Recent evidence points to isolated deficiency of the largest multimers of von Willebrand factor (VWF)-known as von Willebrand syndrome type 2A (VWS-2A)-as a risk factor for bleeding from gastrointestinal (GI) angiodysplasia. This disorder is not widely recognized, perhaps because most patients do not exhibit generalized hemostatic impairment (bleeding is generally restricted to GI angiodysplasia) and because all but the largest multimers of VWF remain detectable in the plasma (thus, routine screening tests for VWS-2A are usually normal). The "Rosetta stone" for elucidating this syndrome was the enigma of Heyde's syndrome (aortic stenosis plus bleeding GI angiodysplasia), particularly the striking observation that aortic valve replacement generally cures GI bleeding and that preoperative deficiency of the largest VWF multimers undergoes long-term normalization after valve replacement. We critically review the evidence implicating VWS-2A as a risk factor for bleeding GI angiodysplasia. We hypothesize that VWS-2A secondary to cardiovascular disease other than severe aortic stenosis, such as peripheral arterial occlusive disease, could explain why elderly patients often develop recurrent GI bleeding or iron deficiency anemia from GI angiodysplasia.