This disclosure provides methods and compositions for treating TTP based on transfusion of a relatively small number of genetically modified red blood cells. The genetically modified red blood cells express a fusion protein including a fragment of ADAMTS13 that is enzymatically active against von Willebrand factor (VWF). The fragments of ADAMTS13 can be resistant to the inhibitors, e.g., the auto-immune antibodies, which are responsible for the acquired form of TTP.