Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia administered all-trans-retinoic acid

Abstract

All-trans-retinoic acid (ATRA) induces complete remission (CR) in up to 90% of acute promyelocytic leukemia (APL) patients with rapid amelioration of the bleeding syndrome. Previous studies indicate that ATRA treatment in vitro of the APL NB4 cell line can affect their procoagulant activity (PCA). To assess whether ATRA has this effect also in vivo, we prospectively studied the PCA of bone marrow blasts from APL patients on therapy with ATRA alone or associated with chemotherapy. Samples were obtained before, during, and after ATRA. To characterize the coagulopathy, we measured a series of plasma hemostatic variables before and during the first two weeks of therapy, as follows: (1) markers of hypercoagulability; (2) natural anticoagulants; (3) fibrinolysis proteins; and (4) elastase. The results by enzymatic and immunologic methods show that both total (tissue factor-like) and factor VII-independent (cancer procoagulant- like) blast cell PCAs, present before therapy, were reduced during (69% and 65% decrement, respectively) and virtually undetectable after ATRA. The plasma hemostatic assessment of patients before treatment was elevated hypercoagulability markers, low mean protein C, normal fibrinolysis proteins, and increased elastase. After starting ATRA, hypercoagulability markers were reduced within 4 to 8 days, protein C augmented, the overall fibrinolytic balance was unmodified, and elastase remained elevated. These results were not different either with or without chemotherapy and are consistent with the clinical findings of rapid improvement of the coagulopathy.

The pathogenesis and management of the coagulopathy of acute promyelocytic leukaemia

“…These findings were confirmed in studies of APML cells following administration of ATRA in vivo. Comparison of APML cells before and after treatment with ATRA demonstrated decreased CP and TF levels with an associated decrease in procoagulant activity (Falanga et al, 1995). Similarly, treatment with ATRA has been shown to downregulate annexin A2 expression (Liu et al, 2011).…”

“…ATRA induces terminal differentiation of leukaemic promyelocytes and leads to an immediate improvement in bleeding symptoms and almost complete resolution of the associated coagulopathy within 1-2 weeks of treatment (Dombret et al, 1993;Falanga et al, 1995), but the exact mechanisms behind this have not been completely defined. In vitro studies have shown ATRA to interfere with procoagulant and fibrinolytic mechanisms.…”

Bleeding and thrombosis in acute promyelocytic leukemia

“…In vitro studies have demonstrated that ATRA‐induced APL cell differentiation causes loss of expression of CP [22] and TF [23, 24]. TF and CP expression is decreased in bone marrow cells of APL patients given ATRA for remission induction and this decrease precedes normalization of lab abnormalities of coagulation [25]. Thus, tumor‐associated PCA plays a direct role in the clotting complications ofAPL.…”

“…The use of more sensitive diagnostic tests proves that there is increased activity of all three pathways in APL. Levels of thrombin‐antithrombin complex (TAT), prothrombin fragment 1 + 2 (F1 + 2), and fibrinopeptide A, which are all indicators of clotting activation are increased [13, 25, 34]. Elevated levels of FDPs and u‐PA, coupled with depressed plasminogen and α‐2‐antiplasmin levels serve as proof of hyper fibrinolysis [13, 44, 45].…”

“…Elevated levels of FDPs and u‐PA, coupled with depressed plasminogen and α‐2‐antiplasmin levels serve as proof of hyper fibrinolysis [13, 44, 45]. Activation of the nonspecific proteases is evidenced by increased levels of leukocyte elastase and fibrinogen split products of elastase [13, 25, 45]. Relatively normal levels of coagulation inhibitors such as protein C and antithrombin III differentiate APL‐associated coagulopathy from classical DIC.…”