title: Thrombotic thrombocytopenic purpura.
abstract: This overview summarizes the history of thrombotic thrombocytopenic purpura (TTP) from its initial recognition in 1924 as a most often fatal disease to the discovery in 1997 of ADAMTS-13 deficiency as a major risk factor for acute disease manifestation. The cloning of the metalloprotease, ADAMTS-13, an essential regulator of the extremely adhesive unusually large von Willebrand factor (VWF) multimers secreted by endothelial cells, as well as ADAMTS-13 structure and function are reviewed. The complex, initially devised assays for ADAMTS-13 activity and the possible limitations of static in vitro assays are described. A new, simple assay using a recombinant 73-amino acid VWF peptide as substrate will hopefully be useful. Hereditary TTP caused by homozygous or double heterozygous ADAMTS-13 mutations and the nature of the mutations so far identified are discussed. Recognition of this condition by clinicians is of utmost importance, because it can be easily treated and--if untreated--frequently results in death. Acquired TTP is often but not always associated with severe, autoantibody-mediated ADAMTS-13 deficiency. The pathogenesis of cases without severe deficiency of the VWF-cleaving protease remains unknown, affected patients cannot be distinguished clinically from those with severely decreased ADAMTS-13 activity. Survivors of acute TTP, especially those with autoantibody-induced ADAMTS-13 deficiency, are at a high risk for relapse, as are patients with hereditary TTP. Patients with thrombotic microangiopathies (TMA) associated with hematopoietic stem cell transplantation, neo-plasia and several drugs, usually have normal or only moderately reduced ADAMTS-13 activity, with the exception of ticlopidine-induced TMA. Diarrhea-positive-hemolytic uremic syndrome (D+ HUS), mainly occurring in children is due to enterohemorrhagic Escherichia coli infection, and cases with atypical, D- HUS may be associated with factor H abnormalities. Treatment of acquired idiopathic TTP involves plasma exchange with fresh frozen plasma (FFP), and probably immunosuppression with corticosteroids is indicated. We believe that, at present, patients without severe acquired ADAMTS-13 deficiency should be treated with plasma exchange as well, until better strategies become available. Constitutional TTP can be treated by simple FFP infusion that rapidly reverses acute disease and--given prophylactically every 2-3 weeks--prevents relapses. There remains a large research agenda to improve diagnosis of TMA, gain further insight into the pathophysiology of the various TMA and to improve and possibly tailor the management of affected patients.
authors.affiliation: Department of Hematology and Central Hematology Laboratory, Inselspital, University Hospital, Bern, Switzerland. bernhard.laemmle@insel.ch
authors.forename: B
authors.initials: B
authors.lastname: Lämmle
authors.forename: J A
authors.initials: JA
authors.lastname: Kremer Hovinga
authors.forename: L
authors.initials: L
authors.lastname: Alberio
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000378:metabolism; D000071120:ADAMTS13 Protein; D000818:Animals; D006405:Hematology / Q000266:history*; D006463:Hemolytic-Uremic Syndrome / Q000175:diagnosis / Q000453:epidemiology; D006579:Heterozygote; D049673:History, 20th Century; D006720:Homozygote; D006801:Humans; D008957:Models, Genetic; D010455:Peptides / Q000737:chemistry; D011697:Purpura, Thrombotic Thrombocytopenic / Q000175:diagnosis* / Q000453:epidemiology* / Q000235:genetics; D012307:Risk Factors; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D010455:Peptides; D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human