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Sickle cell anaemia (SCA) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the β-globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso-occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide (NO) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell-derived microparticle (MP) generation is also involved in the vaso-occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO. New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US-FDA-approved therapy to prevent painful vaso-occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L-glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on SCA.

Introduction: Circulating microparticles (MP) have been described in sickle cell anaemia (SCA); however, their interaction with endothelial markers remains unclear. We investigated the relationship between MP, protein C (PC), free protein S (PS), nitric oxide (NO), endothelin-1 (ET-1) and adrenomedullin (ADM) in a large cohort of paediatric patients.Method: A total of 111 children of African ethnicity with SCA: 51 in steady state; 15 in crises; 30 on hydroxyurea (HU) therapy; 15 on transfusion; 17 controls (HbAA) of similar age/ethnicity. MP were analysed by flow cytometry using: Annexin V (AV), CD61, CD42a, CD62P, CD235a, CD14, CD142 (tissue factor), CD201 (endothelial PC receptor), CD62E, CD36 (TSP-1), CD47 (TSP-1 receptor), CD31 (PECAM), CD144 (VE-cadherin). Protein C, free PS, NO, pro-ADM and C-terminal ET-1 were also measured.Results: Total MP AV was lower in crisis (1.26×106 ml−1; 0.56–2.44×106) and steady state (1.35×106 ml−1; 0.71–3.0×106) compared to transfusion (4.33×106 ml−1; 1.6–9.2×106, p0.9, p

article i nfo Low circulating protein C (PC) levels have been observed in sepsis, especially in patients with Neisseriae Menin- gitidesinfections. Poor clinicaloutcome and high limbamputation rateshave been associated ininfected patients with low circulating PC levels. Published studies using activated PC replacement therapy patients with sepsis haveshown reducedmortality rates,however,itsuse has beenassociatedwithsevere bleedingevents.Paediatric sepsis studies using non-activated plasma-derived PC (Ceprotin®) are lacking. We present a retrospective study in children with sepsis who were treated with Ceprotin® focusing on amputation rate post treatment. Thirty subjects were identified. Median age at diagnosis was 2 years. Twenty-one (70%) were treated for Nesseria Meningitides and one (3%) for Streptococcus-A β-haemolyticus, another 8 (26%) patients with malignancies were treated for neutopenic sepsis. Following Ceprotin® administration, a significant increase in leukocyte count (p = 0.004), neutrophil count (p = 0.001) and PC (pretreatment = 13%, posttreatment = 88.5%; p = 0.0001) was seen. Prothrombin time (pretreatment =30.3 seconds, posttreatment =16.5; p = 0.000) and activated partial thromboplastin time (pretreatment =61.8 sec, postreatment =42.6 sec; p = 0.000) were significantly reduced, while fibrinogen levels were significantly elevated (pretreatment =1.9 g/dL, posttreatment =4.4 g/dL; p = 0.000). The median time between admission to intensive care and Ceprotin® ad- ministration was 10 hrs. Limb amputation rate was reduced (16-23% versus 30-50% from previous studies) and there were no haemorrhagic events observed. This study demonstrates the safe administration of non-activated plasma-derived PC concentrate in patients with sepsis who are coagulopathic and it associated with a reduction in amputation rates.

