Siemens: Innovative Trends in Hemostasis Herbert Maier / November 2014 Martin/SK Siemens: Innovative Trends in Hemostasis

… Sysmex® CS-Series CS-5100 with Cap Piercing CS-2100i CS-2000i w/o Cap Piercing

Innovation Highlight with the CS-series INNOVATION through Sample - Quality Check HIL – Check Hemolytic – Icteric – Lipemic through simultaneous multi wavelength analysis

Influence of Hemolysis on COAGULATION Results PT PTT Source: Lippi et al (2006) Fib D-Dimer 4

– Effect of citrate concentration SAMPLE UNDERFILLING – Effect of citrate concentration Minimum fill volume: 0.109M citrate PT (Innovin) 60% APTT (Actin FS) 70% 0.129M citrate PT 70% APTT 90% (Adcock et al 1998)

Innovation Highlight with the CS-series Only SYSTEM with AUTOMATIC CHECK for SAMPLE INTERFERENCES The pre-analytical sample check guarantees the result reliability and eliminates the most frequent cause of errors in measurement: Interferences in sample material 800nm 405nm 575nm 660nm 340nm

Pre-analytical Sample Integrity (PSI) Checks Probe 1 Probe 2 340 800 575 405 600 Hemolytic ! Upper level Icteric Lower level Lipemic 1st volume check 2nd volume check Pre-analytical Sample Integrity (PSI) Checks Slide overview: Comprehensive, automatic Pre-analytical Sample Integrity checks to reduce errors and help ensure accurate results. Key benefit: Confidence and peace of mind, with minimized risk. Pre-analytics is one of the biggest challenges that labs face for hemostasis testing, as it impacts TAT, capacity, and accuracy and quality of results. It is also resource-intensive because of manual sample inspection. Pre-analytical errors and unsuitable samples account for up to 70% of lab errors.1 Underfilling of sample tubes may cause significant sample dilution and provide falsely prolonged clotting times.2 Hemolytic specimens are the leading cause of pre-analytical variability and have been shown to negatively affect medical care.3 Icteric specimens cannot reliably be identified by visual inspection alone, requiring photometric detection instead.1 Lipemic specimens have been shown to affect the activity levels of clotting factors.2 The Sysmex CS-5100 System features a set of fully comprehensive Pre-analytical Sample Integrity checks (PSI™) that help to reduce pre-analytical errors due to incorrect sample-tube volumes and hemolysis, icterus, and lipemia (HIL). The Sysmex CS-series analyzers are the only hemostasis systems that currently offer this advanced technology. PSI checks automate primary-tube sample volume checking to identify potential inaccuracies caused by improper sample collection. Results from sample tubes with incorrect volumes are flagged for review. PSI checks use simultaneous multi-wavelength analytical scanning with user-defined criteria to detect HIL in each sample that enters the system, and then manage unsuitable test specimens prior to analysis. Problematic samples can be masked after testing based on lab preference, which supports patient care. Qualitative detection of HIL with a pre-analytic scan of the patient sample performed at 3 wavelengths: 405, 575, and 660 nm. By automating and standardizing sample management, the system helps labs reduce error and achieve first-run accuracy, giving labs confidence in the results that they report to clinicians. References 1. Lippi G, Banfi G, Buttarello M, et al. Recommendations for detection and management of unsuitable samples in clinical laboratories. Clin Chem Lab Med. 2007;45(6):728-736. 2. Favaloro E, Lippi G, Adcock D. Preanalytical and postanalytical variables: the leading causes of diagnostic error in hemostasis? Semin Thromb Hemost. 2008;34:612-634. 3. Lippi G, Blanckaert N, Bonini P, et al. Haemolysis: an overview of the leading cause of unsuitable specimens in clinical laboratories. Clin Chem Lab Med. 2008;46(6):764-772. ! 70%1 30% Pre-analysis Analysis Results 1. Lippi G, Banfi G, Buttarello M, et al. Recommendations for detection and management of unsuitable samples in clinical laboratories. Clin Chem Lab Med. 2007;45(6):728-736.

Results Accuracy 70%1 30% Hemolytic Correct first time Analysis ! 300 400 500 600 700 800 Wavelength (nm) Absorbance 340 800 575 405 600 Lipemia Hemolysis Icterus ! Hemolytic Results Accuracy Slide overview: Delivering accurate results through simultaneous multi-wavelength scanning. Key benefit: Confidence and peace of mind, with minimized risk. High-quality, accurate test results are key to ensuring patient safety, with poor results potentially leading to misdiagnosis or the need for repeat testing. The Sysmex CS-5100 System has been designed to deliver accurate results on all test samples and does so using a wide optical spectrum. Simultaneous multi-wavelength scanning of clotting reactions (at 340, 405, 575, 660, and 800 nm) reduces the effects of interfering substances on absorbance spectra by automatically selecting optimal wavelengths. The system has 20 reaction detectors, meaning that multiple samples can be scanned at the same time, promoting high throughput across all of the different test profiles. Scanning is performed in two stages. First, during pre-analysis, an HIL scan is run to check for presence of hemolytic, icteric, or lipemic samples. If any of these conditions are found, during the second (analysis) scan, the system switches the detection wavelength based on the reaction curve of the condition detected and picks the most appropriate wavelength to attempt to achieve a more accurate result. The system also reports a flag against the result for verification of the result. The problematic sample can be rejected before testing based on lab preference, which supports patient care. With the Sysmex CS-5100 System, labs can be confident that each result will be accurate, with minimized risk of error through interference of common substances. This gives peace of mind to clinicians and patients that the diagnosis will more likely be correct the first time. Correct first time Pre-analysis Results 1. Lippi G, Banfi G, Buttarello M, et al. Recommendations for detection and management of unsuitable samples in clinical laboratories. Clin Chem Lab Med. 2007;45(6):728-736.

