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The Prothrombin Time (PT) assay is clinically the most often requested coagulation test, as used primarily for monitoring of Vitamin K antagonist therapy where results are typically expressed as an International Normalized Ratio (INR). The INR reflects the patient's PT adjusted for the specific test reagent and instrument combination used by applying two correction factors, namely the International Sensitivity Index (ISI) and the Mean Normal Prothrombin Time (MNPT), according to the formula: INR = (patient PT/MNPT)ISI. When the manufacturer provides an ISI, laboratories are encumbered to check or locally validate the assigned value. Where a manufacturer does not provide an ISI, the laboratory needs to define its own (local ISI) value. The MNPT typically has to be locally defined, based on the population being tested. The main current CLSI recommendation for defining ISI values comprises use of commercial reference ('certified') plasma calibration sets, but FDA cleared material is limited, and different results may arise using different products. The MNPT can be defined using a WHO/CLSI recommended procedure requiring 20 normal individuals or with some calibration sets. Overall, there is limited data to validate the performance of these processes in laboratory practice, and ongoing evidence from external quality assurance (proficiency testing) programs indicates continued failure in INR harmonization, suggesting that ISI and MNPT values used by laboratories (and presumably assessed using current recommended processes) continue to be inaccurate. To assess some novel approaches to the laboratory estimation and/or validation of ISI and MNPT values for use in the INR calculation, and including the process of 'transference', normally used to assess the comparability of analytical systems or to transfer reference intervals between comparable systems. We have successfully adapted these comparative procedures, including 'transference', to permit ongoing estimation and/or validation of ISI and MNPT values for use in INR calculations for a range of instrumentation, which has led to improved harmonization of INR values obtained in our pathology network. These processes do not require the use of any normal individual plasmas or calibrator sets and greatly simplifies the INR process. Evidence for validation of the processes used is provided by ongoing satisfactory performance in external quality assurance (proficiency testing). Source


Favaloro E.J.,Institute of Clinical Pathology and Medical Research
Blood Transfusion | Year: 2016

von Willebrand disease (VWD) is reportedly the most common bleeding disorder and is caused by deficiencies and/or defects in the adhesive plasma protein von Willebrand factor (VWF). Functionally, normal VWF prevents bleeding by promoting both primary and secondary haemostasis. In respect to primary haemostasis, VWF binds to both platelets and sub-endothelial matrix components, especially collagen, to anchor platelets to damaged vascular tissue and promote thrombus formation. VWF also stabilises and protects factor VIII in the circulation, delivering FVIII to the site of injury, which then facilitates secondary haemostasis and fibrin formation/ thrombus stabilisation. As a result of this, patients with VWD suffer a bleeding diathesis reflective of a primary defect caused by defective/deficient VWF, which in some patients is compounded by a reduction in FVIII. Management of VWD, therefore, chiefly entails replacement of VWF, and sometimes also FVIII, to protect against bleeding. The current report principally focuses on the future potential for "personalised" management of VWD, given the emerging options in recombinant therapies. Recombinant VWF has been developed and is undergoing clinical trials, and this promising therapy may soon change the way in which VWD is managed. In particular, we can envisage a personalised treatment approach using recombinant VWF, with or without recombinant FVIII, depending on the type of VWD, the extent of deficiencies, and the period and duration of treatment. © SIMTI Servizi Srl. Source


Gray T.J.,St. Vincents Hospital | Webb C.E.,Institute of Clinical Pathology and Medical Research | Webb C.E.,University of Sydney
International Journal of General Medicine | Year: 2014