Essential thrombocythemia (ET) patients are at risk of developing thrombotic events. Qualitative platelet (PLT) abnormalities and activation of endothelial cells (ECs) and PLTs are thought to be involved. Microparticles (MPs) can originate from PLTs (PMPs), ECs (EMPs), or red cells (RMPs). Previous studies have indicated that MPs contribute to ET pathophysiology. Endothelial modulators (eg, nitric oxide [NO], adrenomedullin [ADM], and endothelin-1 [ET-1]) are also involved in the pathophysiology of this condition. We hypothesized that treatments for reducing PLT count might also indirectly affect MP generation and endothelial activity by altering endothelial modulator production. The rationale of this study was that hydroxyurea (HU), a cytostatic drug largely used in ET, induces the production of a potent vasoactive agent NO in ECs. An observational retrospective study was designed to investigate the relationship between MPs, NO, ADM, and ET-1 in ET patients on treatment with HU, anagrelide (ANA), aspirin (ASA), and a group of patients before treatment. A total of 63 patients with ET diagnosis: 18 on HU + ASA, 15 on ANA + ASA, 19 on ASA only, and 11 untreated patients, and 18 healthy controls were included in this study. Blood samples were analyzed for MP (absolute total values) and functional markers (percentage values) by flow cytometry. PLT-derived MPs were studied using CD61, CD62P, CD36, and CD63, whereas endothelial-derived MPs were studied using CD105, CD62E, and CD144. Endothelial modulator markers (NO, ADM, and ET-1) were measured by ELISA. Total MP count was higher in the group treated with ANA + ASA (P 0.01). MP markers modified in ET patients returned to levels of healthy controls following treatment, in particular, in patients on ANA treatment. NO and ADM values were higher in the HU group (P 0.001). HU and ANA treatment also affected MP production in a cell origin-specific manner. HU and ANA, although acting via different pathways, have similar final effects. For instance, HU causes vasodilatation by increasing NO and ADM levels, whereas ANA impairs vasoconstriction by reducing ET-1. In conclusion, therapy with HU cytostatic drugs and ANA can reduce PLT count in ET, and also affect endothelial modulatory agents, with HU sustaining vasodilation and prothrombotic MP concentration, whereas ANA decreases vasoconstriction.

This paper lays a theoretical foundation from which it builds a typology of innovation search activities that can be used to characterize the openness of organisations. The typology is subsequently used as the conceptual lens when reviewing the extant literature in order to draw out recommendations for future research. This paper proposes that there are major issues with the extant literature and provides some recommendations for addressing these issues. This paper is of value to innovation scholars and those interested in building typologies as theoretical artefacts. More must be done to discover and to probe into why and how organisational elements interrelate and complement each other to impact the performance of organisations. Therefore, we suggest that scholars looking at innovation performance should consider combinations of search activities rather than the activities in isolation. Unfortunately existing studies tend to concentrate on either single activities or on the dichotomised choice between i...

This paper presents a case study of the co-operative design, development, and implementation of an XBRL-enabled interorganizational system (IOS) by the Australian Prudential Regulation Authority, the Reserve Bank of Australia (central bank), and the Australian Bureau of Statistics to revolutionize reporting by financial institutions in Australia. The findings illustrate that the complexity of data consumption patterns drove increased interdependence within the financial information supply chain requiring the co-operative development of context sensitive data exchanges and commodity-like IT infrastructures. The paper concludes that the co-operative model to IOS development exhibited here is likely to be more suited to the development of systems for financial information supply chains than the hub and spoke model characteristic of IOS in other sectors. Copyright © 2009 ASAC. Published by John Wiley & Sons, Ltd. Cet article est une etude de cas portant sur la conception co-operative, la mise au point et la mise en application d'un systeme d'informations inter-organisationnel (IOS) base sur le XBRL par l'Australian Prudential Regulation Authority, la Reserve Bank of Australia (la banque centrale) et l'Australian Bureau of Statistics afin de revolutionner la communication des informations par les institutions financieres en Australie. Il montre que la complexite des modeles de consommation de donnees a entraine une interdependance accrue dans la chaine d'approvisionnement d'informations financieres exigeant le developpement co-operatif des echanges de donnees sensibles au contexte et des infrastructures technologiques de base. L'article conclut qu'en matiere de mise au point de l'IOS, le modele co-operatif (presente dans l'etude) est probablement plus indique pour la realisation de systemes pour les chaines d'approvisionnement d'informations financieres que le modele en etoile qui caracterise l'IOS dans d'autres secteurs. Copyright © 2009 ASAC. Published by John Wiley & Sons, Ltd.

