Impaired dexamethasone-related increase of anticoagulants is associated with the development of osteonecrosis in childhood acute lymphoblastic leukemia

Abstract

Coagulation alterations may be involved in osteonecrosis in childhood acute lymphoblastic leukemia. Retrospectively, we evaluated the available coagulation parameters at diagnosis and during induction treatment of 161 acute lymphoblastic leukemia patients: 24 with symptomatic osteonecrosis (median age: 13.8 years, range 4.0-17.2) and 137 without osteonecrosis (median age: 4.9 years, range 1.0-16.7). Coagulation parameters of both groups were similar at diagnosis. After four weeks of treatment including dexamethasone, levels of antithrombin and protein S were significantly less in osteonecrosis-positive than in osteonecrosis-negative patients. Subsequently, after four doses of asparaginase and tapering dexamethasone, these coagulation parameters equally decreased in both groups. Consequently, nadirs of antithrombin and protein S were significantly lower in osteonecrosis-positive than in osteonecrosis-negative patients, even reaching levels below lower normal limits in the osteonecrosis-positive group. A reduced dexamethasone related increase of antithrombin and protein S, and subsequent decline below normal levels after introduction of asparaginase, may result in a hypercoagulable state, contributing to development of symptomatic osteonecrosis.Key words: osteonecrosis, hypercoagulability, antithrombin, protein S, acute lymphoblastic leukemia. lymphoblastic leukemia. Haematologica 2008; 93:1570-1574 Citation: te Winkel ML, Appel IM, Pieters R, and van den Heuvel-Eibrink MM. Impaired dexamethasone-related increase of anticoagulants is associated with the development of osteonecrosis in childhood acute

Symptomatic osteonecrosis in childhood leukemia survivors: prevalence, risk factors and impact on quality of life in adulthood

“…23 In some other cohorts, reported incidences have been higher, ranging from 7.1 to 14%. 15,[24][25][26][27] The time of occurrence we describe here is also comparable with many existing studies who reported a 14-27 month median time interval from leukemia diagnosis to ON occurrence. 15,[20][21][22][23][24][25] After allogeneic transplantation for childhood leukemia, Faraci et al found a 3.9% prevalence of clinically and radiologically documented ON.…”

“…30 The fact that adolescents are prone to develop ON may also be explained by age-related differences in steroid-induced changes in the coagulation system during leukemia treatment. 26 Finally, a PAI-1 gene polymorphism predicts ON in children aged ten years and over with ALL, suggesting that this inhibitor of fibrinolysis plays a role in the pathophysiology. 32 For HSCT patients, GVHD is a risk factor for ON, probably due to intensive use of steroid and immunosuppression.…”

Osteonecrosis in children with acute lymphoblastic leukemia

“…8,39,49 GCs might affect antithrombin and protein S levels, with the latter further worsened by the additional administration of asparaginase, thus leading to hypercoagulability. 50 …”

Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia

“…6 Some ALL treatment regimens have a much higher frequency of osteonecrosis than others, suggesting that some nonglucocorticoid drugs (eg, asparaginase and methotrexate) may modify the risk of osteonecrosis. 7 Hypercoagulability 15,19 and hyperlipidemia 20 have been associated with osteonecrosis in clinical settings outside of ALL treatment. Multiple candidate gene studies have indicated several polymorphisms in genes putatively related to the development of osteonecross, such as SERPINE 1, 21 VDR, 5 and CYP3A4, 22 but there are conflicting results, 21,23 no genome-wide association studies (GWAS) have been performed, and most genomic studies have failed to account extensively for nongenetic risk factors.…”