Technological Advances in the Hemostasis Laboratory

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Jan 17, 2014 - increase test panels, plasma indices for preanalytical check of interfering .... cuvette.8 A major breakthrough then occurred following.
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Technological Advances in the Hemostasis Laboratory Giuseppe Lippi, MD1

Mario Plebani, MD2

Emmanuel J. Favaloro, PhD, FFSc (RCPA)3

1 Laboratory of Clinical Chemistry and Hematology, Academic Hospital

of Parma, Parma, Italy 2 Department of Laboratory Medicine, Academic Hospital of Padova, Padova, Italy 3 Department of Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Pathology West, Westmead Hospital, New South Wales, Australia

Address for correspondence Giuseppe Lippi, MD, U.O. Diagnostica Ematochimica, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci, 14, 43126-Parma, Italy (e-mail: [email protected]; [email protected]).

Semin Thromb Hemost 2014;40:178–185.

Abstract

Keywords

► ► ► ► ►

coagulation hemostasis testing errors automation quality

Automation is conventionally defined as the use of machines, control systems, and information technologies to optimize productivity. Although automation is now commonplace in several areas of diagnostic testing, especially in clinical chemistry and immunochemistry, the concept of extending this process to hemostasis testing has only recently been advanced. The leading drawbacks are still represented by the almost unique biological matrix because citrated plasma can only be used for clotting assays and few other notable exceptions, and by the highly specific pretreatment of samples, which is particularly distinct to other test systems. Despite these important limitations, a certain degree of automation is also now embracing hemostasis testing. The more relevant developments include the growing integration of routine hemostasis analyzers with track line systems and workcells, the development of specific instrumentation tools to enhance reliability of testing (i.e., signal detection with different technologies to increase test panels, plasma indices for preanalytical check of interfering substances, failure patterns sensors for identifying insufficient volume, clots or bubbles, cappiercing for enhancing operator safety, automatic reflex testing, automatic redilution of samples, and laser barcode readers), preanalytical features (e.g., positive identification, automatic systems for tube(s) labeling, transillumination devices), and postphlebotomy tools (pneumatic tube systems for reducing turnaround time, sample transport boxes for ensuring stability of specimens, monitoring systems for identifying unsuitable conditions of transport). Regardless of these important innovations, coagulation/ hemostasis testing still requires specific technical and clinical expertise, not only in terms of measurement procedures but also for interpreting and then appropriately utilizing the derived information. Thus, additional and special caution has to be used when designing projects of automation that include coagulation/hemostasis testing because peculiar and particular requirements must be taken into account.

There are several forces that contribute to incessantly evolve the processes of in vitro diagnostic testing. These include progresses in the understanding of human biology and pathophysiology;

discovery of novel diagnostic and prognostic biomarkers; development of innovative techniques or perfection of existing ones; and miniaturization of biomedical devices, along with

published online January 17, 2014

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

Issue Theme Quality in Hemostasis and Thrombosis, Part III; Guest Editors, Emmanuel J. Favaloro, PhD, FFSc (RCPA), Giuseppe Lippi, MD, and Mario Plebani, MD.

DOI http://dx.doi.org/ 10.1055/s-0033-1364206. ISSN 0094-6176.

Technological Advances in the Hemostasis Laboratory continuous technological advancements in automation, instrumentation, and computer science. Technological progress is a primary driver of in vitro diagnostics and offers a kaleidoscope of opportunities to help streamline and standardize work, eliminate repetitive tasks, and reduce the risk of human errors. It is undeniable that the reality of laboratory diagnostics has undergone major evolution over the past 30 years, wherein innovative and fully automated analytical systems have almost completely replaced manual testing, and new tests are increasingly added as knowledge of the mechanisms of coagulation in health and disease increases.1–3 The major technological advances that have occurred in recent years will be synthetically reviewed in the following article, these having globally contributed to make the coagulation laboratory a more efficient and safer workplace.

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Table 1 Technological advances in the hemostasis laboratory Automation Total laboratory automation Workcell Instrumentation tools Signal detection with different technologies to increase test panels Plasma indices for preanalytical check of interfering substances Failure patterns sensors for identifying insufficient volume, clots, or bubbles Sample mixers for appropriate resuspension of corpuscular elements

Automation

Cap-piercing for enhancing operator safety and sample quality

Automation is commonly defined as the use of machines, control systems, and information technologies to optimize productivity.4 The implementation of various types of automation in laboratory diagnostics is mainly driven by the opportunity to simplify, reduce, or even completely eliminate several repetitive, complex, and potentially harmful operations that otherwise entail human intervention. Automation also provides a great advantage for performing those activities that require a high degree of precision and accuracy. The vast majority of routine activities of a clinical laboratory can now be automated, including sample identification, sorting, centrifugation, decapping, aliquoting, transport to different analytical modules, recapping, storage, retrieval, and rerun, to achieve a fully standardized and more reproducible sample processing. Unquestionable benefits arise from automation, including prevention and reduction of human errors, process streamlining, consistent operating procedures, improved productivity and throughput, reduced turnaround time (especially for common routine tests), enhanced safety for both patients and operators, samples and data traceability, tube consolidation, overall costs reduction, as well as fulfillment of demands of regulatory agencies in the setting of certification or accreditation procedures. Laboratory automation is a rather heterogeneous term, and may range from automatization of minor steps of the analytical process to total laboratory automation (TLA), which develops through standard configurations that are designed to manage different laboratory workload volumes, or to customize operations by combination of separate modules and track options in different configurations, to achieve the most appropriate solution to fulfill different needs in terms of shape and size, test types, and workload (►Table 1). Although automation is now commonplace in several areas of diagnostic testing, especially in clinical chemistry and immunochemistry, the concept of extending automation to embrace hemostasis testing has only recently been proposed, with different potential approaches. The leading drawback to automation in hemostasis testing is represented by the almost unique biological matrix, as citrated plasma can only be used for clotting assays with few other notable exceptions. The pretreatment of hemostasis samples is also