The resurgence of West Nile virus (WNV) in North America and Europe in recent years has raised the concerns of local authorities and highlighted that mosquito-borne disease is not restricted to tropical regions of the world. WNV is maintained in enzootic cycles involving, primarily, Culex spp. mosquitoes and avian hosts, with epizootic spread to mammals, including horses and humans. Human infection results in symptomatic illness in approximately one-fifth of cases and neuroinvasive disease in less than 1% of infected persons. The most consistently recognized risk factor for neuroinvasive disease is older age, although diabetes mellitus, alcohol excess, and a history of cancer may also increase risk. Despite the increasing public health concern, the current WNV treatments are inadequate. Current evidence supporting the use of ribavirin, interferon α, and WNV-specific immunoglobulin are reviewed. Nucleic acid detection has been an important diagnostic development, which is particularly important for the protection of the donated blood supply. While effective WNV vaccines are widely available for horses, no human vaccine has been registered. Uncertainty surrounds the magnitude of future risk posed by WNV, and predictive models are limited by the heterogeneity of environmental, vector, and host factors, even in neighboring regions. However, recent history has demonstrated that for regions where suitable mosquito vectors and reservoir hosts are present, there will be a risk of major epidemics. Given the potential for these outbreaks to include severe neuroinvasive disease, strategies should be implemented to monitor for, and respond to, outbreak risk. While broadscale mosquito control programs will assist in reducing the abundance of mosquito populations and subsequently reduce the risks of disease, for many individuals, the use of topical insect repellents and other personal protective strategies will remain the first line of defense against infection. © 2014 Gray and Webb. Source


Geno K.A.,University of Alabama at Birmingham | Gilbert G.L.,Institute of Clinical Pathology and Medical Research | Gilbert G.L.,University of Sydney | Song J.Y.,Korea University | And 5 more authors.
Clinical Microbiology Reviews | Year: 2015

Streptococcus pneumoniae (the pneumococcus) is an important human pathogen. Its virulence is largely due to its polysaccharide capsule, which shields it from the host immune system, and because of this, the capsule has been extensively studied. Studies of the capsule led to the identification of DNA as the genetic material, identification of many different capsular serotypes, and identification of the serotype-specific nature of protection by adaptive immunity. Recent studies have led to the determination of capsular polysaccharide structures for many serotypes using advanced analytical technologies, complete elucidation of genetic basis for the capsular types, and the development of highly effective pneumococcal conjugate vaccines. Conjugate vaccine use has altered the serotype distribution by either serotype replacement or switching, and this has increased the need to serotype pneumococci. Due to great advances in molecular technologies and our understanding of the pneumococcal genome, molecular approaches have become powerful tools to predict pneumococcal serotypes. In addition, more-precise and -efficient serotyping methods that directly detect polysaccharide structures are emerging. These improvements in our capabilities will greatly enhance future investigations of pneumococcal epidemiology and diseases and the biology of colonization and innate immunity to pneumococcal capsules. © 2015, American Society for Microbiology. All Rights Reserved. Source


Sartor M.M.,Institute of Clinical Pathology and Medical Research | Gottlieb D.J.,University of Sydney
Cytometry Part B - Clinical Cytometry | Year: 2013

Levels of residual disease (RD) are an independent predictor of progression-free survival (PFS) and overall survival (OS) in patients treated for chronic lymphocytic leukemia (CLL). We modified the international standardized approach (ISA) to RD detection using flow cytometry by developing a single tube 10 color antibody assay. Method: A single tube incorporated the following monoclonal antibodies: CD81FITC, CD22PE, CD3ECD, CD5PercP5.5, CD20PECY7, CD79bAPC, CD38A700, CD43APC Alexa750, CD19eFluor 450, and CD45KO. A modified ISA gating strategy was developed that removed contaminating events. Sensitivity assays were performed using dilution with normal peripheral blood and bone marrow. Clinical samples were compared using the ISA and the single tube assay. Results: Dilution studies showed that sensitivity of 0.001% was achievable when a minimum of 1.8 × 106 total events were acquired. One hundred twenty-nine samples were analyzed and showed RD levels from 0.003 to 22%. In 80 samples analyzed with both assays, there was an excellent correlation between the two methods (slope = 1.0, intercept = 0.07 and R2 = 0.992) and results from Bland-Altman analysis showed a bias of 0.04 ± 0.38 with 95% confidence interval of -0.71 to 0.79. Removal of contaminating events in the single tube assay led to a significant reduction in RD values (P = 0.0014). Conclusion: The single tube 10-color assay for the detection of RD in CLL provides equivalent results to the ISA but requires fewer cells, uses fewer reagents, and allows for simpler analysis. By directly removing contaminating events, it improves the accuracy of CLL RD detection and may reclassify the status of some patients following chemotherapy. © 2013 International Clinical Cytometry Society. Source

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