Effects of all-trans-retinoic acid and arsenic trioxide on the hemostatic disturbance associated with acute promyelocytic leukemia

To study the in vivo effect of all-trans-retinoic acid (ATRA) and arsenic t rioxide (As2O3) On the expression of tissue factor (TF) and the other hemos tatic disturbance, a series of parameters were measured either in bone marr ow blasts or plasma from acute promyelocytic leukemia (APL) patients. The p lasma parameters were measured by ELISA or chromogenic studies. The TF tran scription was assessed using reverse transcription-polymerase chain reactio n I(RT-PCR) technique. The results indicated that the blast cell procoagula nt activity (PCA), TF antigen of APL cell lysate, as well as the transcript ion of APL TF mRNA elevated at diagnosis, were reduced after ATRA or As2O3 therapy. The plasma level of P-selectin, TF, thrombin - antithrombin comple x (TAT), soluble fibrin monomer complex, thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), plasmin-antiplasmin complex, tissue plasminogen activator (t-PA) activity, urokinase plasminogen activator (u-PA) and its r eceptor (u-PAR), and D-dimer (D-D) significantly increased. Fibrinogen (Fg) , antigen level of protein C (PC), plasminogen (PLC) activity, alpha (2)-pl asminogen inhibitor activity (alpha (2)-PI), and plasminogen activator inhi bitor (PAI) activity were decreased at diagnosis. The protein C activity (P C:A) and protein S (PS) remained unchanged. All the parameters were restore d to normal ranges after complete remission (CR) except elevation of TF and TAT in both groups as well as PC:A, PS, and t-PA in the ATRA group. In con clusion, there existed activation of platelets and consumption of anticoagu lants as well as activation of coagulation and fibrinolytic system before t reatment. Both ATRA and As2O3 therapy downregulated the expression of TI; m RNA, decreased the PCA and TF level in APL cells, significantly inhibited c oagulation activation, corrected secondary hyperfibrinolysis and the other hemostatic abnormalities, and thus greatly improved the bleeding symptom in early stage of the treatment. (C) 2001 Elsevier Science Ltd. All rights re served.