Nonimmunosuppression strategies to treat autoantibody-mediated TTP. VWF is secreted from activated endothelial cells as ULVWF multimers, which recruit flowing platelets and form thrombi. (A) In the presence of flow and/or platelet binding, VWF is stretched to expose its A2 domain that is cleaved by ADAMTS13, resulting in dissociation of platelet aggregates. (B) In the absence of ADAMTS13 activity because of hereditary mutations of ADAMTS13 or acquired autoantibodies that block ADAMTS13 function, a disulfide bond reducing agent, such as N-acetylcysteine, or the C-terminal TSP1 repeats of ADAMTS13^99,100  may be able to reduce the disulfide bridges linking VWF polypeptide subunits disassembling the VWF multimers. (C) In the setting of insufficient ADAMTS13 activity as described in panel B, aptamer or nanobody may bind to the VWF-A1 domain, inhibit the interaction between ULVWF and platelet receptor GPIb, and eliminate thrombus formation under flow. (D) Anti-ADAMTS13 inhibitory autoantibodies may be bypassed through the use of novel recombinant ADAMTS13 preparations that have been engineered to retain VWF cleaving activity while deleting autoantibody-binding epitopes.