Rituximab for acute plasma-refractory thrombotic thrombocytopenic purpura. A case report and concise review of the literature

Thrombotic thrombocytopenic purpura (TTP) is a rare disease which responds well to plasma exchange treatment in the majority of patients. We report on a patient with acute TTP caused by severe autoantibody-mediated ADAMTS-13 deficiency, in whom remission was not achieved by initial treatment consisting of plasma exchange (PE), plasma infusion and corticosteroids, followed by vincristine and splenectomy. In view of the ongoing activity of TTP, treatment was initiated with rituximab, a chimaeric monoclonal antibody directed against the CD 20 antigen present on B lymphocytes. The patient received 4 weekly infusions of 375 mg/m2, each administered after the daily PE session and withholding PE until 48 hours later. Three weeks after the last infusion of rituximab a complete clinical and laboratory remission of this first episode of acute refractory TTP was documented. A concise review of the literature on the role of rituximab in patients with a first episode of acute plasma-refractory TTP suggests that rituximab in that situation may produce clinical remission in a significant proportion of patients, result in a lowered plasma requirement and avoid the complications of salvage immunosuppressive therapy. The use of rituximab in acute refractory TTP appears to be safe, with no excess infectious complications. We conclude that rituximab should be considered in TTP patients with acquired ADAMTS-13 deficiency who fail to respond clinically after 7-14 days of standard treatment with daily PE and glucocorticoids.

Regulation of Foxo-1 and the angiopoietin-2/Tie2 system by shear stress

Transcription factor Foxo-1 can be inactivated via Akt-mediated phosphorylation. Since shear stress activates Akt, we determined whether Foxo-1 and the Foxo-1-dependent, angiogenesis-related Ang-2/Tie2-system are influenced by shear stress in endothelial cells. Expression of Foxo-1 and its target genes p27Kip1 and Ang-2 was decreased under shear stress (6dyn/cm(2), 24h), nuclear exclusion of Foxo-1 by phosphorylation increased. eNOS and Tie2 were upregulated. No effects on Ang-1 expression were detected. In conclusion, Foxo-1 and Ang-2/Tie2 are part of the molecular response to shear stress, which may regulate angiogenesis.

Sensitivity of osteoblasts, fibroblasts, bone marrow cells, and dendritic cells to 5-aminolevulinic acid based photodynamic therapy

INTRODUCTION: Photodynamic therapy with 5-aminolevulinic acid (5-ALA-PDT) exerts cell type specific effects on target cells. Since chondrocytes were found to be more resistant than osteoblasts to 5-ALA-PDT, the pre-treatment of osteochondral grafts with 5-ALA-PDT may represent a means to devitalize the osseous portion while maintaining functional cartilage. The present study was designed to determine the effects of 5-ALA-PDT in vitro on cell populations residing in skeletal tissues. METHODS: Osteoblasts, fibroblasts, bone marrow cells, and dendritic cells were incubated with 0.5 mM 5-ALA for 4 h. Protoporphyrin IX (PpIX) accumulation and after exposure to light cellular functions were assessed for up to 6 days. RESULTS: Accumulation of PpIX reached a plateau at 0.5 mM in osteoblasts, fibroblasts, and dendritic cells, and at 2.0 mM in bone marrow cells. At 0.5 mM 5-ALA, similar responses to illumination were observed in all cells with a survival rate of less than 12% at a light dose of 20 J/cm(2). The function of osteoblasts (proliferation, levels of mRNA encoding collagen type I, alkaline phosphatase activity) and fibroblasts (proliferation, levels of mRNAs encoding collagens type I and III) was not affected, when the cells were treated with 5-ALA and light doses of < or =10 J/cm(2). Paralleling the reduction of viable cells after 5-ALA-PDT, the capacity of dendritic cells to stimulate T cells in a mixed leukocyte reaction decreased to 4+/-2% at 20 J/cm(2). CONCLUSION: The investigated cell types were sensitive to 5-ALA-PDT and the residual cell debris did not elicit an allogenic response. These findings, together with the resistance of chondrocytes to 5-ALA-PDT, encourage the further investigation of this protocol in the pretreatment of osteochondral allografts.