Peripheral Blood Cell Mitochondrial Dysfunction in Myelodysplastic Syndrome Can Be Improved by a Combination of Coenzyme Q10 and Carnitine.

Structural mitochondrial abnormalities and genetic aberrations in mitochondrial proteins have been known in Myelodysplastic syndrome (MDS), yet there is currently little data regarding MDS's metabolic properties and energy production cells. In the current study, we used state-of-the-art methods to assess OXPHOS in peripheral blood cells obtained from MDS patients and healthy controls. We then assessed the effect of food supplements-Coenzyme Q10 and carnitine on mitochondrial function and hematological response. We show here for the first time that there is a significant impairment of mitochondrial respiration in peripheral blood cells in low-risk MDS, which can be improved with food supplements. We also show that these supplements may improve the cytopenia and quality of life.

Clinical significance of serologic markers related to red blood cell autoantibodies production after red blood cell transfusion-severe autoimmune hemolytic anemia occurring after transfusion and alloimmunization: successful treatment with rituximab.

BACKGROUND: The association of autoantibody formation with blood transfusion was previously noted. Severe autoimmune hemolytic anemia (AIHA) diagnosed after red blood cell (RBC) transfusion determined us to undertake this study and investigate the incidence and clinical significance of autoantibodies occurring after transfusion by a retrospective review of blood bank and medical records. STUDY DESIGN AND METHODS: We report a lymphoma patient who developed severe autohemolysis after blood transfusion and alloantibody production. The hemolysis was refractory to steroids and chemotherapy and ceased after rituximab. We also retrospectively assessed the blood bank records for a 2-year period to identify the patients who developed autoantibodies after blood transfusion and examined laboratory, clinical features, and outcome. RESULTS: From January 2005 through December 2006, 375 direct antiglobulin tests (DATs) and 3409 indirect antiglobulin tests (IATs) were found to be positive. Thirty-eight patients with positive DATs and IATs had demonstrable RBC warm-type autoantibodies occurring after blood transfusion; 27 of them had also one or more alloantibodies. Clinical and laboratory signs of hemolysis were absent in all patients (except the case reported). In another 5 patients alloantibodies were retrieved from RBC eluate and serum without evidence of autoantibodies; therefore, a delayed serologic transfusion reaction was diagnosed. CONCLUSION: RBC autoantibodies are quite commonly found after blood transfusion. Nevertheless, clinically significant AIHA is a rare but at times a life-threatening phenomenon. We describe a first case of successful treatment with rituximab of refractory posttransfusion AIHA. Rituximab must be further evaluated for this indication.

Post-transfusion purpura: a challenging diagnosis.

BACKGROUND: Post-transfusion purpura is a rare syndrome characterized by severe thrombocytopenia and bleeding caused by alloimunization to human platelet specific antigens following a blood component transfusion. The suggested incidence is 1:50,000-100,000 transfusions, most often occurring in multiparous women. The diagnosis is not easy because these patients, who are often critically ill or post-surgery, have alternative explanations for thrombocytopenia such as infection, drugs, etc. OBJECTIVES: To describe patients with initially misdiagnosed PTP and to emphasize the diagnostic pitfalls of this disorder. PATIENTS AND RESULTS: During a period of 11 years we diagnosed six patients with PTP, four women and two men. The incidence of PTP was approximately 1:24,000 blood components transfused. We present the detailed clinical course of three of the six patients in whom the diagnosis was particularly challenging. The patients were initially misdiagnosed as having heparin-induced thrombocytopenia, systemic lupus erythematosus complicated by autoimmune thrombocytopenia, and disseminated intravascular coagulation. A history of recent blood transfusion raised the suspicion of PTP and the diagnosis was confirmed by appropriate laboratory workup. CONCLUSIONS: PTP seems to be more frequent than previously described. The diagnosis should be considered in the evaluation of life-threatening thrombocytopenia in both men and women with a recent history of blood transfusion.

Incidence of Profound Hypogammaglobulinemia and Infection Rate in Lymphoma Patients Following the Combination of Chemotherapy and Rituximab.

