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Transplantation-associated thrombotic microangiopathy (TA-TMA) is an infrequent but devastating syndrome that occurs in allogeneic hematopoietic stem cell transplant recipients, and is associated with a variety of transplantation-related factors, including conditioning regimens, immunosuppressive agents, GVHD and opportunistic infections. Progress in managing this condition has been hampered by lack of a consensus definition and poor understanding of the pathophysiology of the disorder. Two different groups recently have proposed consensus definitions, yet they fail to distinguish the primary syndrome from the secondary causes, such as a variety of infections, medication exposure or other conditions. Increasing evidence suggests that TA-TMA is a multifactorial disorder that is distinct from thrombotic thrombocytopenic purpura (TTP), and likely represents the final common pathway of a number of endothelial cell insults. TA-TMA responds poorly to conventional treatment for TTP, including plasma exchange, but newer agents, including daclizumab and defibrotide show promise. In addition, other agents known to modify endothelial responses to injury, including statins, prostacyclin analogues, endothelin-receptor antagonists and free radical scavengers, may lead to improved outcomes for patients affected by this disorder.

We studied occurrence, risk factors and outcome of patients with transplant-associated microangiopathy (TAM) after allogeneic stem cell transplantation (HSCT). A total of 221 consecutive patients were transplanted between 1995 and 2002. TAM is defined as evidence of hemolysis and schistocytes in the first 100 days. Outcomes analyzed included TAM and overall survival. Of 221 patients, 68 had TAM. The cumulative incidence was 31 (25-38)% at 100 days. Patients with TAM had higher LDH, higher bilirubin, higher creatinine and more often neurologic symptoms. TAM was not associated with stem cell source, cyclosporine levels and was not more frequent in recent years. In multivariate analysis, risk factors for TAM included donor type, age, gender, ABO-incompatibility and acute graft-versus-host disease (aGvHD). In patients with TAM, 1-year survival was lower than in patients without TAM (27 +/- 18% for TAM with high schistocyte counts; 53 +/- 15% for TAM with low schistocyte counts; vs 78 +/- 7% in patients without TAM; P<0.0001). TAM was independently associated with mortality adjusting for donor type, age and aGvHD occurrence and severity. TAM is frequent after HSCT and is associated with mortality even after adjustment for aGvHD grade. Risk factors of TAM are similar to aGvHD. TAM may represent endothelial damage driven by donor-host interactions.

Thrombotic microangiopathy (TMA) is a significant complication after hematopoietic stem-cell transplantation (HSCT); however, there is little information on it following reduced-intensity cord blood transplantation (RI-CBT). We reviewed the medical records of 123 adult patients who received RI-CBT at Toranomon Hospital between January 2002 and August 2004. TMA was diagnosed in seven patients based on intestinal biopsy (n = 6) or autopsy results (n = 1). While these patients showed some clinical symptoms such as diarrhea and/or abdominal pain, mental status alterations or neurological disorders were not observed in any of them. Laboratory results were mostly normal at the onset of TMA; >2% fragmented erythrocytes (n = 1), <10 mg/dl haptoglobin (n = 1), and >200 IU/dl lactic dehydrogenase (LD) (n = 4). On endoscopic examination, TMA lesions, consisting of ulcers, erosions, and diffuse exfoliation, were distributed spottily from terminal ileum to rectum. Intestinal graft-versus-host disease (GVHD) and cytomegalovirus (CMV) colitis were confirmed in five and four patients, respectively. With therapeutic measures including supportive care (n = 4), fresh frozen plasma (n = 1), and a reduction of immunosuppressive agents (n = 1), TMA improved in four patients. The present study demonstrates that intestinal TMA is a significant complication after RI-CBT. Since conventional diagnostic criteria can overlook TMA, its diagnosis requires careful examination of the gastrointestinal tract using endoscopy with biopsy.