Fully Traceable Results Operator ID Time and date Report Calibration curve and measurement result information Certificate Operation and error logs Maintenance and QC history Fully Traceable Results Slide overview: Full traceability and audit capabilities automatically logged in the system. Key benefit: Confidence and peace of mind, with minimized risk. In today's heavily regulated environment, labs need to be more careful than ever to not only provide accurate results, but also to keep records of what has happened and ensure traceability so that they can be certified. The Sysmex CS-5100 System provides labs with thorough traceability of sample results through easy-to-use audit trails on the analyzer, which also provides greater clinical insight. The system tracks a range of different variables for each result. Includes operator ID, time and date stamps, calibration curve and measurement-result information, operation and error logs, maintenance and QC history, automatic backup and data storage. Tracking data is accessed through an intuitive user interface with detailed sample traceability and easy-to-use audit trails for up to 60 results per sample, for 10,000 samples. This allows labs and authorities to track and control quality issues, helping to ensure greater security and giving confidence and peace of mind to labs, regulators, clinicians, and patients. Automatic backup and data storage

Ease of Use Real-time reagent and consumable monitoring Results validation QC procedures Configurable maintenance Ease of Use Slide overview: Intuitive and easy-to-use software supports lab technologists running complex processes. Key benefit: Confidence and peace of mind, with minimized risk. If analyzers aren't easy to use, users can feel uncomfortable, can take longer to complete work, and may be more likely to make mistakes. The Sysmex CS-5100 System uses powerful, user-friendly Sysmex CS-series operating software, which provides a dynamic, customizable user environment based on the Windows 7 platform. The system includes familiar operator software, with intuitive icons, symbols, and onboard help. With minimal training, lab technologists can use the system easily and quickly and effectively perform required tasks. This ease of use supports 24/7 routine and specialty testing in the lab with various work shifts. The intuitive user interface offers: Real-time reagent and consumable monitoring Complete, easy-to-understand, onboard reagent-status information with supporting graphics and data Large, intuitive status symbols QC procedures Automatic QC run with change of reagent vial and at user-defined time intervals Results validation Automatic validation of results with bidirectional LIS connectivity Configurable maintenance Automated maintenance procedures at times convenient for each lab based on testing schedules Onboard help Clear status messages and a comprehensive onboard help system help users quickly and easily identify and resolve issues. With this level of sophisticated support and ease of use, the complex operations that the Sysmex CS-5100 System performs are much easier to handle. Lab technologists can focus on delivering real value by interpreting results, with the confidence that the system is supporting them. CS systems

Features CS-Series– Reagent handling Cooled down to 8-10°C Up to 120h Positive barcode identification of all reagents, controls and standards at every position ECONOMIC & FLEXIBLE 40 cooled Reagents High on-board Stability Low dead volume through tilted reagent positioning Multi lot management

Features CS-Series – Instrument Operation USER FRIENDLY OPERATION TWO - DIMENSIONAL BARCODE Simple, Save, Efficient Allows the automated data input into the system software: e.g. lot specific values Calibrators – nominal values Controls – target values & ranges PT-reagents – ISI, derived Fibrinogen Avoids misentry and is immediately available with the new reagent

Features CS-Series – Instrument Operation USER FRIENDLY OPERATION

Features CS-Series– Test portfolio COMPREHENSIVE TEST PORTFOLIO The broad test portfolio, combined with multi- lot- management guarantees a high degree of specialization. UP to 10 calibration curves per reagent can be stored and displayed in a clear software menu. Multiple lots per reagent can be loaded on board and facilitate the workflow Routine Bleeding risk Thrombophilia Fibrinolysis Monitoring vWF:Risto* ETP* *in preparation

Features CS-Series – THROUGHPUT CS-2000i CS-5100   Parameter Tests/h Profile A/h PT* 180 400 Profile B/h APTT* Profile C/h PT and APTT Profile D/h PT, APTT, ATIII 94 Profile E/h PT, APTT, ATIII, INN DD 96 313 *Thromborel S and Pathromtin SL

