Disordered hemostasis associated with severely depressed fibrinolysis demonstrated using a simultaneous thrombin and plasmin generation assay during L‐asparaginase induction therapy in pediatric acute lymphoblastic leukemia

Abstract

Background L‐asparaginase (L‐Asp)‐associated thromboembolisms are serious complications in pediatrics patients with acute lymphoblastic leukemia (ALL), especially at ≥10.0 years old, but the pathogenesis remains to be clarified. Procedure We conducted a multicenter, prospective study of 72 patients with ALL aged 1.0 to 15.2 years treated with either a Berlin‐Frankfurt‐Münster (BFM) 95‐ALL oriented regimen or Japan Association of Childhood Leukemia Study ALL‐02 protocol. We divided patients into each treatment protocol and investigated the dynamic changes in coagulation and fibrinolysis using simultaneous thrombin and plasmin generation assay. Patients’ plasma samples were collected at the prephase (T0), intermittent phase (T1), and postphase of L‐Asp therapy (T2), and postinduction phase (T3). Measurements of endogenous thrombin potential (T‐EP) and plasmin peak height (P‐Peak) were compared to normal plasma. Results None of the cases developed thromboembolisms. Median ratios of T‐EP and P‐Peak for the controls in the JACLS group were 1.06 and 0.87 (T0), 1.04 and 0.71 (T1), 1.02 and 0.69 (T2), and 1.20 and 0.92 (T3), respectively, while those in the BFM group were 1.06 and 1.00 (T0), 1.04 and 0.64 (T1), 1.16 and 0.58 (T2), and 1.16 and 0.85 (T3), respectively. In particular, P‐Peak ratios were depressed at T1 and T2 compared to T0 in the BFM group (P < .01). Moreover, P‐Peak ratios in patients ≥10.0 years old were lower at T1 in the BFM group (P = .02). Conclusions The results demonstrated that hemostatic dynamics appeared to shift to a hypercoagulable state with marked hypofibrinolysis associated with L‐Asp therapy, especially in patients ≥10.0 years old following the BFM regimen.

A Pathological Clarification of Sepsis-Associated Disseminated Intravascular Coagulation Based on Comprehensive Coagulation and Fibrinolysis Function

“…To the best of our knowledge, the present study is the first to examine simultaneous coagulation and fibrinolysis at the initial diagnosis of sepsis-associated DIC using the established parameters derived from CFWA and T/P-GA. 16,17 The successful quantification of synchronized coagulation and fibrinolysis is described together with a classification system based on comparisons of specific parameters. We have previously presented similar comprehensive analyses of coagulation and fibrinolysis using these techniques in pediatric patients with DIC secondary to several types of acute leukemia [29][30][31] and Kawasaki disease. 18 Use of CFWA and T/P-GA in for Quantitative Evaluation of Sepsis-Associated DIC…”

Altered Fibrinolysis in Hematological Malignances

“…They all found low levels of plasminogen, and further, PAI-1 levels were found to be increased in three studies 11,15,17 indicating a hypofibrinolytic state. This was corroborated by Ishihara et al 15 who measured a low plasmin generation potential during L-asparaginase treatment using a thrombin and plasmin generation assay. 40 In addition to low levels of One case study 34 reported primary hyperfibrinolysis as a complication of ALL.…”

“…Three cohort studies investigated fibrinolysis following chemotherapy treatment. 11,15,17 Two studies 15,17 reported increased PAI-1 levels suggesting hypofibrinolysis. This was contradicted by Cetkovsky et al 11 demonstrating increased t-PA indicating hyperfibrinolysis but normal PAI-1 levels.…”

“…Four studies 11,15,17,19 investigated fibrinolysis in ALL patients after treatment with L-asparaginase. They all found low levels of plasminogen, and further, PAI-1 levels were found to be increased in three studies 11,15,17 indicating a hypofibrinolytic state. This was corroborated by Ishihara et al 15 who measured a low plasmin generation potential during L-asparaginase treatment using a thrombin and plasmin generation assay.…”

Indospicine combined with arginine deprivation triggers cancer cell death via caspase‐dependent apoptosis

“…Genetic and metabolic alterations in many cancer cells make them more sensitive to the lack of certain exogenous amino acids (Sharma et al, 2019; Szefel et al, 2019; Zou et al, 2019). This provided a rational for the development of metabolic anticancer therapies based on the application of recombinant enzymes degrading individual amino acids, such as asparaginase for the treatment of pediatric leukemias (Covini et al, 2012; Beckett and Gervais, 2019; Ishihara et al, 2019; Tabe et al, 2019). Restriction of the semi‐essential amino acid arginine (Arg) was proposed as a promising approach for the treatment of tumors deficient in Arg anabolism (Wheatley and Campbell, 2002; Wheatley, 2005).…”