| Abstract|| |
Context: Thromboembolism in children with acute lymphoblastic leukemia (ALL) is most commonly reported after the initiation of antileukemic therapy, indicating a possible interaction of disease and therapy. Aims: To study the effect of 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 plasminogen activator inhibitor type 1 (PAI-1) levels were assayed by ELISA method. Statistical Analysis Used: The statistical analysis was done using Statistical Package for Social Sciences version 17.0. Results: No major change in PT and APTT was observed during chemotherapy; however, fibrinogen levels declined significantly (P = 0.04), following L-asparaginase treatment. D-DI levels were significantly raised at diagnosis (P < 0.001) and throughout 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 respective baseline levels (P < 0.05). The tPA levels were significantly reduced in the patients at diagnosis and throughout therapy (P < 0.001). PAI-1 levels were comparable to controls at presentation and showed a rising trend during therapy. Conclusions: The results of this study indicated that both the malignant process and the drugs used in combined chemotherapy cause thrombin activation, decrease in natural inhibitors, and hypofibrinolysis, resulting in hypercoagulability. Thus, ALL per se is a hypercoagulable state and the prothrombotic condition at the time of diagnosis gets enhanced during induction chemotherapy.
Keywords: Acute lymphoblastic leukemia, childhood, coagulation profile, induction chemotherapy
|How to cite this article:|
Sehgal S, Sharma S, Chandra J, Nangia A. Coagulation profile during induction chemotherapy in childhood acute lymphoblastic leukemia. Indian J Pathol Microbiol 2017;60:50-6
|How to cite this URL:|
Sehgal S, Sharma S, Chandra J, Nangia A. Coagulation profile during induction chemotherapy in childhood acute lymphoblastic leukemia. Indian J Pathol Microbiol [serial online] 2017 [cited 2019 Dec 7];60:50-6. Available from: http://www.ijpmonline.org/text.asp?2017/60/1/50/200029
| Introduction|| |
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. In developed countries, this disease has become curable in 4 out of 5 children with the use of intensive multidrug chemotherapy.,,, However, attention needs to be directed toward the morbidity and mortality caused not only by the disease but also by the treatment regimens used in these patients.
Thromboembolism is a well-known complication of ALL which can be symptomatic or asymptomatic. The risk of thrombosis in children with ALL ranged from 1.1% to 36.7% in various series., The pathogenesis of hypercoagulability in ALL is multifactorial. It can be due to the disease per se or due to contributing factors including immobility, infection, use of central venous access devices, and anticancer therapy.
Thromboembolism in children with ALL is most commonly reported after the initiation of antileukemic therapy, indicating a possible interaction of disease and therapy. Much is already known about the effect of chemotherapeutic drugs, especially L-asparaginase, on the coagulation system. The past studies done on the effect of chemotherapy on coagulation parameters in ALL patients revealed variable results. Furthermore, there is a paucity of Indian literature on the hemostatic alterations in ALL patients and, specifically, on the changes in coagulation profile with the administration of chemotherapy. It is important to know whether any coagulation parameter is particularly altered in ALL patients on chemotherapy and can be used in the early diagnosis of a hypercoagulable state. This can be helpful in preventing thrombotic episodes and its clinical consequences in these patients.
The present study was undertaken to note any change in coagulation inhibitor levels (protein C [PC], protein S [PS], antithrombin ORIGINAL ARTICLE), or fibrinolytic system during induction chemotherapy in children with ALL.
| Subjects and Methods|| |
The study was conducted in the Department of Pathology and the Department of Paediatrics, Lady Hardinge Medical College, and Kalawati Saran Children's Hospital, New Delhi, from November 2010 to March 2012. A total of 37 newly diagnosed ALL patients up to 18 years of age who were receiving chemotherapy in this hospital were included in the study (Group I) after obtaining informed consent from the parents. Patients with multiorgan failure, previous history of thrombosis, deranged liver function tests/renal function tests were excluded from the study. Further, patients who had received corticosteroids for >7 days before hospital admission were not included in the study.
