Discovery and characterization of an antibody directed against exosite I of XXXX .

@entity1 @entity556 @entity548 @entity1334 @entity1410
UNASSIGNED: Essentials An IgA paraprotein with anti- @entity556 activity was not associated with a severe @entity548 phenotype. This observation challenges the paradigm that anticoagulant therapy necessarily increases @entity548 risk. Characterization of the antibody showed that it specifically binds to @entity556 exosite I. A therapeutic drug with the properties of this antibody might be an antithrombotic that doesn't cause @entity548 . SUMMARY: Background We report the case of a 54-year-old female who presented with a @entity548 . Coagulation tests were markedly prolonged due to the presence of an anti- @entity556 IgA paraprotein at 3 g L(-1) . The @entity1 made a complete recovery and has had no @entity548 during a 7-year follow-up, despite the persistence of the paraprotein. Objectives To determine how the paraprotein prolonged clotting tests by defining its target and its epitope. Methods The paraprotein was purified and added to normal pooled plasma for in vitro clotting assays. Binding studies were conducted to determine the affinity of the IgA for @entity556 . The @entity1334 was isolated and crystallized with @entity556 . Results The purified IgA was sufficient to confer the @entity1 's in vitro coagulation profile in normal pooled plasma, and was found to bind specifically and with high affinity to @entity556 . A crystal structure of the @entity1334 fragment in complex with @entity556 revealed an exosite I interaction involving CDRH3 of the antibody. Conclusions Although the @entity1 originally presented with a subdural bleed, the @entity1410 resolved without intervention, and no other @entity548 event occurred during the subsequent 7 years. During this period, the @entity1 's IgA paraprotein levels have remained constant at 3 g L(-1) , suggesting that the presence of a high-affinity, exosite I-directed antibody is consistent with normal hemostasis. A therapeutic derivative of this antibody might therefore permit antithrombotic dose escalation without an associated increase in the risk of @entity548 .
