Use of Recombinant Thrombomodulin for Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation Ameliorate Disease Severity
Authors: Fujiwara Hideaki , Maeda Yoshinobu , Sando Yasuhisa , Nakamura Makoto , Tani Katsuma , Ishikawa Takanori , Nishimori Hisakazu , Matsuoka Ken-Ichi , Fujii Nobuharu , Kondo Eisei , Tanimoto Mitsune 
Published: October 2019

Abstract

Background and Objectives: Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (SCT) is a devastating complication of SCT and lacks optimal managements with a high mortality. Its pathogenesis is not well understood but suggested that endothelial toxicity caused by chemoradiotherapy, infections, immunosuppressive drugs, graft-versus-host-disease (GVHD) and infections have been thought to play important roles. Recently recombinant human soluble thrombomodulin (rTM) was reported to be a safe and efficient treatment of disseminated intravascular coagulation for hematological malignancies. rTM which contains active extracellular domain of thrombomodulin, inactivates coagulation and the thrombin-rTM complexes activates protein C to activated protein C (APC). APC in activates factors Va and VIIIa with protein S, and subsequently lead to further thrombin formation. And, also rTM possesses cytoprotective effects against calcineurin inhibitor induced endothelial cell damage, anti-inflammatory activity such as decrease of high-mobility group box 1 protein, IL-6 and TNF-a. Hence we compared the efficacy of rTM with TMA to other conventional treatments.
Patients and Methods: Of 223 patients who had received SCT in our institute from January 2009 to March 2014, 16 patients diagnosed as TMA after allogeneic stem cell transplantation were identified from database. Diagnosis of TMA was based on the Bone Marrow Transplant Clinical Trials Network (BMT-CTN). Patients treated with rTM as a first-line therapy were categorized as rTM group and treated with other therapies as a first-line therapy were as control group.
Results: TMA occurrence was total 16 cases (7.2%). rTM group had 9 patients and control group had 7 patients. rTM group had male dominant (M/F 8/1 vs. 1/6) compared to control group. Both group showed similar age, disease distribution (rTM; 2 Leukemia, 5 Lymphoma and 2 ATLL vs. control; 3 Leukemia, 2 CML-BC and 2 ML), disease risk (rTM; 2 standard (1-2 CR or MDS) and 7 high vs. control; 7 high), hematopoietic cell transplantation specific comorbidity index, type of donor source (rTM; 5 related PBSC and 4 unrelated BM vs. control; 4 related PBSC and 3 unrelated BM), HLA compatibility (rTM; 4 haplo-identical donor vs. control; 3 haplo), conditioning regimen (rTM; 8 reduced intensity vs. control; 5 reduced intensity), GVHD prophylaxis (rTM; 5 CyA/Tac and short MTX, 4 Tac/ATGmPSL vs. control; 5 CyA/Tac and short MTX, 2 Tac/ATGmPSL) and year of transplant. Median onset of TMA in rTM group and control group were on day 24.5 (16-274) and day 72 (7-338) (p=0.13) post SCT, respectively. Compared with control group, rTM group revealed significantly superior overall survival after the onset of TMA (Figure1, p=0.043). Seven patients (77.8%) of rTM group recovered from TMA, while no patients recovered in control group. Acute GVHD were occurred in 5 cases of rTM group and in 4 cases of control group (p=0.29). Grade II to IV acute GVHD were occurred in 3 of rTM group and in 4 cases of control groups (Figure 2, P=0.66). Leading causes of death were 4 GVHD of 5 cases in rTM group and 3 TMA of 7 cases in control group. Both group had no lethal hemorrhagic event.
Conclusion; The use of rTM in TMA improved overall survival after the onset of TMA in this retrospective small number analysis. rTM reduced TMA mortality but GVHD was still a major cause of death in TMA survivors. Larger prospective studies are warranted to fully evaluate the efficacy of rTM.
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
No relevant conflicts of interest to declare.