There is a dearth of research on the capabilities of innovative small-to-medium software enterprises (SMSEs). Understanding how SMSEs build and apply business and information systems (IS) capabilities is important, as such firms account for over 90% of software enterprises operating in Europe and the US. This paper elaborates and applies dynamic capability theory to explore and help understand the web of conditions and factors that shaped and influenced business and IS capability development and application in one European SMSE. Drawing on the overarching theory of dynamic capabilities, a theoretical model is presented that posits relationships among (1) a firm's past activities; (2) its integration, learning and reconfiguration, and transformation capabilities; (3) its financial, complementary, locational, and technological asset positions; and (4) the products and services that result, and which are of value to an SMSE's customers. The paper refines and elaborates the model by describing and enumerating the business and IS capabilities, assets, and products and services of the SMSE under study. To properly assess whether this firm's products and services were of value to its customers, research was also conducted at two customer sites in Ireland and the US, in addition to the investigation at the primary research site in Dublin. The study therefore informs both practitioners’ and researchers’ understandings of this complex and under-researched phenomenon: for practitioners, it highlights the characteristics required to build innovative software solutions; for researchers, it illustrates the patterns and regularities associated with the development and application of business and IS capabilities.

There is a growing interest in the application of information technologies (IT) for Knowledge Management (KM) in the public sector; there is, however, a dearth of research on the design and development of effective, integrated Knowledge Management Systems (KMS). Consequently, public sector organisations and private sector enterprises are offered little in the way of guidance in designing KMS from the bewildering range of information technologies said to capture, store, retrieve, transfer and apply knowledge. Action research, with its emphasis on praxis and on the importance of 'situated, practical theory,' is an ideal vehicle for deepening the IS field's understanding of the design of IT-enabled Knowledge Management Systems for use in Government and Non-Government Organisations. This paper reports on the outcomes of two related participatory action research studies involving a University R&D team, practitioners from the United Nations Population Fund (UNFPA), and a Government Department. The first of these studies focused on the design and development, using UNFPA practitioners' practical theory, of a desktop-based IT artefact for knowledge sharing. The second action research study extends and applies the lessons learned from the first to develop an enterprise-wide core IT artefact for the Government Department's Knowledge Management System. This paper contributes to both research and practice by: (1) offering a conceptual schema based on practical theory to inform the design and development of a core IT artefact for KMS and (2) describing the functions and features of a typical core IT artefact. The study also differentiates between core and non-core IT artefacts for knowledge sharing in organisations.

Researchers report mixed findings on the successful application of information technologies (IT) for knowledge management (KM). The primary dif- ficulty is argued to be the use of information management techniques and con- cepts to design and develop KM Tools. Also problematic is the existence of a multiplicity of KM technologies, the application and use of which differs across organizations. This paper argues that these problems stem, in part, from the infor- mation system field's over-reliance on design concepts from the functionalist par- adigm. Hence, our contention that alternative perspectives, which bring into focus issues of ontology and epistemology, need to be brought to bear in order to under- stand the challenges involved in the design and deployment of IT artefacts in knowledge management systems (KMS). The philosophy of technology, with its emphasis on the primacy of praxis, and which incorporates ontological and epis- temological concepts from phenomenology and hermeneutics, is applied to the findings of a participative action research study to illustrate how social actors inter- pret and understand worldly phenomena and subsequently share their knowledge of the life-world using IT. The outcome of this marriage of situated practical theory and philosophy is a set of design principles to guide the development of a core KM Tool for KMS.

Severe bacterial sepsis, particularly secondary to meningococcaemia, is a well-recognized cause of purpura fulminans resulting from severe acquired protein C (PC) deficiency. Recently, PC and activated protein C (APC) concentrate replacement therapy has been shown to improve outcome in patients with meningococcaemia- associated purpura fulminans and severe sepsis respectively. Despite these impressive findings, PC and APC concentrates are not currently widely available. We describe a 31-year-old patient with pneumococcal septic shock, purpura fulminans (PF) and severe acquired PC deficiency, whom we successfully treated with conventional therapy and high-volume plasma exchange as a source of PC.

