Successful treatment of thrombotic thrombocytopenic purpura with a month-long therapeutic plasma exchange and immunosuppressive agents

OBJECTIVES: To describe the clinical course and treatment response of a case of thrombotic thrombocytopenic purpura (TTP) after a month of therapeutic plasma exchange (TPE) and immunosuppressive agents and to review related published literature regarding TTP and its response to TPE and immunosuppressive agents.CASE AND DISCUSSION: A 64-year-old female presented with fever, bicytopenia, change in sensorium, and seizure of one day duration. Metabolic panel showed normal electrolytes with normal brain imaging. Hematologic work-up showed anemia, thrombocytopenia and leukocytosis with normal differential count. Reticulocyte was elevated. Peripheral smear showed significant schistocytes with nucleated red blood cells and marked thrombocytopenia. Thrombotic thrombocytopenic purpura was the initial consideration with the fulfilment of four out of the pentad of TTP, namely: microangiopathichaemolytic anemia, thrombocytopenia, fever and neurologic symptoms. Therapeutic plasma exchange was immediately initiated with daily platelet count and Lactate dehydrogenase (LDH) determination to assess response. However, despite daily plasma exchanges and continuous plasma infusion, there was inadequate response. In this light, immunosuppressive agents were started in the following order: high dose methylprednisolone, weekly rituximab and intravenous cyclophosphamide. On the 31st hospital day, after daily TPE and combined immunosuppression, she achieved complete response with a platelet count of 170 X 109/L to 250 X 109/L (baseline-14 X 109/L) and LDH 227U/L (baseline-1,191 U/L).CONCLUSION: This study presented a challenging case of TTP which was successfully treated with the standard of care together with the available adjunctive treatment options.

Use of reverse phase protein microarrays and reference standard development for molecular network analysis of metastatic ovarian carcinoma.

Cancer can be defined as a deregulation or hyperactivity in the ongoing network of intracellular and extracellular signaling events. Reverse phase protein microarray technology may offer a new opportunity to measure and profile these signaling pathways, providing data on post-translational phosphorylation events not obtainable by gene microarray analysis. Treatment of ovarian epithelial carcinoma almost always takes place in a metastatic setting since unfortunately the disease is often not detected until later stages. Thus, in addition to elucidation of the molecular network within a tumor specimen, critical questions are to what extent do signaling changes occur upon metastasis and are there common pathway elements that arise in the metastatic microenvironment. For individualized combinatorial therapy, ideal therapeutic selection based on proteomic mapping of phosphorylation end points may require evaluation of the patient's metastatic tissue. Extending these findings to the bedside will require the development of optimized protocols and reference standards. We have developed a reference standard based on a mixture of phosphorylated peptides to begin to address this challenge.

Signal pathway profiling of ovarian cancer from human tissue specimens using reverse-phase protein microarrays.

Defects in cell signaling pathways play a central role in cancer cell growth, survival, invasion and metastasis. An important goal of proteomics is to characterize and develop "circuit maps" of these signaling pathways in normal and diseased cells. We have used reverse-phase protein array technology coupled with laser capture microdissection and phospho-specific antibodies to examine the activation status of several key molecular "gates" involved in cell survival and proliferation signaling in human ovarian tumor tissue. The levels of activated extracellular-regulated kinase (ERK1/2) varied considerably in tumors of the same histotype, but no significant differences between histotypes were observed. Advanced stage tumors had slightly higher levels of phosphorylated ERK1/2 compared to early stage tumors. The activation status of Akt and glycogen synthase kinase 3beta, key proteins and indicators of the state of the phosphatidylinositol 3-kinase/Akt pro-survival pathway also showed more variation within each histotype than between the histotypes studied. Our results demonstrate the utility of reverse phase protein microarrays for the multiplexed analysis of signal transduction from discreet cell populations of cells procured directly from human ovarian tumor specimens and suggest that patterns in signal pathway activation in ovarian tumors may be patient-specific rather than type or stage specific.