Soluble Recombinant Thrombomodulin Is a Potentially Promising Agent without Causing Severe Hemorrhagic Events for Hematological Malignancy-Induced Disseminated Intravascular Coagulation
Authors: Kurita Naoki , Nishikii Hidekazu , Yokoyama Yasuhisa , Sakata-Yanagimoto Mamiko , Obara Naoshi , Okoshi Yasushi , Suzukawa Kazumi , Hasegawa Yuichi , Chiba Shigeru 
Published: October 2019

Abstract
Abstract 3413

Background:
Disseminated intravascular coagulation (DIC) is a lethal complication in patients with hematological malignancies. Although standard therapy against DIC remains to be established, soluble recombinant thrombomodulin (rTM), which serves as a receptor for thrombin, has been developed and its effectiveness for DIC was recently reported (Saito et al, J Thromb Haemost 2006). We retrospectively analyzed 55 DIC episodes treated with rTM in patients with hematological malignancies.

Patients and Methods:
55 consecutive DIC episodes in 47 patients with hematological malignancies (AML except for APL, 21; APL, 8; ALL, 8; lymphoma, 8; myeloma, 2) hospitalized between November 2009 and July 2012 in University of Tsukuba Hospital were retrospectively analyzed. Diagnosis of DIC was based on DIC score of Japanese Ministry of Health and Labor Welfare criteria (Kobayashi et al, Bibl Haematol 1983). DIC was induced by hematological malignancy itself and severe infection secondary to hematological malignancy in 39 and 16 episodes, respectively. In every episode, 380 units/kg/day of rTM was administered intravenously from the onset of DIC for median of 7 (range, 2–22) days. The fibrin degradation products (FDP) level, DIC score, recovery time from DIC (recovery, the day when DIC score was decreased to 5 or less), and overall survival were analyzed.

Results:
Median DIC score at the onset was 7 (range, 6–11). 15 episodes were accompanied by bleeding tendency. Average of FDP level at the onset was 64.6 ƒÊg/dl (range, 20.6–202.4) in malignancy-induced DIC and 30.1 ƒÊg/dl (range, 13.2–72.0) in infection-induced DIC (P=0.03). FDP level 14 days after rTM administration was 10.1 ƒÊg/dl (SD: 3.7–27.9) and 20.3 ƒÊg/dl (SD: 9.3–44.3), respectively (P=0.04). Recovery rates from DIC 7 days after rTM administration were 72% in malignancy-induced DIC and 39% in infection-induced DIC (Fig. 1, P=0.02), and 100-day overall survival after the onset of DIC were 89% and 15% (Fig. 2, P<0.01), respectively. In multivariate analysis, infection-induced DIC was an only significant risk factor and presence of bleeding tendency, FDP level at the onset, DIC score at the onset, period of rTM administration, and number of rTM administration did not influence the recovery from DIC and overall survival. There were no severe hemorrhagic events after rTM administration or deterioration of bleeding tendency that led to discontinuation of rTM.

Discussion and Conclusion:
The recovery rate from hematological malignancy-induced DIC in the current cohort was comparable to that of rTM-treated DIC group (66%) and can be superior to that of heparin-treated DIC group (50%) in a previously reported phase III trial (Saito et al, J Thromb Haemost 2006). Although the use of heparin has fostered bleeding tendency in a number of previous DIC reports, bleeding tendency was reduced after rTM administration in all the DIC episodes analyzed with the current cohort. Therefore, this analysis traced the core conclusion of the previous phase III trial, emphasizing that rTM can be an effective anti-DIC agent without causing adverse hemorrhagic event even in DIC cases with preexisting bleeding tendency. However, the result was still significantly worse in infection-induced DIC secondary to hematological malignancies.

Disclosures:
Chiba: Asahi Kasei Pharma: Research Funding.