The new role of the coagulation protein VWF in triggering inflammation

Research from the RCSI University of Medicine and Health Sciences found a new role in coagulation protein: von Willebrand factor (VWF), which plays an important role
in regulating the immune response at the site of vascular injury.
This means that the protein's newfound role in repairing damaged blood vessels, in addition to its role in blood clotting, could lead to the development of
new treatments for patients with inflammation and clotting disorders.
The article is published in
a new issue of Nature Communications.

von Willebrand factor (VWF) is a large sialate glycoprotein that circulates
in normal plasma as a series of heteropolymers.
Plasma VWF binds to exposed subendothelial collagen at the site of vascular injury, recruiting and binding platelets to the site of injury, leading to the formation of primary platelet embolism, which plays an important role
in maintaining normal hemostasis.
In addition, VWF has a high affinity for procoagulant factor VIII, which protects it from proteolysis and premature clearance
.
VWF deficiency is known as "von Willebrand disease" and affects 1 in 1,000 people in Ireland
.
People with this condition are
at increased risk of severe heavy bleeding.
In contrast, people with high levels of protein in their blood are at risk of
developing severe blood clots.
For example, very high VWF levels are associated with
unusual blood clots in the lungs of people with severe COVID-19.

In addition to hemostasis, recent studies have identified other biological roles of VWF, including inhibition of angiogenesis and promotion of tumor cell apoptosis
.
There is growing evidence that VWF plays an important role
in enhancing the inflammatory response.
Acute activation of endothelial cells (EC) triggers the secretion
of high molecular weight polymer (HMWM) VWF stored in Weibel Palade bodies (WPBs).
Thus, elevated plasma VWF levels have been reported to be associated with different types of sepsis, as well as many other vascular pathologies, including COVID-19, cerebral malaria, sickle cell disease, systemic inflammatory response syndrome, and some cancers
, in severity and/or clinical outcomes.
A growing number of findings suggest that VWF affects several different aspects
of inflammation.
However, the molecular mechanism by which VWF exerts its pro-inflammatory effects remains poorly
understood.

In this paper, the authors investigate the effect
of the binding of the multimer VWF to macrophages on the innate inflammatory response.
It has been demonstrated that binding of VWF to macrophages triggers significant pro-inflammatory intracellular signaling within macrophages, leading to p-38 and subsequent HIF-1α activation, as well as significantly enhancing glycolysis in the short term, affecting the mitochondrial morphology of macrophages (mitochondria appear fragmented) and upregulating HIF-1α expression
.
This interaction with VWF is mediated in part by macrophage LRP1 and results in the secretion and expression of pro-inflammatory cytokines and chemokines, triggering macrophage polarization towards the M1 (classical activation or "pro-inflammatory") phenotype, promoting monocytes chemotaxis
.
Collectively, these data define the biological role
of VWF in linking primary haemostasis to innate immunity at the site of vascular injury.

This study is the first to show that VWF not only regulates blood clotting at the site of injury, but also triggers a local immune response
.
Understanding this new biological role of VWF in modulating the inflammatory response may provide an opportunity
to develop entirely new treatment options for patients with inflammation and coagulation disorders such as von Willebrand disease, deep vein thrombosis, and myocardial infarction.

Professor James O'Donnell, lead author of the study and director of the Centre for Vascular Biology in the School of Pharmacy and Biomolecular Sciences at the Royal College of Science, Ireland, said: "It has been known for over 50 years that von Willebrand factor plays a key role in preventing bleeding, and it acts as a glue at the site of injury
.
This research now helps us further our understanding of VWF's role in linking blood clotting and inflammation, paving the way
for the development of new treatments.
" ”

The study was conducted
by RCSI in collaboration with Trinity College Dublin and the National Centre for Coagulation at St James's Hospital Dublin.
The study was funded
by Science Foundation Ireland and the National Institutes of Health (NIH).