matter physiologically?
Are there simpler explanations being ignored?

In this case, the answer to all three questions points to the same conclusion: interesting biochemistry, but probably not clinically relevant.

What Should Happen Next

If the authors truly believe in their mechanism, they need to:

Measure actual Mpro concentrations in patient blood
Demonstrate clotting at physiologically relevant concentrations
Explain why only specific factors are affected
Show this mechanism contributes meaningfully compared to established pathways

Until then, this remains an intriguing “what if” rather than a proven mechanism of COVID-19 pathology.