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Coagulation profile during induction chemotherapy in childhood acute

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Article in Indian Journal of Pathology and Microbiology · January 2017

DOI: 10.4103/0377-4929.200029

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 Coagulation profile during induction chemotherapy in
Original Article

childhood acute lymphoblastic leukemia

Shivali Sehgal, Sunita Sharma, Jagdish Chandra1, Anita Nangia
Departments of Pathology and 1Paediatrics, Lady Hardinge Medical College, Kalawati Saran Children’s Hospital, New Delhi, India

Address for correspondence:

Dr. Shivali Sehgal, Department of Pathology, Lady Hardinge Medical College, New Delhi ‑ 110 001, India.
E‑mail: [email protected]

ABSTRACT Access this article online

Website: www.ijpmonline.org
Context: Thromboembolism in children with acute lymphoblastic leukemia (ALL) PMID: xxxxxxxxx (when available)
is most commonly reported after the initiation of antileukemic therapy, indicating DOI: 10.4103/0377-4929.200029
a possible interaction of disease and therapy. Aims: To study the effect of Quick Response Code:
induction chemotherapy on coagulation parameters in pediatric ALL patients.
Settings and Design: Thirty‑seven newly diagnosed patients of ALL up to
18 years of age were evaluated along with 30 age‑ and sex‑matched controls.
Subjects and Methods: At the time of diagnosis (day 0), various coagulation
parameters were tested. These were sequentially analyzed on day 14 (after
the completion of L‑asparaginase doses) and on day 28 of therapy (after the
completion of induction). Prothrombin time (PT), activated partial thromboplastin
time (APTT), fibrinogen, protein C (PC) activity, and protein S (PS) activity
were done by a clot‑based method. Antithrombin (AT) assay was performed by
chromogenic method. D‑dimer (D‑DI), tissue plasminogen activator (tPA), and in various series.[5,6] The pathogenesis of
plasminogen activator inhibitor type 1 (PAI‑1) levels were assayed by ELISA hypercoagulability in ALL is multifactorial.
method. Statistical Analysis Used: The statistical analysis was done using It can be due to the disease per se or due to
Statistical Package for Social Sciences version 17.0. Results: No major change contributing factors including immobility,
in PT and APTT was observed during chemotherapy; however, fibrinogen
infection, use of central venous access
levels declined significantly (P = 0.04), following L‑asparaginase treatment.
D‑DI levels were significantly raised at diagnosis (P < 0.001) and throughout devices, and anticancer therapy.
induction therapy (P < 0.001). PC, PS, and AT were reduced in the initial part
of induction, followed by a rise in the second half of therapy, reaching their Thromboembolism in children with
respective baseline levels (P < 0.05). The tPA levels were significantly reduced ALL is most commonly reported after
in the patients at diagnosis and throughout therapy (P < 0.001). PAI‑1 levels the initiation of antileukemic therapy,
were comparable to controls at presentation and showed a rising trend during indicating a possible interaction of disease
therapy. Conclusions: The results of this study indicated that both the malignant and therapy.[7] Much is already known
process and the drugs used in combined chemotherapy cause thrombin activation, about the effect of chemotherapeutic
decrease in natural inhibitors, and hypofibrinolysis, resulting in hypercoagulability.
drugs, especially L‑asparaginase, on the
Thus, ALL per se is a hypercoagulable state and the prothrombotic condition at
the time of diagnosis gets enhanced during induction chemotherapy. coagulation system. The past studies
done on the effect of chemotherapy on
coagulation parameters in ALL patients
KEY WORDS: Acute lymphoblastic leukemia, childhood, coagulation profile,
induction chemotherapy revealed variable results. Furthermore,
there is a paucity of Indian literature on
This is an open access article distributed under
INTRODUCTION the terms of the Creative Commons Attribution-
NonCommercial-ShareAlike 3.0 License, which
allows others to remix, tweak, and build upon
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. In the work non-commercially, as long as the
developed countries, this disease has become curable in 4 out of 5 children with the use author is credited and the new creations are
licensed under the identical terms.
of intensive multidrug chemotherapy.[1‑4] However, attention needs to be directed toward
the morbidity and mortality caused not only by the disease but also by the treatment For reprints contact: [email protected]
regimens used in these patients. How to cite this article: Sehgal S, Sharma S,
Chandra J, Nangia A. Coagulation profile during
induction chemotherapy in childhood acute
Thromboembolism is a well‑known complication of ALL which can be symptomatic or lymphoblastic leukemia. Indian J Pathol
asymptomatic. The risk of thrombosis in children with ALL ranged from 1.1% to 36.7% Microbiol 2017;60:50-6.

