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The complex nature of
the prothrombotic state in acute lymphoblastic leukemia of
childhood
Jose Carlos Jaime-Perez, David Gomez-Almaguer
Correspondence: Dr.
Med. José Carlos
Jaime-Pérez,
M.D., PhD.
Servicio de Hematología, Edificio "Dr. Rodrigo
Barragán Villarreal", 2° piso, Hospital Universitario
"Dr. José E. González" de la UANL, Avenida Madero y
Gonzalitos, Colonia Mitras Centro, C.P. 64460, Monterrey, N.L.,
México.
Phone: 81-(8)348-6136, 81-(8)348-8510.
Fax: 81-(8)675-6717.
The administration of modern chemotherapeutic regimens for the treatment of
acute lymphoblastic leukemia (ALL) in children can be associated with severe
venous thromboembolic complications, mostly during the induction of remission
(IR) stage. Although diverse factors have been implicated in this hypercoagulable
state, intensive E. coli L-asparaginase (L-aspar) administration
appears to be paramount, through a decrease in the biosynthesis and activity
of natural anticoagulant proteins, sometimes compounded by the presence of inherited
prothrombotic risk factors (1). L-aspar pharmacological interaction with additional
agents employed during IR is also of particular relevance (2,3); In this respect,
a recent study including 336 ALL children during IR therapy demonstrated that
the concurrent administration of L-aspar with prednisone, rather than dexamethasone,
was associated with almost six times the frequency of thromboembolic episodes
(10.4% vs 1.8%) (2).
It is now evident that different IR protocols for ALL can lead to different
rates of thrombotic complications; differences in drugs and drug sources, dosages,
time courses, and administration routes could explain this variation. In the
last COALL study, for example, a deep venous thrombosis rate of 2.8% was documented
(4). In contrast, in the PARKAA studies this rate reached 29% and 36.7% (5,6).
In this last report, acquired antiphospholipid antibodies, rather than inherited
prothrombotic risk factors, were found to be associated with thromboembolic
events (6). The influence of both, hereditary and acquired disturbances of coagulation
in the development of thromboembolic episodes might also depend on the treatment
protocol (4). The design of future research in this field must, therefore, take
into account the differences in the drugs administered as one of the variables
responsible for thromboembolism during ALL treatment.
Additional research findings could further contribute to our understanding of
this intricate hypercoagulable state. 1) We have documented an in vitro
agonist effect of L-asparaginase on platelets from ALL children (7), raising
the possibility of a similar platelet agonist effect in vivo. 2) The
administration of vincristine at the same time that L-aspar and prednisone induces
apoptosis of malignant lymphoblasts in vivo, with an apoptotic index
up to 40% (3). Apoptosis participates in a numerous group of biological phenomena,
including thrombogenesis, probably through tissue factor activation (8). Apoptosis
can also trigger the release of microparticles containing circulating blood-borne
tissue factor (9). 3) The formation of potentially thrombogenic heterotypic
complexes has been documented between platelets and mononuclear cells, rendering
theoretically possible their formation between platelets and leukemic lymphoid
cells. In this context, the finding that activated platelets bind preferentially
to mononuclear cells appears relevant (10). 4) Experimental evidence for the
induction of platelet thrombi by bacteria, which frequently invade neutropenic
children during IR therapy, has been recently provided (11).
Some of these factors appear to be particularly important: the administration
of L-aspar and its complex interaction with natural anticoagulants and with
additional chemotherapeutic agents, and the existence of a pool of circulating
tissue factor (9), which could potentially be activated by several circumstances
that develop in ALL patients during IR therapy. In addition, the platelet contribution
to the development and maintenance of the hypercoagulable state in ALL could
be considerable, providing an appropriate membrane surface rich in procoagulant
phospholipids, probably carrying circulating tissue factor (9) and, once the
platelet becomes activated, exposing high-affinity specific receptors for factors
V, VIII, IX, and X (12).