Thrombotic microangiopathy after bone marrow transplantation (post-BMT TMA) is a serious transplant-related complication. We identified 16 patients with TMA after allogeneic BMT who showed histopathological evidence of intestinal TMA in their gut specimens (six autopsies, 10 biopsies). In all, 14 patients had grade II-IV acute graft-versus-host disease (GVHD). The first seven patients were retrospectively diagnosed with TMA. Since six of them were diagnosed with progressive GVHD at that time because there was no awareness of the existence of intestinal TMA, they received more intensive treatment for GVHD, but all died between days +49 and +253. In contrast, the remaining nine patients were recently diagnosed with intestinal TMA on the basis of colonoscopic biopsies. For eight of these patients, the immunosuppressants were reduced, and the patients' intestinal symptoms improved gradually. Six of the nine patients were still alive 12 months after the diagnosis of TMA. Our findings suggest that the gut may be a site involved in post-BMT TMA, presenting as ischemic enterocolitis. Differentiating intestinal TMA from acute GVHD is important in patients suffering from severe and refractory diarrhea after BMT., (Copyright 2004 Nature Publishing Group)

We monitored the levels of various cytokines and chemokines, as well as an adhesion molecule and factors related to vascular endothelial damage, in three patients with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome after bone marrow transplantation. Measurements were done at the onset of this condition and during plasma exchange for treatment. At the onset of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, the levels of interleukin-8, thrombomodulin, and plasminogen activator inhibitor-1 were all markedly increased. A close relationship was observed between improvement in symptoms by plasma exchange and a decrease in interleukin-8 level, suggesting that this chemokine may be related to the development of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome after bone marrow transplantation.

Hemolytic uremic syndrome (HUS) after transplantation is difficult to treat, and there is no consensus regarding optimal mode of treatment. We attached transdermal isosorbide tape as a nitric oxide (NO) donor to patients with HUS after bone marrow transplantation (BMT). This was very effective in ameliorating the hemolysis and increasing platelet numbers. We report here the successful use of an isosorbide in a patient with HUS after transplantation. Bone Marrow Transplantation (2000) 25, 109-110.

Thrombotic microangiopathy (TMA) is a serious complication of BMT. Several factors are important in the etiology of TMA, such as cyclosporin A, GVHD, irradiation, intensive conditioning chemotherapy and infection, which cause damage to vascular endothelial cells leading to activation of these cells. We describe two young children with TMA following high-dose chemotherapy with autologous BMT. Development of TMA was accompanied by reactivation of HHV-6, which was identified by both an increase in the copy number of HHV-6 DNA in the peripheral blood and a significant increase in antibody titers to HHV-6. Thus, it was suggested that reactivation of HHV-6 together with high-dose chemotherapy played an important role in the pathogenesis of TMA in these patients. Since HHV-6 is known to infect vascular endothelial cells, and CMV which is virologically closely related to HHV-6, has been reported to be a pathogen that causes TMA, infection with HHV-6 of vascular endothelial cells may induce TMA via damage and activation of these cells.

A 44-year-old male with Ph+ chronic myeloid leukaemia (CML) underwent histoidentical allogeneic bone marrow transplantation 18 months after initial diagnosis. He received pretransplant conditioning with busulphan and cyclophosphamide (Bucy). GVHD prophylaxis consisted of methotrexate, cyclosporine (CsA) and methylprednisolone. On day +50, he developed a microangiopathic haemolytic anaemia with indirect bilirubinaemia, 10% fragmented red cells (FC) and an elevated LDH (1213 U/l: normal range 100-185 U/l). Clinical symptoms consisted of edema and hypertension. The patient was not febrile and had no neurological changes. A clinical diagnosis of severe (grade 4) multifactorial (acute GVHD, CMV infection and cyclosporine) BMT-TM was made. He responded following 19 plasma exchanges with replacement with fresh frozen plasma.

Thrombotic microangiopathy (TM), manifesting clinically as thrombotic thrombocytopenic purpura or hemolytic uremic syndrome, is an uncommon complication after bone marrow transplantation (BMT). A retrospective analysis of potential risk factors for TM following allogeneic BMT was performed. Clinical data were analyzed from seven patients diagnosed with severe TM and 409 patients who underwent BMT during the same time period and who survived for at least 100 days afterwards. Six of the seven patients with TM received intensive GVHD prophylaxis consisting of cyclosporine, methotrexate and glucocorticoids, whereas only 66 of the 409 patients without TM received this regimen (P < 0.001, Fisher's exact test). This regimen was administered to patients older than 40 years, or recipients of a mismatched or unrelated allograft. Univariate analysis also revealed an increased risk of TM associated with the use of an unrelated bone marrow donor (P = 0.02), but no significant association with patient age or gender, diagnosis, amount of prior chemotherapy, transplant conditioning regimen or severity of GVHD. A multivariate exact logistic regression analysis revealed that only the type of GVHD prophylaxis had a significant impact on the risk for TM. The combined use of cyclosporine, methotrexate and glucocorticoids as GVHD prophylaxis may predispose to the development of TM following BMT.