It is now clear that modern organisations can derive significant benefits from an effective and efficient deployment of IT to the extent that information systems can have a significant impact on managerial decision making. However, managing the IT functional area and utilising IT expertise for decision making support are difficult endeavours. New models for managing IS resources and, more importantly, for distributing IT expertise amongst organisational actors are needed if IT is to contribute to organisations’ decision making processes at the highest level. This study used network analysis to capture the reality of the role and contribution of the IT departments of four organisations. Based on these data, the researchers drew a number of important conclusions for improving the collaboration between IT staff and other organisational actors. This research also indicates that network analysis can be a powerful vehicle in investigating the ways in which IT can be used to improve decision making and sharpen a...

Activated protein C (APC) is a natural anticoagulant that plays a pivotal role in coagulation homeostasis. Severe inherited or acquired deficiency results in a clinical syndrome called purpura fulminans. In addition, APC also appears to have potent cytokine-modifying properties and is protective in animal models of sepsis. The dual functional properties of APC are particularly relevant to severe meningococcemia, where acquired PC deficiency is accompanied by multiorgan failure and purpura fulminans. The authors conducted an open-label prospective study assessing the efficacy of PC replacement therapy in patients with severe meningococcal septicemia, purpura fulminans, and multiorgan failure. The morbidity and mortality were compared with predicted morbidity using the Glasgow Meningococcal Septicemia Prognostic Score. Thirty-six patients with a mean age of 12 years (range 3 months to 72 years) were enrolled in the study. The mean ± SD for plasma PC was 18 ± 7 IU/mL. PC was significantly lower than antithrombin or protein S and was also significantly lower than PC levels in a cohort of patients who developed meningococcemia without multiorgan failure and purpura fulminans. A total of 3 of 36 (8%) patients died, which compares favorably with predicted mortality of 18 of 36 (50%). Amputations were required in 4 of 33 (12%) survivors and in 2 of 31 (6.5%) patients who received PC within 24 hours of admission into the hospital, in comparison with the predicted amputation rate of 11 of 33 (30%). In conclusion, PC replacement therapy in severe meningococcal septicemia was associated with a reduction in predicted morbidity and mortality. The beneficial effect of PC replacement may reflect both the anticoagulant and anti-inflammatory properties of the PC pathway.

The strategic choices of organizations have traditionally been influenced by their environmental interactions. Consequently, the field of information systems has become increasingly concerned with providing managers with external information. However, such systems are largely based on research that was conducted prior to the important organizational and environmental changes of the late 1980s and 1990s. Much of this research focuses on hierarchical differentiation when providing information (especially external information) to managers. This paper presents the findings of a study that investigated the sourcing, dissemination and use of external information in organizations. The results show that managerial demand for such information is unrelated to managerial level, but is influenced by functional affiliation. The study also contradicts many of the previously held beliefs about managerial preferences for information channels and media. These findings have important implications for the field of information systems, especially personnel involved in systems design.

The work reported in this paper is an attempt to build upon existing research in the DSS area in order to enable the accurate measurement of the degree and extent of DSS usage in organisations. We put forward a framework for the classification of DSS usage which uses two dimensions, the novelty and specifiability of decision situations. This framework can be used by IS researchers to classify DSS applications meaningfully and make comparisons not only across large samples of systems, but also across organisations. In order to prove the validity of our novel approach, we studied and classified 24 Irish organisations based on the extent to which they used DSS for different decision situations using two specific measurements: DSS spread and DSS complexity. The results obtained confirm our initial empirical results (obtained with a smaller sample of organisations). The framework we have developed is a useful vehicle for categorising the extent to which organisations have managed to integrate their DS...

Business Process Reengineering (BPR) advocates the fundamental examination and redesign of business processes, recognising that the legacy of scientific management has been the excessive fragmentation of work practices in organisations today. This is reflected in the hierarchical structuring of organisations around functional departments, with individual and departmental goals displacing overall organisational goals. This paper discusses the development of a specific methodology for BPR. The practical application of this methodology in an actual BPR project in one organisation is discussed and some of the findings and lessons learned from the project are presented.

