|Year : 2018 | Volume
| Issue : 1 | Page : 22-33
Disseminated intravascular coagulation scoring in children with newly diagnosed acute leukemia
Hoda M.A Hassab1, Mostafa A.S Salama1, Wessam M El Gendy2, Yasmine F El Chazli1
1 Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
|Date of Web Publication||7-Sep-2018|
Yasmine F El Chazli
55 Port Saied Street, El-Shatby, Alexandria, 21526
Source of Support: None, Conflict of Interest: None
Background Patients with acute leukemia (AL) commonly present with abnormalities in laboratory tests of blood coagulation. Coagulation abnormalities and disseminated intravascular coagulation (DIC) have been extensively studied in acute promyelocytic leukemia, but only a limited number of studies addressed this issue in children with other types of AL.
Objective The aim of this study was to detect DIC by using the International Society of Thrombosis and Haemostasis scoring system, for both nonovert and overt DIC, among newly diagnosed children with AL.
Participants and methods The study was a diagnostic test accuracy study including 25 children presenting with newly diagnosed AL (lymphoblastic and myeloid) and admitted to the Hematology–Oncology Unit at Alexandria University Children’s Hospital. They were consecutively recruited between October 2016 and March 2017. Coagulation studies including prothrombin time, D-dimer, fibrinogen, antithrombin III, and protein C levels were assessed, and the International Society of Thrombosis and Haemostasis scoring system was used for defining nonovert and overt DIC.
Results The age of patients included in the present study ranged from 17 to 149 months, with a median of 48 months; males and females were almost equally represented. At baseline assessment, 10 (40%) of 25 patients had a positive overt DIC score and only seven (28%) of 25 had a positive nonovert DIC score. Bleeding manifestations were a common problem in the present study, as 16 (64%) patients presented with bleeding symptoms, being more frequently in patients with an overt DIC positive score (P=0.040). The median platelet count (P=0.023), D-dimer level (P=0.000), and fibrinogen level (P=0.010) showed a significant statistical difference between patients with either positive or negative overt DIC score, whereas neither white blood cells count, absolute blasts count, hemoglobin, prothrombin time, antithrombin III nor protein C levels did.
Conclusion Our data confirm that children with AL have some hemostatic derangement at baseline. A positive overt or nonovert DIC score was not statistically related to a worse end of induction remission status or a significantly higher 28-day mortality rate. Larger multicenter studies are needed to determine the most clinically relevant hemostatic abnormalities and adapt more sensitive and specific scoring system for DIC in children with hematological malignancies.
Keywords: childhood acute leukemia, coagulopathy, disseminated intravascular coagulation, disseminated intravascular coagulation score
|How to cite this article:|
Hassab HM, Salama MA, El Gendy WM, El Chazli YF. Disseminated intravascular coagulation scoring in children with newly diagnosed acute leukemia. Alex J Pediatr 2018;31:22-33
|How to cite this URL:|
Hassab HM, Salama MA, El Gendy WM, El Chazli YF. Disseminated intravascular coagulation scoring in children with newly diagnosed acute leukemia. Alex J Pediatr [serial online] 2018 [cited 2018 Sep 26];31:22-33. Available from: http://www.ajp.eg.net/text.asp?2018/31/1/22/240742
| Introduction|| |
Disseminated intravascular coagulation (DIC) is defined as ‘an acquired syndrome characterized by the intravascular activation of coagulation with a loss of localization arising from different causes. It can originate from and cause damage to the microvasculature, which if sufficiently severe, can produce organ dysfunction’ . This definition highlights the fact that DIC is secondary to other causes, which are commonly sepsis or trauma, but can also be related to malignancies . The systemic activation of coagulation can proceed to subclinically ‘nonovert’ form, eventually leading to exhaustion of platelets and coagulation factors, and ‘overt’ bleeding and/or thrombosis .
There is no single laboratory test that can establish or rule out the diagnosis of DIC. In a relevant clinical scenario involving one of the conditions known to be associated with DIC, several laboratory parameters are analyzed together as part of a diagnostic algorithm. The International Society of Thrombosis and Haemostasis (ISTH) scoring system of routine global coagulation tests provides a framework for diagnosing DIC, which also standardizes criteria for clinical studies . This score has been validated in different settings using prothrombin time (PT), platelet counts and fibrinogen (FBG) levels, together with elevated fibrin degradation products; a cumulative score of 5 or more is considered positive for DIC . Caution should be taken when interpreting the individual laboratory parameters of DIC, and it is very important that clinical practice relies on a high index of suspicion for increasing abnormalities, with particular emphasis on serial monitoring as assessed by the ‘nonovert DIC’ score of the ISTH, where subtle hemostatic dysfunction could provide forewarning of an overt DIC process ,. Coagulation abnormalities and DIC have been extensively studied in acute promyelocytic leukemia (APL) in both adults and children, but only a limited number of studies addressed this issue in children with acute lymphoblastic leukemia (ALL) and non-APL acute myeloid leukemia (AML).
