Our findings thus convert Heyde’s syndrome from a linear model consisting of AS leading to increased shear, leading to AVWS via unfolding of vWf and cleavage by ADAMTS-13,33 leading to gastrointestinal hemorrhage and anemia, to a vicious circle in which the anemia itself further increases shear, leading to both release of TGF-β1 from platelets and activation of released TGF-β1, resulting in further AS progression (Figure 7). The gene discussed is TGFB1; the disease is aortic stenosis.