This paper summarizes the limitations of the rationalistic approach for the design, implementation and appraisal of executive support systems and advances in an interpretive cultural approach addressing their symbolic, boundary redefining and cultural attributes. Recognizing both perspectives provides richer insights about the meaning and role of such systems in organizations. This suggests that the efforts of managers, developers and researchers must embrace not only instrumental technology, but also the wider organizational and symbolic issues involved in the implementation of such systems.

Several factors have been proposed by researchers to explain why organizations are motivated to introduce executive information systems (EIS) now. These are identified and categorized in this paper and the results of an empirical study which examined the relevance of these factors in practice are presented. The findings of the study question the relevance and validity of some of the factors that have been identified – most notably that EIS are being introduced at the request of executives who are becoming increasingly computer literate and see EIS as a means of coping with today's extremely competitive business environment. The study findings suggest that IS department push and EIS envy are factors which play a significant role in the emergence of EIS in organizations.

The use of expert systems in support of the marketing function is a relatively new field within expert systems. This paper reports on the issues arising in the development of an expert system for a key area of marketing—that of new product pricing. The paper describes the approach followed in the acquisition, modelling, and encoding of marketing expertise. The system developed is described, and sample consultations are outlined. An important aspect of the system detailed in this study is that it has been validated by marketing personnel in a range of business and has been used by a number of companies to support them in their new product pricing.

Children with sickle cell anemia may undergo acute splenic sequestration. Splenectomy is performed in an attempt to reduce further events. Histologic studies of spleens have revealed the presence of granuloma-like nodules, known as Gamna-Gandy bodies with amorphous inclusions; however, their significance is unknown. The medical case records and histologic samples of consecutive children with sickle cell anemia treated with splenectomy between 2001 and 2007 at Our Lady's Children's Hospital, Dublin, were reviewed. Seventeen patients were identified. Gamna-Gandy bodies were studied by scanning electron microscopy and x-ray fluorescence spectroscopy. Gamna-Gandy bodies were identified in 7 (41%) patients, and amorphous inclusions were always seen. Patient age correlated significantly with Gamna-Gandy bodies (P = .002). Scanning electron microscopic analysis demonstrated the crystalline nature of Gamna-Gandy bodies and the chemical composition (C 47.1%; O(2) 29.7%; P 9.0%; K(+) 0.4%; Ca(2+) 6.4%; Fe(2+) 7.4%), whereas x-ray diffraction studied the structure (CaPO(4) ∙ FeOH). A crystal-formation gradient was observed, increasing from the red pulp to the white pulp. Our study shows that Gamna-Gandy bodies contain crystals and that their formation is age dependent. We also demonstrated the crystal structure and chemical composition and the relationship between Gamna-Gandy bodies and chest crises presplenectomy or postsplenectomy.

This chapter presents an action research-based case study of the development of pKADS (portable knowledge asset development system), an open source, desktop-based knowledge management (KM) tool, implemented in Java and targeted at government and nongovernment organizations. pKADS was a collaborative project involving Business Information Systems, University College Cork, Ireland and the United Nations Population Fund (UNFPA), and was funded by the government of Ireland. Development of the application took just three months, using an agile development approach and some reuse of existing open source code. The chapter discusses the background to the pKADS project and prior UNFPA KM efforts, the technical and conceptual architectures of the pKADS application, the roles played by open source components and open data standards, the rationale for releasing pKADS as open source software, and the subsequent results. Future research, in the form of developing open source, Intranet/Internet-based KM tools for the Government of Ireland—eGovernment Knowledge Platform (eGovKP) is also briefly discussed.