50 © 2017 Indian Journal of Pathology and Microbiology | Published by Wolters Kluwer - Medknow
 Sehgal, et al.: Coagulation during induction chemotherapy in childhood ALL

the hemostatic alterations in ALL patients and, specifically, on History was taken and physical examination was done for the
the changes in coagulation profile with the administration of cases regularly to clinically rule out any thromboembolic event.
chemotherapy. It is important to know whether any coagulation
parameter is particularly altered in ALL patients on chemotherapy Thirty age‑ and sex‑matched controls (Group II) were taken
and can be used in the early diagnosis of a hypercoagulable state. from among children undergoing minor elective surgery. All
This can be helpful in preventing thrombotic episodes and its the aforementioned coagulation tests were performed in them.
clinical consequences in these patients.
Treatment of ALL comprises phases of induction, consolidation,
The present study was undertaken to note any change in interim maintenance, reinduction and reconsolidation, and
coagulation inhibitor levels (protein C [PC], protein S [PS], maintenance. The various drugs used during induction phase are
antithrombin [AT]), or fibrinolytic system during induction prednisolone, vincristine, L‑asparaginase, daunomycin, cytosine
chemotherapy in children with ALL. arabinoside, and methotrexate. Out of these, L‑asparaginase is
given only in the initial half of induction chemotherapy.
SUBJECTS AND METHODS
The statistical analysis was done using the Statistical Package
The study was conducted in the Department of Pathology and the for Social Sciences version 17.0 [SPSS Inc. Released 2008. SPSS
Department of Paediatrics, Lady Hardinge Medical College, and Statistics for Windows, Version 17.0. Chicago: SPSS Inc.]. The
Kalawati Saran Children’s Hospital, New Delhi, from November data were expressed as mean ± standard deviation. Besides
2010 to March 2012. A total of 37 newly diagnosed ALL patients descriptive statistics, the comparison of baseline values of nine
up to 18 years of age who were receiving chemotherapy in this parameters (PT, APTT, fibrinogen, D‑DI, PC, PS, AT, tPA, PAI‑1)
hospital were included in the study (Group I) after obtaining between the cases and controls was done using “Mann–Whitney
informed consent from the parents. Patients with multiorgan U‑test” for nonparametric data and “independent sample t‑test”
failure, previous history of thrombosis, deranged liver function for parametric data.
tests/renal function tests were excluded from the study. Further,
patients who had received corticosteroids for >7 days before The change of variables during chemotherapy (day 0 [D0], D14,
hospital admission were not included in the study. and D28) in the cases was done using repeated measure analysis (an
extension of the paired t‑test), followed by post hoc comparison by
A clean venipuncture was performed and 2.7 ml of blood was the Bonferroni method. The P < 0.05 was considered statistically
collected in a citrate vacutainer (containing 0.3 ml of 3.2% significant. The sequential analysis was performed only in thirty
trisodium citrate). Platelet‑poor plasma was prepared for patients, for whom three complete sets of data were available.
coagulation tests as soon as possible by centrifuging the samples
at 2000 g (relative centrifugal force) for 15 min. Prothrombin RESULTS
time (PT), activated partial thromboplastin time (APTT), and
fibrinogen estimation were done on the same day using CA‑50 Out of 37 cases (Group I), only thirty cases could be followed
semi‑automated coagulation analyzer. The remaining plasma up until the end of induction therapy (6 patients expired
was stored in separately labeled aliquots, for each coagulation and 1 patient left the hospital without completing induction
test, and stored in a deep freezer at –40°C. Before performing the chemotherapy against medical advice). These thirty cases
tests, the plasma samples were thawed in a water bath set at 37°C. were included in Group IA. Sequential analysis of the various
coagulation parameters on D0, D14, and D28 of therapy was
PT, APTT, and fibrinogen estimation (Clauss principle) performed for only these patients.
were done by a clot‑based method in the patients at the
time of diagnosis. D‑dimer (D‑DI) level was assayed using The age of the patients in Group I ranged from 2 to 14 years,
Asserachrom® D‑DI‑Diagnostica Stago (France) ELISA kit. with a mean of 5.57 ± 3.56 years. Maximum number of
PC and PS activity were determined by clot‑based method cases was between 2 and 4 years of age (37.84% of the cases).
using STA‑STACLOT®‑Diagnostica Stago (France ‑ performed Twenty‑six (70.27%) cases were male and 11 (29.73%) were
manually). AT assay was performed by chromogenic method female, with a male to female ratio of 2.36:1.
using STA‑STACHROM® AT III‑Diagnostica Stago (France). The
fibrinolytic system was analyzed by assaying tissue plasminogen Results at the time of presentation
activator (tPA) and plasminogen activator inhibitor type 1 (PAI‑1) Table 1 shows the comparison of coagulation tests of patients at
levels by ELISA (t‑PA (human) – DRG Diagnostics ELISA the time of diagnosis with control values. The difference between
and Asserachrom® PAI‑1‑Diagnostica Stago (France) ELISA), PT, APTT, and fibrinogen was not found to be statistically
respectively. significant. The D‑DI levels were significantly higher in Group I
as compared to Group II (P < 0.001).
All the coagulation tests were repeated in the cases after the
completion of L‑asparaginase doses (day 14 [D14]) and after the PC activity (mean value = 54.13 ± 43.45%) and PS activity (mean
completion of induction chemotherapy (day 28 [D28]). value = 50.39 ± 31.24%) of Group I were found to be