| Aim|| |
The aim of this study was to detect DIC by using ISTH scoring systems for both nonovert and overt DIC, among newly diagnosed children with acute leukemia (AL).
| Participants and methods|| |
Twenty-five children presenting with newly diagnosed AL (ALL or AML excluding M3 subtype) and admitted to the Hematology–Oncology Unit at Alexandria University Children’s Hospital at El-Shatby. Children aged between 1 and 18 years old were consecutively recruited between October 2016 and March 2017. Patients were excluded if they had any history suggesting of hereditary bleeding or coagulation defect, hypercoagulable state, or history of previous thrombosis, recent intake of blood components (plasma, platelets, and cryoprecipitate) or intake of any drugs affecting coagulation.
The study was designed as a diagnostic test accuracy study. An informed consent was obtained from parents or legal guardians of all included children. The study has been approved by ‘Alexandria University Ethical Committee’ before starting.
All children were subjected to history taking and physical examination. The routine laboratory testing was done, including complete blood count, bone marrow examination, immunophenotyping, chemistry, and C-reactive protein. Bleeding manifestations were graded according to WHO Severity Grading System . Coagulation studies including PT and partial prothrombin time (PTT), D-dimer, FBG, antithrombin III (ATIII) and protein C (PC) levels were assessed using Sysmex CA-1500 (Sysmex Corporation, Siemens Healthcare Diagnostic Inc., Marburg, Germany). The ISTH scores for overt and nonovert DIC ([Table 1] and [Table 2]) were calculated for all patients at baseline (within 24 h of admission) and repeated every 48–72 h . D-dimer was chosen as a fibrin-related marker in this study, and it was scored as ‘no increase’ for level within the normal range (0–550 µg/l), as ‘moderate increase’ for levels up to five times upper limit of normal (>550–2750 µg/l), and as ‘strong increase’ for levels more than five times upper limit of normal (>2750 µg/l) . The trend for platelets, PT and D-dimer was scored ‘−1 or 1’ if the variation was more than 30% from the previous value . The study period extended from baseline assessment to disappearance of blasts from the periphery after the start of induction remission chemotherapy as shown in [Figure 3]. The patients were treated according to the modified Children’s Cancer Group (CCG) protocols (CCG 1991-standard risk and CCG 1961-high risk)  for ALL and Medical Research Council Acute Myeloid Leukaemia 12 protocol (MRC AML12) . Supportive care was provided according to the international guidelines for care of patients with cancer and upon the discretion of the attending physician . The frequency of transfusions was noted, and none of the patients received anticoagulation or coagulation factor concentrates ([Figure 1]).
|Table 2 Scoring system for nonovert disseminated intravascular coagulation|
Click here to view
|Figure 3: Median and IQR of overt and nonovert DIC scores at different sampling times from baseline assessment till the complete disappearance of blast cells from the periphery. DIC, disseminated intravascular coagulation; IQR, interquartile range|
Click here to view
Data were collected and entered into the computer using IBM SPSS (statistical package for the social sciences; SPSS Inc., Chicago, Illinois, USA) program for statistical analysis, version 21. Data were entered as numerical or categorical, as appropriate. Kolmogorov–Smirnov test of normality revealed significance in the distribution of some variables, so the nonparametric statistics was adopted. The Fisher exact and Monte Carlo corrections for χ2-test were used when indicated. All statistical analyses were performed using two-tailed tests and α error of 0.05.
| Results|| |
The age of the patients included in the present study ranged from 17 to 149 months with a median age of 48 months; males and females were almost equally represented. The four main governorates referring to the Alexandria University Children’s Hospital were represented with about half of the patients from Alexandria. The number of patients with ALL was approximately four times that of patients with AML, reflecting the relative frequency of ALL and AML in the pediatric population.