Management literature is renowned for producing concepts and frameworks but few of these are translated into software-based tools, even when they could be valuable to management. The area of innovation modelling is unfortunately a case in point. Management has heretofore been unable to effectively capture, communicate, and share its innovation models. Owing to the limited cognitive abilities of the human mind and the complexity and ambiguity surrounding innovation in organisations, the role of software-based tools in the future of innovation modelling should not be overlooked. But no standard approach to representing innovation models exists. The objective of this paper is to describe a prototype of an innovation modelling tool that resulted from our 24-month research initiative. We also include descriptions of an ontology upon which the prototype is built and the design science approach through which it emerged.

Background EU law requires a haemoglobin of ≥ 12·5 g/dl for women or ≥ 13·5 g/dl for men at the time of donation. As capillary and venous haemoglobin values may differ in the same subject, we examined whether a capillary haemoglobin level of 12·0 g/dl for women or 13·0 g/dl for men, is equivalent to a venous haemoglobin level of ≥ 12·5 g/dl and ≥ 13·5 g/dl, respectively, to avoid unnecessary loss of blood donations. Methods Over a continuous 42-month period, 36 258 paired capillary and venous samples were taken from 25 762 females and 10 496 males, when the capillary haemoglobin was

Recent studies have highlighted the utility of the resource-based view (RBV) in understanding the development and application of IT capabilities and resources in organisations. Nevertheless, IS research has inadvertently carried over several fundamental problems and weaknesses with the RBV from reference disciplines. This chapter proposes an integrative theory, model and research propositions that draws on dynamic capabilities theory from the resource-based view of the firm in institutional economics, and commitment theory in institutional sociology, to explain and understand the process by which IT capabilities and resources are developed and applied in organizations. In so doing, this study addresses the paucity of theory on the role of IT capabilities in building and leveraging firm-specific IT resources. The chapter also addresses the aforementioned problems and weaknesses to build a logically consistent and falsifiable theory, with relatively superior explanatory power, for application in both variance and process-based research, whether positivist or interpretivist in orientation.

It is widely believed that knowledge work is a relatively new phenomenon and that it constitutes the main form of activity in post-industrial organizations. While the term remains undefined, knowledge work is taken to refer to the knowledge that individuals apply in performing role-related business activities in “knowledge-intensive” organizations. In this scheme of things, the conventional wisdom holds that the subjective knowledge of individual social actors is applied to “objectified” organizational knowledge (i.e., data held in various paper and electronic repositories) as the raw material of the production process. Thus, knowledge is considered to be both an input to, and an output of, business processes: It also is argued to underpin the process by which knowledge inputs are transformed to outputs.

In the spring of 2002, a team within Digifone, in the Republic of Ireland, deliberated on how they would generate revenues from a Third Generation (3G) mobile license. Their plan was to facilitate third-party mobile commerce services, and receive a percentage of the resulting revenue. A key challenge would be differentiating the value of content based on transaction context. Mediation technology, based on open standards, was seen as the solution. The case describes Digifone’s evaluation of an XML vocabulary as the basis for a mediation and billing solution. The Digifone experience suggests that the key to exploiting 3G technology is inter-industry agreement on measurement standards to effectively manage the value of the associated services — a “bar code” for measuring value and distributing revenue amongst value Web participants.

The assumption that functionally rational notations can represent organisational spaces is central to engineering diagrammatical approaches in the delivery of advanced technology. This is reflected in a approach to notations which assumes objective, rationalistic ontologies. This form of rationalism in the modelling approach undermines notions of social context and social impact but, as such, has received little attention in the engineering literature to date. This paper opens the debate on research into notations and their relationship to sound method, suggesting that researchers need to rethink the ways in which the world is represented in engineering documentation, especially Requirements Engineering and Business Process Re-Engineering (BPRE). Empirical data from 9 companies and 48 people involved in manufacturing systems projects is presented which provides evidence for this position.

