Cyclosporine A-associated thrombotic thrombocytopenic purpura following lung transplantation.

THROMBOTIC thrombocytopenic purpura (TTP) and hemolytic uremia syndrome (HUS) are the clinical sequelae of thrombotic microangiopathy. These two disorders are often regarded as a spectrum of a disease (TTP– HUS). TTP is an uncommon but well documented complication of cyclosporine A (CsA) therapy. The clinical syndrome is characterized by the pentad of thrombocytopenia, anemia, renal impairment, neurologic involvement, and fever. TTP–HUS appears to be the result of endothelial damage. CsA may cause TTP via direct injurious effects on endothelial cells generated by numerous potential mechanisms. CsA can reduce thrombomodulin-dependent generation of activated protein C from endothelial cells, thus inducing a thrombogenic state. It may also alter both the prostacyclin to thromboxane A ratio, and change the balance between the release and inhibition of von Willebrand factor, and the delicate balance of numerous other modulators leading to thrombosis. TTP associated with CsA use has been previously reported following bone marrow, kidney, heart, and liver transplantation. We report three cases of TTP in patients receiving CsA following lung transplantation. Between October 1994 and July 1997, we performed 31 lung transplants. Three patients developed TTP (9.7%). All three patients (two bilateral, one single lung recipient) manifested the classic pentad of TTP. All patients were maintained on CsA from the time of their transplant until their TTP was diagnosed. Two patients had levels that were considered above the therapeutic range prior to the development of TTP. The first patient was a 56-year-old female who underwent bilateral lung transplantation for lymphangioleiomatosis. Postoperatively she was started on intravenous CsA to maintain a level between 300 and 400 ng/mL and was subsequently converted to oral cyclosporine (Neoral). She had a relatively uneventful postoperative course. Five months later she was readmitted with nausea, vomiting, and abdominal distention. She was diagnosed with C. difficile colitis and initially improved with treatment. She then deteriorated. Lethargy and disorientation were replaced by obtundation. Her course included anemia (schistocytes were present on peripheral blood smears), progressive renal failure, thrombocytopenia (low of 13,000), and fever. The diagnosis of TTP was entertained late in her course so CsA was continued. Her highest trough CsA level was 485 ng/mL by HPLC 8 days prior to the diagnosis of TTP. Her condition deteriorated rapidly over 72 hours and she succumbed. The second patient, a 66-year-old male, was readmitted 9 months after bilateral lung transplantation for emphysema. His early postoperative course had been complicated by several episodes of pneumonia, and on this admission he was found to have an empyema which was treated surgically. When he manifested the signs of TTP, his CsA was discontinued and he was started on FK506. He required hemodialysis and support with blood products. After approximately 1 week, total plasma exchange (TPE) was instituted and he slowly improved. After 2 weeks of improvement, the diagnosis of TTP was doubted and TPE was stopped. He then relapsed with disorientation and thrombocytopenia, and did not subsequently improve until TPE was reinstituted. It was gradually weaned off over 2 months as an outpatient and he has subsequently done well. The final patient underwent single lung transplantation for a-1 antitrypsin deficiency. In her first postoperative week, she was treated with pulse-dose steroids for suspected rejection from which she appeared to improve. She had an isolated CsA trough level of 497 ng/mL 10 days postoperatively. Forty-eight hours later she had increasing fatigue and mental status changes that required reintubation. She had a rapid deterioration in her renal function requiring dialysis. A precipitous fall in her hematocrit to 21.9%, thorombocytopenia to a low of 14,000/mm, fever, and a grand mal seizure followed. Her CsA was discontinued and FK506 was started. The patient’s peripheral blood smear showed moderate schistocytes and a bone marrow biopsy was normal except for an increased number of megakaryocytes. She received intravenous g-globulin for 10 days and a total of 35 plasma exchanges with FFP. She was weaned off TPE and was discharged in good condition with adequate renal function and a normal platelet count. Due to the relative rarity of the disease, analysis of a large group of transplant patients has not been possible. It is,