Several findings presented here support this hypothesis and identify plasmin as a physiological protease that contributes to ATTR amyloid deposition: the presence of abundant serine protease activity within amyloid deposits, increased ATTR amyloid deposition resulting from α2-antiplasmin deficiency, the presence of immunoreactive plasminogen/plasmin in amyloid deposits, and the accumulation of plasmin heavy and light chains in amyloid-containing hearts and tongues. The gene discussed is PLG; the disease is amyloidosis.