A clean venipuncture was performed and 2.7 ml of blood was collected in a citrate vacutainer (containing 0.3 ml of 3.2% trisodium citrate). Platelet-poor plasma was prepared for coagulation tests as soon as possible by centrifuging the samples at 2000 g (relative centrifugal force) for 15 min. Prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen estimation were done on the same day using CA-50 semi-automated coagulation analyzer. The remaining plasma was stored in separately labeled aliquots, for each coagulation test, and stored in a deep freezer at –40°C. Before performing the tests, the plasma samples were thawed in a water bath set at 37°C.
PT, APTT, and fibrinogen estimation (Clauss principle) were done by a clot-based method in the patients at the time of diagnosis. D-dimer (D-DI) level was assayed using Asserachrom ® D-DI-Diagnostica Stago (France) ELISA kit. PC and PS activity were determined by clot-based method using STA-STACLOT ®-Diagnostica Stago (France - performed manually). AT assay was performed by chromogenic method using STA-STACHROM ® AT III-Diagnostica Stago (France). The fibrinolytic system was analyzed by assaying tissue plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1) levels by ELISA (t-PA (human) – DRG Diagnostics ELISA and Asserachrom ® PAI-1-Diagnostica Stago (France) ELISA), respectively.
All the coagulation tests were repeated in the cases after the completion of L-asparaginase doses (day 14 [D14]) and after the completion of induction chemotherapy (day 28 [D28]).
History was taken and physical examination was done for the cases regularly to clinically rule out any thromboembolic event.
Thirty age- and sex-matched controls (Group II) were taken from among children undergoing minor elective surgery. All the aforementioned coagulation tests were performed in them.
Treatment of ALL comprises phases of induction, consolidation, interim maintenance, reinduction and reconsolidation, and maintenance. The various drugs used during induction phase are prednisolone, vincristine, L-asparaginase, daunomycin, cytosine arabinoside, and methotrexate. Out of these, L-asparaginase is given only in the initial half of induction chemotherapy.
The statistical analysis was done using the Statistical Package for Social Sciences version 17.0 [SPSS Inc. Released 2008. SPSS Statistics for Windows, Version 17.0. Chicago: SPSS Inc.]. The data were expressed as mean ± standard deviation. Besides descriptive statistics, the comparison of baseline values of nine parameters (PT, APTT, fibrinogen, D-DI, PC, PS, AT, tPA, PAI-1) between the cases and controls was done using “Mann–Whitney U-test” for nonparametric data and “independent sample t-test” for parametric data.
The change of variables during chemotherapy (day 0 [D0], D14, and D28) in the cases was done using repeated measure analysis (an extension of the paired t-test), followed by post hoc comparison by the Bonferroni method. The P < 0.05 was considered statistically significant. The sequential analysis was performed only in thirty patients, for whom three complete sets of data were available.
| Results|| |
Out of 37 cases (Group I), only thirty cases could be followed up until the end of induction therapy (6 patients expired and 1 patient left the hospital without completing induction chemotherapy against medical advice). These thirty cases were included in Group IA. Sequential analysis of the various coagulation parameters on D0, D14, and D28 of therapy was performed for only these patients.
The age of the patients in Group I ranged from 2 to 14 years, with a mean of 5.57 ± 3.56 years. Maximum number of cases was between 2 and 4 years of age (37.84% of the cases). Twenty-six (70.27%) cases were male and 11 (29.73%) were female, with a male to female ratio of 2.36:1.
Results at the time of presentation
[Table 1] shows the comparison of coagulation tests of patients at the time of diagnosis with control values. The difference between PT, APTT, and fibrinogen was not found to be statistically significant. The D-DI levels were significantly higher in Group I as compared to Group II (P < 0.001).
|Table 1: Comparison of coagulation tests at the time of diagnosis with control values|
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PC activity (mean value = 54.13 ± 43.45%) and PS activity (mean value = 50.39 ± 31.24%) of Group I were found to be significantly lower than that of Group II (P < 0.001 for both). AT activity (mean value of 112.32 ± 29.44%) was comparable to that of controls (P = 0.73).
The tPA levels (mean = 142.62 ± 111.44 pg/ml) were significantly reduced in the patients as compared to controls (P < 0.001). PAI-1 levels of Group I (mean value of 53.85 ± 39.94 ng/ml) were higher than those of Group II; however, the difference was not statistically significant (P = 0.12).
