Enhanced activity of an ADAMTS-13 variant (R568K/F592Y/R660K/Y661F/Y665F) against platelet agglutination in vitro and in a murine model of acute ischemic stroke.

Journal of Thrombosis and Haemostasis : JTH
K SouthD A Lane

Abstract

Essentials ADAMTS13 requires a substrate-induced conformational change to attain full activity in vitro. The efficacy of wild type ADAMTS13 in models of thrombosis/stroke may be enhanced by pre-activation. A pre-activated ADAMTS13 variant exhibits enhanced proteolysis of platelet agglutinates. This ADAMTS13 variant is protective in a murine model of stroke at a lower dose than WT ADAMTS13. SUMMARY: Background ADAMTS-13 circulates in a closed conformation, only achieving full proteolytic activity against von Willebrand factor (VWF) following a substrate-induced conformational change. A gain-of-function (GoF) ADAMTS-13 variant (R568K/F592Y/R660K/Y661F/Y665F) is conformationally preactivated. Objectives To establish how the hyperactivity of GoF ADAMTS-13 is manifested in experimental models mimicking the occlusive arterial thrombi present in acute ischemic stroke. Methods The ability of GoF ADAMTS-13 to dissolve VWF-platelet agglutinates was examined with an assay of ristocetin-induced platelet agglutination and in parallel-flow models of arterial thrombosis. A murine model of focal ischemia was used to assess the thrombolytic potential of GoF ADAMTS-13. Results Wild-type (WT) ADAMTS-13 required conformational activation to attain...Continue Reading

References

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Oct 28, 2016·Journal of Thrombosis and Haemostasis : JTH·K SouthD A Lane

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Citations

Mar 11, 2020·Biomolecules·Yamina MohamediAlvaro J Obaya
Apr 21, 2020·Platelets·Senna Staessens, Simon F De Meyer
Aug 6, 2019·Frontiers in Neurology·Xin ChenDanhong Wu
Apr 10, 2021·Journal of Thrombosis and Haemostasis : JTH·Maxime GaubertiDenis Vivien
Feb 3, 2022·Journal of Thrombosis and Haemostasis : JTH·Manasa K NayakAnil K Chauhan

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Methods Mentioned

BETA
ELISAs
ELISA
fluorescence imaging
Fluorescence
glycosylation

Software Mentioned

slidebook

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