To the editor: Mean red cell mass and hematocrit levels are higher in men than women. How or why this is the case has never been explained. If decreased erythropoiesis due to iron loss or blood loss in females or increased erythropoiesis due to androgens in males were causative, there would be a

International audience; The research project reported in this paper constitutes an attempt to build upon existing research in the DSS area, namely the well-known framework for DSS developed by Gorry and Scott Morton. The authors put forward a revised framework which researchers in the field can use to classify DSS applications meaningfully and make comparisons across large samples of systems and organizations. The findings of a three year action research study were used to develop a framework for the classification of DSS usage which was then tested empirically. The organizations studied were classified based on the extent to which they used DSS for different decision situations using two specific measurements: DSS spread and DSS complexity. The results obtained suggest that the framework which was developed in this research is a useful vehicle for categorizing the degree of maturity of organizations regarding their usage and development of actual DSS applications.

Abstract 5193 Essenthial thrombocythemia (ET) patients are at risk of developing an arterious or venous thrombotic event. Recent studies have shown that there is no clear association between platelet (PLT) count and thrombotic events, but that white cell count plays a role. Qualitative PLT abnormalities, activation of endothelial cells (EC) and PLT may be involved in these processes. Following activation of blood cells, plasma membrane vescicles are released, these are known as microparticles (MP) ( Total-MP were increased in all patients groups compared to controls (p This study confirms previous findings that MP are present in ET. We also showed that MP are affected by treatment and that MP are mainly PMP and express CD62P and CD36, a marker of immature PLT, which suggests that reticulated PLT partecipate in these processes. We also showed that HU increase NO and ADM levels, while AN reduces ET-1. As NO and ET-1 have antagonistic actions on endothelial cells, we suggest that HU and AN may have overlapping effects on endothelium, although using different biochemichal pathways. The finding that treatment influences PC1 (PMP and EMP) supports the idea that in ET, treatment impacts directly on MP. The finding that NO and RMP have a negative loading within PC4, suggests that they have an antagonist-action to PMP and EMP in ET. Disclosures: Pizzolo: Hoffmann-La Roche: Consultancy, Honoraria.

Abstract 3157 Poster Board III-94 Introduction Transfusion circulatory overload (TACO) is a complication of transfusion, often confused with transfusion acute lung injury (TRALI), and is probably under-reported. The pathophysiology is believed to be caused by increased hydrostatic blood pressure leading to fluid leakage in the alveolar space, emulating congestive cardiac failure. We report on a large cohort of TACO cases in Ireland. Methods All consecutive TACO cases reported to the National Haemovigilance Office of Ireland between 2000-2008 were retrospectively reviewed. The incidence of TACO was calculated on units issued from the Irish Blood Transfusion Service (IBTS). Comparative analysis of patient demographic and clinical data was made using Fisher's exact test. Results 179 TACO cases were reviewed. 149 (83%) involved red cell concentrate (RCC), platelets (PLT) n=4 (2%); fresh frozen plasma (FFP) /solvent detergent plasma (SDP) n=16 (8%); multiple components n=10 (6%). During the study period, a total 1,614,973 blood components (RCC, FFP, SDP and PLT) were issued corresponding to a TACO incidence of 1/10.000 of all components issued. TACO incidence per RCC, platelets and plasma issued was 1/8000, 1/48000 and 1/15000 respectively, excluding the cases where multiple components were transfused. While the majority of patients developing TACO were elderly (> 70years)(n= 120, 67%), up to eight cases (4%) were reported in young patients ( 70 years, all of whom had underlying cardio–vascular conditions. Four (22%) patients died, one death which was possibly attributed to transfusion, and a further three patients (17%) required admission to intensive care. Four (22%) cases involved young female patients (age < 30 years) who had no underlying cardiovascular condition, but one patient had asthma. These patients were being treated for obstetric bleeding, and all recovered. Conclusion This study reports a TACO incidence of 1 /10 000 units issued from the IBTS. Although this incidence is based on units issued rather than transfused, it probably reflects significant underreporting, and perhaps even under-recognition. This study identified TACO has significant impact on patient outcome with approximately 8% (15) of patients suffering significant morbidity and a further 2% (5) of patients dying following onset of TACO. Finally, patients receiving large volume transfusion in emergency situations even young patients are at risk of developing TACO. Disclosures No relevant conflicts of interest to declare.

