Abstract
Abnormalities of plasma von Willebrand factor (VWF) have been recognized to be associated with thrombotic thrombocytopenic purpura (TTP) for over 20 years. Patients with chronic, relapsing TTP have VWF multimers that are larger than normal, similar in size to those secreted by cultured endothelial cells. Recent observations have documented that a deficiency of a VWF-cleaving protease (termed ADAMTS13) may be responsible for the presence of these unusually large VWF multimers. Multiple mutations of the ADAMTS13 gene can result in ADAMTS13 deficiency and cause congenital TTP; autoantibodies neutralizing ADAMTS13 protease activity have been associated with acquired TTP.
In Section I, Dr. Evan Sadler reviews the structure, biosynthesis, and function of the ADAMTS13 protease. He describes the mutations that have been identified in congenital TTP and describes the relationship of ADAMTS13 deficiency to the development of both congenital and acquired TTP. Dr. Sadler postulates that the development of TTP may be favored by conditions that combine increased VWF secretion, such as during the later stages of pregnancy, and decreased ADAMTS13 activity.
In Section II, Dr. Bernhard Lämmle describes the assay methods for determining ADAMTS13 activity. Understanding the complexity of these methods is essential for understanding the difficulty of assay performance and the interpretation of assay data. Dr. Lämmle describes his extensive experience measuring ADAMTS13 activity in patients with TTP as well as patients with acute thrombocytopenia and severe illnesses not diagnosed as TTP. His data suggest that a severe deficiency of ADAMTS13 activity (< 5%) is a specific feature of TTP. However, he emphasizes that, although severe ADAMTS13 deficiency may be specific for TTP, it may not be sensitive enough to identify all patients who may be appropriately diagnosed as TTP and who may respond to plasma exchange treatment.
In Section III, Dr. James George describes the evaluation and management of patients with clinically suspected TTP, as well as adults who may be described as having hemolytic-uremic syndrome (HUS). Dr. George presents a classification of TTP and HUS in children and adults. Appropriate evaluation and management are related to the clinical setting in which the diagnosis is considered. A clinical approach is described for patients in whom the diagnosis of TTP or HUS is considered (1) following bone marrow transplantation, (2) during pregnancy or the postpartum period, (3) in association with drugs which may cause TTP either by an acute immune-mediated toxicity or a dose-related toxicity, (4) following a prodrome of bloody diarrhea, (5) in patients with autoimmune disorders, and (6) in patients with no apparent associated condition who may be considered to have idiopathic TTP. Patients with idiopathic TTP appear to have the greatest frequency of ADAMTS13 deficiency and appear to be at greatest risk for a prolonged clinical course and subsequent relapse. Management with plasma exchange has a high risk of complications. Indications for additional immunosuppressive therapy are described.
Thrombotic Thrombocytopenic Purpura: Etiopathogenesis, Diagnostics and Basic Principles of Treatment