Comparison of the anticoagulant effect of a direct thrombin inhibitor and a low molecular weight heparin in an acquired antithrombin deficiency in children with acute lymphoblastic leukaemia treated with l‐asparaginase: an in vitro study

Abstract

SummaryThrombosis occurs in 37% of children with acute lymphoblastic leukaemia (ALL) and is related to an l‐asparaginase‐induced acquired antithrombin (AT) deficiency. The incidence dictates the need for anticoagulant prophylaxis. Direct thrombin inhibitors (DTI) are independent of AT for effect and may thus have advantages in this population. The objective of this study was to determine the interaction of an AT deficiency with the anticoagulant effects of a DTI and a low molecular weight heparin (LMWH). Plasma samples from children with ALL were pooled (mean AT 0·53 U/ml). LMWH 0·3 and 0·7 U/ml or melagatran 0·3 and 0·5 μmol/l were added to the pools, then divided and AT was added back to one aliquot. In additional experiments, AT was added to AT immuno‐depleted plasma. Endogenous thrombin generation capacity (ETGC) was assessed by the continuous method. In plasma with LMWH, there was a 66–88% decrease in ETGC in AT‐normalised samples compared with neat. Conversely, no significant difference in ETGC with or without AT added for melagatran was seen. Experiments with AT‐depleted plasma showed no effect of AT level on anticoagulant activity of DTI, but a significant relationship for LMWH. By contrast to LMWH, DTI provides a consistent anticoagulant response independent of AT levels in children with AT deficiency.

L-Asparaginase and Venous Thromboembolism in Acute Lymphocytic Leukemia

“…The study demonstrated a consistent anticoagulant effect of direct thrombin inhibitors (melagatran) independent of antithrombin level in plasma. Conversely, the anticoagulant effect of LMWH was markedly dependent on antithrombin level [37]. In this context, novel oral anticoagulants such as rivaroxaban or dabigatran, which are direct inhibitors of thrombin or factor Xa, do not require monitoring of antithrombin level and may presumably have a lower risk of failure; however, further studies are warranted to confirm these speculations.…”

“…Only a fraction of patients were re-exposed to asparaginase; the criteria for continuation versus discontinuation of asparaginase are not provided. anticoagulants are direct inhibitors of thrombin or Xa and are not dependent on antithrombin for their activity [37]. The aforementioned pediatric study demonstrated that the use of enoxaparin and antithrombin was more effective than antithrombin alone in preventive VTE during L-asparaginase therapy [33], which indicates that the new oral anticoagulants may be as effective as or perhaps more effective than LMWH and/ or antithrombin replacement in the prevention of asparaginase-related VTE.…”

“…None of the patients in either group had major bleeding episodes [33]. Given the fact that the use of enoxaparin and antithrombin may be more effective than antithrombin alone in VTE prevention [33], we hypothesize that direct thrombin inhibitors, which do not require the presence of antithrombin [37] may be as effective as or perhaps more effective than enoxaparin in preventing the risk Whether the use of specific forms of L-asparaginase can reduce the risk of thrombosis remains unclear; however, E. coli asparaginase is superior to Erwinia asparaginase in terms of disease control and overall survival [24,25], hence may be preferentially used in the absence of allergies or neutralizing antibodies. In a small study of 18 patients, L-asparaginase encapsulated within erythrocytes appeared to have lower toxicities, compared with six patients treated with E. coli asparaginase.…”

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

“…Clinical data are again lacking but in vitro experiments using plasma from children with L-Asp-induced AT deficiency have demonstrated a consistent anticoagulant response with direct thrombin inhibitors, independent of AT levels, whereas a profound effect on the action of LMWH related to AT concentration was seen. 68 The new oral direct thrombin inhibitors and anti-Xa anticoagulants are currently being assessed in medical patients for thromboprophylaxis, and if these trials demonstrate efficacy and safety then study in L-Asp-treated patients would be warranted. It is likely that pharmacological thromboprophylaxis will have an increasing role in the management of L-Asp-exposed patients.…”

Antithrombin III Doses Rounded to Available Vial Sizes in Critically Ill Pediatric Patients

“…3,8 Additionally, higher AT III levels can result in more effective low-molecular-weight heparin doses. 10 The formulary AT III product at this institution is Thrombate III (Grifols, Research Triangle Park, NC). According to the manufacturer, AT III doses are calculated by the equation [units required (IU) = (desired AT level % − baseline AT level %) × body weight (kg)/1.4].…”