Connectivity Sysmex® CS-5100 ADVIA® LabCell® Automation Solution ADVIA® LabCell® Automation Solution Aptio™ Automation System Aptio™ Automation System ADVIA CentraLink® Data Management System Connectivity* Slide overview: Comprehensive automation solution from the market leader. Key benefit: Helps ensure effective ROI. When choosing the Sysmex CS-5100 System, labs are not just choosing a single hemostasis analyzer, or even a family of hemostasis analyzers, but actually choosing a provider that offers a comprehensive solution for labs. Siemens allows labs to benefit from multi-disciplinary connectivity with Siemens automation and data management solutions.* ADVIA® LabCell® Automation System Full-scale, track-based automation system to link together multiple central-lab analyzers in a single workflow stream, managed from a central point. Aptio™ Automation System Automatic PSI checks bring extra confidence to track automation sample handling. Point-in-space sample transfer design. ADVIA CentraLink® Data Management System Synchronized, coordinated data-management system that covers multiple Siemens instruments within a single lab, from a single point, and can link to both the LIS and HIS. With increased expectations of connectivity from all stakeholders, the ability to link everything together using these solutions provides huge benefits for labs. Automation solutions and connectivity facilitate improved workflow, leading to greater productivity and reduced costs. Compatible Siemens coagulation, immunoassay, chemistry, and hematology systems enable scalable automation connectivity.* Point-in-space sample transfer with manual backup sample-loading options. Integrated PSI checks reduce manual intervention during track-automated analysis. Using centralized data management to coordinate and share results and samples across multiple analyzers and to different data systems (i.e., LIS and HIS) also improves workflow and helps to minimize errors. By choosing Siemens as a partner, labs can be confident of achieving scalable, efficient, and effective automation across the entire lab, maximizing productivity, reducing cost, and ensuring an effective return on investment. *The product is still under development and not yet commercially available. Its future availability cannot be ensured.

Sysmex® CA 660: Reliable and proven technology Same proven technology as the Sysmex CA-500 Systems + 2D barcode reader simplifies daily work + Increased throughput for D-dimer* + Improved graphical display of reaction curves *Available only on CA-660 17

LAS Connectivity; a smarter solution True “Point in Space” design according to CLSI standards. A more efficient transfer of the sample (not the tube) from the track. Integration of the system SW with the LAS control SW; more information is communicated. Manual sample loading option in case of LAS stoppage

! Consistent Results CA 600 CS-2100i CS-5100 Results Results Results Slide overview: Consistent results across different labs for the same patient allow clinical trends to be analyzed. Key benefit: Quality service to patients at all times, helping to deliver better overall care. Patients are often seen at multiple locations. In such cases, a test run at one site might not be comparable with a test run at another site, so it can be difficult to see clinical progress over time. The Sysmex CS family of analyzers offers total compatibility for true lab-to-lab consistency, sharing assays and assay applications, consumables, controls and calibrators, reference ranges, result correlation, and user interface. Critically, this provides excellent correlation of results across the family of analyzers (for example, comparing PT and D-dimer testing between the Sysmex CS-2000i System†† and Sysmex CS-5100 System††). This means that if a patient has a test while at the main hospital site using the Sysmex CS-5100 System, but then goes to a local hospital with a Sysmex CS-2000i for further ongoing testing, the sets of results can be compared, yielding a trend that produces an accurate impression of clinical progress. Having this kind of information allows clinicians to treat patients appropriately, helping ensure that they receive the best possible care and thereby improve outcomes. ††Not available for sale in the U.S. CA 600 CS-2100i CS-5100

INNOVANCE® VWF Ac An new assay for Von Willebrand activity testing Herbert Maier / November 2014 Martin/SK INNOVANCE® VWF Ac An new assay for Von Willebrand activity testing Sysmex CS-5100 Hemostasis System* Title slide. *Not available for sale in the U.S. Note: Sysmex is a registered trademark of Sysmex Corporation.

VWF Ac – a particle enhanced GPIb binding assay There are two naturally gain-of-function mutations in the recombinant GPIbα fragment: G233V and M239V Due to the high affinity VWF can bind without the support of ristocetin to the mutant rGPIbα 21

New: INNOVANCE VWF Ac innovative technology using recombinant GPIb receptor real functional assay for detection of quantitative and qualitative VWF deficiencies turbidimetric, latex based assay - no need for stirring use of gain-of-function GPIb receptor mutation - no need for ristocetin excellent precision and lot-to-lot consistency available on all Siemens automated coagulation instruments

Herbert Maier / November 2014 Martin/SK INNOVANCE® Free PS Ag An assay for easy, specific, and stable protein S antigen testing Sysmex CS-5100 Hemostasis System* Title slide. *Not available for sale in the U.S. Note: Sysmex is a registered trademark of Sysmex Corporation.

Intended Use and Assay Principle INNOVANCE® Free PS Ag Assay For the quantitative determination of free protein S in human plasma Assay principle: Particle-enhanced immunoassay Quantitative determination of free protein S using polystyrene particles covalently coated with monoclonal antibodies Turbidimetric detection Excellent specificity

INNOVANCE® Free PS Assay Principle 2 Mab† binding only free PS, Ag Latex particles with antibody A + Latex particles with antibody B Turbidimetric detection of aggregates + Free protein S from human plasma Antibodies do not bind to protein S/C4b-binding protein complexes †Own development

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