title: A role for tissue plasminogen activator in thrombotic thrombocytopenic purpura.
abstract: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by generalized microvascular occlusion. TTP has been related to severe deficiency of ADAMTS13, an enzyme that cleaves von Willebrand factor multimers into less adhesive molecules. However, ADAMTS13 deficiency correlates poorly with severity of thrombocytopenia or microangiopathic hemolysis, with the frequency of neurologic complications or the response to plasma exchange. Also, some patients with severe hereditary ADAMTS13 deficiency consistently relapse every few weeks, whereas others remain asymptomatic into their forties. Taken together, these findings suggest that an additional element is missing in the pathophysiology of TTP. We postulate that both low ADAMTS13 activity and low tissue-plasminogen activator activity are required to trigger TTP attacks. Tissue-plasminogen activator end product, plasmin, extensively degrades von Willebrand factor, breaking-down the bonds between platelets and the blood vessel wall, so that low tissue-plasminogen activator activity prevents a mechanism similar to that of ADAMTS13. The hypothesis that low tissue-plasminogen activator activity plays an important role in TTP pathogenesis is further substantiated by TTP comorbidity. Problems prevalent in patients with TTP attacks or with long-term TTP remission, including increased body mass index, major depression, cognitive abnormalities, hypertension, and premature death, are somehow associated with low tissue-plasminogen activator activity.
authors.affiliation: Department of Hematology, Hospital Federal dos Servidores do Estado, Ministry of Health, Rio de Janeiro, Brazil. Electronic address: sclapauch@ig.com.br.
authors.forename: Silvia
authors.initials: S
authors.lastname: Hoirisch-Clapauch
authors.affiliation: Institute of Psychiatry, Federal University of Rio de Janeiro, National Institute for Translational Medicine, INCT-TM, Brazil.
authors.forename: Antonio Egidio
authors.initials: AE
authors.lastname: Nardi
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency; D000071120:ADAMTS13 Protein; D015551:Autoimmunity; D001792:Blood Platelets / Q000378:metabolism; D015992:Body Mass Index; D003480:Cushing Syndrome / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood*; D012074:Remission Induction; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D014841:von Willebrand Factor; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human