Of 193 children who underwent hematopoietic stem cell transplantation (HSCT) for various malignancies, 10 developed hemolytic uremic syndrome (HUS) 1 1/2-5 months later. All 10 had microangiopathic hemolytic anemia, thrombocytopenia and impaired renal function. Six of 10 presented with pericardial effusion, while three presented with hypertension. No child required plasma exchange, and all patients have survived without life-threatening long-term sequelae. By univariate analysis, the underlying diagnosis of neuroblastoma and a history of cisplatin (CDDP) administration were significantly associated with the development of HUS (P < 0.0001). By multivariate analysis using logistic regression, neuroblastoma and use of total body irradiation (TBI) as a conditioning regimen were significant contributing factors for HUS (P = 0.0001 and 0.036, respectively). Although CDDP administration could not be evaluated because of its strong correlation with the underlying diagnosis, we speculate that CDDP may enhance the nephrotoxicity of TBI, leading to a high incidence of HUS in patients with neuroblastoma.

Hemolytic uremic syndrome (HUS) has been reported in patients receiving bone marrow transplantation. However, only a few cases of HUS following autologous peripheral blood stem cell transplantation (PBSCT) have been reported. We present a case of HUS developing after autologous PBSCT in a 40-year-old man with non-Hodgkin's lymphoma. It appears that the chemotherapeutic agents administered during the conditioning regimen for PBSCT may have played an important role in the development of HUS in our patient. In the present case, the combination therapy of vincristine, methylprednisolone, and ticlopidine hydrochloride was effective.

Bone marrow transplant-associated thrombotic microangiopathy (BMT-TM) ranges in severity from a self-limiting to a fatal disorder. There is no specific therapy for this condition to date. We have previously described a simple clinical grading system (grade 0-4) for BMT-TM; patients with grade 3-4 BMT-TM do poorly. A previous study in our institution suggested that a combination of exchange with cryosupernatant replacement and protein-A immunoadsorption (PAI) might be of benefit. Therefore we performed a pilot study to evaluate the effectiveness of cryosupernatant alternating with PAI exchange for 2 weeks in a series of 13 patients with grade 3-4 BMT-TM. Twelve of 13 patients had undergone allogeneic-BMT a median of 25 days (range of 5-458 days) prior to the onset of grade 3-4 BMT-TM. The thirteenth patient had undergone autologous peripheral stem cell transplant 11 days prior to grade 4 BMT-TM. Pre-therapy, 10 patients had grade 4 BMT-TM and three had grade 3. Eight (62%) showed a response to treatment. Post-therapy, four responders had grade 3, three had grade 2 and one had grade 0 BMT-TM. The median follow-up of the responders is 90 days (range 21 to 464). Three responders have died at 21, 44, and 226 days following the development of BMT-TM of interstitial pneumonia in one, aspergillus in one, and multiorgan failure syndrome (MOFS) in one. The remaining responders are alive 66-465 days post-TM. All non-responders died of MOFS at 6-31 days post-TM. These results suggest that combined exchange with cryosupernatant alternating with PAI is effective therapy for some patients with moderate to severe BMT-TM and may improve survival.

Microangiopathic disease and diffuse alveolar haemorrhage (DAH) are uncommon serious complications of bone marrow transplantation (BMT), but an association between these two conditions has not been previously recognised. We report 4 patients in whom these two complications occurred after allogeneic BMT for haematological malignancy. The patients were 16-39 years of age, and received transplants for acute myeloid leukemia, chronic myeloid leukemia and non-Hodgkin's lymphoma (n = 2). Donors were HLA-identical siblings (n = 3), and a matched unrelated volunteer. The patient with AML was receiving a second transplant for relapse 3 years after her first BMT, and was prepared with busulphan and melphalan; other patients received total body irradiation and cyclophosphamide. Microangiopathy occurred 20-48 days after BMT, and was associated with renal impairment in all cases, and mental confusion in 3. Cyclosporin levels were in the toxic range in 2 cases. DAH occurred 18-55 days after BMT, in 3 cases 2-7 days after the onset of microangiopathy, but preceding it by 14 days in the other case. Patients were treated with fresh frozen plasma, plasma exchange, supplemental oxygen and ventilation in 2 cases. Two patients died of progressive respiratory failure, while 2 patients recovered with evidence of continuing microangiopathic disease, and died of myocardial infarction or fungal infection. We report an association between microangiopathic disease and DAH in these BMT patients, and suggest that damage to the pulmonary vascular endothelium may be the common pathophysiological event, although no specific causative factor could be identified.

