title: In vivo thrombin and plasmin activities in patients with acute promyelocytic leukemia (APL): effect of all-trans retinoic acid (ATRA) therapy.
abstract: APL-associated hemostasis disorders result from at least two distinct mechanisms due to the release of procoagulant activities and plasminogen activators from the leukemic cells. These two mechanisms (thrombin activation and plasmin activation) may cleave the fibrinogen molecule, but their respective roles in low fibrinogen levels and bleeding diathesis genesis remain in dispute. In vivo ATRA therapy induces a rapid correction of both low fibrinogen level and bleeding tendency, but no clear explanation of this beneficial effect has been proposed. We prospectively investigated 27 APL patients at presentation for diffuse intravascular coagulation (DIC) markers (prothrombin activation fragment and thrombin/antithrombin complexes) and plasmin-dependent primary fibrinogenolysis markers (alpha 2 plasmin inhibitor consumption +/- plasmin/alpha 2 plasmin inhibitor complexes). Fourteen of these patients were then serially studied during the first 2 weeks of ATRA therapy. Four of them, however, developed an hyperleukocytosis requiring additional chemotherapy before the end of the 2nd week. At presentation, low level of fibrinogen was clearly associated with alpha 2 plasmin inhibitor deficiency (p < 0.01), while DIC was equally present in fibrinogenopenic and non-fibrinogenopenic patients. Moreover, was observed a rapid simultaneous correction of low fibrinogen levels and plasmin activation markers in APL patients undergoing ATRA therapy (before day 5), but a more prolonged persistence of DIC markers (until day 14). Initial bleeding syndrome seemed more frequent in patients with initial low fibrinogen level. These data indicate that plasmin-dependent primary fibrinogenolysis is the major etiologic factor of low fibrinogen level in APL patients. In vivo differentiation ATRA therapy induces a rapid decrease in the plasmin activation and a normalization of fibrinogen level, while DIC may in vivo persist for several weeks. Prospective studies evaluating antifibrinolytic agents as therapy of APL-associated hemostasis disorders should be considered. Additionally, prophylactic heparin therapy might be useful after day 5 in patients undergoing ATRA therapy, since they present a prolonged procoagulant tendency.
authors.affiliation: Department of Hematology, Hôpital Saint-Louis, Paris, France.
authors.forename: H
authors.initials: H
authors.lastname: Dombret
authors.forename: M L
authors.initials: ML
authors.lastname: Scrobohaci
authors.forename: M T
authors.initials: MT
authors.lastname: Daniel
authors.forename: J M
authors.initials: JM
authors.lastname: Micléa
authors.forename: S
authors.initials: S
authors.lastname: Castaigne
authors.forename: C
authors.initials: C
authors.lastname: Chomienne
authors.forename: P
authors.initials: P
authors.lastname: Fenaux
authors.forename: L
authors.initials: L
authors.lastname: Degos
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000933:Antifibrinolytic Agents; D001778:Blood Coagulation Disorders / Q000209:etiology; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D005341:Fibrinolysin / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013917:Thrombin / Q000378:metabolism*; D014212:Tretinoin / Q000627:therapeutic use*; D000979:alpha-2-Antiplasmin / Q000032:analysis
chemical_list: D000933:Antifibrinolytic Agents; D000979:alpha-2-Antiplasmin; C037742:plasmin-plasmin inhibitor complex; D014212:Tretinoin; D005340:Fibrinogen; D013917:Thrombin; D005341:Fibrinolysin