title: 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.
authors.affiliation: Hematology Division, Ospedali Riuniti, Bergamo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Falanga
authors.forename: L
authors.initials: L
authors.lastname: Iacoviello
authors.forename: V
authors.initials: V
authors.lastname: Evangelista
authors.forename: D
authors.initials: D
authors.lastname: Belotti
authors.forename: R
authors.initials: R
authors.lastname: Consonni
authors.forename: A
authors.initials: A
authors.lastname: D'Orazio
authors.forename: L
authors.initials: L
authors.lastname: Robba
authors.forename: M B
authors.initials: MB
authors.lastname: Donati
authors.forename: T
authors.initials: T
authors.lastname: Barbui
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000378:metabolism*; D001854:Bone Marrow Cells; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D005342:Fibrinolysis; D006487:Hemostasis; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D001779:Blood Coagulation Factors; D015853:Cysteine Proteinase Inhibitors; D009363:Neoplasm Proteins; D014212:Tretinoin; D013925:Thromboplastin; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant