Hypercoagulability during induction therapy of acute lymphoblastic leukemia is of scarce clinical relevance. Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto.

Recently Sams et all and Solano et aI2 claimed a high incidence of disseminated intravascular coagulation (DIC) during the remission induction in adult patients with acute lymphoblastic leukemia (ALL) before any treatment with L-asparaginase. Sams et all found low fibrinogen levels (<160 mg/dL) in 3 1 of 45 patients (68W), with severe hypofibrinogenaemia (< 100 mg/dL) in 14 (3 1%). Venous thromboembolism or hemorrhagic complications occurred in 4 and 9 cases, respectively. Solano et al: even in the absence of clinical complications, found hypofibrinogenemia (< 100 mg/dL) in 13 of 34 patients (38%). Nevertheless, both series lack a thorough investigation of markers of hypercoagulability and fibrin split products were positive only in 10 of 79 total patients (12%), so that the assumption of DIC as main underlying cause of hypofibrinogenemia is questionable. We studied prospectively 50 ALL consecutive adult patients treated according to the Gruppo Italian0 Malattie Ematologiche Maligne dell'Adulto (GIMEMA) ALL 0288 trial: vincristine 2 mg/m2 intravenously (IV) days I , 8, 15, 22; daunorubicin 40 mg/m2 IV days I , 8, 15; prednisone 60 mg/m2/d from day I to day 14 and 40 mg/m2/ d from day 15 to day 3 I ; Escherichia coli L-asparaginase 6,000 U/ m2/d subcutaneously (SC) from day 15 to day 21; cyclophosphamide, randomly assigned, at the daily dose of 800 mg/m2 IV days I and 2. The effects of L-asparaginase on the hemostatic system (with or without supplementation of antithrombin 111 concentrate) have been reported el~ewhere.~.~ In our studies the basal values before administration of L-asparaginase were obtained at the day I5 of the induction protocol; thus, we evaluated coagulation activation after 2 weeks of chemotherapy (without L-asparaginase), similarly to Sams et all and Solano et al.' We considered the following parameters: fibrinogen 2.5 pg/L (nv < 2.5), thrombin-antithrombin complexes (TAT) >4 pg/L (nv 0.7 to 3.7), prothrombin fragment 1 + 2 (FI + 2) > I .2 nmol/L (nv 0.44 to 1 . I ) , D-dimer (D-D) >I50 pg/L (nv 33 to 124) (Table I ) . Hypofibrinogenemia ( 160 mg/dL (range 160 to 560, median value 250), with an isolated alteration of at least one marker of hypercoagulability in 2 I of them. However, an increase in two or more indices suggesting a prothrombotic state was found only in nine patients (two with hypofibrinogenemia) (18%) (Table I ) . Decreased levels of plasminogen or a-2-antiplasmin were found in 10 patients (20%), but in none of them was a concomitant hypofibrinogenemia present. No patient had decreased levels of antithrombin 111, protein c , or protein S. No thrombotic episode or major hemorrhagic complication was recorded during the first 2 weeks of chemotherapy, before L-asparaginase was started. Therefore, the blood coagulation activation during remission induction with vincristine + daunorubicin + prednisone f cyclophosphamide in our experience does not induce severe laboratory alterations and its meaning is questionable, being not related to the presence or the absence of hypofibrinogenemia. Moreover, only a minority of patients showed an alteration of at least two indices of hypercoagulability. Finally, in our patients no thrombosis or major hemorrhage occurred before L-asparaginase, in contrast with the data of Sarris et a].' We conclude that chemotherapy not including Lasparaginase in adult patients with ALL can induce a hypercoagulable state but not severe enough to lead to severe laboratory alterations or clinical manifestations in the majority of cases; a similar conclusion has been recently claimed also for patients with acute myelogenous leukemia (AML).5 We point out that the thrombotic risk in ALL patients seems mainly caused by the hypercoagulable state after the administration of L-asparaginase: in this series 2 patients (of the 25 not receiving antithrombin 111 concentrate) developed venous thrombosis after E co/i L-a~paraginase.~ Moreover, in a previous ret-