Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death.

Platelet production requires compartmentalized caspase activation within megakaryocytes. This eventually results in platelet release in conjunction with apoptosis of the remaining megakaryocyte. Recent studies have indicated that in low-risk myelodysplastic syndromes (MDS) and idiopathic thrombocytopenic purpura (ITP), premature cell death of megakaryocytes may contribute to thrombocytopenia. Different cell death patterns have been identified in megakaryocytes in these disorders. Growing evidence suggests that, besides apoptosis, necrosis and autophagic cell death, may also be programmed. Therefore, programmed cell death (PCD) can be classified in apoptosis, a caspase-dependent process, apoptosis-like, autophagic and necrosis-like PCD, which are predominantly caspase-independent processes. In MDS, megakaryocytes show features of necrosis-like PCD, whereas ITP megakaryocytes demonstrate predominantly characteristics of apoptosis-like PCD (para-apoptosis). Triggers for these death pathways are largely unknown. In MDS, the interaction of Fas/Fas-ligand might be of importance, whereas in ITP antiplatelet autoantibodies recognizing common antigens on megakaryocytes and platelets might be involved. These findings illustrate that cellular death pathways in megakaryocytes are recruited in both physiological and pathological settings, and that different forms of cell death can occur in the same cell depending on the stimulus and the cellular context. Elucidation of the underlying mechanisms might lead to novel therapeutic interventions.

Cost-effectiveness of pathogen inactivation for platelet transfusions in the Netherlands.

The objective of this study is to estimate cost-effectiveness of pathogen inactivation for platelet transfusions in the Netherlands. We used decision tree analysis to evaluate the cost-effectiveness of the addition of pathogen inactivation of pooled platelets to standard procedures for platelet transfusion safety (such as, donor recruitment and screening). Data on transfusions were derived from the University Medical Centre Groningen (the Netherlands) for 1997. Characteristics of platelet recipients (patient group, age, gender and survival) and data/assumptions on viral and bacterial risks were linked to direct and indirect costs/benefits of pathogen inactivation. Post-transfusion survival was simulated with a Markov model. Standard methods for cost-effectiveness were used. Cost-effectiveness was expressed in net costs per life-year gained (LYG) and estimated in baseline- and sensitivity analysis. Sensitivity was analysed with respect to various assumptions including sepsis risk, reduction of the discard rate and discounting. Stochastic analysis to derive 90% simulation intervals (SIs) was performed on sepsis risk. Net costs per LYG for pathogen inactivation were estimated 554,000 euro in the baseline-weighted average over the three patient groups (90% SI: 354,000-1092,500 euro). Sensitivity analysis revealed that cost-effectiveness was insensitive to viral risks and indirect costing, but highly sensitive to the assumed excess transfusions required and discounting of LYG. Given relatively high net costs per LYG that are internationally accepted for blood transfusion safety interventions, our estimated cost-effectiveness figures for pathogen inactivation may reflect acceptable cost-effectiveness in this specific area. Two main assumptions of our model were that the pathogen inactivation was 100% effective in preventing transmission of the pathogens considered and was not associated with major and/or costly adverse reactions. Validation of several crucial parameters is required, in particular the Dutch risk for acquiring and dying of transfusion-related sepsis.

Splenectomy for the treatment of thrombotic thrombocytopenic purpura.

Plasma exchange is the treatment of choice for patients with thrombotic thrombocytopenic purpura (TTP) and results in remission in >80% of the cases. Treatment of patients who are refractory to plasma therapy or have relapsing disease is difficult. Splenectomy has been a therapeutic option in these conditions but its value remains controversial. We report on a series of 33 patients with TTP who were splenectomised because they were plasma refractory (n = 9) or for relapsed disease (n = 24). Splenectomy generated prompt and unmaintained remissions in all except five patients, in whom remission was delayed (n = 4) or who died with progressive disease (n = 1). Four postoperative complications occurred: one pulmonary embolism and three surgical complications. Median follow-up after splenectomy was 109 months (range 28-230 months). The overall postsplenectomy relapse rate was 0.09 relapses/patient-year and the 10-year relapse-free survival (RFS) was 70% (95% CI 50-83%). In the patients with relapsing TTP, relapse rate fell from 0.74 relapses/patient-year before splenectomy to 0.10 after splenectomy (P < 0.00001). Two patients died from first postsplenectomy relapse. Although these results are based on retrospective data and that the relapse rate may spontaneously decrease with time, we conclude that splenectomy, when performed during stable disease, has an acceptable safety profile and should be considered in cases of plasma refractoriness or relapsing TTP to reach durable remissions and to reduce or prevent future relapses.

