Angiodysplasia in von Willebrand Disease: Understanding the Clinical and Basic Science

Abstract

Severe and intractable gastrointestinal bleeding caused by angiodysplasia is a debilitating problem for up to 20% of patients with von Willebrand disease (VWD). Currently, the lack of an optimal treatment for this recurrent problem presents an ongoing challenge for many physicians in their management of affected patients. Over the past few years, studies have pointed to a regulatory role for the hemostatic protein, von Willebrand factor (VWF), in angiogenesis, providing a novel target for the modulation of vessel development. This article will review the clinical implications and molecular pathology of angiodysplasia in VWD.

Figure 1. Heyde’s syndrome refers to the triad of conditions including aortic stenosis, AVWS, and GI bleeding as a result of angiodysplasia

In individuals with aortic valve stenosis, the aortic valve can be become narrow causing blood jet. This high flow rate often makes VWF more susceptible to cleavage by ADAMTS13 resulting in the loss of HMWM of VWF and AVWS. Consequently, patients can develop angiodysplasia in the GI tract which can lead to severe and intractable bleeding.

Figure 2. Ang-2 is synthesized by ECs and stored in WPBs alongside VWF

Confocal images of BOECs from healthy control non-VWD individuals with VWF (green), Ang-2 (red), and DAPI nuclear (blue) staining. Ang-2 co-localizes with VWF in yellow WPBs around the nucleus.

Figure 3. VWF is a negative regulator of angiogenesis

(A) VEGF-mediated angiogenesis is regulated by extracellular VWF binding integrin αvβ3 to inhibit VEGFR-2 signaling and by intracellular VWF promoting the formation of WPBs to sequester the pro-angiogenic molecule Ang-2. (B) A lack of VWF allows Ang-2 to escapes the cell to promote EC proliferation, motility, and sprouting via signaling of the Tie-2 receptor.