Unbalanced Coagulation-Fibrinolysis Potential during L-Asparaginase Therapy in Children with Acute Lymphoblastic Leukaemia^[*]

Summary

Treatment of acute lymphoblastic leukaemia (ALL) with L-asparaginase (L-asp) may be associated with thrombotic complications, but the pathogenetic mechanisms of thrombus formation and persistence remain unclear. We studied the procoagulant activity (PCA) of peripheral blood mononuclear cells and some components of the plasma fibrinolytic system in L0 children with ALL undergoing remission induction therapy which includes L-asp. Mononuclear cells obtained 14 days after starting L-asp treatment generated significantly higher amounts of PCA (identified as tissue factor) than cells isolated before the first dose of L-asp and 7 days after the cessation of L-asp administration (p <0.01). Augmented PCA coincided with an increase in the plasma D-dimer. The plasma levels of type 1- plasminogen activator inhibitor were found signiticantly elevated during L-asp therapy (p <0.05), whereas plasminogen levels were markedly decreased (p <0.05). These findings suggest that, during the course of L-asp treatment, the coagulation-fibrinolysis balance is shifted towards promotion of fibrin formation and deposition. Although it remains to be conclusively established whether Lasp per se or the concurrent administration of multiple chemotherapeutic agents is responsible for these changes, the latter could contribute to the thrombotic complications associated with remission induction therapy for ALL.

Dedicated to Professor M. Verstraete on the occasion of his 65th birthday

• References

• 1 Priest JR, Ramsey NK C, Latchaw RE, Lockman LA, Hasegawa DK, Cortes TD, Coccia PF, Edson CR, Nerbit M, Krivit W. Thrombotic and hemorrhagic strokes complicating early therapy for childhood acute lymphoblastic leukemia. Cancer 1980; 46: 1545-1554
• 2 Priest JR, Ramsay NK, Steinherz PG, Tubergen DG, Cairo MS, Sitarz AL, Bishop AJ, White L, Trigg ME, Levitt CJ, Cich JA, Coccia PF. A syndrome of thrombosis and hemorrhage complicating L-asparaginase therapy for childhood acute lymphoblastic leukemia. J Pediatr 1982; 100: 984-989
• 3 Kucuk O, Kwaan HC, Gunnar W, Vasquez RM. Thromboembolic complications associated with L-asparaginase therapy. Cancer 1985; 55: 702-706
• 4 Priest JR, Ramsay NK, Bennet AJ, Krivit W, Edson J. The effect of L-asparaginase on antithrombin, plasminogen, and plasma coagulation during therapy for acute lymphoblastic leukemia. J Pediatr 1982; 100: 990-995
• 5 Barbui T, Finazzi G, Vigano S, Mannucci PM. L-asparaginase lowers protein C antigen. Thromb Haemostas 1984; 52: 216
• 6 Conard J, Horellou MH, Van Dreden P, Potevin F, Zittourn R, Samama M. Decrease in protein C in L-asparaginase-treated patients. Br J Haematol 1985; 59: 725-727
• 7 Pui C-H, Chesney CM, Bergum PW, Jackson CW, Rapaport SI. Lack of pathogenetic role of proteins C and S in thrombosis associated with asparaginase-prednisone-vincristine therapy for leukaemia. Br J Haematol 1986; 64: 283-290
• 8 Homans AC, Rybak ME, Baglini RL, Tiarks C, Steiner ME, Forman EN. Effect of L-asparaginase administration on coagulation and platelet function in children with leukemia. J Clin Oncol 1987; 5: 811-817
• 9 Pui C-H, Jackson CW, Chesney CM, Abilgaard CF. Involvement of von Willebrand factor in thrombosis following asparaginase-prednisone-vincristine therapy for leukemia. Am J Hematol 1987; 25: 291-298
• 10 Vellenga E, Kluft C, Mulder NH, Wingaards G, Nieweg HO. The influence of L-asparaginase therapy on the fibrinolytic system. Br J Haematol 1984; 57: 247-254
• 11 Legnani C, Palareti G, Pession A, Poggi M, Vecchi V, Bianchini B, Coccheri S. Intravascular coagulation phenomena associated with prevalent fall in fibrinogen and plasminogen during L-asparaginase treatment in leukemic children. Haemostasis 1988; 18: 179-186
• 12 Bauer KA, Teitel JM, Rosenberg RD. L-asparaginase induced antithrombin III deficiency: Evidence against the production of a hypercoagulable state. Thromb Res 1983; 29: 437-442
• 13 Edgington TS. Recognition coupled responses of the monocyte: activation of coagulation pathways. Nouv Rev Fr Hematol 1983; 25: 1-6
• 14 Lyberg T, Prydz H. The role of cellular cooperation in thromboplastin synthesis. Nouv Rev Fr Hematol 1983; 25: 291-293
• 15 Osterud B, Olsen JO, Benjaminsen AW. The role of complement in the induction of thromboplastin synthesis. Haemostasis 1984; 14: 386-392
• 16 Edwards RL, Rickies FR. Macrophage procoagulants. In: Progress in Hemostasis and Thrombosis Spaet TH. (ed). Grune Stratton; New York: 1984. 7 183-201
• 17 Geczy CL. Induction of macrophage procoagulant by products of activated lymphocytes. Haemostasis 1984; 14: 400-411
• 18 Semeraro N, Lattanzio A, Montemurro P, Papanice M, De Lucia O, De Beilis G, Giordano D. Mechanisms of blood clotting activation in inflammation: Role of mononuclear phagocytes. Int J Tiss Reac 1985; 7: 313-320
• 19 Semeraro N. Different expression of procoagulant activity in macrophages associated with experimental and human tumors. Haemostasis 1988; 18: 47-54
• 20 Sprengers ED, Kluft C. Plasminogen activators inhibitors. Blood 1987; 69: 381-387
• 21 Boyum A. Isolation of lymphocytes, granulocytes and macrophages. Scand J Immunol 1976; (Suppl. 05) 9-15
• 22 Semeraro N, Biondi A, Lorenzet R, Locati D, Mantovani A, Donati MB. Direct induction of tissue factor synthesis by endotoxin in human macrophages from diverse anatomical sites. Immunology 1983; 50: 529-535
• 23 Colucci M, Paramo JA, Collen D. Generation in plasma of a fast acting inhibitor of plasminogen activator in response to endotoxin stimulation. J Clin Invest 1985; 75: 818-824
• 24 Declerck PJ, Alessi MC, Verstreken M, Kruithof EK, Juhan-Vague I, Collen D. Measurement of plasminogen activator inhibitor 1 in biological fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 1988; 71: 220-225