N-acetylcysteine in preclinical mouse and baboon models of thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic disorder diagnosed by thrombocytopenia and hemolytic anemia, associated with a deficiency in von Willebrand factor (VWF) cleaving protease ADAMTS13. Current treatment is based on plasma infusion for congenital TTP, or plasma exchange, often in combination with immunosuppressive agents, for acquired TTP. These treatment methods are however not always effective and therefore new treatment methods are highly necessary. N-acetylcysteine (NAC), an FDA-approved anti-mucolytic agent, could be a possible new treatment strategy for TTP as it was demonstrated to reduce disulfide bonds in VWF, thereby decreasing VWF multimer size and hence its prothrombotic potential. We investigated whether NAC, without concurrent plasma exchange and immunosuppressive therapy, is effective in preventing and resolving TTP signs using well-established murine and baboon models for TTP. In mice, prophylactic administration of NAC was effective in preventing severe TTP signs. This was supported by in vitro data, demonstrating the VWF-multimer reducing properties of NAC in solution. Nonetheless, in both mice and baboons, administration of NAC was not effective in resolving pre-existing TTP signs; thrombocytopenia, hemolytic anemia and organ damage could not be reversed, as thrombus resolution could not be achieved. Failure to improve clinical outcome occurred even though a reduction in VWF multimers was observed, demonstrating that NAC was efficient in reducing disulfide bonds in circulating VWF multimers. In conclusion, prophylactic administration of NAC, without concurrent plasma exchange, is effective in preventing severe TTP signs in mice but NAC is not effective in resolving acute TTP signs in mice and baboons. ispartof: Blood vol:129 issue:8 pages:1030-1038 ispartof: location:United States status: published