Effects of all-trans retinoic acid or chemotherapy on the molecular regulation of systemic blood coagulation and fibrinolysis in patients with acute promyelocytic leukemia

M. S. Tallman, P. Lefèbvre, R. M. Baine, M. Shoji, I. Cohen, D. Green, H. C. Kwaan, Elisabeth M. Paietta, F. R. Rickles

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Abstract

We studied the pathogenesis of the bleeding disorder in acute promyelocytic leukemia by measuring procoagulant, profibrinolytic, and proinflammatory mediators in peripheral blood and bone marrow cells from 25 previously untreated patients. Patients were induced with either all-trans retinoic acid (ATRA) or chemotherapy. Plasma levels of fibrinopeptide A (FPA), fibrin D-dimer, thrombin antithrombin (TAT) complex, prothrombin fragment 1.2 (F1.2), urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (t-PA) and plasminogen activator-inhibitor 1 (PAI-1) were measured before and after therapy, as was the cellular expression of the genes for tissue factor (TF) and interleukin-1β (IL-1β). The mean plasma levels of fibrin D-dimer, F1.2, TAT and FPA were markedly elevated prior to therapy and declined during the first 30 days of treatment with either ATRA or chemotherapy, but more rapidly and to a greater extent in patients treated with ATRA. ATRA treatment was associated with a significant decrease in TF gene expression in bone marrow cells during the first 30 days of treatment, whereas IL-1β gene expression, which decreased in the cells of six patients treated with either chemotherapy or ATRA, actually increased in the remaining six patients treated with either chemotherapy or ATRA. In patients with APL, treatment with either chemotherapy or ATRA rapidly ameliorates the coagulopathy, as indicated by an abrupt decline in markers of clotting activation. An increase in cytokine gene expression (e.g. IL-1β) may provide an explanation for the persistent hypercoagulability observed in some patients with APL, regardless of therapeutic approach. Our data confirms and extends earlier observations by others that ATRA is more effective than chemotherapy alone in rapidly reducing the procoagulant burden of APL tumor cells. However, our data also suggests that cytokine expression in some patients may be accelerated by either chemotherapy or ATRA. The implications of this observation for understanding the retinoic acid syndrome will require further studies.

Original languageEnglish (US)
Pages (from-to)1341-1350
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume2
Issue number8
DOIs
StatePublished - Aug 2004
Externally publishedYes

Fingerprint

Acute Promyelocytic Leukemia
Blood Coagulation
Fibrinolysis
Tretinoin
Drug Therapy
Interleukin-1
Fibrinopeptide A
Gene Expression
Thromboplastin
Bone Marrow Cells
Therapeutics
Cytokines
Thrombophilia
Antithrombins
Plasminogen Activator Inhibitor 1
Urokinase-Type Plasminogen Activator
Tissue Plasminogen Activator
Tumor Burden
Thrombin
Hemorrhage

Keywords

  • Acute promyelocytic leukemia
  • Coagulopathy

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effects of all-trans retinoic acid or chemotherapy on the molecular regulation of systemic blood coagulation and fibrinolysis in patients with acute promyelocytic leukemia. / Tallman, M. S.; Lefèbvre, P.; Baine, R. M.; Shoji, M.; Cohen, I.; Green, D.; Kwaan, H. C.; Paietta, Elisabeth M.; Rickles, F. R.

In: Journal of Thrombosis and Haemostasis, Vol. 2, No. 8, 08.2004, p. 1341-1350.

Research output: Contribution to journalArticle

Tallman, M. S. ; Lefèbvre, P. ; Baine, R. M. ; Shoji, M. ; Cohen, I. ; Green, D. ; Kwaan, H. C. ; Paietta, Elisabeth M. ; Rickles, F. R. / Effects of all-trans retinoic acid or chemotherapy on the molecular regulation of systemic blood coagulation and fibrinolysis in patients with acute promyelocytic leukemia. In: Journal of Thrombosis and Haemostasis. 2004 ; Vol. 2, No. 8. pp. 1341-1350.
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AU - Lefèbvre, P.

AU - Baine, R. M.

AU - Shoji, M.

AU - Cohen, I.

AU - Green, D.

AU - Kwaan, H. C.

AU - Paietta, Elisabeth M.

AU - Rickles, F. R.

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N2 - We studied the pathogenesis of the bleeding disorder in acute promyelocytic leukemia by measuring procoagulant, profibrinolytic, and proinflammatory mediators in peripheral blood and bone marrow cells from 25 previously untreated patients. Patients were induced with either all-trans retinoic acid (ATRA) or chemotherapy. Plasma levels of fibrinopeptide A (FPA), fibrin D-dimer, thrombin antithrombin (TAT) complex, prothrombin fragment 1.2 (F1.2), urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (t-PA) and plasminogen activator-inhibitor 1 (PAI-1) were measured before and after therapy, as was the cellular expression of the genes for tissue factor (TF) and interleukin-1β (IL-1β). The mean plasma levels of fibrin D-dimer, F1.2, TAT and FPA were markedly elevated prior to therapy and declined during the first 30 days of treatment with either ATRA or chemotherapy, but more rapidly and to a greater extent in patients treated with ATRA. ATRA treatment was associated with a significant decrease in TF gene expression in bone marrow cells during the first 30 days of treatment, whereas IL-1β gene expression, which decreased in the cells of six patients treated with either chemotherapy or ATRA, actually increased in the remaining six patients treated with either chemotherapy or ATRA. In patients with APL, treatment with either chemotherapy or ATRA rapidly ameliorates the coagulopathy, as indicated by an abrupt decline in markers of clotting activation. An increase in cytokine gene expression (e.g. IL-1β) may provide an explanation for the persistent hypercoagulability observed in some patients with APL, regardless of therapeutic approach. Our data confirms and extends earlier observations by others that ATRA is more effective than chemotherapy alone in rapidly reducing the procoagulant burden of APL tumor cells. However, our data also suggests that cytokine expression in some patients may be accelerated by either chemotherapy or ATRA. The implications of this observation for understanding the retinoic acid syndrome will require further studies.

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