Indian Journal of Pathology and Microbiology ¦ Volume 60 ¦ Issue 1 ¦ January-March 2017 51

 Sehgal, et al.: Coagulation during induction chemotherapy in childhood ALL

significantly lower than that of Group II (P < 0.001 for both). AT However, the mean values did not differ significantly between
activity (mean value of 112.32 ± 29.44%) was comparable to that the three time points (P = 0.99).
of controls (P = 0.73).
The PC and PS activity were significantly lower than control
The tPA levels (mean = 142.62 ± 111.44 pg/ml) were significantly values throughout induction therapy. Both the anticoagulants
reduced in the patients as compared to controls (P < 0.001). significantly reduced on D14 of therapy and returned to respective
PAI‑1 levels of Group I (mean value of 53.85 ± 39.94 ng/ml) were baseline levels on D28 (P = 0.02 for both) [Figure 1]. AT activity
higher than those of Group II; however, the difference was not was significantly lower than controls on D14 of therapy (P < 0.001)
statistically significant (P = 0.12). and comparable on D28. It was found to significantly reduce in
the initial part of induction and return to normal values in the
Sequential analysis of coagulation parameters during latter part (P = 0.006) [Figure 1].
induction
Table 2 shows the sequential analysis of coagulation parameters Sequential analysis revealed that the mean tPA levels did not vary
during induction chemotherapy. The mean PT value did not significantly during induction therapy (P = 0.87) [Figure 2]. The
change significantly during chemotherapy (P = 0.71). Further, tPA levels on D0, D14, and D28 of therapy remained significantly
it was found that APTT did not change significantly between lower than control values (P < 0.001). The PAI‑1 levels showed
the three time points (P = 0.27); however, it was significantly a rising trend during induction chemotherapy [Figure 3],
prolonged on D14 of therapy. Fibrinogen levels significantly with values becoming higher than controls on D14 (P = 0.02)
dipped down on D14 of therapy and returned to normal values and D28 (P = 0.001). However, on repeated measure analysis,
on D28 (P = 0.003). The D‑DI levels remained significantly higher the change in levels was not found to be statistically
than control values throughout induction therapy (P < 0.001). significant (P = 0.13).