Most of the described findings, summarized in Table 1, need to be
validated in vivo. New research will continue to add
potential etiologies for the genesis and persistence of the
prothrombotic state during IR therapy for childhood ALL. The
specific combination of disease and drug-related factors that
favors the shifting of the hemostatic mechanism towards a
prothrombotic mode with clinical thromboembolic manifestations in
a particular child remains to be defined.
References
- Nowak-Gottl U, Heinecke A, von Kries R, Nurnberger W, Munchow N, Junker R. Thrombotic events revisited in children with acute lymphoblastic leukemia: impact of concomitant Escherichia coli asparaginase/prednisone administration. Thromb Res 2001;103:165-72.
- Nowak-Gottl U, Ahlke E, Fleischhack G, Schwabe D, Schobess R, Schumann C, et al. Thromboembolic events in children with acute lymphoblastic leukemia (BFM protocols): prednisone versus dexamethasone administration. Blood 2003;101:2529-33.
- 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 leukaemia. Br J Haematol 2000;111:875-8.
- Mauz-Korholz C, Junker R, Nowak-Gottl U. Prothrombotic risk factors in children with acute lymphoblastic leukemia treated with delayed E. coli asparaginase (COALL-92 and 97 protocols). Thromb Haemost 2000;83:840-3.
- Male C, Chait P, Ginsberg JS, Hanna K, Andrew M, Halton J, et al. Comparison of venography and ultrasound for the diagnosis of asymptomatic deep vein thrombosis in the upper body in children: results of the PARKAA study. Prophylactic Antithrombin Replacement in Kids with ALL Treated with Asparaginase. Thromb Haemost 2002;87:593-8.
- 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.
- Jaime-Perez JC, Gomez-Almaguer D. Platelet aggregation is stimulated by L-asparaginase in children with acute lymphoblastic leukaemia and in normal individuals. Haematologica 2002;87:891-2.
- Wang J, Weiss I, Svoboda K, Kwaan C. Thrombogenic role of cells undergoing apoptosis. Br J Haematol 2001;115:382-91.
- Balasubramanian V, Grabowski E, Bini A, Nemerson Y. Platelets, circulating tissue factor, and fibrin colocalize in ex vivo thrombi: real-time fluorescence images of thrombus formation and propagation under defined flow conditions. Blood 2002;100:2787-92.
- Rinder HM, Bonan JL, Rinder CS, Ault KA, Smith BR. Activated and unactivated platelet adhesion to monocytes and neutrophils. Blood 1991;78:1760-9.
- Sjobring U, Ringdahal U, Ruggeri Z. Induction of platelet thrombi by bacteria and antibodies. Blood 2002;100:4470-7.
- Ahmad SS, London FS,
Walsh N. The assembly of the factor X-activating complex on
activated human platelets. J Thromb Haemost 2003;1:48-59.
Table 1. Documented and theoretical prothrombotic risk factors in ALL of childhood.
- Decreased synthesis/activity of natural anticoagulants associated to L-asparaginase administration and inherited prothrombotic risk factors (1)
- Concurrent administration of prednisone, rather than dexamethasone, and L-asparaginase (2)
- Dosages, sources, routes of administration, and time courses of both, steroids and L-asparaginase in the different treatment protocols
- Platelet activation by L-asparaginase (7) (in vitro)
- Acquired antiphospholipid antibodies (6)
- Vincristine and prednisone-induced in vivo lymphoblast apoptosis, potentially leading to tissue factor activation (3, 8) (T)
- Release of microparticles containing circulating tissue factor (9) (in vitro, T)
- Preferential binding of activated platelets to mononuclear cells (10) (lymphoblasts?), leading to formation of thrombogenic heterotypic complexes (T)
- Induction of thrombi by bacteria (11) (in vitro, T)
- Exposure of high-affinity platelet receptors for factors V, VIII, IX, and X by activated platelets (12) (in vitro, T)
T indicates theoretical risk factor