Bleeding symptoms were a common problem in the study patients. Sixteen (64%) patients had bleeding at baseline assessment, and patients with ALL and those with AML bled equally. When compared with the overt DIC negative group, significantly more patients showed bleeding in the overt DIC positive group (FEP=0.040), but the difference was not significant between the nonovert DIC groups (FEP=1.000). The WHO grading system was used for categorization of bleeding severity. Grade 1 was the major type of bleeding among study patients (87.5%); they presented with mild bleeding manifestations, namely, skin bleeding, oropharyngeal bleeding, subconjunctival hemorrhage, and hematuria. Grade 2 was mild to moderate bleeding, and it presented in only one girl with menorrhagia not requiring transfusion together with mucocutaneous bleeding. Grade 4 was also represented in only one patient with retinal hemorrhage affecting his vision; this patient had a positive overt DIC score but a negative nonovert DIC score.
At the end of induction remission phase, only 12 (48%) patients have achieved a complete remission by both morphological and immunological criteria. There was no statistically significant relation between the end of induction remission status and the overt or nonovert DIC scores, although more patients in the DIC negative groups attained complete remission. Three patients died by the end of induction (after the study period), owing to sepsis. There was no statistically significant relation between the 28-day mortality and either the overt or nonovert DIC scores.
Regarding the complete blood count of patients at baseline, only the platelet count was significantly associated with positive overt DIC score (P=0.023). Regarding coagulation markers assessed in this study, the overt DIC positive patients had a significantly higher median D-dimer level and lower FBG level (P=0.000 and 0.010, respectively). The same was not true concerning positive nonovert DIC patients who only had a significantly lower PC level (P=0.027) compared with negative ones.
The median overt DIC score at baseline assessment was 4, with a score ranging from 0 to 7. The median nonovert score was 4 with a range from 0 to 9 ([Figure 3]). Throughout the study period, the percentage of patients with a positive DIC score varied. Up to 55% of the patients had a positive overt DIC score with the highest median of 5 during hydration phase before starting chemotherapy ([Figure 2]). By day 10, only two patients were tested, and on days 12 and 14, the only one remaining patient who still had some blasts in the periphery had a negative DIC score. A similar pattern was observed for nonovert DIC score with fluctuation over the study period. On day 10, only two patients were tested, and one of them had a positive score, giving a 50% positive nonovert score; on the next two samples, this patient’s score became negative and the score decreased gradually as shown in [Figure 2] and [Figure 3]. When looking at the 20 patients who were followed up during remission induction phase, 17 (85%) patients had a positive DIC score at least once over the study period, and the same was true for the nonovert DIC score ([Table 3],[Table 4],[Table 5],[Table 6]).
|Figure 2: The distribution of DIC score at different sampling times from baseline assessment till the complete disappearance of blast cells from the periphery (positive in red and negative in green). (a) To the left, overt DIC score; (b) to the right, nonovert DIC score. DIC, disseminated intravascular coagulation|
Click here to view
|Table 3 Demographic data and diagnostic characteristics of the studied patients|
Click here to view
|Table 4 Clinical and laboratory criteria of patients at baseline assessment and comparison between patients according to their overt and nonovert disseminated intravascular coagulation score status|
Click here to view
|Table 5 Laboratory criteria of patients at baseline assessment and comparison between patients according to their overt and nonovert disseminated intravascular coagulation score status|
Click here to view
|Table 6 Coagulation parameters at baseline assessment and comparison between patients according to their overt and nonovert disseminated intravascular coagulation score status|
Click here to view
| Discussion|| |
There is a strong relationship between the presence of malignant disease and the occurrence of coagulation abnormalities and thrombosis . Very commonly, patients with solid tumors and leukemia present with abnormalities in laboratory tests of blood coagulation, even without clinical manifestations of thromboembolism or hemorrhage . Reports of cases with hemostatic disturbances associated with leukemia were published by Friedman et al.  as early as 1964, and several case reports and series followed using different diagnostic criteria for DIC ,. In the present study, the prevalence of both nonovert and overt DIC was determined by using ISTH scoring systems among children with AL before and during chemotherapy for remission induction, to investigate the magnitude and clinical importance of hemostatic disturbances related to AL.
