title: Cell-based laboratory evaluation of coagulation activation by antineoplastic drugs for the treatment of lymphoid tumors.
abstract: OBJECTIVE
  Combining vorinostat, L-asparaginase, and doxorubicin (Dox) led to improved response rates in the treatment of lymphoid tumors. However, deep-vein thrombosis has been noted as one of the most serious side effects with these drugs, and how these regimens cause deep-vein thrombosis is unclear.
  
  
  METHODS
  We investigated the procoagulant effects of vorinostat, L-asparaginase, and doxorubicin in lymphoid tumors, focusing on tissue factor, phosphatidylserine, and antithrombin. The human vascular endothelial cell line EAhy926 as well as the lymphoid neoplastic cell lines HUT78 (cutaneous T-cell lymphoma), Molt4 (acute T-lymphoblastic leukemia), and Ramos (Burkitt lymphoma) were employed to investigate these procoagulant effects.
  
  
  RESULTS
  Vorinostat, L-asparaginase, and doxorubicin induced exposure of phosphatidylserine and procoagulant activity on the surface of lymphoid tumor cells. Vorinostat and doxorubicin also induced phosphatidylserine exposure and increased procoagulant activity on EAhy926 cells. Expression of tissue factor antigen was induced by doxorubicin on the surface of each type of cells, whereas expression of tissue factor mRNA was unchanged. Secretion of antithrombin from HepG2 cells was reduced only by L-asparaginase.
  
  
  CONCLUSIONS
  These data suggest that vorinostat and doxorubicin may induce procoagulant activity in vessels through apoptosis of tumor cells and through phosphatidylserine exposure and/or tissue factor expression on vascular endothelial cells. L-asparaginase may induce a thrombophilic state by reducing the secretion of anticoagulant proteins such as antithrombin. The laboratory methods described here could be useful to evaluate the procoagulant effects of antineoplastic drugs.
authors: Laboratory Molecular Genetics of Hematology, Field of Applied Laboratory Science, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Misae
authors: M
authors: Tsunaka
authors: Laboratory Molecular Genetics of Hematology, Field of Applied Laboratory Science, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Reina
authors: R
authors: Arai
authors: Laboratory Molecular Genetics of Hematology, Field of Applied Laboratory Science, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Ayaka
authors: A
authors: Ohashi
authors: Laboratory Molecular Genetics of Hematology, Field of Applied Laboratory Science, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Takatoshi
authors: T
authors: Koyama
keywords: L-asparaginase; Vorinostat; deep-vein thrombosis; doxorubicin; phosphatidylserine; tissue factor