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Primera edición: 10 de Agosto, 2004

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Especialidades
Principal: Hematología
Relacionadas: Pediatría,  Medicina Interna,  Farmacología

Enviar correspondencia a:
Jaime-Pérez, José Carlos,

Patrocinio y reconocimiento
Investigación apoyada por el Consejo Nacional de Ciencia y Tecnología (CONACYT, México), proyecto # 30930-M.

Abstract
Background and objectives. Acute lymphoblastic leukemia (ALL) accounts for 30% of all childhood malignancies. The enzyme L-asparaginase (L-aspar) constitutes a fundamental component of modern chemotherapeutic regimens for the treatment of ALL. Its administration however, can be associated with severe thromboembolic complications. Diverse studies have documented a decrease in the natural anticoagulant proteins C, S and antithrombin III (ATIII) in children receiving the enzyme. We postulate the hypothesis that L-asparaginase could have a platelet agonist effect, thus contributing to the hipercoagulable state observed in ALL. Patients and methods. Fifteen children under thirteen years of age with a new diagnosis of ALL were included. The treatment protocol included L-asparaginase, 6 000 UI/m², twice a week per 6 weeks. Platelet aggregometry included adenosin diphosphate, adrenaline, collagen and ristocetin. Saline dilutions of L-asparaginase were assayed as additional agonists. The control group consisted of 15 normal donors. Results. Platelet aggregometry documented a direct in vitro agonist effect of L-asparaginase on platelets from children with ALL as well as on those of normal donors. Conclusion. L-asparaginase can act as a potent platelet agonist in vitro. This effect could be one additional procoagulant factor and could contribute to the prothrombotic state observed in ALL.