At baseline assessment, 10 (40%) of 25 patients had a positive overt DIC score and only seven (28%) of 25 had a positive nonovert DIC score. Having ALL or AML was not significantly associated with a positive overt or nonovert DIC score (FEP=0.615, FEP=0.274). Different percentages of DIC at presentation of AL have been reported in the literature. Some of them showed a lower percentage of DIC, as did Ribeiro and Pui  who have reported a 5.2% prevalence of DIC in a large series of children with AL, but with significantly higher percentage of positive DIC at presentation for AML compared with ALL (13.8 vs. 3.1%). Several other studies have reported varying rates of positive DIC at presentation of leukemia, as summarized in [Table 7], but none of them included such a large number of patients as Ribeiro and Pui . The comparison of rates of DIC in patients with AL among these studies is difficult, as till the mid-2000s, diagnostic criteria for DIC were not unified, some studies were retrospective, and many of them included only adults or adults and children analyzed together. Moreover, most of these studies have included different subtypes of leukemia in their analysis. Few reports have pointed to a higher rate of positive DIC in T-ALL versus B-ALL and in monocytic AML compared with other subtypes (excluding APL) ,,.
|Table 7 Summary of the studies addressing the prevalence of disseminated intravascular coagulation in acute leukemia in adults and children at presentation|
Click here to view
The presence of DIC was also noted during remission induction in the present study. The patients were followed as long as they had evidence of blasts in their peripheral blood smear. The percentage of positive overt and nonovert DIC score was the highest on the follow-up sample (within 48–72 h of admission and starting hydration fluids), reaching 55%, and this may be related to the starting process of leukemic blast lysis with subsequent activation of the coagulation system . The rise of the percentage of patients with nonovert DIC after day 3 of chemotherapy is probably owing to decreased ATIII and PC associated with use of l-asparaginase and the occurrence of infections ,. The percentage of positive overt and nonovert DIC scores on the day of start of induction might be falsely low, as most of the patients with low platelets count have received platelets transfusion during preparation for the initial routine lumbar puncture. Overall, 17 (85%) of 20 patients showed a positive DIC score at least once during the study period. This is a relatively high number compared with the other studies, as shown in [Table 7]. Although the discrepancies in the study populations, the types of AL included and the diagnostic criteria used for DIC make the interpretation of these differences quite difficult, it definitely highlights the magnitude of the problem and the need for further more systematic approach to DIC diagnosis in patients with AL.
Bleeding manifestations were a common problem in the present study; 16 (64%) patients presented with bleeding symptoms but most of them were mild, and there was no difference regarding the WHO grade of bleeding between positive and negative overt DIC patients (MCP=0.714). Significantly more bleeders were overt DIC positive (P=0.040), but this was not true concerning nonovert DIC score. These results indicate that a positive overt DIC score could be a good indicator of bleeding in patients with AL. This was confirmed by several studies where positive DIC patients were more likely to have bleeding manifestations. Dixit et al.  have reported that 27 (40.3%) children presented with some bleeding manifestations, and six (60%) patients with DIC at presentation had bleeding manifestations. In their study, DIC was not a significant risk factor for bleeding in patients with ALL, but was more commonly associated with severe bleeding manifestations in patients with AML. Chojnowski et al.  have reported that bleeding was found in 27 (38.6%) patients with childhood AL at diagnosis and was much more frequent in patients with AML, but they correlated the bleeding manifestations with the severity of thrombocytopenia. Higuchi et al. , who studied an adult ALL population reported that patients with DIC at presentation had significantly more frequent and severe hemorrhagic symptoms compared with those without DIC (P<0.001), but this difference was not significant in their pediatric patients.
Regarding the possible prognostic role of DIC at presentation in patients with AL, in the present study, neither the presence of overt or nonovert DIC was significantly related to the end of induction remission status of the patients (MCP=0.450 and 1.000, respectively) nor was the 28-day mortality (FEP=0.543 and 1.000, respectively). This is in agreement with Chojnowski et al.  who have reported no significant correlation between coagulation activation markers and the possibility of achieving remission in children with AL, and this was further confirmed by Higuchi et al.  in adolescents and adults with ALL. In contrast, mortality rate during the first month was higher in the group of AL with DIC than in AL without DIC (P<0.025) as reported by Zuazu et al.  in a study including adult patients with AL, but these results may be because of the presence of patients with complicated APL. The largest and probably the most relevant study regarding this issue in children was published by Ribeiro and Pui , who have reported that the presence of coagulation abnormalities at diagnosis of ALL did not influence the rate of remission induction (P=0.55). In contrast, fewer patients with coagulopathy at diagnosis of AML in their study achieved a complete remission, compared with patients who lacked this complication (P=0.003); this was mainly owing to fatal hemorrhagic complications in patients with DIC. It is important to note that the determination of a prognostic role of DIC at presentation of AL is complicated, as different chemotherapeutic, supportive care and transfusion protocols were used in the mentioned studies with possibly varying effects on the coagulation parameters and development of DIC, highlighting the importance of larger multicenter studies with unified diagnostic and management protocols.
