S G Shelat1, P Smith, J Ai, X L Zheng. 1. Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, PA 19104, USA.
Abstract
BACKGROUND: Many patients with acquired thrombotic thrombocytopenic purpura (TTP) harbor autoantibodies that may bind and/or inhibit ADAMTS-13 proteolytic activity and accelerate its clearance in vivo. METHODS: To test this hypothesis, we determined ADAMTS-13 activity and antigen levels in parallel plasma samples from patients clinically diagnosed with TTP. Collagen binding, GST-VWF73 and FRETS-VWF73 assays were used to determine ADAMTS-13 activity and to detect inhibitory autoantibodies. Enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation plus Western blotting (IP/WB) were used to detect total anti-ADAMTS-13 IgG (inhibitory and non-inhibitory). RESULTS: Among 40 patients with TTP (21 idiopathic and 19 non-idiopathic), inhibitory autoantibodies were detected (by FRETS-VWF73) in 52% of idiopathic and 0% of non-idiopathic TTP patients. In contrast, non-inhibitory IgG autoantibodies were detected in 29% of idiopathic and 50% of non-idiopathic TTP patients. The concentration of inhibitory IgG autoantibody in idiopathic TTP patients was significantly higher than that of non-inhibitory IgG in either idiopathic or non-idiopathic TTP patients. Idiopathic TTP patients demonstrated significantly reduced ADAMTS-13 activity compared with non-idiopathic patients, but only slightly lower ADAMTS-13 antigen levels. Interestingly, patients with inhibitory autoantibodies exhibited significantly lower ADAMTS-13 antigen levels than those with only non-inhibitory IgG autoantibodies or no autoantibody. Serial plasma exchanges increased levels of ADAMTS-13 activity and antigen concurrently in patients with inhibitory autoantibodies. CONCLUSION: The identification of severe ADAMTS-13 deficiency and autoantibodies or inhibitors appears to be assay-dependent; the inhibitory IgG autoantibodies, in addition to binding and inhibiting ADAMTS-13 proteolytic activity, may accelerate ADAMTS-13 clearance in vivo.
BACKGROUND: Many patients with acquired thrombotic thrombocytopenic purpura (TTP) harbor autoantibodies that may bind and/or inhibit ADAMTS-13 proteolytic activity and accelerate its clearance in vivo. METHODS: To test this hypothesis, we determined ADAMTS-13 activity and antigen levels in parallel plasma samples from patients clinically diagnosed with TTP. Collagen binding, GST-VWF73 and FRETS-VWF73 assays were used to determine ADAMTS-13 activity and to detect inhibitory autoantibodies. Enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation plus Western blotting (IP/WB) were used to detect total anti-ADAMTS-13 IgG (inhibitory and non-inhibitory). RESULTS: Among 40 patients with TTP (21 idiopathic and 19 non-idiopathic), inhibitory autoantibodies were detected (by FRETS-VWF73) in 52% of idiopathic and 0% of non-idiopathic TTP patients. In contrast, non-inhibitory IgG autoantibodies were detected in 29% of idiopathic and 50% of non-idiopathic TTP patients. The concentration of inhibitory IgG autoantibody in idiopathic TTP patients was significantly higher than that of non-inhibitory IgG in either idiopathic or non-idiopathic TTP patients. Idiopathic TTP patients demonstrated significantly reduced ADAMTS-13 activity compared with non-idiopathic patients, but only slightly lower ADAMTS-13 antigen levels. Interestingly, patients with inhibitory autoantibodies exhibited significantly lower ADAMTS-13 antigen levels than those with only non-inhibitory IgG autoantibodies or no autoantibody. Serial plasma exchanges increased levels of ADAMTS-13 activity and antigen concurrently in patients with inhibitory autoantibodies. CONCLUSION: The identification of severe ADAMTS-13 deficiency and autoantibodies or inhibitors appears to be assay-dependent; the inhibitory IgG autoantibodies, in addition to binding and inhibiting ADAMTS-13 proteolytic activity, may accelerate ADAMTS-13 clearance in vivo.
Authors: G G Levy; W C Nichols; E C Lian; T Foroud; J N McClintick; B M McGee; A Y Yang; D R Siemieniak; K R Stark; R Gruppo; R Sarode; S B Shurin; V Chandrasekaran; S P Stabler; H Sabio; E E Bouhassira; J D Upshaw; D Ginsburg; H M Tsai Journal: Nature Date: 2001-10-04 Impact factor: 49.962
Authors: X Long Zheng; Haifeng M Wu; Dezhi Shang; Erica Falls; Christopher G Skipwith; Spero R Cataland; Charles L Bennett; Hau C Kwaan Journal: Haematologica Date: 2010-04-07 Impact factor: 9.941
Authors: Cui Jian; Juan Xiao; Lingjie Gong; Christopher G Skipwith; Sheng-Yu Jin; Hau C Kwaan; X Long Zheng Journal: Blood Date: 2012-01-30 Impact factor: 22.113
Authors: Silvia Ferrari; Kristina Palavra; Bernadette Gruber; Johanna A Kremer Hovinga; Paul Knöbl; Claudine Caron; Caroline Cromwell; Louis Aledort; Barbara Plaimauer; Peter L Turecek; Hanspeter Rottensteiner; Friedrich Scheiflinger Journal: Haematologica Date: 2013-11-15 Impact factor: 9.941
Authors: Eric M Ostertag; Khalil Bdeir; Stephen Kacir; Michelle Thiboutot; Gayathri Gulendran; Lenka Yunk; Vincent M Hayes; David G Motto; Mortimer Poncz; X Long Zheng; Douglas B Cines; Don L Siegel Journal: Transfusion Date: 2016-04-04 Impact factor: 3.157
Authors: Pablo Laje; Dezhi Shang; Wenjing Cao; Masami Niiya; Masayuki Endo; Antoneta Radu; Nicole DeRogatis; Friedrich Scheiflinger; Philip W Zoltick; Alan W Flake; X Long Zheng Journal: Blood Date: 2009-01-13 Impact factor: 22.113
Authors: Stephen W Rothwell; Evelyn Sawyer; Jennifer Dorsey; William S Flournoy; Timothy Settle; David Simpson; Gary Cadd; Paul Janmey; Charles White; Kathleen A Szabo Journal: J Mater Sci Mater Med Date: 2009-05-18 Impact factor: 3.896