Key words
Acute lymphoblastic leukemia; childhood leuke

Bibliografía del artículo

1. Pui CH. Acute lymphoblastic leukemia, in Williams Hematology, 6^th ed, Beutler E, Lichtman M, Coller B, and Selighson U (eds), p 1141-1161. McGraw Hill, New York, 2001.
2. Greaves M. Science, Medicine and the Future. Childhood leukemia. Br Med J 2002;324:283-7.
3. Felix CA, Lange BJ, Chessells JM. Pediatric acute lymphoblastic leukemia. Hematology 2000;**:285-302.
4. Richards S, Burrett J, Hann I, Chessells J, Hill F, Bailey C. Improved survival with early intensification: combined results from the Medical Research Council childhood ALL randomized trials, UKALL X and UKALL XI. Medical Research Working Party on Childhood Leukemia. Leukemia 1998;12:1031-1036.
5. Nachman JB, Sather HN, Sensel MG, Triggh ME, Cherlow JM, Lukens JN. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Eng J Med 1998;338:1663-1671.
6. Amylon MD, Shuster J, Berard C, Link MP, Wharam M. Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study. Leukemia 1999;13:335-342.
7. Woo MH, Hak LJ, Storm MC, Sandlund JT, Rivera GK, et al. Anti-asparaginase antibodies following E. coli asparaginase therapy in children with acute lymphoblastic leukemia. Leukemia 1998;12:1257-1533.
8. Larson RA, Fretzin MH, Dodge RK, Schiffer CA. Hypersensitivity reactions to L-asparaginase do not impact on the remission duration of adults with acute lymphoblastic leukemia . Leukemia 1998;12:660-665.
9. Nowak-Gotti U, Wermes C, Junker R, Koch HG, Schobess R, Fleischhack G. Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT 667 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors. Blood 1999;93:1595-1599.
10. Mitchell L, Andrew M, Hanna K, Abshire T, Chait P, Halton J, et al. A prospective cohort study determining the prevalence of thrombotic events in children with acute lymphoblastic leukemia and a central venous line who are treated with L-asparaginase: results of the Prophylactic Antithrombin Replacement in Kids with ALL Treated with Asparaginase Group (PARKAA). Cancer 2003;97:508-16.
11. Mitchell LG, Sutor AH, Andrew M. Hemostasis in childhood acute lymphoblasitic leukemia : coagulopaty induced by disease or treatment. Semin Thromb Hemost 1995;21:390-401.
12. Corso A, Castagnola C, Bernasconi C. Thrombotic events are not exclusive to the remission induction period in patients with acute lymphoblastic leukemia: a report of two cases of cerebral sinus trombosis. Ann Hematol 1997;75:117-119.
13. McCabe WM, Jennings LK. Laboratory evaluation of platelet function, in: Platelet Protocols, Research and Clinical Laboratory Procedures, McCabe WM and Jennings LK, (eds) p. 40-50. Academic Press, San Diego, CA, 1999.
14. Avramis VI, Sencer S, Periclou AP, sather H, Bostrom BC, Cohen LJ, Ettinger AG, Ettinger LJ, franklin J, gaynon OS, Hilden JM, Lange B, Majlessipour F, Mathew P, Needle M, Neglia J, Reaman G, Holsenberg JS. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children´s Cancer Group study. Blood 2002;99:1986-1994.
15. Jaime-Pérez JC, Gómez-Almaguer D. The complex nature of the prothrombotic state in acute lymphoblastic leukemia of childhood. Haematologica 2003;88:(07)ELT25
16. Castaman G, Rodeghiero F, Dini E. Thrombotic complications during L-asparaginase treatment for acute lymphoblastic leukemia. Haematologica 1990;75:567-569.
17. Woo MH, Hak LI, Storm MC, Sandlund JT, Ribeiro RC, Rivera GK, Rubnitz JE, Harrison PL, wang B, Evans WE, Pui CH, Relling MV. Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of acute lymphoblastic leukemia. J Clin Oncol 2000;18:1525-1532.
18. Bonno M, Kawasaki H, Hori H, Umemoto M, Sakurai M,. Rapid desensitization for L-asparaginase sensitivity. J Aller Clin Immunol 1998;101:497-502.
19. Groninger E, de Graaff SSN, Meeuwesen-de-Boer GJ, Sluiter WJ, Poppema S. Vincristine induced apoptosis in vivo in peripheral blood mononuclear cells of children with acute lymphoblasatic leukemia. Br J Haematol 2000;111:875-878.
20. Wang J, Weiss I, Svoboda K, Kwaan C. Thrombogenic role of cells undergoing apoptosis. Br J Haematol 2001;115:382-391.
21. Silverstein RL, Nachman RL. Thrombospondin binds to monocytes-macrophages and mediates platelet-monocyte adhesion. J Clin Invest 1987;79:867-874.
22. Peters MJ, Dixon G, Kotowicz KT, Hatch DJ, Heyderman RS, Klein NJ. Circulating platelet-neutrophil complexes represent a subpopulation of activated neutrophils primed for adhesion, phagocytosis and intracellular killing. Br J Haematol 1999:106:391-399.
23. Larsen E, Celi A, Gilbert GE, Furie BC, Erban JK, Bonfanti R, Wagner DD, Furie B. PADGEM protein: a receptor that mediates the interaction of activated platelets with neutrophils and monocytes. Cell 1989; 59:305-312.
24. Nowak-Göttl U, Alkhe E, Fleischhack G, Schwabe D, Schobess R, Schumann C, Wermes C, Junker R. Thromboembolic events in children with acute lymphoblastic leukemia (BFM protocols): prednisone versus dexamethasone administration. Blood 2003;101:25-29-33.
25. Manoharan A, Gemmell R, Brighton T, Dunkley S, Lopez A, Kkyle P. Thrombosis and bleeding in myeloproliferative disorders: identification of at-risk patients with whole blood platelet aggregation studies. Br J Haematol 1999;105:618-625.
26. Nowak-Gottl U, Boos J, Wolff JE, Lill H, Veltmann H, Werber G, Ahlke E, Jurgens H. Asparaginase decreases clotting factors in vitro: a possible pitfall Int J Clin Lab Res. 1995;25(3):146-8.