Tacrolimus‐induced asymptomatic thrombotic microangiopathy diagnosed by laboratory tests in pig‐to‐rhesus corneal xenotransplantation: A case report

Abstract

Tacrolimus-associated thrombotic microangiopathy (TA-TMA) is a rare complication. TA-TMA is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage due to thrombus. We report asymptomatic TA-TMA diagnosed by laboratory tests in pig-to-rhesus corneal xenotransplantation. Corneal transplantation had been conducted from a wild-type SNU miniature pig to a rhesus macaque. The veterinary records were retrospectively reviewed in this case. The immunosuppressive regimen consisted of rituximab, basiliximab, and IVIg as inductive therapies, and steroids with tacrolimus (0.1 mg/kg/day) as maintenance therapies. Although there were no clinical symptoms, increased levels of lactate dehydrogenase, total bilirubin, blood urea nitrogen, and creatinine and decreased levels of hemoglobin and platelet were observed in laboratory tests on Day (D) 61. Systemic TA-TMA was tentatively diagnosed. Tacrolimus was discontinued starting on D71. Dalteparin, clopidogrel bisulfate (D77-D99), and IVIg (D72) were administered as a conservative treatment. Abnormal laboratory results were reversed on D99. When low-dose tacrolimus (0.07 mg/kg/day) was re-administered on D131 to prevent rejection of the graft, TMA was detected again by laboratory tests on D161, confirming the initial diagnosis. Discontinuation of tacrolimus on D162 and re-administration of Dalteparin (D161-D196) corrected the laboratory values on D161. This report shows that in pig-to-rhesus corneal xenotransplantation, clinically asymptomatic TMA can be induced by tacrolimus, and the discontinuation of tacrolimus and administration of anticoagulant seems sufficient to correct the laboratory TMA.

Long‐term safety outcome of systemic immunosuppression in pig‐to‐nonhuman primate corneal xenotransplantation

“…These hematologic abnormalities recurred when tacrolimus was re‐administered, confirming the diagnosis. The laboratory tests normalized after discontinuation of tacrolimus and re‐administration of dalteparin …”

Long‐term survival of full‐thickness corneal xenografts from α1,3‐galactosyltransferase gene‐knockout miniature pigs in non‐human primates

“…A more effective means to evaluate B cells would be through the use of either anti‐CD19 Ab alone or in combination with anti‐CD20 Ab after treatment with rituximab; and (e) the data from the last examination, at the time of sacrifice, were collected (POD 83) for one of the recipients with a surviving graft. Since the recipient suffered from sudden illness with severe thrombocytopenia and anemia, we suspect tacrolimus‐related microangiopathy . In such cases, tacrolimus should be discontinued, and the subject should be treated with methylprednisolone sodium succinate, dalteparin, clopidogrel, and IVIG .…”

“…Since the recipient suffered from sudden illness with severe thrombocytopenia and anemia, we suspect tacrolimus‐related microangiopathy . In such cases, tacrolimus should be discontinued, and the subject should be treated with methylprednisolone sodium succinate, dalteparin, clopidogrel, and IVIG . However, the recipient had to be sacrificed for the welfare of the animal because the subject was under circumstances in which treatment could not be appropriately administered.…”

Corneal xenotransplantation: Where are we standing?

“…Regarding general health status, NHP recipients with porcine corneal transplants maintained good appetite and physical activity during the long-term period of immunosuppression using CSs-, costimulatory blockade agents-, and rituximab/tacrolimus/basiliximab-based regimens, although costimulatory blockade agents and rituximab/tacrolimus/basiliximab induced early weight loss ( Choi et al, 2015 , 2018 ; Kim et al, 2017 , 2018a ). A case of asymptomatic tacrolimus-associated thrombotic microangiopathy, diagnosed via laboratory tests, was reportedly treated with a discontinuation of tacrolimus and administration of anticoagulant ( Kim et al, 2018b ). Long-term immunosuppression with the mentioned above immunosuppressive regimens have neither significantly affected white blood cell counts, liver enzyme levels, blood urea nitrogen/creatinine levels, and hematocrit nor caused electrolyte imbalance in rhesus recipients ( Choi et al, 2018 ).…”