Intraoperative blood transfusion requirement is the main determinant of early surgical re-intervention after orthotopic liver transplantation.

Liver transplantation is the treatment of choice in selected patients with end-stage liver disease. Postoperative complications often require surgical re-intervention. This study is a retrospective single-centre study to assess the incidence and type of surgical re-intervention during the in-hospital period after liver transplantation and to identify predictors of this re-intervention. From 1994 to 2002, 231 consecutive adult liver transplantations were performed. Re-intervention was classified as biliary, vascular, bleeding, septicaemia, re-transplantation or as miscellaneous. One hundred and thirty-nine surgical re-interventions were performed in 79 of 231 patients (34%). Septicaemia (44%) and bleeding (27%) were the most frequent indications for re-intervention, followed by biliary (10%) re-intervention. Vascular re-intervention, re-transplantation, and re-intervention for miscellaneous reasons, were performed in 7% each. Of all analysed variables (gender, age, diagnosis, acute liver failure, Child-Pugh classification, Karnofsky score, previous abdominal surgery, creatinine clearance, prothrombin time, anti-thrombin, platelet count, surgical technique, cold ischaemia time, warm ischaemia time, functional anhepatic time, anatomic anhepatic time, revascularisation time, year of transplantation, aprotinin administration, transfused platelet concentrate, and red blood cell transfusion requirements), only the number of transfused red blood cell concentrates (RBCs) was identified as a predictor of surgical re-intervention. Median RBC transfusion requirement during liver transplantation was 2.9 l (range 0-18.8 l) in the re-intervention group compared with 1.5 l (range 0-13.4 l) in the non-re-intervention group (P<0.001). This study revealed intraoperative blood loss as the main determinant of early surgical re-intervention after liver transplantation and emphasises the need for further attempts to control blood loss during liver transplantation.

Pharmaco-economics of blood transfusion safety: review of the available evidence.

BACKGROUND AND OBJECTIVES: Pharmaco-economics provides a standardized methodology for valid comparisons of interventions in different fields of health care. The role of pharmaco-economics in the safety of blood and blood products has, however, been very limited to date. This review discusses the pharmaco-economic evaluations of strategies to enhance blood product safety that have been published in the scientific literature. MATERIALS AND METHODS: We reviewed pharmaco-economic methodology with special reference to cost-effectiveness analysis. We searched the literature for cost-effectiveness in blood product safety. RESULT: Net costs per quality adjusted life-year (QALY) gained varied from cost-saving for human immunodeficiency virus (HIV)- and hepatitis C virus (HCV) antibody screening and leucoreduction to several million US dollars per QALY gained for solvent-detergent treatment of plasma, nucleic acid amplification testing and HIV p24 antigen testing. CONCLUSIONS: To date the safety of blood transfusion has been largely determined by available technology, irrespective of pharmaco-economics. Net costs up to several million US dollars per QALY gained were found for interventions implemented.

In vitro megakaryocyte expansion in patients with delayed platelet engraftment after autologous stem cell transplantation.

Increasing the number of megakaryocytic cells in stem cell transplants by ex vivo expansion culture may provide an approach to accelerate platelet engraftment after high-dose chemotherapy. However, it is unknown if a relationship exists between the expansion potential of progenitor cells and the time to platelet engraftment in vivo. Therefore, we questioned if those patients who potentially would benefit most from expanded cell supplements are able to generate megakaryocytic cells efficiently in vitro. The in vitro megakaryocyte proliferation was analyzed from 19 leukapheresis samples from a group of multiple myeloma patients who all showed rapid neutrophil engraftment, but varied from 7 to 115 days post-transplant to achieve platelet levels >20x10(9)/l. CD34+ cells were isolated and analyzed for their potential to form megakaryocytic colonies (CFU-Mk) in colony assays and megakaryocytic (CD61+) cells in suspension cultures. The frequency and size of CFU-Mk and the expansion potential of CD61+ cells varied eightfold between individual patients. A similar range was found with CD34+ cells isolated from normal bone marrow (n=9). Rapid platelet engraftment occurred in patients receiving both high or low CFU-Mk doses and with high and low expansion of CD61+ cells. Four patients who experienced prolonged (>3 weeks) thrombocytopenia received low CFU-Mk doses, but the expansion potential was around median values or higher. Therefore, we conclude that the megakaryocyte proliferation is not impaired and that in vitro expansion could increase the number of megakaryocytic cells, although other factors could be more relevant in platelet engraftment in this group of patients.