Transplant-associated thrombotic microangiopathy
Authors: Edward Renaudon‐Smith, Josu De La Fuente, Barbara J. Bain
Journal: American Journal of Hematology (2016)

A 16-year-old boy underwent a 9/10 matched unrelated bone marrow transplant for congenital dyserythropoietic anemia. He had previously had a splenectomy. Early transplant complications included Epstein–Barr virus and human herpesvirus 6 reactivation. Long-term immune suppression was with cyclosporin. At day 127 post-transplant, he developed weight gain, peripheral edema, ascites, and pleural effusions and received three doses of the VEGF inhibitor, bevacizumab, for possible capillary leak syndrome. He subsequently developed renal and respiratory failure, and seizures with radiological evidence of posterior reversible encephalopathy syndrome. Blood tests showed: white cell count 0.9 × 109/L, hemoglobin concentration 65 g/L, platelet count 10 × 109/L, bilirubin 54 μmol/L, creatinine 154 μmol/L, and lactate dehydrogenase 1,175 iu/L; haptoglobin was undetectable. A direct antiglobulin test was negative and the urine protein/creatinine ratio was 213 mg/mmol (normal range <20). His blood film showed the features of a microangiopathic hemolytic anemia complicated by hyposplenism and acute kidney injury (Images). In addition to thrombocytopenia and red cell fragments, there were nucleated red blood cells, Howell–Jolly bodies, Pappenheimer bodies, echinocytes, and acanthocytes. Some fragments were echinocytic and some were acanthocytic. ADAMTS13 was 80%. A diagnosis of transplant-associated thrombotic microangiopathy (TA-TMA) was made, with cyclosporin and bevacizumab as potential precipitants. Following their discontinuation, he was treated with a total of thirteen doses of the complement inhibitor, eculizumab, in addition to defibrotide and dexamethasone. Total hemolytic complement activity (CH50) levels were used to monitor drug activity and regular blood film and hemolytic marker analysis was used to assess response to therapy and guide treatment duration. He has made a full clinical recovery and at day 230 showed 100% donor chimerism. TA-TMA is defined by thrombocytopenia and microangiopathic hemolytic anemia with evidence of organ dysfunction—commonly renal failure or neurological impairment. TMA complicates 10–20% of allogeneic stem cell transplants and has a mortality rate of ∼80% 1. Endothelial damage appears to be central to the pathophysiology. Etiology of this complex condition in the transplant setting includes intensive conditioning chemotherapy, irradiation, immunosuppressive medication, infection, and graft-versus-host disease (GVHD). More recently a pathophysiological role for terminal complement pathway activation has been recognized 2. Treatment options include replacing calcineurin inhibitors with alternative immunosuppressive agents and the use of rituximab and defibrotide. Plasma exchange is not considered to be effective and is not recommended. Anti-complement therapy with eculizumab has been reported 3 and its use was associated with a good outcome in our patient. This case highlights a number of risk factors for the development of this condition, including GVHD, viral infection, and use of cyclosporin. In addition, an association of TMA with bevacizumab has recently been recognized 4. Close monitoring of the peripheral blood film and other blood parameters in patients at risk of TA-TMA is indicated.