Intestinal thrombotic microangiopathy induced by FK506 in rats

Abstract

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.

Clinicopathological manifestations and treatment of intestinal transplant-associated microangiopathy

“…In addition, we recently established a rat model of intestinal microangiopathy induced by tacrolimus alone. 25 The pathology was consistent with human i-TAM after allo-HSCT, and rats recovered from microangiopathy after withdrawal of tacrolimus. Therefore, we hypothesized that 'not intensified' strategy for i-TAM would minimize drug-induced endothelial damage and improve outcome, and divided patients into four groups according to the way of immunosuppressant use.…”

Prophylactic and therapeutic treatment of graft-versus-host disease in Japan

“…The addition of mPSL to Tac and sMTX strongly suppressed acute GVHD in unrelated donor BMT but not chronic GVHD [35]. It has been suggested that calcineurin inhibitors are involved in the development of intestinal thrombotic microangiopathy, a life-threatening complication after allogeneic transplantation, in humans and rats [38][39][40]. The blood concentration of Tac was not necessarily high in patients who developed Tac-related encephalopathy [41].…”

The case of successful therapy with rituximab secondary hemolytic-uremic syndrome in a patient after the second allogeneic hematopoietic stem cell transplantation

“…Клиническая картина дан-ного осложнения зависит от органа-мишени. Описаны развитие перикардита, поражение почек в виде гемо-литико-уремического синдрома (ГУС), головного моз-га и кишечника [1][2][3]. Зачастую ТА-ТМА может про-текать под «маской» других состояний, вызванных токсичностью препаратов и характерных для раннего посттрансплантационного периода, таких как замед-ленное восстановление гемопоэза, инфекционные осложнения, реакция «трансплантат против хозяина» (РТПХ), дисфункция почек и неврологические нару-шения [4].…”