Table 1: Comparison of coagulation tests at the time of diagnosis with control values
Test Group Range Mean±SD P
PT (s) I (37 cases) 10.10-19.10 13.63±1.92 0.11* (NS)
II (30 controls) 10.70-15.20 12.98±1.14
APTT (s) I (37 cases) 22.60-180.00 40.54±34.36 0.19† (NS)
II (30 controls) 27.30-34.40 30.46±1.98
Fibrinogen (g/l) I (37 cases) 1.30-14.20 3.82±2.11 0.73† (NS)
II (30 controls) 1.90-5.70 3.67±1.06
D‑Dimer (ng/ml [FEU]) I (37 cases) 100.00-4400.00 1613.62±1094.68 <0.001†
II (30 controls) 100.00-500.00 288.83±142.83
PC (%) I (37 cases) 2.00-150.00 54.13±43.45 <0.001†
II (30 controls) 35.00-142.00 93.60±29.48
PS (%) I (37 cases) 5.00-120.00 50.39±31.24 <0.001†
II (30 controls) 30.00-132.00 94.37±26.73
AT (%) I (37 cases) 2.00-140.00 112.32±29.44 0.73* (NS)
II (30 controls) 53.00-146.00 110.03±24.32
tPA (pg/ml) I (37 cases) 5.00-600.00 142.62±111.44 <0.001†
II (30 controls) 500.00-2900.00 981.30±721.53
PAI‑1 (ng/ml) I (37 cases) 0.00-175.00 53.85±39.94 0.12† (NS)
II (30 controls) 5.00-108.00 38.52±33.40
*By independent sample t‑test, †By Mann-Whitney U‑test, P<0.05: Significant. SD: Standard deviation; PT: Prothrombin time; APTT: Activated partial thromboplastin time; PC: Protein C; PS: Protein S;
AT: Antithrombin; tPA: Tissue plasminogen activator; PAI‑1: Plasminogen activator inhibitor type 1; NS: Not significant

Table 2: Sequential analysis of coagulation parameters during induction chemotherapy

Test Day 0 Day 14 Day 28 P
PT (s) 13.79±1.96 13.98±3.57 16.54±19.61 0.71* (NS)
APTT (s) 41.96±38.01 56.50±49.81 38.70±27.06 0.27* (NS)
Fibrinogen (g/l) 3.59±2.24 2.25±1.40 3.52±1.53 0.003*
D‑Dimer (ng/ml [FEU]) 1524.27±1131.45 1545.67±870.47 1548.53±626.94 0.99* (NS)
PC (%) 57.03±43.44 32.23±29.04 59.77±46.90 0.02*
PS (%) 50.55±32.56 29.72±29.52 44.97±33.89 0.02*
AT (%) 110.60±32.01 78.87±38.75 102.87±35.15 0.006*
tPA (pg/ml) 152.03±117.90 168.97±264.22 141.23±167.47 0.87* (NS)
PAI‑1 (ng/ml) 52.14±33.73 64.17±46.58 72.27±40.40 0.13* (NS)
*By repeated measure analysis, P<0.05: Significant. Values of various coagulation parameters are expressed as mean ± SD. SD: Standard deviation; PT: Prothrombin time; APTT: Activated partial thromboplastin
time; PC: Protein C; PS: Protein S; AT: Antithrombin; tPA: Tissue plasminogen activator; PAI‑1: Plasminogen activator inhibitor type 1; NS: Not significant

52 Indian Journal of Pathology and Microbiology ¦ Volume 60 ¦ Issue 1 ¦ January-March 2017

 Sehgal, et al.: Coagulation during induction chemotherapy in childhood ALL

of fibrinolytic pathways, and alterations of endothelium toward

a thrombogenic state.[8]

Thrombosis has been reported in ALL patients both at the time of

diagnosis and during chemotherapy. Most of the thromboembolic
episodes have been reported during the induction phase of
treatment.[9] Coagulation parameters were analyzed before the
start of therapy to note the baseline changes in hemostasis, which
highlighted the effect of the disease per se. Hemostatic parameters
were then analyzed sequentially during induction therapy to
observe the changes due to antileukemic drugs.

Coagulation parameters at the time of diagnosis in

Figure 1: The trend of protein C, protein S, and antithrombin during
acute lymphoblastic leukemia
induction chemotherapy
Most of the studies have shown that PT and APTT were within
normal limits at the time of presentation of ALL,[10,11] similar to
the current series. Fibrinogen level was also found comparable
to that of controls by other authors;[12,11] however, Hunault‑Berger
et al.[13] observed a lower fibrinogen level while Priest et al.[10] had
reported higher baseline values.

Giordano et al.[11] reported raised D‑DI levels; however, the mean

value was lower than that in this study (299 ± 32 ng/ml).

Dixit et al.[14] demonstrated reduced activity of all three natural

anticoagulants. Other series[10,11,15‑19] have reported variable
results.