Many laboratory parameters might be affected in children with leukemia at presentation. In the present study, the only laboratory parameters showing a significant statistical difference between patients with either positive or negative overt DIC score were the platelet count (P=0.023), D-dimer level (P=0.000), and FBG level (P=0.010). Ribeiro and Pui  have reported that patients with ALL showing abnormal coagulation parameters were more likely to have a high leukocyte count. Higuchi et al.  have found that adult patients with ALL who had DIC presented with a higher white blood cells (WBC) count (P<0.05) than those who did not. This was also reported by Uchiumi et al.  who identified high WBC count as independently associated with DIC, and when the analysis was restricted to patients with hyperleukocytosis (leukocyte counts >100×109/l), the incidence of DIC became extremely high (62.5%). Coagulopathy may develop in patients with ALL in relation to the elevated WBC count, as DIC is caused by high cell turnover and associated high levels of released tissue factor, which then triggers the extrinsic pathway via FVII . Other studies have failed to find such a correlation between WBC count and DIC as shown by Sletnes et al.  and Dixit et al. . No relationship was found by Chojnowski et al.  or by Albayrak et al.  between the major coagulation markers and the leukemic blast count in the peripheral blood of children with AL.
In the present study, the median hemoglobin level at baseline was lower in overt DIC patients compared with negative ones (6.7 vs. 7.7 g/dl; P=0.567), in concordance with the study published by Dixit et al. . In contrast, Higuchi et al.  found no difference in hemoglobin level between positive and negative DIC groups, and Ribeiro and Piu  have even reported a higher hemoglobin level in ALL DIC positive children (9.8 vs. 7.7 g/dl; P<0.001). These discrepancies may be owing to different sampling time and transfusion practices adopted in each of the previous studies and appear to have no significant effect on the course of DIC, as in the present study, no more packed red blood cells (PRBCs) transfusions were required in the DIC positive patients compared with the negative DIC ones all over the study period.
The platelet count is commonly affected in children presenting with AL, thus the utility of using a low platelets count as a criterion for DIC scoring in such situations is questionable. In the present study, the median platelet count in overt DIC patients was 14×103/mm3 (range: 3–53) versus 50×103/mm3 (range: 7–190) for DIC negative group (P=0.023), which means that in the positive overt DIC group almost all patients scored the highest score of ‘2’ for the platelet criterion according to the ISTH scoring system, which may lead to overdiagnosis of overt DIC in this category of patients. This problem can be partially corrected by calculating the nonovert DIC score, as the weight of the low platelets is less important and adding a score for the platelet trend (−1, 0, or +1) can better reflect either an ongoing pathological process or an improving condition. In the present study, the median platelet count in the positive nonovert DIC was higher compared with the negative nonovert group (46×103/mm3, range: 12–93 vs. 22×103/mm3, range: 3–190; P=0.745). It is also important to note that platelet transfusions may further complicate the interpretation of scores. It might be interesting to add a score for response to platelet transfusion or platelet refractoriness, as a patient with ongoing DIC would consume transfused platelets and only show minimal post-transfusion platelet increments if any . In agreement with the present study, Dixit et al.  reported that the mean platelet count was lower in patients with ALL with DIC than without DIC (P<0.05). Ribeiro and Pui  also found that children with ALL or AML and coagulopathy had a lower platelet count (P=0.058 and 0.08, respectively); it is important to note that platelet count was not included in their DIC diagnostic criteria. Higuchi et al.  have confirmed that DIC positive children with ALL had significantly lower counts at presentation (median: 22 vs. 60×103/mm3; P<0.001) using the Japanese Ministry of Health and Welfare DIC score, which does not include platelet count, and the same was true for adult patients with ALL. Sletnes et al.  did not find significant differences in platelet count between patients with or without DIC in adult patients with ALL.
Different coagulation markers have been studied in patients with AL, and most of them have shown significant disturbance of coagulation markers at presentation of leukemia. In the present study, the median PT and PTT were within normal range, being slightly longer in DIC positive patients, but this was not statistically significant. This is in agreement with Giordano et al. , who reported children with ALL to have PT and PTT in the normal range at baseline. PT and PTT may not be prolonged in patients with cancer-associated DIC, as the coagulation factor levels are only moderately decreased, and activation of the coagulation system by the malignancy or associated high levels of FVIII:C can even shorten the PTT initially . In contrast, Dixit et al.  have reported significantly prolonged PT and PTT at presentation in children with ALL (P<0.001 and <0.05, respectively) and only prolonged PT in patients with AML (P<0.05). Sehgal et al.  found only a significant prolongation of PTT in children with ALL compared with normal controls (P=0.033). In case of prolonged values, it is also important to exclude other etiologies such as vitamin K deficiency or liver affection .
