Coagulation disorders associated with acute promyelocytic leukemia: corrective effect of all-trans retinoic acid treatment.
The bleeding diathesis in patients with acute promyelocytic leukemia (APL) is generally attributed to disseminated intravascular coagulation (DIC), initiated by the release of procoagulant activity from leukemic cells. Primary fibrinogenolysis, mediated by the release of leukocyte proteases, may also contribute to this disorder. We analyzed coagulation parameters in 15 non-septic APL patients. Before treatment, there was evidence of thrombin activation with DIC: increased levels of circulating thrombin-antithrombin III complexes, prothrombin fragments 1 + 2 and D-Dimer complexes. This DIC syndrome was probably limited, since no prothrombin time decrease, no significant factor V consumption, and normal levels of coagulation inhibitors (antithrombin III and protein C) were observed in APL patients when compared to normal controls. In this context, marked hypofibrinogenemia suggested primary fibrinogenolysis as the predominant etiology. Despite normal or high tissue plasminogen activator (tPA) and plasminogen activator inhibitor (PAI-1) antigen levels, the plasma PAI-1 activity and the formation of tPA/PAI-1 complexes were lower in APL patients than in normal controls, suggesting a proteolytic degradation of PAI-1, not able to complex tPA. Two other fibrinolytic inhibitor molecules (alpha-2 plasmin inhibitor antigen and histidine-rich glycoprotein antigen) were also significantly reduced, as well as the two subunits of fibrin stability factor XIII, although only subunit A is known to be susceptible to thrombin action. Evidence of degraded forms of von Willebrand factor in the plasma suggested an extended proteolytic activity. Four patients treated with all-trans-retinoic acid (ATRA) as a single differentiating agent were studied serially. A dissociation between these two syndromes--DIC and fibrinogenolysis/proteolysis--was observed. The rapid correction of the lysis markers contrasted with a more prolonged persistence of the procoagulant activity. We observed persistently high elastase/alpha 1-proteinase inhibitor complex levels during ATRA therapy, despite progressive correction of all lysis markers. Thus, the release of elastase from promyelocytic leukemic cells is probably not the only determinant of the fibrinogenolytic/proteolytic syndrome. In summary, the present findings provide new arguments for the association of DIC and proteolysis syndromes in APL-associated coagulation disorders. Further prospective studies are needed in order to confirm the persistence of thrombin activation in course of ATRA therapy.
Dombret
H
H
Service Clinique des Maladies du Sang, Hopital Saint-Louis, Paris, France.
Scrobohaci
M L
ML
Ghorra
P
P
Zini
J M
JM
Daniel
M T
MT
Castaigne
S
S
Degos
L
L
D000293:Adolescent; D002454:Cell Differentiation; D002648:Child; D004211:Disseminated Intravascular Coagulation / Q000188:drug therapy / Q000503:physiopathology*; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors; D014212:Tretinoin / Q000627:therapeutic use*
D005338:Fibrin Fibrinogen Degradation Products; D014212:Tretinoin; D005337:Fibrin; D005340:Fibrinogen; D013917:Thrombin