A paradoxical role of ADAMTS13: enhancing collagen-induced platelet aggregation and activation via AKT phosphorylation

Background: ADAMTS13 is an anti-thrombotic metalloenzyme that cleaves ultra large von Willebrand factor (VWF), preventing platelet accumulation at sites of vascular injury. Deficiency of plasma ADAMTS13 activity leads to thrombotic thrombocytopenic purpura (TTP) and is a risk factor for the development of other inflammatory thrombotic disorders. However, it is not known if ADAMTS13 is of other biological functions. Objectives: Present study aims to determine the effects of ADAMTS13 on agonist-induced platelet activation and aggregation and its underlying molecular mechanisms. Methods: A light transmission assay was used to determine platelet aggregation; flow cytometry was used to determine the platelet activation, phosphatidylserine exposure, and AKT phosphorylation. Results: A full-length recombinant ADAMTS13 but not its truncated form (MDTCS or TSP2-CUB) enhanced a fibrillar collagen induced aggregation of isolated human and murine platelets. This enhancing effect was ADAMTS13 concentration- and conformation-dependent but did not depend on its proteolytic activity. Interestingly, recombinant ADAMTS13 did not enhance AYPGKF, an agonist of protease-activated receptor 4 (PAR4), or 2MeSADP-induced murine platelet aggregation. Flow cytometry demonstrated that recombinant ADAMTS13 plus a fibrillar collagen resulted in significantly more activation and phosphatidylserine exposure of murine platelets than the collagen did alone, likely via an increase of AKT phosphorylation. Conclusions: Our results demonstrate a novel but paradoxical role of recombinant ADAMTS13, possibly promoting hemostasis while inhibiting thrombosis at the same time. The findings provide novel insight into the excellent therapeutic efficacy of recombinant ADAMTS13 for thrombosis but without an increased risk of bleeding.