Evans syndrome is an uncommon disease characterized by a combination of autoimmune hemolytic anemia and autoimmune thrombocytopenia concomitantly or sequentially with a positive direct Coombs test in the absence of any underlying known cause. Here, we present a case of an adult patient who underwent living-donor liver transplant that was preceded by bone marrow transplant 20 years earlier from the same HLA identical donor and who received a single-agent immunosuppressive therapy for only 2 months as prophylaxis against graft-versus-host disease. Two months after transplant, he developed Evans syndrome with severe anemia and thrombocytopenia. After administration of steroids and intravenous immunoglobulin, the patient’s anemia and thrombocytopenia improved dramatically. Through the 7 years of follow-up, the patient has not developed graft-versus-host disease or acute or chronic rejection. This case demonstrates a rare complication posttransplant and the possibility of functional tolerance of liver grafts after a combined liver and bone marrow transplant from the same donor.
Key words : Autoimmune hemolytic anemia, Autoimmune thrombocytopenia, Bone marrow transplantation, Immunosuppressive therapy, Organ tolerance
Evans syndrome is a rare disorder characterized by a combination of autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) simultaneously or consecutively with a positive direct Coombs test and in the absence of any known underlying cause. It is a chronic disease with exacerbations and remissions and is characterized by the presence of autoantibodies against erythrocytes and platelets.1
After liver transplant, hematologic complications are common, especially anemia and thrombocytopenia. These complications usually resolve within the first month after transplant. Several factors could result in these complications, including blood loss, iron deficiency, sepsis, hypersplenism, and/or bone marrow suppression from infections, drugs, or chronic diseases. Evans syndrome is seldom seen after solid-organ transplant, especially after liver transplant.
Here, we present a patient who underwent living-donor liver transplant and had a history of bone marrow transplant 20 years earlier from the same HLA identical donor. The patient had no history of lifelong immunosuppressive therapy, and posttransplant recovery was complicated by Evans syndrome. The patient provided written informed consent before the start of the study, which was approved by the Ethics Committee of Kyoto University in accordance with the Declaration of Helsinki of 1996.
A 55-year-old adult male patient received living-donor liver transplant in 2010 at the Kyoto University Hospital because of end-stage liver disease from hepatitis C virus infection. The donor was his HLA identical older sister (HLA-A2 and A11, HLA-B44 and B61, HLA-DR13 and DR15). Immunosuppression therapy after transplant included tacrolimus monotherapy as a prophylaxis against graft-versus-host disease (GVHD). He had a history of acute myeloid leukemia 20 years ago, which had been treated by bone marrow transplant from the same donor, as well as diabetes mellitus, hypertension, and hypothyroidism.
One month after transplant, the patient presented with cytomegalovirus duodenitis and was treated with ganciclovir. One month after that, routine laboratory results revealed severe anemia and thrombocytopenia (hemoglobin level of 6.1 g/dL, platelet count of 9000/μL, white blood cell count of 2.6 x 109/L, and reticulocyte level of 42.7%) (Figure 1).
Because of these findings, further investigations were performed. A peripheral blood smear showed red blood cell fragments/polychromasia. He also had a positive direct Coombs test, high platelet-associated immunoglobulins (195 ng/106 platelets), and hypercellular bone marrow. All of these laboratory investigations were consistent with AIHA and ITP.
The patient received intravenous immunoglobulin (IVIG) at 0.4 g/kg/day for 5 days plus prednisone at 50 mg/day for 5 days; tacrolimus administration was stopped. The patient responded to this treatment, and his blood profile showed platelet count of 95 × 103/μL, hemoglobin level of 10.9 g/dL, white blood cell count of 69 × 109/L, and reticulocyte level of 20.1%.
During treatment, the patient developed Pneumocystis pneumonia with positive β-D-glucan, negative serum Aspergillus species galactomannan, and patchy or nodular ground-glass attenuation on high-resolution computed tomography. Trimethoprim-sulfamethoxazole was administered at 20 mg/kg with prednisolone at 80 mg/day. With treatment, the patient improved within 3 weeks.
