Recombinant Human Thrombomodulin in the Treatment of Acute Myeloid Leukemia Patients Complicated by Disseminated Intravascular Coagulation: Retrospective Analysis of the Outcomes Between the Patients with Heparin and with Recombinant Human Thrombomodulin Therapy

Thrombomodulin is a thrombin receptor on the endothelial cell surface that plays an important role as a regulator of coagulation. Recombinant human thrombomodulin (rTM) is a promising anticoagulant that activates protein C, which leads to inactivation of factor (F) Va and FVIIIa and decreased thrombin formation. In addition, rTM is a novel anticoagulant with a long half-life. When compared with heparin therapy, rTM therapy more significantly improves DIC and alleviates bleeding symptoms in DIC patients. However, it is unknown as to whether or not the treatment with rTM affects patient's outcome. Therefore, we retrospectively analyzed 103 patients with acute myeloid leukemia (AML) (except adult acute promyelocytic leukemia), and compared the outcomes between the patients with heparin therapy and with rTM.

The diagnosis of de novo AML patients was based on the morphology, histopathology, cytogenetics, expression of leukocyte-differentiation antigens, and the French-American-British (FAB) classification. The patients examined in the current study (aged 18–84 years) were diagnosed with AML from January 2004 to March 2010. Patients younger than 65 years of age were treated with idarubicin (12 mg/m² per day) for 3 days (days 1–3) and cytarabine (100 mg/m² per day) by continuous infusion for 7 days (days 1–7). Patients 65 years of age or older were treated with daunorubicin (40 mg/m² per day) for 3 days (days 1–3) and 200 mg/m² per day behenoyl cytarabine for 8 days (days 1–8). The continuous infusion of dalteparin sodium (75 IU/kg per day) or recombinant human thrombomodulin (380 U/kg per day) was used to treat DIC.

The diagnostic criteria for DIC previously proposed by the Japanese Ministry of Health and Welfare (JMHW) were employed in this study. The criteria are based on a scoring system including the presence of underlying disease (0 or 1 points), organ failure (0 or 1 points), and the results of coagulation tests of fibrinogen (0 to 2 points), fibrin/fibrinogen degradation products (FDP, 0 to 3 points), and the prothrombin time (0 to 2 points). DIC is diagnosed when the DIC score is greater than 4.

Comparisons between the qualitative variables were carried out using the χ² test. The survival probabilities were estimated by the Kaplan-Meier method, and differences in the survival distributions were evaluated using the log-rank test. These statistical analyses were performed with the software package Stata version 11 (StataCorp LP, College Station, TX, USA). For all analyses, the P values were 2-tailed, and a P value less than.05 was considered to be significant.

DIC developed in 45 patients. 31 patients were treated with dalteparin sodium and 14 patients were treated with recombinant human thrombomodulin. The FAB subtypes, age distribution, major laboratory data (CBC, LDH, and CRP) were not significantly different between two groups. No patient died within 4 weeks after diagnosis who were treated with rTM. On the other hand, 3 patients died within 4 weeks after diagnosis who were treated with dalteparin sodium because of bleeding. The DIC resolution rates for the rTM and dalteparin sodium groups were 85.7 %( 12/14) and 67.7 %( 21/31). The overall survival was worse in the DIC group compared with the non- DIC group on the log-rank test (P=0.003). The overall survival was superior in the rTM group compared with dalteparin sodium group (P=0.016).

We conclude that treatment with rTM is safe and efficient, when compared with dalteparin sodium. Based on this retrospective study, randomized control study could be attempted in the future.

No relevant conflicts of interest to declare.