Thrombotic microangiopathy, which encompasses both thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), is a severe and life-threatening complication following bone marrow transplantation (BMT). It has been reported after allogeneic BMT but may also occur after autologous BMT. Here we describe a case of microangiopathic hemolytic anemia and progressive renal failure subsequent to autologous BMT.

Thrombotic microangiopathy (TMA) is a well-recognised disorder which may occur in up to 6% of patients following bone marrow transplantation (BMT). Reported cases of post-BMT TMA vary widely in their reported clinical features, severity and response to therapy. Several factors are important in the aetiology, including cyclosporin A (CsA), graft-versus-host disease, irradiation, intensive conditioning chemotherapy and infection. A unifying pathogenetic mechanism is suggested, wherein these factors may interact to produce post-BMT TMA. On the basis of differences in clinical features and prognosis, we propose the classification of post-BMT TMA into four distinctive although overlapping subtypes: multifactorial fulminant TMA, conditioning-associated haemolytic-uraemic syndrome, CsA-associated nephrotoxicity with microangiopathic haemolytic anaemia (MAHA) and CsA-associated neurotoxicity with MAHA. Treatment of post-BMT TMA, especially of the poor-prognosis multifactorial fulminant subtype, is currently unsatisfactory, although occasional cases may respond to plasma exchange.

Twenty-four patients autografted for malignant lymphoma have been followed. All were conditioned with BEAC (BCNU, etoposide, ara-C, cyclophosphamide), in 10 patients combined with total body irradiation (TBI) 7.5 Gy. Within 1 month of ABMT, a capillary leak syndrome was seen in four patients (one death) and isolated pericarditis in one. Nineteen patients survive disease-free at > or = 6 months, median (range) 24 (11-48) months. In 15 of 19 patients, a decrease in glomerular filtration rate (GFR) of > 20% was observed, 6 (6-24) months after ABMT. In six of these patients (five treated with TBI), the renal dysfunction was still progressing 11-36 months after ABMT. Five patients (four conditioned with TBI) developed a haemolytic uraemic syndrome (HUS) with Coombs negative haemolytic anaemia, platelet consumption and renal impairment, with onset 3-6 months after ABMT. Haemolysis and platelet consumption, but not renal impairment, were reversible in all patients. One death from HUS was seen. Because of the adverse effects described we have abandoned the combination of BEAC with TBI.

Bone marrow transplant (BMT) is increasingly being offered as therapy for certain hematologic and other advanced malignancies. We present one representative patient in detail and summarize data from a series of 10 patients who received a BMT and, as a late complication, developed a hemolytic uremic syndrome (HUS). All patients presented with the triad of microangiopathic hemolytic anemia, renal insufficiency and thrombocytopenia from 30 to 875 days after BMT, and despite aggressive supportive management, plasma exchange, IgG administration and/or ex vivo staphylococcal protein A column plasma treatment, eight of 10 patients died from complications related to HUS between 11 to 139 days after diagnosis. In contrast to other reports of HUS after BMT, the present series of patients is heterogeneous with respect to underlying diagnosis, type of BMT (allogeneic or autologous), pretransplant conditioning regimen, presence of graft-versus-host disease, and use of cyclosporin. Additionally, nine of 10 patients were in clinical remission at the time of diagnosis of HUS, and six of 10 patients had achieved a complete recovery following BMT. The cause of HUS in this series of patients is probably multifactorial and related to the intensive pretransplant conditioning regimen.

Eight cases of haemolytic uraemic syndrome occurring after bone marrow transplantation are presented and the other 15 reported cases are reviewed. Two patients were recipients of autologous marrow whereas all cases previously reported occurred after allogeneic transplantation. Six patients had not received cyclosporin and two had no evidence of cytomegalovirus infection. The roles of cyclosporin, cytomegalovirus infection, graft-versus-host disease, total body irradiation (TBI) and chemotherapeutic drugs as aetiological agents are discussed. It is postulated that TBI, perhaps potentiated by cyclophosphamide, is likely to be the most important factor but that other agents may act additively with TBI and influence the time course and severity of the disease.