title: Poor responder to plasma exchange therapy in acquired thrombotic thrombocytopenic purpura is associated with ADAMTS13 inhibitor boosting: visualization of an ADAMTS13 inhibitor complex and its proteolytic clearance from plasma.
abstract: BACKGROUND
  Plasma exchange (PE) is the first-line treatment for primary acquired thrombotic thrombocytopenic purpura (aTTP) with severe deficiency of ADAMTS13 activity (ADAMTS13:AC). Some patients are poor responders to PE, raising concern over multiple pathogenetic pathways.
  
  
  METHODS
  Based on 52 aTTP patients in our national cohort study, we monitored plasma levels of ADAMTS13, clinical and laboratory findings, and outcomes. In a representative poor responder to PE, we examined an ADAMTS13 inhibitor (ADAMTS13:INH) complex in plasma milieu, by means of a large-pore isoelectric focusing (IEF) analysis.
  
  
  RESULTS
  Of 52 aTTP patients, 20 were good responders and 32 were poor responders. In the latter group, plasma ADAMTS13:AC levels never increased to more than 10% of normal during 14 days after PE initiation. Mean (±SD) plasma ADAMTS13:INH titers (Bethesda unit/mL) were 5.7 (±4.5) before PE, but decreased to 1.4 (±0.8) on the fourth PE day and then remarkably increased to 14.8 (±10.0) on the 10th PE day, termed "inhibitor boosting," and then slowly decreased to undetectable level over 1 month. On admission, none of the routinely available clinical and laboratory markers differentiated these two groups. However, elevated pre-PE levels of ADAMTS13:INH were correlated with a poor response. We visualized an ADAMTS13:INH (immunoglobulin G) complex in a patient plasma by an IEF analysis and found proteolytic fragment of ADAMTS13 antigen by a two-dimensional IEF and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis.
  
  
  CONCLUSIONS
  Findings from this cohort of aTTP patients demonstrated that inhibitor boosting often occurs in aTTP patients in Japan. Poor responders could be predicted by elevated pre-PE ADAMTS13:INH levels on admission, but not by routinely collected clinical or laboratory data.
authors.affiliation: Department of Blood Transfusion Medicine, Nara Medical University, Kashihara City, Japan.
authors.forename: Ayami
authors.initials: A
authors.lastname: Isonishi
authors.affiliation: South Carolina Center of Economic Excellence for Medication Safety and Efficacy, the Southern Network on Adverse Reactions (SONAR), the South Carolina College of Pharmacy, and the WJB Dorn Veterans Administration Hospital, Columbia, South Carolina.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bennett
authors.affiliation: Department of Discovery Research and Technical Assessment, Baxter Bioscience, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Plaimauer
authors.affiliation: Department of Discovery Research and Technical Assessment, Baxter Bioscience, Vienna, Austria.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Scheiflinger
authors.affiliation: Department of Blood Transfusion Medicine, Nara Medical University, Kashihara City, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Blood Transfusion Medicine, Nara Medical University, Kashihara City, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fujimura
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000097:blood / Q000172:deficiency; D000071120:ADAMTS13 Protein; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001323:Autoantibodies / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D007223:Infant; D007564:Japan; D008297:Male; D008875:Middle Aged; D010951:Plasma Exchange; D011480:Protease Inhibitors / Q000097:blood*; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood / Q000628:therapy; D012189:Retrospective Studies
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D011480:Protease Inhibitors; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human