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(American Journal of Pathology. 2006;169:142-153.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051238

L-Asparaginase-Induced Antithrombin Type I Deficiency

Implications for Conformational Diseases

David Hernández-Espinosa^*, Antonia Miñano^*, Constantino Martínez^*, Elena Pérez-Ceballos^*, Inmaculada Heras^*, José L. Fuster, Vicente Vicente^* and Javier Corral^*

From the Centro Regional de Hemodonación,^* Universidad de Murcia; and the Servicio de Oncología Pediátrica, Hospital Virgen de la Arrixaca, Murcia, Spain

Serpinopathies, a group of diseases caused by mutations that disrupt the structurally sensitive serpins, have no known acquired cause. Interestingly, L-asparaginase treatment of acute lymphoblastic leukemia patients causes severe deficiency in the serpin antithrombin. We studied the consequences of this drug on antithrombin levels, activity, conformation, and immunohistological and ultrastructural features in plasma from acute lymphoblastic leukemia patients, HepG2 cells, and plasma and livers from mice treated with this drug. Additionally, we evaluated intracellular deposition of 1-antitrypsin. L-Asparaginase did not affect functional or conformational parameters of mature antithrombin; however, patients and mice displayed severe type I deficiency with no abnormal conformations of circulating antithrombin. Moreover, L-asparaginase impaired secretion of antithrombin by HepG2 cells. These effects were explained by the intracellular retention of antithrombin, forming aggregates within dilated endoplasmic reticulum cisterns. Similar effects were observed for 1-antitrypsin in plasma, cells, and livers, and intracellular aggregates of additional proteins were observed in frontal cortex and pancreas. This is the first report of a conformational drug-associated effect on serpins without genetic factors involved. L-Asparaginase treatment induces severe, acquired, and transient type I deficiency of antithrombin (and 1-antitrypsin) with intracellular accumulation of the nascent molecule, increasing the risk of thrombosis.