Fatal Pulmonary Embolism and Antithrombin III Deficiency in Adult Lymphoblastic Leukaemia during L-Asparaginase Therapy

Abstract

We describe 2 adult patients with acute lymphoblastic leukaemia (ALL) who died from pulmonary embolism following L-asparaginase treatment. Since this drug is known to cause a decrease in antithrombin III, the most important protein physiologically involved in the neutralization of thrombin, we studied the behaviour of this inhibitor in 14 ALL patients treated with a protocol including a 14-day course of L-asparaginase. A significant but transient fall of biological and immunological antithrombin III and a concomitant reduction of fibrinogen were documented.

Fatal Liver Failure in an Adult Patient with Acute Lymphoblastic Leukemia following Treatment with <i>L</i>-Asparaginase

“…In the literature, adverse drug reactions associated with L -asparaginase have often been related to a decreased hepatic protein synthesis, including ATIII and fibrinogen [6, 7,9,10,11]. In addition, L -asparaginase has been shown to induce micro- and macrovesicular steatosis of the liver [2, 8, 12, 14].…”

“…Adverse effects of L -asparaginase include mainly hypersensitivity reactions, acute pancreatitis, coagulation disorders, immune suppression, and liver injury [4]. Coagulation disorders comprise hemorrhage and thromboembolic events [5,6,7,8,9,10] and are explained by impaired hepatic synthesis of coagulation factors such as antithrombin (AT) III, fibrinogen, and protein C. Bushman et al [11] suggested that low plasma concentrations of ATIII may be a consequence of a decreased translation and/or secretion of the protein in hepatocytes.…”

Antithrombin III during High-Dose Cytosine Arabinoside Therapy with or without Asparaginase

“…Reports about the influence of ASNase on AT III synthesis are mostly related to patients receiving a prolonged administration of ASNase (mean total dose 140,000 U) [11][12][13], but the decrease in AT III has been reported to occur precociously from the start of the therapy [9,12], In our cases, a mean decrease in plasma AT III concentration and activity of about 25% occurred after 4 days from only 1 administration of 10,000 U of ASNase, with a return to normal range within 1 week. A second administration of HID ARAC + ASNase within 8 days from the first course seems to prolong this slight decrease in AT III.…”

“…High dose Ara-C (HIDARAC) regimen has been re ported to be an effective therapy of acute leukemia [1][2][3]; successively, this schedule has been modified by a sequential administration of asparaginase (ASNase) to obtain a synergic effect between Ara-C and AS Nase [4][5][6]. A mild and transient liver toxicity has been reported in 75% of patients who underwent HIDARAC therapy [6,7], Moreover, liver toxicity oc curs very frequently during ASNase administration [8]; coagulation abnormalities are also frequent [8][9][10], and antithrombin III (AT III) levels are dra matically lowered [9][10][11][12], so that an increased risk of thromboembolism has been noticed [11][12][13]. ASNaseinduced depression in AT III appears to be secondary to a reduced production by the liver, where AT III is synthesized [14].…”

Pulmonary Embolism and <i>L</i>-Asparaginase Therapy

“…In a recent article Barbui et al [1983] describe 2 patients with acute lymphoblastic leukemia who died from pulmonary embolism following L-asparaginase (L-ASE) treatment. Thromboembolic manifestations have been described following L-ASE therapy with a significant decrease of antithrombin III by other authors [Pitney, 1980;Conard, 1980;Vellenga, 1980;Tura, 1981].…”