Hypercoagulability during l‐asparaginase treatment: the effect of antithrombin III supplementation in vivo

Abstract

To evaluate the occurrence of hypercoagulability during treatment with L-asparaginase (L-ase), thrombin-antithrombin complex (TAT) and D-dimer levels in plasma were serially measured in 15 consecutive adult patients with acute lymphoblastic leukaemia or lymphoblastic lymphoma who had recently completed a chemotherapy cycle with cytosine arabinoside and methotrexate. The first eight patients (group A) received i.v. L-ase alone (20,000 U/m2 on alternate days over 10 d); the last seven patients (group B) received, in addition to L-ase, bolus injection of antithrombin concentrate (2000 U) on alternate days for a total of six administrations, beginning with the second L-ase infusion. Increased levels of TAT (P less than 0.05) and D-dimer (P less than 0.01) were observed prior to L-ase, possibly related to inflammation and cytolysis secondary to previous chemotherapy. In patients treated with L-ase alone, further elevation of TAT (P less than 0.05) and persistence of increased D-dimer were observed, associated with marked reduction of the anticoagulant activities of protein C, protein S and antithrombin III. At variance, in patients receiving antithrombin III supplementation there was no increase of TAT and a normalization of D-dimer levels occurred during L-ase treatment. In these patients, mean plasma antithrombin III activity was maintained at levels higher than 70% of normal throughout the treatment. The rate of decline of fibrinogen, factor IX, protein C and protein S was unaffected by antithrombin III supplementation, indicating that hypercoagulability has little if any relevance for the reduction of coagulation factors and inhibitors induced by L-ase treatment. The usefulness of antithrombin III concentrates in preventing thromboembolic complications in patients submitted to L-ase treatment remains to be determined.

Changes in antithrombin and fibrinogen levels during induction chemotherapy with L-asparaginase in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma. Use of supportive coagulation therapy and clinical outcome: the CAPELAL study

“…13,[22][23][24][25][26] Several studies have also evaluated the potential benefit of AT concentrates in children and adults with ALL. Most measured surrogate markers evaluating thrombin generation [27][28][29][30] and only one reported a lower incidence of thrombosis in patients treated with AT (0 events in 17 treated cases vs. 10 events in 37 patients not receiving AT, p=0.021). 21 Although none of our patients died from thrombosis, overall and diseasefree survival rates were decreased among the patients who had experienced a thrombotic event.…”

Personal practice: How we manage the risk of bleeding and thrombosis in children and young adults with acute lymphoblastic leukaemia

“…Inconsistent effect on haemostatic laboratory parameters (Gugliotta et al, 1990;Mitchell et al, 2003b). Evidence for clinical benefit weak (Mitchell et al, 2003b).…”

“…Both reports concluded that FFP was unlikely to be of clinical benefit in this situation. Gugliotta et al (1990) monitored clotting levels and AT levels in 15 adult patients receiving E.Coli L-asparaginase in whom half also received six doses of AT supplementation, 2000 units intravenously, on alternate days commencing at the second L-asparaginase infusion. They found that FFP had no influence on haemostatic parameters whilst AT concentrates prevented L-asparaginase-dependent activation of coagulation as evident by normalization of D-dimer and maintenance of normal thrombin-antithrombin (TAT) complex levels.…”

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

“…AT supplementation has been explored in paediatric and adult populations during L-Asp therapy, with initial studies concluding that although enhanced thrombin generation and d-dimer levels associated with therapy returned towards normal with AT replacement, further randomised trials were required to demonstrate whether a clinical benefit existed. 54,62 The more recent PARKAA study showed a trend towards efficacy and safety with AT concentrate in prevention of thrombosis in children treated with LAsp, but the study was not powered to answer this question. 64 The CAPELAL study reported lower rates of thrombosis in adults who received prophylactic AT concentrate (4.5%) than in those who had not (12.7%).…”

“…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. 53,54 Fibrinolytic system Fibrinolysis is the process by which fibrin clots are dissolved and is a requirement of normal haemostasis. The serine protease plasmin is the predominant fibrinolytic enzyme, but circulates as a proenzyme, plasminogen.…”