Transforming the major autoantibody site on ADAMTS13: spacer domain variants retaining von Willebrand factor cleavage activity

摘要

Immune thrombotic thrombocytopenic purpura (iTTP) is an acute, rare life-threatening condition associated with antibodies to ADAMTS13, resulting in severe enzyme deficiency, failure of von Willebrand factor (VWF) cleavage, excess platelet-VWF binding and microthrombi formation, resulting in multi-organ damage. iTTP is an immune-mediated condition and antibodies to ADAMTS13 are polyclonal.1,2 Despite this, and as replicated by a number of groups, nearly 100% of patients demonstrate a specific target region of antibody binding to the spacer domain in the N terminal region of the metalloprotease, ADAMTS13.3-7 Antibodies can be detected in other ADAMTS 13 domains, typically the TSP 2-8 regions or CUB domains, but to a lesser degree than spacer domain antibodies. Furthermore, spacer antibodies are more likely to inhibit ADAMT13 enzyme activity, as opposed to antibodies in the C terminal region of ADAMTS13, which result in increased ADAMTS13 clearance.