Increased levels of tissue factor activity and procoagulant phospholipids during treatment of children with acute lymphoblastic leukaemia

Abstract

The use of L-asparaginase (L-ASP) in paediatric patients with acute lymphoblastic leukaemia (ALL) is associated with thrombotic complications. We evaluated the activities of tissue factor (TFa), thrombomodulin (TMa) and procoagulant phospholipids (PPL) in 26 consecutive children with ALL (25 B-ALL and one T-ALL) treated by the French Acute Lymphoblastic Leukemia group (FRALLE)-2000 protocol. Samples were obtained at diagnosis, after glucocorticoid (GC) therapy, during the induction phase with L-ASP, vincristine (VCR) and adriamycin (ADR), during the re-induction and within the week after treatment. Plasma levels of TFa, TMa and PPL increased gradually and significantly during the different phases of the treatment, with higher levels observed during the induction period, and decreased after treatment discontinuation. In vitro studies showed that the different drugs used for ALL treatment could induce a weak expression of TF and procoagulant activity (PCA) on normal and leukaemia blood cells, while a marked effect was observed on endothelial cells. In conclusion, these data indicate that, in addition to the well-identified increased in coagulation factors and inhibitor deficiencies, the injury of the endothelium could lead to the release of TF and PPL and could contribute to the hypercoagulability of children treated for ALL.

The coagulopathy and thrombotic risk associated with L-Asparaginase treatment in adults with acute lymphoblastic leukaemia

“…In vitro experiments indicate that L-Asp can induce a modest increase of TF expression on lymphoblasts, whereas a marked increase was observed on endothelial cell lines. 60 These in vitro observations again support the possible role of endothelial and/or leukocyte activation in upregulation of TF during the L-Asp-associated hypercoagulable state.…”

“…60 TM activity was also increased compared with controls but remained in the same range as values seen at diagnosis. In vitro experiments indicate that L-Asp can induce a modest increase of TF expression on lymphoblasts, whereas a marked increase was observed on endothelial cell lines.…”

Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study

“…[6][7][8][9] All children with ALL enrolled in the different treatment protocols received the same E coli ASP, originally distributed by Kyowa, Hakko, Kyogo, Japan. Relevant thrombosis-prone drugs, days of administration, single and cumulative doses stratified according to the ALL induction protocols are depicted in Figure 1.…”

“…Relevant thrombosis-prone drugs, days of administration, single and cumulative doses stratified according to the ALL induction protocols are depicted in Figure 1. [6][7][8][9] Depending on the clinical practice at the participating centers, polychemotherapy was administered by central venous lines, that is, Broviac, or port catheters implanted within the first weeks of therapy. Subjects lost to follow-up, without parental consent, without complete remission of the disease and children with concomitant chronic diseases, hepatic failure, or severe septicemia were excluded from the analysis (n ϭ 96).…”

“…10,11 The score was initially investigated in a database pilot cohort of 456 consecutively enrolled children with ALL treated according to the BFM 92/95 and COALL 92/97 protocols 6,7 and then validated in a cohort of 339 newly recruited children with ALL (BFM 2000 and FRALLE 2000). 6,8,9 On the basis of the receiver operating characteristic (ROC) report generated in the pilot cohort, the cutoff value with the highest accuracy to discriminate between patients at risk was chosen: The VTE risk by score was low (Յ 2.5) and high (Ͼ 2.5). The study flow chart is depicted in Figure 2.…”