Intestinal thrombotic microangiopathy following reduced-intensity umbilical cord blood transplantation

Narimatsu, Hiroto; Kami, Masahiro; Hara, Shigeo; Matsumura, Tomoko; Miyakoshi, Shigesaburo; Kusumi, Eiji; Kakugawa, Yasuo; Kishi, Yukiko; Murashige, Naoko; Kikuchi, Yuji; Masuoka, Kazuhiro; Yoneyama, Akio; Wake, Atsushi; Morinaga, Shinichi; Kanda, Yoshinobu; Taniguchi, Satoshi

doi:10.1038/sj.bmt.1705099

Cited by 26 publications

(33 citation statements)

References 20 publications

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“…16,17 However, the patients suffering from TMA-associated FK506 recovered on withdrawal of FK506. 14 Our experimental animals also recovered from intestinal TMA after withdrawal of FK506 injection.…”

Section: Discussionmentioning

confidence: 99%

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Intestinal thrombotic microangiopathy induced by FK506 in rats

Fujino¹,

Kim

Ito

2007

Bone Marrow Transplant

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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.

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Section: Discussionmentioning

confidence: 99%

“…Immunosuppressants were thought to be one of the causative agents for TMA. 16,17 As intestines are a common target site of GVHD, and FK506 is often used as an immunosuppressant for prophylaxis of GVHD, it is very important to clarify the relationship between an occurrence of intestinal TMA and FK506.…”

Section: Introductionmentioning

confidence: 99%

Intestinal thrombotic microangiopathy induced by FK506 in rats

Fujino¹,

Kim

Ito

2007

Bone Marrow Transplant

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“…However, it is difficult to make a definite diagnosis of TMA due to the heterogeneity of etiologies and clinical findings. Nishida et al (2004) and Narimatsu et al (2005) reported case series of localized intestinal TMA. Of note, the patient's intestinal symptoms were improved after the reduction of immunosuppressants (Nishida et al 2004;Narimatsu et al 2005).…”

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confidence: 99%

“…Nishida et al (2004) and Narimatsu et al (2005) reported case series of localized intestinal TMA. Of note, the patient's intestinal symptoms were improved after the reduction of immunosuppressants (Nishida et al 2004;Narimatsu et al 2005). In support of this, Fujino et al (2007) established a rat model of intestinal TMA induced by tacrolimus without irradiation.…”

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confidence: 99%

Diagnosis of Intestinal Graft-versus-Host Disease and Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation

Yamada-Fujiwara

Miyamura

Fujiwara

et al. 2012

Tohoku J. Exp. Med.

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Severe diarrhea is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Acute graft-versus-host disease (GVHD) has been one of the major causes of diarrhea after HSCT, which is triggered by donor-derived cytotoxic T-lymphocytes. On the other hand, intestinal thrombotic microangiopathy (TMA) sometimes coexists with acute GVHD, and intensified immunosuppression to treat acute GVHD could exacerbate intestinal TMA, presumably through the vascular endothelial cell damage. The differential diagnosis between intestinal TMA and acute GVHD of the gut has mainly relied on the pathological findings, as clinical diagnosis of intestinal TMA has not been established. Therefore, we aimed to assess the feasibility of our clinical diagnosis for the patients with diarrhea after HSCT. We made tentative clinical criteria for intestinal TMA and acute GVHD of the gut, based on the clinical manifestations, laboratory data and colonoscopic findings, and started treatment before pathological diagnosis were made. Subsequently, a pathologist retrospectively assessed the accuracy of clinical diagnosis in a blind manner. In this study, we enrolled 19 patients complicating watery diarrhea after HSCT, and diagnosed as having acute GVHD (n = 10), intestinal TMA (n = 3), or both (n = 6) according to our criteria. We demonstrated that our clinical diagnosis for intestinal TMA and acute GVHD of the gut was overall correct, in terms of the response to the therapy and the pathological diagnosis. The present study may provide a clue on making clinical diagnosis of patients with watery diarrhea after HSCT, which enables us to start a prompt therapy.

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“…Mucosal damage caused by preparative regimens allows the transition from colonization to blood stream infection 6 and increases the risk of thrombocytopenic microangiopathy, 7 which have been reported to be significant problems after RI-CBT. The success of the second RI-CBT in our patient might be mainly attributed to the use of the fludarabine and cyclophosphamide regimen.…”

mentioning

confidence: 99%