Figure 2: The trend of tissue plasminogen activator levels during Reduction of PC and PS at the time of diagnosis might possibly
induction chemotherapy be because of consumption of these proteins due to subclinical
coagulation activation (suggested by raised D‑DI levels). Normal AT
activity indicates that the reduction in level due to consumption
was compensated by increased hepatic synthesis[19] of the protein.

Giordano et al.[11] demonstrated high PAI‑1 levels at the time of

diagnosis of ALL. In the current study, PAI‑1 levels although
higher than controls were found to be comparable on statistical
analysis. The levels of tPA were significantly lower as compared
to controls. Contrary to these findings, Semeraro et al.[20] observed
high tPA levels at the time of diagnosis while the PAI‑1 levels were
within the normal range for age. Low levels of tPA and higher
values of PAI‑1 were suggestive of decreased fibrinolysis, leading
to persistence of the thrombus.
Figure 3: The trend of plasminogen activator inhibitor type 1 levels
during induction chemotherapy To summarize, the present study showed that the onset of
leukemia was associated with hemostatic derangement favoring
On follow‑up of thirty cases (Group IA), no clinical evidence of hypercoagulability. The coagulopathy was due to thrombin
thrombosis was observed in any of the patients during induction activation (as evidenced by raised D‑DI). The decreased
chemotherapy. fibrinolysis (due to reduced tPA and raised PAI‑1) and low levels
of PC and PS contributed to the hypercoagulable state at the time
DISCUSSION of diagnosis.

The pathogenesis of cancer‑related thrombosis is complex and During induction chemotherapy

reflects the action of different mechanisms including activation The current study noticed that PT increased slightly (by 1.38%)
of blood coagulation via procoagulant substances, impairment from D0 to D14, and more so (by 18.31%) from D14 to D28, but

Indian Journal of Pathology and Microbiology ¦ Volume 60 ¦ Issue 1 ¦ January-March 2017 53