BACKGROUND: The Anti-CD20 monoclonal antibody Rituximab suppresses B-lymphocytes and may induce hypogammaglobulinemia in treated patients. The incidence and clinical significance of rituximab induced hypogammaglobulinemia in lymphoma patients is underestimated. METHODS: We retrospectively analyzed the rates of hypogammaglobulinemia, infection and infection-related mortality in 136 lymphoma patients who were treated with a combination of chemotherapy and rituximab. RESULTS: Rituximab given in more than 8 doses (OR 6.05, 95% CI: 1.24-29.5), relative hypogammaglobulinemia at time of lymphoma diagnosis (OR 4.2, 95% CI: 1.26-14.1) and the combination of fludarabine with rituximab (OR 3.4, 95% CI: 1.24-9.47) were factors significantly associated with prolonged (more than 6 months) hypogammaglobulinemia. The combination of fludarabine and rituximab (OR 6.4, 95% CI: 1.49-27.0) and secondarily prolonged hypogammaglobulinemia (OR 4.5, 95% CI: 1.19-18.5) were found to be predictive factors for severe infections and infection-related mortality. CONCLUSION: These data suggest the importance of following serum immunoglobulin levels before and after combination immuno-chemotherapy, particularly in patients with recurrent infections or relapsed/refractory disease.

Cytokine release by activated T-cells in large granular lymphocytic leukemia associated with autoimmune disorders.

INTRODUCTION: Patients with T-cell large granular lymphocytic leukemia (T-LGLL) have a high incidence of autoimmune disorders. The pathogenesis of associated T-LGLL and autoimmune abnormalities is not clear. In this study we have investigated the role of cytokines in the development of immune complications in LGLL. PATIENTS AND METHODS: We studied clinical and laboratory features of 15 patients diagnosed with T-LGLL. The patients had various autoimmune disturbances: persistent neutropenia, immune thrombocytopenia, pure red-cell aplasia, Hashimoto's thyroiditis, sicca syndrome, systemic lupus erythemathosus, systemic scleroderma. The T-LGLL cells obtained from these patients were activated by phytohemagglutinin and incubated for 3 days. Using ELISA technique we analysed the release of sIL-2R, IL-4, IL-6, IL-8, IL-10, IL-12 and TNF-alpha in the supernatant. RESULTS: Cytokine analysis of supernatants obtained from the LGLL T cells stimulated with PHA revealed increased sIL-2R production in 40% (six patients), TNF-alpha - in 47% (seven patients), IL-6 - in 67% (10 patients), IL-10 - in 47% (seven) and IL-8 - in 60% (nine) of patients. Levels of IL-4 and IL-12 were not elevated compared to controls. No correlation was found between LGL count, CD4 versus CD8 expansion, or in the clinical findings of the patients and cytokine release in vitro. CONCLUSION: Our findings showing the potential of LGLL cells for cytokine release in vitro suggests that these cells may play a major role in the immune disturbances observed in large granular lymphocytic leukemia accompanied by autoimmunity features.

Look-back study of Hepatitis C in teenagers after blood transfusions as neonates.

AIM: To conduct a single-centre "look-back" study of the prevalence of hepatitis C in teenagers who had received blood products as newborns, prior to hepatitis C virus (HCV) blood donor screening. METHODS: Using blood bank records, we identified 732 surviving teenagers aged 14-18 years who had received blood products as neonates during 1986-1990. Letters recommending HCV antibody testing were sent to 732 surviving teenagers; 581 recipients were contacted and invited to undergo testing, and, of these, 429 consented (59% of the survivors). HCV antibody testing was performed on all and HCV-RNA was tested on those who were antibody positive. RESULTS: Three teenagers (0.7%, 95% CI 0.54-0.86) tested positive for HCV antibodies and all three were HCV-RNA positive. There were no cases in which antibodies were detected and polymerase chain reaction (PCR) was negative. Two of the three had mildly elevated liver enzymes and all three had mild inflammatory activity and low fibrosis scores on liver biopsy. CONCLUSIONS: The look-back process, even in a single centre with a stable urban population, is relatively inefficient in screening at-risk populations. Although the prevalence of hepatitis C in this sample was relatively low, paediatricians should offer screening to teenagers and young adults who received blood products in the neonatal period.

Vincristine-loaded platelet infusion for treatment of refractory autoimmune hemolytic anemia and chronic immune thrombocytopenia: rethinking old cures.

