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
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
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在小儿急性淋巴细胞白血病的 L-天冬酰胺酶诱导治疗期间，使用同时凝血酶和纤溶酶测定法证实了与严重抑制纤溶相关的止血紊乱
DOI：
10.1002/pbc.28016
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发表时间：
2019
影响因子：
3.2
通讯作者：
Shima Midori
中科院分区：
文献类型：
--
作者：
Ishihara Takashi;Nogami Keiji;Ochi Satoshi;Ishida Toshiaki;Kosaka Yoshiyuki;Sawada Akihisa;Inoue Masami;Osone Shinya;Imamura Toshihiko;Hosoi Hajime;Shima Midori
背景L-天冬酰胺酶（L-Asp）相关血栓栓塞是儿科急性淋巴细胞白血病（ALL）患者的严重并发症，尤其是≥10.0岁的患者，但其发病机制仍有待阐明。在72例年龄为1.0 - 15.2岁的ALL患者中进行的前瞻性研究，接受柏林-法兰克福-明斯特（BFM）治疗95-ALL导向方案或日本儿童白血病协会研究ALL-02方案。我们将患者分为每种治疗方案，并采用凝血酶和纤溶酶同时生成试验研究凝血和纤溶的动态变化。在L-Asp治疗的前期（T0）、间歇期（T1）、后期（T2）和诱导后阶段（T3）采集患者的血浆样本。内源性凝血酶电位（T-EP）和纤溶酶峰高（P-峰）的测量进行了比较，正常plasma. ResultsNo的情况下发展血栓栓塞。JACLS组中对照组的T-EP和P-Peak的中位比值分别为1.06和0.87（T0）、1.04和0.71（T1）、1.02和0.69（T2）以及1.20和0.92（T3），而BFM组分别为1.06和1.00（T0）、1.04和0.64（T1），T2组分别为1.16和0.58; T3组分别为1.16和0.85。特别是，BFM组在T1和T2时的P-峰值比低于T0（P< .01）。此外，≥10.0岁患者的P-Peak比值在BFM组T1时较低（P= 0.02）。结论：结果表明，止血动力学似乎转变为高凝状态，与L-Asp治疗相关的显著低纤溶，特别是在≥10.0岁的患者中，遵循BFM方案。
BackgroundL‐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.ProcedureWe 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.ResultsNone 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).ConclusionsThe 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.