Nitric Oxide (NO) and endothelin-1 (ET-1) are key modulators of endothelial vessels and actively participate in the pathophysiology of vaso-occlusive events. Sickle cell anemia (SCA) is an important model for the study of blood cells/endothelium interactions. In SCA vaso-occlusive events may be severe and cumulative. Adrenomedullin (ADM) is a strong hypotension-inducer and mediates diuresis, natriuresis and vasodilation. Adrenomedullin levels are raised in chronic cardiovascular conditions. The aim of this study was to investigate the role of adrenomedullin in SCA and its relationship to endothelin-1 and nitric oxide. A cohort of 111 children with HbSS SCA was studied with 18 age-matched controls of sub-Sahara African ethnicity. The patients were in four clinical groups: steady state (n=55, mean age 5.3 years), patients undergoing chest crisis (n=9, mean age 5.3 years), on hydroxyurea (n=30, mean age 7.2 years), on transfusion therapy (n=17, mean age 6.5 years). A third cohort of patients with HbSC genotype (n=13, mean age 6 years) all in steady state was also included. Pro-adrenomedullin and c-terminal endothelin-1 precursor (CT-proET-1) were measured by coated tube assays according to the method by Morgenthaler et al (Clin Chem.2005;51:1823–29) and Papassotiriou et al (Clin Chem.2006;52(6):1144–51), nitric oxide was quantified according to the Griess reaction. Results (median and interquartile range) are shown in table 1. Overall pro-adrenomedullin levels were raised in chest crisis: 0.38 nmol/l (0.31–0.49) vs steady state: 0.27 nmol/l (0.25–0.32; p Table 1. ADM, ET-1, NO and hematological/biochemical values in SCA patients and controls. IR= interquartile range. Figure 1. ADM and NO levels in sickle cell patients and controls. Bars indicate median and interquartile range. Figure 1. ADM and NO levels in sickle cell patients and controls. Bars indicate median and interquartile range.

Microparticles (MP) originate from blebbing and shedding from cell membrane surfaces in physiological and pathological conditions. Increased levels are generated by a number of mechanisms including platelet activation, vascular endothelial damage, thrombin activity, C5b-9 activation, and PF4-heparin-antibody interaction. Increased circulating MP have been described in patients with sickle cell anemia (SCA). Elevated monocyte-derived MP expressing tissue factor have been reported in patients in crisis. The lack of a standardised method for MP quantification remains problematic. We measured MP (numbers and functional markers), protein C and free protein S, in a large cohort of pediatric patients to investigate the role of MP in SCA and their relation to protein C and free protein S plasma levels. One hundred and eleven children of sub-Saharan African ethnicity with SCA (hemoglobin (Hb) SS) were studied: 51 without previous history of crisis in steady state (mean age 5.3 years); 15 in crisis (9 chest crises, 6 other, mean age 5.4 years); 30 on hydroxyurea (mean age 7.2 years); 15 on transfusion therapy (mean age 6.5 years); 17 children of sub-Saharan African ethnicity of similar age (mean age 4.6 years) were used as control group (Hb AA). MP were analyzed by flow cytometry, according to Biró et al (J Thromb Haemost.2004; 2(10):1842–51), using Annexin V and antibodies against, CD61, CD42a, CD62P (P-selectin), CD235a, CD14, CD142 (tissue factor), CD201 (endothelial protein C receptor or EPCR), CD62E (E-selectin), CD36 (thrombospondin or TSP-1), CD47 (TSP-1 receptor), CD31 PECAM (platelet-endothelial cellular adhesion marker), CD144 (VE-cadherin). Protein C (chromogenic) and free protein S (latex based assay) were measured in all subjects. Correlation was measured by Pearson Rank test, and comparisons between groups were analyzed by Mann-Whitney test. Total MP AV were lower in crisis (1.26 × 106/ml; 0.56–2.44 × 106) and steady state (1.35 × 106/ml; 0.71– 3.0 × 106) compared to transfusion (4.33 × 106/ml; 1.6–9.2 × 106p0.9, p