The Role of von Willebrand Factor in Vascular Inflammation: From Pathogenesis to Targeted Therapy

Abstract

Beyond its role in hemostasis, von Willebrand factor (VWF) is an emerging mediator of vascular inflammation. Recent studies highlight the involvement of VWF and its regulator, ADAMTS13, in mechanisms that underlie vascular inflammation and immunothrombosis, like leukocyte rolling, adhesion, and extravasation; vascular permeability; ischemia/reperfusion injury; complements activation; and NETosis. The VWF/ADAMTS13 axis is implicated in the pathogenesis of atherosclerosis, promoting plaque formation and inflammation through macrophage and neutrophil recruitment in inflamed lesions. Moreover, VWF and ADAMTS13 have been recently proposed as prognostic biomarkers in cardiovascular, metabolic, and inflammatory diseases, such as diabetes, stroke, myocardial infarction, and sepsis. All these features make VWF an attractive therapeutic target in thromboinflammation. Several lines of research have recently investigated "tailor-made" inhibitors of VWF. Results from animal models and clinical studies support the potent anti-inflammatory and antithrombotic effect of VWF antagonism, providing reassuring data on its safety profile. This review describes the role of VWF in vascular inflammation "from bench to bedside" and provides an updated overview of the drugs that can directly interfere with the VWF/ADAMTS13 axis.

Figures

Figure 1

Functional heterogeneity of von Willebrand factor (VWF). VWF is best known for its role in hemostasis and thrombosis, supporting platelet adhesion/aggregation and protecting FVIII from proteolytic degradation in blood flow. However, it is now clear that VWF functions extend much further than that. VWF plays a key role in vascular inflammation, favoring leukocyte recruitment and extravasation, activating complement cascade, and participating in NETosis. In cardiovascular disease, including CAD and stroke, VWF is a predictor of future CV events. In atherosclerosis, VWF promotes plaque formation and inflammation in animal models. An increase in VWF activity or ADAMTS13 deficiency may result in microvascular obstruction and thrombotic microangiopathy (TMA). In sepsis, inflammatory and infective stimuli may induce an acute imbalance in the VWF/ADAMTS13 ratio with possible thrombotic complications (i.e., DIC). Finally, a growing interest is emerging on selective VWF antagonism as a new therapeutic option to provide a further advance in the treatment of thrombotic and inflammatory disorders. VWF: von Willebrand factor; ADAMTS13: a disintegrin and metalloprotease with the thrombospondin motif; TMA: thrombotic microangiopathy; CV: cardiovascular; CAD: coronary artery disease; TTP: thrombotic thrombocytopenic purpura; HUS: hemolytic uremic syndrome.

Figure 2

The “solar system” of VWF-mediated vascular inflammation. VWF is central in the “solar system” of vascular inflammation, and many inflammatory pathways orbit in its “gravitational field.” VWF supports leukocyte and platelet recruitment in inflamed tissue, modulates vascular permeability and edema formation, may promote atherosclerotic plaque formation and inflammation, and provides an activating surface for complement activation and NETosis. All these mechanisms may contribute to tissue injury and organ failure in thromboinflammatory disorders.

Figure 3

VWF-mediated thromboinflammation in high-shear conditions. At high shear rates (e.g., arterioles, microcirculation, and artery stenosis), the inactive globular-shaped VWF rapidly unfolds and elongates in a highly reactive long-chain conformation. The elongated VWF can bind to platelets (a), allowing them to roll and adhere to the damaged endothelial surface. Platelet-decorated UL-VWF strings on activated endothelium represent a solid anchoring matrix for leukocyte adhesion (b), so permitting leukocyte recruitment in the inflamed site. In the bloodstream, VWF also binds to “neutrophil extracellular traps” (NETs) (c), inflammatory mediators (decondensed nucleosomes, extracellular DNA, and proteins) released by activated neutrophils, creating a network able to recruit both platelets and leukocytes and to promote thrombus formation.