Effect of L-asparaginase administration on coagulation and platelet function in children with leukemia.

Abstract

The use of L-asparaginase during remission induction in patients with leukemia is associated with coagulation abnormalities, which may present either as thrombosis or hemorrhage. However, because of the multiple pharmacologic and hematologic variables present in these patients, the exact contribution of L-asparaginase to these coagulation abnormalities is unclear. We studied platelet function and plasma coagulation parameters in 12 pediatric patients with acute lymphoblastic leukemia (ALL) receiving daily L-asparaginase as a single agent when in complete remission. Changes in the prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen, while statistically significant, remained within or close to the normal range during the study. Platelet function also remained normal during the study. In contrast, levels of protein C antigen decreased to a mean of 42%, a significant change from pretreatment values. Levels of antithrombin III (AT III) were likewise depressed to 15 mg/dL (34% of pretreatment value). Despite these changes in the levels of physiologic inhibitors of coagulation, this schedule of L-asparaginase administration was associated with only rare clinical thrombosis, and this study suggests that the development of this complication may be dependent on the presence of additional factors.

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

“…Homans et al 42 demonstrated that AT levels were reduced to 34% of pre-treatment levels when L-Asp was given as a single agent to children with ALL in remission and returned to baseline 14 days after cessation of therapy. The DFCI protocol 87-001 evaluated the in vivo effect of single agent L-Asp on AT levels in untreated paediatric patients with ALL.…”

“…52 The administration of L-Asp as a single agent to children with ALL in remission has been associated with marked reductions in protein C antigen levels. 42 A significant decline in both protein C and free protein S occurred in paediatric patients treated with L-Asp on the DFCI protocol 87-001. 46 Two small studies in adult patients reported results consistent with the pattern seen in children, with marked reductions in the anticoagulant activities of protein C and S following L-Asp.…”

“…Low levels of AT during L-Asp therapy in childhood ALL have been reported by a number of studies. 41,42,46 The effect attributable to L-Asp specifically on AT levels is difficult to interpret in some series due to the failure to measure other components of the haemostatic pathway. The deficiency observed could be a manifestation of failure in hepatic synthetic function, exacerbated by consumption during thrombus formation.…”

“…41 However, a study of patients exposed to single agent L-Asp once in remission reported that although clotting times were prolonged from baseline, the PT remained within normal limits and the APTT was only marginally prolonged. 42 …”

“…[40][41][42] The first study evaluated 26 patients during induction with vincristine, prednisolone and L-Asp and reported prolongation of the PT in 16, the APTT in 23 and the thrombin time in 21 patients. 40 All patients had reduced fibrinogen levels and all parameters returned to normal within 2 weeks of completion of L-Asp.…”