Clinical and Pathological Diagnosis of Transplantation Associated Microangiopathy of Gut: Successful Reduction of Immunosuppressant Which Is Opposite Treatment of GVHD.
Authors: Miyamura Koichi , Yamada Minami , Nishida Tetsuya , Tomiya Yasuo , Harigae Hideo , Kameoka Junichi , Sasaki Takeshi , Ito Masafumi 
Published: October 2019

Abstract
Transplantation associated with thrombotic microangiopathy (TAM) is a serious complication after hematopoietic stem cell transplantation. We reported 7 patients with TMA after allogeneic BMT. All patients had grade II–IV acute graft-versus-host disease (GVHD) Since they were diagnosed with progressive GVHD at that time, they received more intensive treatment for it such as high-dose methylprednisone (mPSL), but all died. Autopsy showed histopathological evidence of intestinal TMA in their gut specimens (Bone Marrow Transplantation33, 1143, 2004). This report suggests that the gut may be a site involved in TAM, presenting as ischemic enterocolitis. Differentiating intestinal TAM from acute GVHD is important in patients suffering from severe and refractory diarrhea after BMT. It is also reported that use of tacrolimus and cyclosporine are risk factors of TAM.
Our new strategy for severe diarrhea was conducted as follows. If patients develop more than 500 ml of diarrhea, we promptly collect the laboratory data of TAM such as red blood cell fragmentation and macroscopic future of colonoscopic examination. Biopsy was performed, but the pathological findings were not used for clinical diagnosis for prompt initiation of treatment.
Abdominal pain, bloody diarrhea, solitary abdominal symptoms without skin or liver GVHD suggested TMA. Subepithelial bleeding and erosion/ulceration of mucosa identified by endoscope also suggested TMA. From these clinical manifestation and laboratory data, we determined whether patients have pure GVHD, pure TMA or both. Then we started treatment. If the patient was judged to have GVHD, steroid was started. If the patient was considered to have TAM, tacrolimus was reduced. If the patient was determined to have mixed type, treatment was decided by the primary physician. Biopsy specimens were examined by a independent pathologist in a blind manner in January 2006.
Eighteen patients were analyzed. Eight patients were judged to have gut GVHD clinically and were treated by steroid. Symptoms improved in 7 patients. The remaining patient who seemed to have steroid-refractory GVHD, was diagnosed with TAM by pathology. Three patients were diagnosed as TAM clinically, and we reduced the tacrolimus dose to half. Two patients showed improvement but one did not. All three were determined to have pathological finding of TAM. The 7 other patients were diagnosed with both TMA and GVHD. In 5 patients, tacrolimus was reduced and 3 improved. In the remaining 2, we are continuing initial treatment and they have improved. Twelve patients who responded to the treatment survived more than 1 year after transplantation.
In the current study, the clinical diagnosis of TAM and the pathological pictures are well correlated. Diarrhea after transplantation is usually a diagnostic component of GVHD, however, solitary gut TAM or comorbidity of TAM should be considered. Reduction of tacrolimus was performed in 8 patients because of the diagnosis of gut TAM. Five patients recovered from diarrhea and have live for a long time. Taken together, gut TAM should be considered as one of the differentiated diagnoses after transplantation, because its treatment is the reduction of immunosuppressants, the opposite of GVHD treatment.