Increased von Willebrand and Factor VIII plasma levels in gynecologic patients with Post-Acute-COVID-Sequela (PASC)/Long COVID, 2024, Bellone et al

Stefania Bellone, Eric R. Siegel, David E. Scheim, Alessandro D. Santin

Highlights

• Growing evidence suggests that persistent microvascular inflammation, clumping/clotting of blood cells and thrombotic complications may be key causes of Long COVID.
• Plasma levels of von Willebrand factor and Factor VIII were uniformly higher in all gynecologic patients with Long COVID vs controls without Long COVID.
• Persistently elevated levels of Von Willebrand and Factor VIII may represent the results of lingering microvascular damage (i.e., spike-induced endotheliosis).

Abstract
Up to 30 % of COVID-infected patients may develop post-acute sequelae of COVID-19 (PASC), also known as Long COVID (LC), a syndrome characterized by a variety of debilitating symptoms lasting for more than 3 months after the acute infection. While the pathophysiological mechanisms behind PASC/LC are not completely understood, growing evidence suggests that an important component of this syndrome may be related to persistent microvascular inflammation causing clumping/clotting of red blood cells and platelets and thrombotic complications.

We retrospectively evaluated the plasma levels of von Willebrand factor (VWF), Factor VIII and D-dimer in 10 gynecologic patients (60 % with an endometrial or ovarian cancer diagnosis) affected by PASC/LC vs 5 control patients (60 % harboring endometrial or ovarian tumors).

We found elevated VWF and Factor VIII levels in all 10 PASC/LC patients (means of 254 % and 229 %, respectively) vs none of the 5 randomly selected cancer control patients (means of 108 % and 95 %, respectively), p = 0.0046 and p < 0.0001, respectively. In contrast, no significant difference was noted in the levels of D-dimer in PASC/LC.

Importantly, abnormally elevated VWF and Factor VIII levels were found to persist for at least 2 years in patients with Long COVID symptoms. VWF and Factor VIII but not D-dimer levels are significantly elevated in the plasma of PASC/LC cancer patients. Abnormally and persistently elevated VWF and Factor VIII levels may represent the results of persistent microvascular damage (i.e., spike-induced endotheliosis) and may be biomarkers of persistent inflammation in gynecologic patients with PASC/LC.

Full text

 

Significant differences:


And maintained over a couple years:



But a very small cohort and even fewer controls, 60% with cancer, older and all female. Only 2/5 controls reported covid infection.
Not clear how they define LC.

Overall though, this seems to be in line with what we've seen from the Pretorius et al and others — though a bigger difference here.

 

I'd be somewhat surprised if this holds up, maybe part of the picture for some in this heterogeneous condition but possibly not more. I think anybody with any knowledge in hematology would have looked at VWF before going down the microclot route or at least looked at it alongside. I'm also fairly certain that Pretorius would have done this as well (and didn't report anything worth mentioning) and if she hadn't I'd be somewhat dissapointed.

How do these values compare to the average population? Isn't VWF a relatively standard value about which a lot is known?

 

I quickly scrolled through some of Pretorius publications searching for “von Willebrand”. Typically this didn’t return anything, but they do report some values here https://cardiab.biomedcentral.com/articles/10.1186/s12933-021-01359-7 (I don’t have the energy to go through the cohorts right now, the findings were discussed here and the cohorts seem pretty bad, but this is also a very early study from more than 3 years ago).

The impression I’ve gotten from many haematologists is that they don’t take a lot of the microclot research seriously because too little effort is put into reporting standard values and a lot of emphasis is put on rather experimental measurements values.

One of the dutch projects funded by Stichting LC is looking at microclots. The researchers include some of these experts in haematology that had previously criticised exactly that. So I’m sure they’ll probably be looking at VWF and other standard measurements as well.

 

See —

Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction (2022, Journal of Thrombosis and Haemostasis)

Also recently —

Biomarkers of sustained systemic inflammation and microvascular dysfunction associated with post-COVID-19 condition symptoms at 24 months after SARS-CoV-2-infection (2023, Frontiers in Immunology)

Inflammatory and Prothrombotic Biomarkers Contribute to the Persistence of Sequelae in Recovered COVID-19 Patients (2023, International Journal of Molecular Sciences)

 

First study seems to be about 6 weeks after the acute infection, third study also seems to be suffering from cohort problems. The second study might also have some problems w.r.t. to that (older population, majority males, smokers, hospitalisation, etc) but looks interesting and rigorous enough to maybe be worthy of an own thread.

 

Pretorius & Kell did report elevated VWF in Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19, though definitely not as dramatic as the results here.

I hope that the Dalton / Sheffield microclots study (also in women only) is looking at VWF, d-dimer, etc.

 

Perhaps of interest:

Von Willebrand factor propeptide in severe coronavirus disease 2019 (COVID-19): evidence of acute and sustained endothelial cell activation

Maybe the elevated VWF seen in the LC patients is non-specific and just reflecting some sort of inflammation or maybe it is indicative of endothelial cell activation.