All-trans retinoic acid (ATRA) is an epoch-making agent for the treatment of acute promyelocytic leukemia (APL), because the mechanism of remission induction is due to induce the differentiation of APL cells, but not to kill the cells. Noticeably, it rapidly improves complicating disseminated intravascular coagulation (DIC). This implies that ATRA may specifically affect the expression of procoagulant activity of APL cells.
We studied the changes of tissue factor (TF) activity, TF mRNA, thrombomodulin (TM) antigen, TM cofactor activity and plasminogen activator (PA) activity in leukemic cells of an ATRA-treated APL patient accompanied by DIC.
TF activity of the APL cells decreased by half and the TM cofactor activity showed twofold increase within 2 days after the ATRA treatment, as compared with pretreatment cells. The abnormalities of plasma coagulation-fibrinolytic parameters began to improve in accordance with these changes, and DIC was subsided by day 5. TF mRNA which was detected by RT-PCR in pretreatment leukemic cells, was undetectable on 4 days after ATRA treatment. Morphological changes of APL cells examined by light microscopy were not apparent until day 8.
These results demonstrate that DIC improvement is due to the synergistic effects of decrease of TF and increase of TM in the APL cells induced by ATRA. These phenomena were observed in very early phase, and thus it is suggested that ATRA modulates directly the production of TF and TM in the leukemic cells, apart from the effect on cell differentiation.