We report our experience with vincristine-loaded platelet infusion in patients with refractory immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome. Ten patients with symptomatic thrombocytopenia and/ or hemolytic anemia who failed to respond to two to six different treatment modalities, including corticosteroids and splenectomy, were treated with infusion of vincristine-loaded platelets. Platelets were harvested by plateletpheresis from a healthy ABO compatible blood donor and incubated with 5 mg vincristine. Excess of vincristine was removed, and platelets were resuspended in 50 ml plasma and infused over 30 min. All 10 patients responded, and 6 of them achieved complete remission. The response was prompt, occurring 3-8 days after vincristine-loaded platelet infusion. Two patients with AIHA are still in remission 9 and 8 years posttreatment with no maintenance treatment. Three ITP patients achieved persisted partial response for 6 years, 5 years, and 11 months; in the remaining 5 patients the response lasted for 2-5 months. No side effects were seen. Our results suggest that this inexpensive and well-tolerated treatment modality may be a useful approach in patients with ITP and AIHA refractory to primary therapy.

Changes in cytokine production and impaired hematopoiesis in patients with anorexia nervosa: the effect of refeeding.

The changes in cytokines and hormones involved in hematopoiesis were studied in the serum of 7 girls with anorexia nervosa, 15-24 yr old, on admission and after 5% and 10% weight gain. Hematopoiesis was studied by in-vitro culturing of circulating granulocyte-macrophage colony forming cells and erythroid burst forming cells. Nutritional status was studied by anthropometric measurements and resting energy expenditure. On admission, granulocyte-macrophage colony forming cells and erythroid burst forming cells were significantly lower than in age-matched controls and increased significantly along weight gain. Blood leptin and erythropoietin levels increased significantly with weight gain. TNF-alpha levels tended to decrease while IL-1beta levels were lower than in the controls on admission (p <0.05) and did not change significantly during weight gain. IL-3, GM-CSF and IL-6 were undetected on admission or along weight gain. The changes in granulocyte-macrophage colony forming cells and erythroid burst forming cells positively correlated with changes in resting energy expenditure and fat free mass. These results may suggest that undernutrition affects hematopoiesis as indicated by the reduction of hematopoietic progenitor cells before treatment and the significant increase with weight gain. The changes in the levels of hormones and cytokines known to be involved in hematopoiesis along refeeding may suggest a role for these factors in anorexia nervosa.

New sporadic case of congenital dyserythropoietic anemia type III in an aged woman: detailed description of ultrastructural findings.

We describe a new case of congenital dyserythropoietic anemia (CDA) type III. This least common type of CDA was diagnosed at the age of 59 in a 70-year-old woman who suffered from a young age from mild macrocytic anemia, while the long follow up since diagnosis documented a benign clinical course. No family history of blood diseases was obtained and no anemia was documented in the medical records of any of her four children. The bone marrow (BM) examination on light microscopy revealed a severe erythroid hyperplasia with the presence of giant multinucleated erythroblasts. Ultrastructural examination of the BM disclosed the presence of many large multinucleated erythroblasts bearing a variety of ultrastructural findings: nuclear clefts, autophagic vacuoles, iron-loaded mitochondria, and intracytoplasmic myelin figures. In addition, extensive hyperlobulation of the nucleus and partial loss of nuclear membrane with "spilling" of nuclear material to the adjacent cytoplasm was also noted in some of the erythroblasts. These last two findings have not been previously described in CDA III.

Medical staff attitudes: views and positions regarding blood transfusion to terminally ill cancer patients.

Blood transfusion is a widely used supportive treatment of cancer patients, most of whom are anemic. In the particular subset of cancer patients that undergoes chemotherapy, blood transfusion is viewed as an essential part of supportive care. However, the place of blood transfusion in anemic terminally ill cancer patients is far less established. There are no well-defined blood transfusion guidelines ("transfusion trigger") for these patients. Hence, transfusion decisions are greatly influenced by the personal views of the medical team. Therefore, a mail survey of 500 physicians (from several specialties) and nurses was initiated to assess their personal opinions on this topic. The overall response rate was relatively high (70%). There was broad agreement that blood transfusions, as a rule, should not be withheld from terminal cancer patients. On the other hand, only nurses were of the opinion that these patients should be transfused "as usual." Significantly, there was but a slight majority (53% of participants) that was of the opinion that transfusions to these patients do not prolong suffering. There emerged a short list of agreed-on suggestions for blood transfusion--namely, Hb level < or = 7 mg/dL, active bleeding (acute and/or occult), functional deterioration of the patient, presence of anemia resulting from chemotherapy, anginal symptoms, dyspnea, and worsening congestive heart failure. The agreed-on suggestions for transfusions in terminally ill cancer patients may serve as a reasonable physician standard for this complex clinical, medical-legal, and emotional issue.