 Sehgal, et al.: Coagulation during induction chemotherapy in childhood ALL

the changes were not significant statistically. APTT increased The rise in activity of all three natural anticoagulants in the latter
by 34.65% from D0 to D14 and decreased by 31.50% from D14 part of induction could be due to the effect of prednisolone which
to D28 reaching almost baseline values; these changes were, is known to increase hepatic synthesis of these proteins and is
however, not statistically significant. Similarly, Giordano et al.[11] given until the end of induction. Lack of L‑asparaginase in the
observed no significant change in PT and APTT during induction latter part of induction enhances this effect.
chemotherapy.
The levels of tPA slightly increased (11.14%) in the initial part
Fibrinogen levels significantly dropped by 37.32% from D0 to D14 of induction and declined (by 16.42%) in the latter part (not
of therapy (P = 0.04), when patients were given L‑asparaginase. statistically significant). However, Saito et al.[23] noticed a rise in
In the latter part of induction (when L‑asparaginase was tPA levels, following 1 week of combination chemotherapy with
withdrawn), the fibrinogen levels significantly increased vincristine, prednisolone, and L‑asparaginase.
by 56.44% (P = 0.002) and were comparable to controls on
D28 (P = 0.58). Recently, Giordano et al.[11] also demonstrated Giordano et al.[11] showed that PAI‑1 levels progressively increased
that the levels significantly dropped during L‑asparaginase and during therapy peaking at the end of the induction phase. In
corticosteroid administration and thereafter increased when the this study, though PAI‑1 levels progressively increased during
two drugs were withdrawn suggesting that L‑asparaginase might induction, the changes were not statistically significant. Saito
be responsible for hypofibrinogenemia. et al.[23] and Semeraro et al.[20] found significantly raised levels
of PAI‑1 during induction therapy in ALL patients. Increased
D‑DI is a marker of clotting activation and secondary fibrinolysis. PAI‑1 levels suggest the activity of antileukemic drugs on the
Giordano et al.[11] showed that D‑DI levels were significantly high vascular endothelium. This is in line with the observation that
at baseline (299 ± 32 ng/ml) and decreased during induction steroids increase synthesis of PA1‑1 from the endothelial cells.[30]
therapy becoming similar to control values (103 ± 09 ng/ml) Low tPA levels with high PAI‑1 levels shift the balance of the
on day 52 of induction therapy. This could be due to reduction hemostatic system toward a hypofibrinolytic state, leading to
of the tumor burden during therapy, leading to normalization persistence of thrombus.
of the hypercoagulable state. Similarly, Yuan et al.[21] noticed
raised D‑DI levels 1 day after treatment with L‑asparaginase. The past literature has shown the presence of coagulopathy in
No significant change in markers of thrombin generation and ALL patients, which gets exacerbated during therapy, and these
fibrinolysis was noted by Appel et al.[22] In the present study, findings have been confirmed in the present study. Incidence
D‑DI levels were high on D0 and remained so throughout the of thrombosis has been variable in different series. Rodeghiero
induction phase. However, contrary to the results mentioned et al.[31] and Hunault‑Berger et al.[13] reported an incidence of
in the above series, no significant change in the levels occurred 14.3% and 9.8%, respectively, during remission induction, while
during therapy. in a study by Giordano et al.,[32] the incidence in the induction
phase was only 3.1%. In the present study, all cases were followed
The activity of all three natural anticoagulants declined in the up during the induction phase and no clinical thromboembolic
initial half of induction when patients were given L‑asparaginase event was recorded in any patient.
and increased to baselines values in the latter part when
L‑asparaginase was withdrawn.[12,15,16,19,13,23‑25] All these studies ALL per se is a hypercoagulable state and the prothrombotic
suggested that L‑asparaginase might be the main agent responsible condition at the time of diagnosis persists during the entire period
for the decline in the levels of natural anticoagulants. Contrary to of induction chemotherapy. The superimposed impaired capacity
above observations, Dixit et al.[14] observed a rise in PC, PS, and to inhibit thrombin during chemotherapy (due to acquired AT
AT activity at the end of induction, but it was not statistically deficiency) enhances the hypercoagulable state.
significant. Oner et al.[16] noted normal PC levels after treatment
with L‑asparaginase. The two most important factors triggering hypercoagulability
are tumor cells (at the time of diagnosis) and chemotherapeutic
Decreased levels of PC lead to decreased inactivation of factor drugs, primarily L‑asparaginase (during remission induction).
V and VIII promoting thrombosis. PC also has a profibrinolytic The results of this study indicated that both the malignant
effect; therefore, its reduced levels lead to decreased fibrinolysis process and the drugs used in combined chemotherapy cause
promoting the hypercoagulable state. thrombin activation, decrease in natural inhibitors, and
hypofibrinolysis resulting in hypercoagulability. The absence of
Decrease in AT activity has been the most consistent change clinical thrombosis in this study suggests that other contributing
demonstrated in the past series.[10,23,26‑29] As previously mentioned, thrombogenic factors might be required for the development of
increased endogenous thrombin generation is ongoing during this complication.
the 1st week of treatment for ALL. This could contribute to the
consumption of AT. This defect along with decreased protein This study highlights the pathogenesis of the hypercoagulable
synthesis due to L‑asparaginase may reflect the cause of decline state in ALL during induction chemotherapy. A larger study
in AT levels. with more number of patients is needed to comment on
54 Indian Journal of Pathology and Microbiology ¦ Volume 60 ¦ Issue 1 ¦ January-March 2017
 Sehgal, et al.: Coagulation during induction chemotherapy in childhood ALL

whether routine screening for coagulation parameters to pick up induction chemotherapy with L‑asparaginase in adult patients with
subclinical thrombosis in ALL patients is recommended or not. acute lymphoblastic leukemia or lymphoblastic lymphoma. Use of
supportive coagulation therapy and clinical outcome: The CAPELAL
study. Haematologica 2008;93:1488‑94.
Acknowledgment 14. Dixit A, Kannan M, Mahapatra M, Choudhry VP, Saxena R. Roles of
We would like to thank Arushi Sehgal and Bhavuk Garg for their protein C, protein S, and antithrombin III in acute leukemia. Am J
technical help. Hematol 2006;81:171‑4.
15. Mitchell L, Hoogendoorn H, Giles AR, Vegh P, Andrew M. Increased
Financial support and sponsorship endogenous thrombin generation in children with acute lymphoblastic
Nil. leukemia: Risk of thrombotic complications in L’Asparaginase‑induced
antithrombin III deficiency. Blood 1994;83:386‑91.
16. Oner AF, Gürgey A, Kirazli S, Okur H, Tunç B. Changes of hemostatic
Conflicts of interest factors in children with acute lymphoblastic leukemia receiving
There are no conflicts of interest. combined chemotherapy including high dose methylprednisolone and
L‑asparaginase. Leuk Lymphoma 1999;33:361‑4.
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