Journal
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume 7, Issue 7, Pages 1128-1133Publisher
WILEY
DOI: 10.1111/j.1538-7836.2009.03449.x
Keywords
antithrombin; l-asparaginase; dexamethasone; HSR; prednisone; UPR
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Funding
- SAF2006-06212 (MCYT FEDER) [SAF2006-06212]
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Background: l-asparaginase (l-ASP) treatment of patients with acute lymphoblastic leukemia causes a severe antithrombin deficiency by intracellular retention of this serpin within the endoplasmic reticulum (ER) of hepatic cells, and a subsequent risk of thrombosis. Interestingly, co-administration of dexamethasone with l-ASP seems to reduce the risk of thrombosis. Objectives: We have investigated the effect of two corticoids, dexamethasone and prednisone, on the conformational consequences of l-ASP treatment on antithrombin. Patients/methods: Levels, activity, conformation and immunohistological features of antithrombin were studied in patients, cell and mice models. Because of the importance of the steroid receptor-heat stress response (HSR) axis, and the role of unfolded protein response (UPR) in conformational diseases, we also evaluated Hsp27, Hsp70, Hsp90, HSF-1 and ER chaperons (Grp78 and Grp94). Results: In all models, l-ASP alone or in combination with prednisone caused the intracellular retention of antithrombin associated with a severe deficiency. In contrast, the combination of l-ASP with dexamethasone ameliorated both the deficiency and intracellular retention of the serpin, which is associated with increased expression of heat shock proteins and ER-chaperons. Conclusions: These results suggest a protective effect of dexamethasone on the conformational consequences of l-ASP on antithrombin as a result of exacerbated HSR and UPR that help to explain the reduced risk of thrombosis reported in patients that follow this scheme of treatment.
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