In the present study, D-dimer was used as a marker of fibrin/FBG degradation, and the normal level was considered to be less than 550 µg/l. More than 90% of patients presented with elevated levels of D-dimer with significantly higher levels in the DIC group at baseline in the present study. In another study from the National Cancer Institute in Egypt, children with ALL before receiving treatment were compared with a control group of healthy children, and there was a significantly elevated plasma D-dimer level in patients with ALL (P=0.017) . In several studies, 30% to up to 100% of children with AL had elevated D-dimer levels at diagnosis, either isolated or in combination with other coagulation abnormalities ,,,,. This might be explained by the coagulation activation engendered by lysis of leukemic blasts and is considered a biomarker of the hyperfibrinolytic pattern of leukemia-associated DIC .
Despite that the median FBG level in the present study was significantly lower in overt DIC positive patients (150 vs. 281 mg/dl; P=0.010), the median level in both groups was above the cutoff for hypofibrinogenemia, and only three patients from the DIC positive groups had a positive FBG score (<100 mg/dl). Dixit et al.  have reported that no patients had any abnormality of FBG at presentation or during the course of chemotherapy in their study, and although mean FBG levels were lower in patients with ALL with DIC, this was statistically insignificant. In older studies addressing DIC in AL, the most frequently used cutoff for FBG was 150 mg/dl, and this cutoff was also adopted by the Japanese Ministry of Health and Welfare and Japanese Society on Thrombosis and Hemostasis DIC criteria ,,,,,,,. Several studies have reported FBG levels in children with AL comparable to normal controls ,,. Moreover, Giordano et al.  have found significantly higher inflammatory cytokines in their patients with ALL at diagnosis compared with controls. It can be concluded that using a higher cutoff for low FBG would enhance the sensitivity of the scoring system especially in patients with AL who elevated acute-phase reactants and inflammatory states.
In the present study, the specific coagulation tests for calculation of nonovert DIC scoring were the ATIII and PC. The median ATIII level was normal at baseline and did not significantly differ between positive and negative overt or nonovert DIC groups. Comparable results were reported in children with AL in other studies ,,,. Fourteen (56%) patients had a decreased PC level at baseline regardless of the DIC score, and the median PC level was low (59.75%, range: 30.6–184.7). It was lower in positive DIC group compared with DIC negative group; this difference was only significant for the nonovert DIC score (P=0.411 and 0.027 respectively). This is in contrast with a recent study by Sehgal et al. , where the PC activity (mean=54.13±43.45%) of children with ALL was significantly lower than that of normal controls (P<0.001) . The median PC was normal (118.5%, range: 58.0–133.0) in the study by Albayrak et al.  of childhood ALL and was even significantly higher in the patient group than in the healthy controls. These findings indicate that children with AL do not experience significant consumption of their natural anticoagulants at presentation, and testing for these coagulation markers does not appear clinically relevant at this stage, especially in resource-limited settings.
In conclusion, our data confirm that children with AL have some hemostatic derangement at baseline. So far, no standardized tests exist for the determination of DIC in these patients, and evidence and guidelines are lacking for laboratory monitoring of the coagulopathy . Two of four parameters of the most commonly used ISTH-DIC score seem to be of little value in patients with AL; low platelet counts are very common in such cases, even in the absence of coagulation activation, and FBG levels that can be elevated as part of the inflammatory response associated with the disease . An internationally validated modified DIC scoring system would be much appreciated in this setting ,,. One of the limitations of the present study is the small number of included patients and the inclusion of different subtypes of AL. Larger multicenter studies are much needed to determine the most clinically relevant hemostatic abnormalities and adapt more sensitive and specific scoring systems.
Authors are appreciative of all Hematology–Oncology Unit staff of Alexandria University Children’s Hospital and to patients and their guardians, who agreed to participate, readily cooperated with the research team and agreed to undergo the necessary investigations.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M, Scientific Subcommittee on Disseminated Intravascular Coagulation of the International Society on T Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001;86:1327–1330.
Thachil J. Disseminated intravascular coagulation − new pathophysiological concepts and impact on management. Exp Rev Hematol 2016;9:803–814.
Levi M. Disseminated intravascular coagulation in cancer patients. Best Pract Res Clin Haematol 2009;22:129–136.