Sequential analysis of coagulation parameters during induction
[Table 2] shows the sequential analysis of coagulation parameters during induction chemotherapy. The mean PT value did not change significantly during chemotherapy (P = 0.71). Further, it was found that APTT did not change significantly between the three time points (P = 0.27); however, it was significantly prolonged on D14 of therapy. Fibrinogen levels significantly dipped down on D14 of therapy and returned to normal values on D28 (P = 0.003). The D-DI levels remained significantly higher than control values throughout induction therapy (P < 0.001). However, the mean values did not differ significantly between the three time points (P = 0.99).
|Table 2: Sequential analysis of coagulation parameters during induction chemotherapy|
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The PC and PS activity were significantly lower than control values throughout induction therapy. Both the anticoagulants significantly reduced on D14 of therapy and returned to respective baseline levels on D28 (P = 0.02 for both) [Figure 1]. AT activity was significantly lower than controls on D14 of therapy (P < 0.001) and comparable on D28. It was found to significantly reduce in the initial part of induction and return to normal values in the latter part (P = 0.006) [Figure 1].
|Figure 1: The trend of protein C, protein S, and antithrombin during induction chemotherapy|
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Sequential analysis revealed that the mean tPA levels did not vary significantly during induction therapy (P = 0.87) [Figure 2]. The tPA levels on D0, D14, and D28 of therapy remained significantly lower than control values (P < 0.001). The PAI-1 levels showed a rising trend during induction chemotherapy [Figure 3], with values becoming higher than controls on D14 (P = 0.02) and D28 (P = 0.001). However, on repeated measure analysis, the change in levels was not found to be statistically significant (P = 0.13).
|Figure 2: The trend of tissue plasminogen activator levels during induction chemotherapy|
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|Figure 3: The trend of plasminogen activator inhibitor type 1 levels during induction chemotherapy|
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On follow-up of thirty cases (Group IA), no clinical evidence of thrombosis was observed in any of the patients during induction chemotherapy.
| Discussion|| |
The pathogenesis of cancer-related thrombosis is complex and reflects the action of different mechanisms including activation of blood coagulation via procoagulant substances, impairment of fibrinolytic pathways, and alterations of endothelium toward a thrombogenic state.
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. 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 acute lymphoblastic leukemia
Most of the studies have shown that PT and APTT were within normal limits at the time of presentation of ALL,, similar to the current series. Fibrinogen level was also found comparable to that of controls by other authors;, however, Hunault-Berger et al. observed a lower fibrinogen level while Priest et al. had reported higher baseline values.
Giordano et al. reported raised D-DI levels; however, the mean value was lower than that in this study (299 ± 32 ng/ml).
Dixit et al. demonstrated reduced activity of all three natural anticoagulants. Other series , 11, ,,,, have reported variable results.
Reduction of PC and PS at the time of diagnosis might possibly 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  of the protein.
Giordano et al. 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. 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.
To summarize, the present study showed that the onset of leukemia was associated with hemostatic derangement favoring hypercoagulability. The coagulopathy was due to thrombin activation (as evidenced by raised D-DI). The decreased fibrinolysis (due to reduced tPA and raised PAI-1) and low levels of PC and PS contributed to the hypercoagulable state at the time of diagnosis.
During induction chemotherapy
The current study noticed that PT increased slightly (by 1.38%) from D0 to D14, and more so (by 18.31%) from D14 to D28, but the changes were not significant statistically. APTT increased by 34.65% from D0 to D14 and decreased by 31.50% from D14 to D28 reaching almost baseline values; these changes were, however, not statistically significant. Similarly, Giordano et al. observed no significant change in PT and APTT during induction chemotherapy.
Fibrinogen levels significantly dropped by 37.32% from D0 to D14 of therapy (P = 0.04), when patients were given L-asparaginase. In the latter part of induction (when L-asparaginase was withdrawn), the fibrinogen levels significantly increased by 56.44% (P = 0.002) and were comparable to controls on D28 (P = 0.58). Recently, Giordano et al. also demonstrated that the levels significantly dropped during L-asparaginase and corticosteroid administration and thereafter increased when the two drugs were withdrawn suggesting that L-asparaginase might be responsible for hypofibrinogenemia.
