Transplantation-Related Thrombotic Microangiopathy Triggered by Preemptive Therapy for Hepatitis C Virus Infection

Abstract

Various strategies exist to reduce graft loss after organ transplantation, including the use of immunosuppressants, steroids, and postoperative antivirotic agents. Combined treatment with an immunosuppressant and a corticosteroid after liver transplantation is the standard protocol to improve graft survival. However, immunosuppressants can have numerous side effects including neurological complications, and steroids can have positive effects on hepatitis C virus (HCV) reinfection (1). Transplantation-related thrombotic microangiopathy (TA-TMA) is a serious complication of organ transplantation that is associated with a variety of transplantation-related factors, including the use of immunosuppressive agents, conditioning regimens, ABO incompatibility, and opportunistic infections (2–4). Immunosuppressants such as cyclosporine A and tacrolimus (FK506) are often linked with the occurrence of TA-TMA (2, 3). Transplantation-related thrombotic microangiopathy typically presents with sudden onset thrombosis and acute organ dysfunction without clinical manifestations. We report on a rapidly progressing case of TA-TMA in a 43-year-old woman with HCV-related cirrhosis, which was strongly associated with the use of an immunosuppressant and anti-HCV preemptive therapy. The patient underwent living- donor liver transplantation because of HCV-related cirrhosis. The patient had a history of three subacute graft rejections, and underwent steroid recycle therapy (1) followed by liver biopsy. She experienced a temporary rise in FK506 level (to >18.0 ng/mL) during the steroid recycle therapy, so the dose was adjusted. She was readmitted 40 days after surgery for additional preemptive therapy for HCV. The treatment regimen comprised 80 ng pegylated interferon (INF)-α2b weekly and 800 mg ribavirin daily. Sudden onset of TA-TMA developed after the start of the therapy. Her blood chemistry measurements abruptly shifted into the abnormal range: her platelet count dropped from 36.5 to 7.8×104 mm3, her serum lactate dehydrogenase level increased from 258 to 688 IU/mL, and her peripheral blood contained more than 1.5% schistocytes. Each parameter reflected the treatment state of TA-TMA. Magnetic-resonance imaging of the brain revealed a hyperintense signal of the left temporal lobe on T2-weighted images, indicating cerebral infarction with hemorrhage, which persisted for 3 weeks. Angiography showed narrowing and irregularity of the middle cerebral artery bilaterally, and a “string of beads” pattern was observed in the posterior cerebral artery bilaterally. A biopsy specimen from the temporal artery failed to show systemic arteritis, and there was no evidence of infection. These findings suggested an FK506-mediated toxic effect of the preemptive therapeutic agent on the cerebral vessels (Fig. 1).FIGURE 1.: The MRI T2-weighted sequence shows hyperintense regions (arrowheads) in the left lateral area at the initial presentation of headache (A). The areas increased bilaterally within 3 weeks (B). The “string of beads” pattern changes resulting from narrowing and irregularity of the cerebral artery were observed bilaterally in angiography (C).A combination of INF-α2b and ribavirin preemptive antiviral therapy is becoming the standard protocol for HCV-related liver transplantation, and might provide long-term benefits in graft survival and delaying the time to HCV recurrence (5, 6). However, INF itself has a number of side effects. It enhances cellular immunity and can lead to the production of autoantibodies, even antiendothelial antibodies. There is a close correlation between the FK506 level and clinical complications related to endothelial cell injury. Thus, the preemptive therapy may have a trigger role in the occurrence of TA-TMA in present case. The ribavirin and steroid therapy was immediately discontinued, and FK506 was replaced with cyclosporine A. Intravenous heparinization (10,000 units/day), prostaglandin E1 (prostandin, 500 μg/day), and the free-radical scavenger (edaravone, 60 mg/day) were continuously administered. Although the disease followed a radical and a repetitive clinical course, the patient recovered as a result of the aggressive early intervention; she made a full recovery with the presence of mild logaphasia and left hemiplasia within 4 weeks. This case highlights the fact that HCV preemptive therapy after steroid-recycle therapy with an immunosuppressant should be performed with caution. Hepatitis C virus-related living-donor liver transplantation is a strong indicator of TA-TMA, and 9 of 26 patients in recent reports had HCV infection (2, 4). We recommend that patients who are receiving preemptive therapy for HCV after high-immunosuppressant trough levels should be closely monitored for the development of TA-TMA, to ensure early diagnosis. Earlier detection and intervention will provide opportunities to improve patient outcomes. Shintaro Yamazaki Tadatoshi Takayama Kazuto Inoue Tokio Higaki Department of Digestive Surgery Nihon University School of Medicine Tokyo, Japan Masatoshi Makuuchi Japanese Red Cross Medical Center Tokyo, Japan