The evaluation of Protein Z levels of children with acute lymphoblastic leukemia during induction therapy

Objective: It is well known that the tendency for thrombosis and hemorrhage increases in patients with concomitant use of steroid and L-asparaginase during induction treatment in acute lymphoblastic leukemia (ALL), the most frequently encountered malign disease of the childhood. In cases with ALL, although many studies investigated how the usage of steroid and ASP affects protein levels playing role in coagulation such as protein C, protein S and antithrombin, one of the other coagulation cascade proteins, protein Z levels have not been examined in any study yet. The objective of this study is to determine PZ levels during induction treatment in pediatric cases with ALL and to examine the relation between steroid and ASP therapies and plasma PZ levels.Materials and Methods: Children with ALL who were treated and followed up in Pediatric Hematology Department of Dokuz Eylül University Faculty of Medicine and Dr. Behçet Uz Children?s Hospital Hematology-Oncology Clinic were included into the study. Twenty four children who newly diagnosed as ALL and going to receive ALL BFM-1995 protocol induction treatment were included into the study group. The patients having additional chronic disease, liver and renal failure, disseminated intravascular coagulation, malnutrition and received fresh frozen plasma during the treatment were excluded from the study. Thirty nine children, without acute or chronic systemic disease, drug usage, and hematological disease in their past history, consistent with the study group in terms of age and gender, were taken as the control group. Peripheral blood of 3 cc was drawn from the study group without applying any chemotherapy (PZ0) at the beginning of the treatment, at 12th day (PZ1), 15th day (PZ2), 18th day (PZ3), and 21st day (PZ4) treatment where ASP treatment is given along with steroid administration according to ALL BFM ? 1995 chemotherapy protocol. In the control group, blood samples were drawn only once. All of the blood samples were drawn into citrated tubes and then centrifuged. Plasma samples were stored at -70ºC. PZ levels were measured by enzyme immunoassay (ELISA) method. Liver and renal function tests, coagulation tests, and blood products given to children were noted. During the first 21 days of the induction treatment, the patients with focal infectious focus, elevated C-reactive protein levels or culture positiveness in the course of fever were accepted as patients with infection. Statistical data were evaluated by SPSS 15.0 software. Chi-square, Mann-Whitney U, and Wilcoxon test were used. P<0.05 was selected as the value reflecting the statistical significance.Results: The median age of the children in the study and the control groups were 5.8 years (17-170 months) and 5.4 years (22-222 months), respectively. In the study group, 12 (50%) were female and 12 (50%) were male; in the control group, 19 (48.7%) were female and 20 (51.3%) were male. It has been demonstrated that the study and the control groups have similar characteristics in terms of age and gender distribution. Mean PZ level at PZ0 was determined to be 1.628±0.485 ?g/ml (minimum 0.976 ?g/ml, maximum 2.909 ?g/ml) in the study group and mean PZ level of the control group was determined to be 1.672±0.662 ?g/ml (minimum 0.705 ?g/ml, maximum 3.40 ?g/ml). No statistical difference was observed between mean PZ0 levels of the study group and mean PZ level of the control group. No statistical significant difference was determined when the PZ levels of 13 cases who received platelet transfusions and 11 cases who did not receive platelet transfusions during the first 21 day of the induction treatment and PZ levels of five cases with infection and 19 cases without infection were compared to each other. In the study group, there was a slight increase in PZ levels between the PZ0 and PZ1 periods which was not statistically significant. Statistically significant decrease was observed between PZ levels in PZ0-PZ4, PZ1-PZ2, PZ1-PZ3, PZ1-PZ4, and PZ3-PZ4 periods. During the induction treatment, hemorrhage and symptomatic thrombosis were not followed up in any patients including those with low PZ levels. Asymptomatic thrombosis was determined in two patients, one as right atrial thrombus in routine echocardiography and the other as left renal infarct in ultrasonography.Conclusions: At the beginning of ALL induction treatment, at diagnosis, PZ values of the study group were similar to those of the control group. Although a slight but not statistically significant increase of PZ levels was determined only with steroid treatment, a statistically significant decrease was observed in the progressive periods of the induction treatment with steroid and ASP usage. However, despite low PZ levels, symptomatic thrombosis or hemorrhage complication didn?t develop in any patients.Key words: Acute lymphoblastic leukemia, hemorrhage, L-asparaginase, protein Z, steroid, thrombosis.