Toh CH, Hoots WK, ISTH SSCoDICot. The scoring system of the Scientific and Standardisation Committee on Disseminated Intravascular Coagulation of the International Society on Thrombosis and Haemostasis: a 5-year overview. J Thromb Haemost 2007;5:604–606.
Toh CH, Alhamdi Y, Abrams ST. Current pathological and laboratory considerations in the diagnosis of disseminated intravascular coagulation. Ann Lab Med 2016;36:505–512.
Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47:207–214.
Levi M, van der Poll T. Disseminated intravascular coagulation: a review for the internist. Intern Emerg Med 2013; 8:23–32.
Wada H, Takahashi H, Uchiyama T, Eguchi Y, Okamoto K, Kawasugi K et al.
The approval of revised diagnostic criteria for DIC from the Japanese Society on Thrombosis and Hemostasis. Thromb J 2017;15:17.
Gaynon PS, Angiolillo AL, Carroll WL, Nachman JB, Trigg ME, Sather HN et al.
Long-term results of the children’s cancer group studies for childhood acute lymphoblastic leukemia 1983-2002: a Children’s Oncology Group Report. Leukemia 2010;24:285–297.
Gibson BES, Wheatley K, Hann IM, Stevens RF, Webb D, Hills RK et al.
Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia 2005;19:2130.
Thachil J, Falanga A, Levi M, Liebman H, Di Nisio M, Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Management of cancer-associated disseminated intravascular coagulation: guidance from the SSC of the ISTH. J Thromb Haemost 2015;13:671–675.
Levi M. Cancer-related coagulopathies. Thromb Res 2014; 133(Suppl 2):S70–S75.
Barbui T, Falanga A. Disseminated intravascular coagulation in acute leukemia. Semin Thromb Hemost 2001;27:593–604.
Friedman IA, Schwartz SO, Leithold SL. Platelet function defects with bleeding. Early manifestation of acute leukemia. Arch Intern Med 1964;113:177–185.
Gralnick HR, Marchesi S, Givelber H. Intravascular coagulation in acute leukemia: clinical and subclinical abnormalities. Blood 1972;40:709–718.
Sutor AH, Wulff J, Ritter J, Pollmann H, Schellong G. Hemostasis and fibrinolysis in acute lymphoblastic leukemia (ALL) in childhood − analysis of life-threatening bleeding. Klin Padiatr 1984;196:166–173.
Ribeiro RC, Pui CH. The clinical and biological correlates of coagulopathy in children with acute leukemia. J Clin Oncol 1986;4:1212–1218.
Sarris AH, Kempin S, Berman E, Michaeli J, Little C, Andreeff M et al.
High incidence of disseminated intravascular coagulation during remission induction of adult patients with acute lymphoblastic leukemia. Blood 1992;79:1305–1310.
Tornebohm E, Blomback M, Lockner D, Egberg N, Paul C. Bleeding complications and coagulopathy in acute leukaemia. Leuk Res 1992;16:1041–1048.
Sletnes KE, Godal HC, Wisloff F. Disseminated intravascular coagulation (DIC) in adult patients with acute leukaemia. Eur J Haematol 1995;54:34–38.
Nur S, Anwar M, Saleem M, Ahmad PA. Disseminated intravascular coagulation in acute leukaemias at first diagnosis. Eur J Haematol 1995;55:78–82.
Sarris A, Cortes J, Kantarjian H, Pierce S, Smith T, Keating M et al.
Disseminated intravascular coagulation in adult acute lymphoblastic leukemia: frequent complications with fibrinogen levels less than 100 mg/dl. Leuk Lymphoma 1996;21:85–92.
Higuchi T, Mori H, Niikura H, Omine M, Okada S, Terada H. Disseminated intravascular coagulation in acute lymphoblastic leukemia at presentation and in early phase of remission induction therapy. Ann Hematol 1998;76:263–269.
Kobayashi N, Maekawa T, Takada M, Tanaka H, Gonmori H. Criteria for diagnosis of DIC based on the analysis of clinical and laboratory findings in 345 DIC patients collected by the Research Committee on DIC in Japan. Bibl Haematol 1983;49:265–275.
Chojnowski K, Wawrzyniak E, Trelinski J, Niewiarowska J, Cierniewski C. Assessment of coagulation disorders in patients with acute leukemia before and after cytostatic treatment. Leuk Lymphoma 1999;36:77–84.
Higuchi T, Toyama D, Hirota Y, Isoyama K, Mori H, Niikura H et al.
Disseminated intravascular coagulation complicating acute lymphoblastic leukemia: a study of childhood and adult cases. Leuk Lymphoma 2005;46:1169–1176.
