Thrombotic microangiopathy (TMA) is one of the severe complications after stem cell transplantation (SCT) and is associated with graft-versus-host disease (GVHD) prophylaxis including FK506. In this study, we experimented on rats using FK506 to demonstrate the occurrence of intestinal TMA. FK506 was administrated into Wistar/ ST rats intraperitoneally for 7 days. Rats were examined histopathologically after FK506 injection using light and electron microscopy and immunohistochemistry. FK506 concentrations in whole blood were measured by enzyme immunoassay. In the acute phase, hemorrhagic lesions with multifocal erosions and crypt loss were found in the small intestines of all treated rats. Capillary vessels were dilated, and a few platelet thrombi were found. Electron microscopy demonstrated degenerative swelling of endothelial cells and platelet aggregates adhering to the vessel walls. In the later phase, epithelial regenerative failure, characterized by crypt ghosts, was found in the affected mucosa. Apoptotic epithelial cells were increased in number. The extent of intestinal injury was proportional to the whole blood levels of FK506. The intestinal lesions in rats were consistent with TMA and induced by the injection of FK506 alone. Apoptotic enteropathy was also observed and similar to intestinal GVHD. In this study, we established an intestinal TMA model induced by immunosuppressant (Tacrolimus) only without irradiation.

To investigate the relationship between the fetal hemoglobincontaining erythroblasts (F blasts) and apoptosis in myelodysplastic syndromes (MDS), we immunohistochemically assessed F blasts, F cells, and apoptosis in 137 patients with MDS. A marked increase in the number of F blasts in the bone marrow was identified in 116 of 137 patients (84.7%), and the number of F cells was elevated in 54 patients (39.4%). Among the erythroblasts stained by anti-glycophorin C antibody, the mean percentage of F blasts was 14.63 ؎ 9.17% in MDS, which was significantly higher than that in non-MDS patients with stress erythropoiesis (4.82 ؎ 3.35%, P Ͻ 0.01), although there were no significant differences in the number of F cells between these groups. In particular, 62 of the 137 MDS patients (45.3%) had an apparent increase in F blasts but no elevation of F cells. The apoptotic rate was significantly higher in the patients with a F blast/F cell (Fb/Fc) ratio у5.0 than in those with a Fb/Fc ratio Ͻ1.0 (P Ͻ 0.01). The results indicate that F cell precursors are incapable of maturing into functioning endstage F cells, presumably owing to apoptotic cell death. The measurement of F blasts in the bone marrow is needed for the precise evaluation of fetal-type erythropoiesis in MDS.

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