Effect of all-trans retinoic acid on procoagulant and fibrinolytic activities of cultured blast cells from patients with acute promyelocytic leukemia

Abstract

The mechanisms underlying acute promyelocytic leukemia (APL) coagulopathy and its reversal by administration of all-trans retinoic acid (ATRA) have been investigated. Bone marrow promyelocytic blasts from nine patients with APL were cultured with or without ATRA 1 mumol/L. Cultured blasts (days 0, 3, 6, and 9) were washed, resuspended in phosphate buffer, lysed by freezing and thawing, and then assayed for procoagulant activity (PCA), elastase activity, tissue factor (TF) antigen, tissue-type plasminogen activator (t-PA) antigen and urokinase- type plasminogen activator (u-PA) antigen. PCA was determined by a recalcification assay. Elastase was measured by an amidolytic assay (S- 2484). TF, t-PA, and u-PA antigens were measured by an enzyme-linked immunosorbent assay (ELISA). Malignant promyelocytes isolated from the patients had increased levels of PCA and TF as compared with the control polymorphonucleates, and low levels of elastase, t-PA, and u- PA; the patient blast PCA level was significantly related to the degree of hypofibrinogenemia. In this system, blast PCA depended on the tissue factor and was significantly correlated to the TF antigen values. In the cultures without ATRA, PCA, TF, and u-PA progressively increased, whereas elastase and t-PA levels remained essentially unchanged. In the presence of ATRA, all parameters (except u-PA) decreased during the culture time. Thus, a major role of the promyelocytic blast cell PCA in the pathogenesis of M3-related coagulopathy is suggested; the ATRA effect on coagulopathy seems mainly mediated by a downregulation of the PCA.

Bleeding and thrombosis in acute promyelocytic leukemia

“…However, a later study demonstrated lower levels of fibrinolytic and proteolytic activity in APL blasts compared with mature neutrophils. In this study, use of ATRA was not associated with changes in protease activity of APL cells [24]. In another study, no correlation was noted between elastase levels and D‐dimer concentration or other hemostatic parameters during treatment with ATRA.…”

“…Both CP and TF have been identified in the human APL cell line NB4 [19, 21]. 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].…”

Platelets in cancer metastasis: To help the “villain” to do evil

“…Thus, cancer cells may produce high levels of blood coagulation factors, including factor V (FV), FVIII, FIX and FXI, 15 while many cancer cell types (e.g., leukaemia and colon cancer) express tissue factor. [30][31][32] These alternations then lead to enhanced coagulant activities and thrombin generation. Indeed, cancer patients are often seen with signs of hypercoagulant activities, such as elevated plasma levels of D-dimers, thrombin-antithrombin complex and prothrombin fragment 1 1 2.…”

“…15,42 Malignancy may also induce the disturbance of fibrinolysis system, either with hyperfibrinolytic or hypofibrinolytic alterations. 15,31 The disturbances of coagulation system may then lead to exaggerated platelet activation.…”

Pathophysiology of the Thrombophilic State in the Cancer Patient

“…Several authors have identified TF in these cells. 47,[67][68][69] Falanga et al [57][58][59] reported the identification of CP in acute myelogenous leukemia blast cells of various phenotypes, with the greatest expression in cultured cells from patients with the acute promyelocytic leukemia (APL) subtype. Recent data showed that all-trans-retinoic acid (ATRA) can influence the expression of PCA in cultured APL cells in vitro.…”