Yanada M, Matsushita T, Suzuki M, Kiyoi H, Yamamoto K, Kinoshita T et al.
Disseminated intravascular coagulation in acute leukemia: clinical and laboratory features at presentation. Eur J Haematol 2006;77:282–287.
Uchiumi H, Matsushima T, Yamane A, Doki N, Irisawa H, Saitoh T et al.
Prevalence and clinical characteristics of acute myeloid leukemia associated with disseminated intravascular coagulation. Int J Hematol 2007;86:137–142.
Dixit A, Chatterjee T, Mishra P, Kannan M, Choudhry DR, Mahapatra M et al.
Disseminated intravascular coagulation in acute leukemia at presentation and during induction therapy. Clin Appl Thromb Hemost 2007;13:292–298.
Libourel EJ, Klerk CP, van Norden Y, de Maat MP, Kruip MJ, Sonneveld P et al.
Disseminated intravascular coagulation at diagnosis is a strong predictor for both arterial and venous thrombosis in newly diagnosed acute myeloid leukemia. Blood 2016;128:1854–1861.
Franchini M, Di Minno MN, Coppola A. Disseminated intravascular coagulation in hematologic malignancies. Semin Thromb Hemost 2010;36:388–403.
Appel IM, Hop WC, van Kessel-Bakvis C, Stigter R, Pieters R. l-Asparaginase and the effect of age on coagulation and fibrinolysis in childhood acute lymphoblastic leukemia. Thromb Haemost 2008;100:330–337.
Asakura H, Ontachi Y, Mizutani T, Kato M, Ito T, Saito M et al.
Decreased plasma activity of antithrombin or protein C is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation. Eur J Haematol 2001;67:170–175.
Zuazu I, Canals C, Sempere A, Martin S, Brunet S, Puig J et al.
Association of acute leukemia with disseminated intravascular coagulation in adults. Analysis of 14 cases. Med Clin (Barc) 1989;93:441–444.
Giammarco S, Chiusolo P, Piccirillo N, Di Giovanni A, Metafuni E, Laurenti L et al.
Hyperleukocytosis and leukostasis: management of a medical emergency. Exp Rev Hematol 2017;10:147–154.
Albayrak M, Gürsel T, Kaya Z, Koçak Ü. Alterations in procoagulant, anticoagulant, and fibrinolytic systems before and after start of induction chemotherapy in children with acute lymphoblastic leukemia. Clin Appl Thromb Hemost 2013;19:644–651.
Stanworth SJ, Navarrete C, Estcourt L, Marsh J. Platelet refractoriness − practical approaches and ongoing dilemmas in patient management. Br J Haematol 2015;171:297–305.
Giordano P, Molinari AC, Del Vecchio GC, Saracco P, Russo G, Altomare M et al.
Prospective study of hemostatic alterations in children with acute lymphoblastic leukemia. Am J Hematol 2010;85:325–330.
Sehgal S, Sharma S, Chandra J, Nangia A. Coagulation profile at diagnosis in patients with acute lymphoblastic leukemia. Indian J Pediatr 2016;83:1082–1086.
Elnady H, Ismail S. D-Dimer in childhood acute lymphoblastic leukemia: effect of the disease and chemotherapy. Egypt Med J Nati Res Center 2007; 6:50–54.
Wijaya H, Chozie NA, Hegar B. Activation of coagulation system and d-dimer levels in children with acute leukemia. Paediatr Indones 2014;54:227–231.
Sehgal S, Sharma S, Chandra J, Nangia A. Coagulation profile during induction chemotherapy in childhood acute lymphoblastic leukemia. Indian J Pathol Microbiol 2017;60:50–56.
] [Full text]
Squizzato A, Rancan E, Thachil J, Di Nisio M. Diagnosis of overt and non-overt disseminated intravascular coagulation: a survey among experts and a call for action from the ISTH. Thromb Res 2017;152:74–76.
Squizzato A, Hunt BJ, Kinasewitz GT, Wada H, Ten Cate H, Thachil J et al.
Supportive management strategies for disseminated intravascular coagulation. An international consensus. Thromb Haemost 2016; 115:896–904.
Aota T, Wada H, Fujimoto N, Sugimoto K, Yamashita Y, Matsumoto T et al.
The valuable diagnosis of DIC and pre-DIC and prediction of a poor outcome by the evaluation of diagnostic criteria for DIC in patients with hematopoietic injury established by the Japanese Society of Thrombosis and Hemostasis. Thromb Res 2016; 147:80–84.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]