D-DI is a marker of clotting activation and secondary fibrinolysis. Giordano et al. showed that D-DI levels were significantly high at baseline (299 ± 32 ng/ml) and decreased during induction therapy becoming similar to control values (103 ± 09 ng/ml) on day 52 of induction therapy. This could be due to reduction of the tumor burden during therapy, leading to normalization of the hypercoagulable state. Similarly, Yuan et al. noticed raised D-DI levels 1 day after treatment with L-asparaginase. No significant change in markers of thrombin generation and fibrinolysis was noted by Appel et al. In the present study, D-DI levels were high on D0 and remained so throughout the induction phase. However, contrary to the results mentioned in the above series, no significant change in the levels occurred during therapy.
The activity of all three natural anticoagulants declined in the initial half of induction when patients were given L-asparaginase and increased to baselines values in the latter part when L-asparaginase was withdrawn.,,,,,,, All these studies suggested that L-asparaginase might be the main agent responsible for the decline in the levels of natural anticoagulants. Contrary to above observations, Dixit et al. observed a rise in PC, PS, and AT activity at the end of induction, but it was not statistically significant. Oner et al. noted normal PC levels after treatment with L-asparaginase.
Decreased levels of PC lead to decreased inactivation of factor V and VIII promoting thrombosis. PC also has a profibrinolytic effect; therefore, its reduced levels lead to decreased fibrinolysis promoting the hypercoagulable state.
Decrease in AT activity has been the most consistent change demonstrated in the past series., 23, ,,, As previously mentioned, increased endogenous thrombin generation is ongoing during the 1st week of treatment for ALL. This could contribute to the consumption of AT. This defect along with decreased protein synthesis due to L-asparaginase may reflect the cause of decline in AT levels.
The rise in activity of all three natural anticoagulants in the latter part of induction could be due to the effect of prednisolone which is known to increase hepatic synthesis of these proteins and is given until the end of induction. Lack of L-asparaginase in the latter part of induction enhances this effect.
The levels of tPA slightly increased (11.14%) in the initial part of induction and declined (by 16.42%) in the latter part (not statistically significant). However, Saito et al. noticed a rise in tPA levels, following 1 week of combination chemotherapy with vincristine, prednisolone, and L-asparaginase.
Giordano et al. showed that PAI-1 levels progressively increased during therapy peaking at the end of the induction phase. In this study, though PAI-1 levels progressively increased during induction, the changes were not statistically significant. Saito et al. and Semeraro et al. found significantly raised levels of PAI-1 during induction therapy in ALL patients. Increased PAI-1 levels suggest the activity of antileukemic drugs on the vascular endothelium. This is in line with the observation that steroids increase synthesis of PA1-1 from the endothelial cells. Low tPA levels with high PAI-1 levels shift the balance of the hemostatic system toward a hypofibrinolytic state, leading to persistence of thrombus.
The past literature has shown the presence of coagulopathy in ALL patients, which gets exacerbated during therapy, and these findings have been confirmed in the present study. Incidence of thrombosis has been variable in different series. Rodeghiero et al. and Hunault-Berger et al. reported an incidence of 14.3% and 9.8%, respectively, during remission induction, while in a study by Giordano et al., the incidence in the induction phase was only 3.1%. In the present study, all cases were followed up during the induction phase and no clinical thromboembolic event was recorded in any patient.
ALL per se is a hypercoagulable state and the prothrombotic condition at the time of diagnosis persists during the entire period of induction chemotherapy. The superimposed impaired capacity to inhibit thrombin during chemotherapy (due to acquired AT deficiency) enhances the hypercoagulable state.
The two most important factors triggering hypercoagulability are tumor cells (at the time of diagnosis) and chemotherapeutic drugs, primarily L-asparaginase (during remission induction). The results of this study indicated that both the malignant process and the drugs used in combined chemotherapy cause thrombin activation, decrease in natural inhibitors, and hypofibrinolysis resulting in hypercoagulability. The absence of clinical thrombosis in this study suggests that other contributing thrombogenic factors might be required for the development of this complication.
This study highlights the pathogenesis of the hypercoagulable state in ALL during induction chemotherapy. A larger study with more number of patients is needed to comment on whether routine screening for coagulation parameters to pick up subclinical thrombosis in ALL patients is recommended or not.
We would like to thank Arushi Sehgal and Bhavuk Garg for their technical help.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Dr. Shivali Sehgal
Department of Pathology, Lady Hardinge Medical College, New Delhi - 110 001
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]