Chimerism analyses were performed using fluorescent in situ hybridization with probes specific for X and Y chromosome as the patient received sex-mismatched bone marrow transplant. We found that all blood cells were derived from the donor. At 7-year follow-up, the patient is still alive, not receiving immunosuppressive therapy, and without any recurrent episodes of acute graft rejection, GVHD, or leukemia.
To the best of our knowledge, this is the second reported case of an adult living-donor liver transplant patient with complications due to Evans syndrome. Of note, our patient has been immunosuppressive therapy-free for almost 7 years without any episodes of acute rejection or GVHD.
Evans syndrome was first described in 1951 by Robert Evans. Patients usually present with AIHA or ITP either simultaneously or sequentially, with these complications sometimes associated with neutropenia. The second cytopenia might appear months or even years after the first one, and this can make the diagnosis more difficult.1
Diagnosis of Evans syndrome usually depends on the presence of low hemoglobin levels, thrombocytopenia, and raised reticulocyte counts, with blood film showing evidence of AIHA, such as polychromasia and spherocytes. Direct Coombs test is usually positive. Antiplatelet and antigranulocyte antibodies can confirm the diagnosis, and bone marrow biopsy is important so that other infiltrative disorders can be excluded.
The first line of therapy usually consists of corticosteroids and/or IVIG. In addition, patients may need blood and/or platelet transfusion as a rescue therapy. Failure to respond to this treatment may necessitate the addition of immunosuppressive drugs such as cyclosporine, mycophenolate mofetil, or danazol; rituximab (an anti-CD20 monoclonal antibody); chemotherapy (vincristine); and/or splenectomy. Splenectomy can induce immediate improvements in the blood profile, but results are usually transient, and relapse occurs in most cases. The last resort in refractory Evans syndrome would be cyclophosphamide, anti-CD52 monoclonal antibody (alemtuzumab), or stem cell transplant.1
After review of the literature, we found only 1 case report of Evans syndrome and GVHD after orthotopic liver transplant in an adult patient with hepatocellular carcinoma, who was treated by corticosteroids and IVIG therapy with no improvement; after rituximab was added, the patient achieved good results.2
We also identified four pediatric cases of Evans syndrome after liver transplant: 3 patients were treated with steroids, IVIG, and/or rituximab, and the fourth patient required emergency splenectomy for rapid improvement of AIHA and platelet count.3
Our case is notable for 2 reasons: it is the second reported adult case of Evans syndrome after living-donor liver transplant, and it demonstrates the possibility of functional tolerance after solid-organ transplant and withdrawal of immunosuppressive therapy if the recipient receives bone marrow transplant from the same donor.
Our patient received tacrolimus monotherapy for only 2 months as a prophylaxis against GVHD; over almost 7 years of postoperative follow-up, the patient has not developed any episodes of acute rejection or GVHD. Patients who have had stem cell or donor bone marrow infusion before and after liver transplant have been shown to tolerate withdrawal of immunosuppressive therapy posttransplant.4
We believe that the mechanism of tolerance here is the full donor chimerism in which the transplanted pluripotent hematopoietic stem cells engrafted in the recipient and produced all of its lineages, including the donor immune system.5
Further studies are needed to determine the best protocol for solid-organ transplant that could eliminate the need for a lifelong immunosuppressive therapy posttransplant.
DOI : 10.6002/ect.2018.0005
From the 1Hepato-Biliary-Pancreatic Surgery and Transplantation Department,
Kyoto University, Kyoto, Japan; and the 2General Surgery Department, Alexandria
University, Alexandria, Egypt
Acknowledgements: The authors have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors received no financial support for the research, authorship, and/or publications of this article.
Corresponding author: Toshimi Kaido, Hepato-Biliary-Pancreatic and Transplant Surgery Department, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyoku, Kyoto 606-8507, Japan
Phone: +81 75 751 4323
Figure 1. Changes in Platelet Count (a) and Hemoglobin Level (B) After Liver Transplant