An update on the pathogenesis and management of acquired thrombotic thrombocytopenic purpura. Yarranton H, Machin SJ. Current Opinion in Neurology 2003;16(3):367-373.

Thrombotic thrombocytopenic purpura (TTP), a clinical syndrome characterized by thrombocytopenia and microangiopathic hemolytic anemia, was almost universally fatal until the introduction of plasma exchange (PE) therapy in the 1970s. Current outcomes have improved dramatically with the initiation of prompt PE, a treatment routinely used without any real understanding of why it is effective. Recent advances suggest that a deficiency of a specific plasma metalloprotease, responsible for the physiological processing of von Willebrand factor (VWF) multimers, plays a substantial role in the pathogenesis of congenital and acquired idiopathic TTP. The VWF-cleaving protease has now been identified as a new member of the ADAMTS family of metalloproteases, designated ADAMTS13. The acquired form of TTP is associated with inhibitory autoantibodies against ADAMTS13, and the congenital chronic relapsing form is caused by mutations in the ADAMTS13 gene, resulting in a constitutional deficiency. The clinical presentation of TTP is diverse and frequently has an insidious onset. Neurological manifestations often fluctuate and vary widely. Such symptoms occur in 63% to 70% of individuals at presentation and ultimately develop in 90% of patients. Coma at presentation is a poor prognostic indicator. Neuroimaging does not aid in the diagnosis of TTP, but if abnormal it may be indicative of more severe disease and the possibility of long-term neurological sequelae. There is also no correlation between EEG and neurological symptoms, but EEG evaluation and monitoring may identify patients who could benefit from anticonvulsant therapy. Renal impairment is reported in 59% of individuals at diagnosis, but is more frequently associated with hemolytic uremic syndrome. (HUS). Chest pain and cardiac problems are not uncommon. Gastrointestinal ischemia may manifest as abdominal pain, nausea and vomiting. Serious retinal detachment is a recognized complication of TTP as well. In terms of laboratory findings, severe thrombocytopenia at presentation correlates with increased mortality. PE has been proved to be the most important therapy in TTP, but clinical data for adjunctive therapies, such as corticosteroids, antiplatelet drugs and other immunosuppressive agents often used in combination with PE, are less well defined. Clinical trials are necessary to determine whether other plasma products are at least as good as fresh frozen plasma (FFP) in plasma exchange. The advent of plasma exchange therapy has dramatically reduced mortality rates from approximately 90% to 10%-30%. PE should be instituted within 24 hours of presentation because delay may result in increased treatment failures and mortality rates. Recent advances in our understanding of the pathological mechanisms of TTP not only provide a rationale for the previously empirical PE therapy (removal of the inhibitory antibodies and replacement of the deficient protease from the plasma infused), but may also help in developing more rational and targeted treatment strategies.