Clinical And Basic Study On The Fibrinolytic Activity In Patients With Acute Promyelocytic Leukemia

Objective:To study the fibrinolytic activity in patients with acute promyelocytic leukemia(APL)and the expression of Annexinâ…¡and uPAR in leukemic cells from APL and their alterations on inductive treatment.Methods:26 APL patients were devided into 2 groups receiving all-trans retinoic acid(ATRA)+Daunorubicin(DNR)and ATRA+arsenic trioxide(ATO)+DNR, respectively.The level of tissue type plasminogen activator antigen(t-PA:Ag), plasminogen activator inhibitor type-1 antigen(PAl-1:Ag)and FDP were measured by ELISA,the activity of t-PA,PAI-1 and plasminogen were determined by chromogenic assay,fibrinogen and D-dimer were detected using automatic STAGO instrument of coagulation.The fibrinolysis markers were detected every week during inductive treatment until complete hematologic remission(CR)was achieved.Cell surface expression of Annexinâ…¡and uPAR and their mRNA levels were measured using flow cytrometry and real time-PCR method,respectly,at first diagnosis and when CR was achieved.37 patients suffering from other types of acute leukemia(AL)were served as control.Results:â‘ The levels of PAI-1:A and PAI-1:Ag in AL patients were higher than normal control,while their activity of plasminogen were lower than normal.The level of FDP in acute myelocytic leukemia(AML)was higher than normal control.The highest level of FDP and the lowest activity of PLG were seen in APL.Cell surface expression of Annexinâ…¡and uPAR on APL,M₄ and M₅ cells were higher than on other types of AL cells.â‘¡Both Annexinâ…¡and uPAR on the surface of APL cells declined through a transcriptional mechanism after treatment with ATRA and/or ATO,which were still higher than on the bone marrow mononuclear cells from control.The decline of Annexinâ…¡and uPAR expression was in parallel with the restoration of plasminogen, fibrinogen,FDP and D-dimer.â‘¢The high fibrinolytic activity in NB4 cells,as well as Annexinâ…¡and uPAR mRNA and protein expression,could be down regulatd by either ATO or DNR.Conclusion:â‘ There existed hyperfibrinolysis status in AML,especially in APL, M₄ and M₅,in which both Annexinâ…¡and uPAR were highly expressed.Abnormally high expression of Annexinâ…¡and uPAR on the surface of these leukemic cells may contribute to the increased production of plasmin,which leads to hyperfibrinolysis in these patients.â‘¡The treatment based on ATRA and ATO induced down-regulation of cell surface expression of Annexinâ…¡and uPAR on APL cells may be a mechanism for the relief of the hemorrhagic complications of APL and the decrease of the incidence of DIC in APL.Cell surface expression of Annexinâ…¡and uPAR on APL cells were still higher than on the bone marrow mononuclear cells from normal control,suggesting ATRA and/or ATO induced correction of hyperfibrinolysis in APL in vivo may not completely depend on the down-regulation of Annexinâ…¡and uPAR expression on APL cells.â‘¢The high fibrinolytic activity in NB4 cells can be corrected either by ATO or DNR through down regulating Annexinâ…¡and uPAR mRNA and protein expression in NB4 cells.