Development of Osteonecrosis Is Associated with Difference in Upregulation of Antithrombin, Protein C and Protein S after Four Weeks of Dexamethasone during Induction Treatment in Childhood Acute Lymphoblastic Leukemia.

Osteonecrosis (ON) is a serious complication of chemotherapy for pediatric acute lymphoblastic leukemia (ALL). Impairment of microcirculation seems to be involved in the pathogenesis of ON. We hypothesized that variation in hypercoagulability plays a role in the etiology of ON during treatment of ALL. Dexamethasone (dexa) and asparaginase (asp) are important drugs in the induction treatment of pediatric ALL that may influence the coagulation system. In the current study differences in coagulation parameters between pediatric ALL patients with and without ON were evaluated. Blood samples were taken at diagnosis and at several time-points during induction of the DCOG-ALL9 treatment schedule. Procoagulant factors (fibrinogen, factor II,V,VII,IX,X), anticoagulant factors (antithrombin (AT), protein C and protein S), parameters of thrombin generation (prothrombin fragment 1+2 (F1+2), thrombin antithrombin (TAT) complex) and of fibrinolysis (α2-antiplasmin (a2AP), plasminogen, plasmin-α2AP (PAP) complex, D-dimers) were determined. In total 137 patients without ON and 24 patients with ON were evaluated. In addition plasminogen activator inhibitor type 1 (PAI-1) activity and tissue plasminogen activator antigen (tPA-ag) concentration were studied in 25 patients, 15 without ON and 10 with ON. At diagnosis no significant differences in any of the coagulation parameters were found between patients with and without ON. After 4 weeks dexa treatment (day 29), AT, protein-C activity and protein-S total (anticoagulants) were significantly less upregulated in ON positive patients as compared to ON negative patients (respectively p=0.043, p=0.029, p=0.023). During tapering of dexa and administration of 4 doses asp at day 29, 33, 36 and 40 these parameters significantly decreased in both ON positive and negative patients. However, the nadir of these anticoagulant proteins reached lower levels in the ON positive patients as compared to ON negative patients and in ON positive patients levels even reached below lower limits of normal reference ranges. No other dexa or asp induced differences in any of the other coagulation parameters were found between ON negative and positive patients. These results indicate that development of ON in pediatric ALL patients seems to be associated with less upregulation of AT, protein C and protein S after 4 weeks treatment with dexa (day 29). ON positive patients subsequently declined below the lower limit of normal reference range during tapering of dexa and administration of asp in contrast to ON negative patients. This may suggest a therapy induced hypercoagulable state contributing to the development of ON.