Recombinant Human Thrombomodulin in the Treatment of Acute Myeloid Leukemia Patients Complicated By Disseminated Intravascular Coagulation: Results of a Multicenter, Retrospective Epidemiologic Study in Japan
Authors: Takezako Naoki , Sekiguchi Naohiro , Noto Satoshi , Ogino Yoshitaka , Miwa Akiyoshi , Ikezoe Takayuki 
Published: October 2019

Abstract
Background: Thrombomodulin is a thrombin receptor that acts an important regulator of coagulation. Recombinant human thrombomodulin (rTM) is a promising anticoagulant that activates protein C, which leads to the inactivation of factor (F) Va and FVIIIa and decreased formation of thrombin. rTM has also been identified as 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 88 patients with acute myeloid leukemia (AML) (except adult acute promyelocytic leukemia), who suffered from DIC and compared the outcomes between the patients with low molecular weight heparin (LMWH) therapy and with rTM in multi-center.
Methods: 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 2013. 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 Chi-square 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.
Results: DIC developed in 88 patients. Median age of patients was 60 years (from 15 to 85) and median duration was 699 days (from 15 to 2552 days). 30 patients were treated with dalteparin sodium and 58 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. The duration of DIC treatment with rTM was significant shorter than that with LMWH (6.3 days vs 15.1 days, p <0.0001). The overall survival was superior in the rTM group compared with dalteparin sodium group (P=0.0425).
Discussion: Patients with DIC resulting from sepsis or hematological malignancies can be successfully treated if sufficient treatments are offered. However, additional anti-coagulant treatments may be required in many cases because of life-threatening abnormal coagulation states. In Japan, LMWH has been recommended by the Japanese Society of Thrombosis Hemostasis/DIC subcommittee for the treatment of DIC because patients were less likely to bleed when treated with LMWH than with unfractionated heparin (UFH) (Level 2b). On the other hand, a randomized controlled study reported that rTM therapy improved DIC and relieved bleeding complications in DIC patients more signiﬁcantly than UFH therapy. To the best of our knowledge, very few institutes compared rTM with heparin as a therapy for DIC during AML induction therapy. Here, we demonstrate that if patients develop DIC, their prognosis will be improved by the administration of rTM.
Conclusion: We conclude that treatment with rTM is safe and efficient, when compared with LMWH. Based on this retrospective study, randomized control study could be attempted in the future.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.