Automatic reflex testing, repetition, reanalysis, and redilution of samples Laser barcode readers Phlebotomy tools Positive identification for preventing identification errors Automatic systems for tube(s) labeling Transillumination devices Postphlebotomy tools Pneumatic tube systems for reducing turnaround time Sample transport boxes for ensuring stability of the specimens Monitoring systems for identifying unsuitable conditions of transport distinct to other test systems, wherein primary blood tubes referred for clotting tests should be subjected to highly specific conditions of centrifugation and storage, that would ultimately make their handling in combination with other sample matrices such as serum, lithium–heparin plasma, or whole blood anticoagulated with ethylene diamine tetraacetic acid (EDTA) complex and demanding. Despite integration of coagulation instrumentation within models of TLA, the process may be challenging for several technical and practical reasons, including the need for dedicated lines for treatment (e.g., centrifugation) and handling of primary blood samples, the need for skilled personnel to systematically review test results, as well as the necessity of specific areas of storage (►Fig. 1). Nevertheless, recent evidence has indicated that connection of routine coagulation analyzers to track-line systems along with other laboratory instrumentation does not impair the quality of routine hemostasis testing and can thus be regarded as a viable solution for modern coagulation laboratories.5 The implementation of more flexible solutions, such as that represented by workcells composed of two or more coagulation analyzers, is another good option to fulfill the preanalytical, analytical, and postanalytical quality requirements of coagulation testing (►Fig. 1), including desired centrifugation conditions, specified aliquoting, and Seminars in Thrombosis & Hemostasis

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Fig. 1 Integration of coagulation instrumentations within a model of total laboratory automation (left) or in workcells (right).

revision of test results within a specific middleware by an expert team of laboratory professionals.

Instrumentation Tools Several lines of evidence attest that the more frequent nonconformances encountered in the coagulation laboratory include samples not received after a specific physician’s request has been forwarded to the laboratory (49%), spurious hemolysis (20%), and undue clotting in plasma and inappropriate collection volume of sample (both 14%), which ultimately alters the strict blood to anticoagulant ratio in primary blood collection tubes.6,7 Although the problem of samples not received principally generates organizational problems, as it may be difficult to troubleshoot whether the failure entails a lack of sample collection or else that it has been lost somewhere in the path from the ward(s) to the laboratory; the presence of cell-free hemoglobin or other interfering substances, clots, or excess anticoagulant (i.e., buffered sodium citrate) impairs the reliability of testing for a variety of biological and analytical aspects. The development of technological aids that increase the ability to identify these potentially serious nonconformances is thereby highly recommended for the hemostasis laboratory, as for other areas of in vitro diagnostics.

Signal Detection The earliest coagulation analyzers can be considered a rather simple evolution of a historical manual testing approach, Seminars in Thrombosis & Hemostasis

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wherein the conventional clot detection has been automated by means of a mechanical hook within an instrument cuvette.8 A major breakthrough then occurred following the introduction of a new generation of sophisticated and “clinical chemistry-like” analyzers, which can now simultaneously use several wavelengths (i.e., from 300 to 800 nm) and different clotting, chromogenic, immunological principles along with platelet aggregation detectors to provide a large and flexible test menu, covering a broad spectrum of antigenic and functional aspects of hemostasis in a true random fashion.8,9 These features, coupled with availability of clot curves display an autovalidation programs, enable performance of large volumes of different tests, contextually increasing the quality of testing.

Serum (and Plasma) Indices The analytical and biological problems related to the presence of interfering substances such as cell-free hemoglobin, hypertriglyceridemia, and hyperbilirubinemia in biological samples have been emphasized in a previous article published in this journal.10 Basically, spurious hemolysis not only causes absorbance interference at those wavelengths typically used by optical instrumentation but also reflects the likelihood that a variety of intracellular and plasma membrane proteins have been released that may trigger activation of blood coagulation and platelets. The interference due to the presence of excess bilirubin is instead mostly attributable to spectral overlap, whereas that of turbidity—typically caused by hypertriglyceridemia—is attributable to light scatter,

Technological Advances in the Hemostasis Laboratory volume displacement effects, and direct interference of lipoproteins in primary and secondary hemostasis. Although the relative thresholds are both instrument and method dependent, it is universally assumed that samples with concentrations of cell-free hemoglobin > 0.5 g/L, bilirubin > 20 mg/dL, and triglycerides > 1,000 mg/dL may cause a clinically significant bias in test results and should not be processed. Several lines of evidence also attest that the visual inspection of samples is highly unreliable and is characterized by a poor interobserved agreement.11 Therefore, in analogy with clinical chemistry and immunochemistry testing, serum (plasma) indices (i.e., hemolysis index, bilirubin index, and lipemia index) are increasingly being developed also for hemostasis testing instrumentation.12 Traditionally, the most widely used methods for assessing interference, especially that attributable to cell-free hemoglobin, entail photometric assays at two or three different wavelengths, such as those developed by Fairbanks et al,13 with further modification by Malinauskas14 (i.e., measurement of cell-free hemoglobin at 415, 380, and 450 nm, or at 415, 450, and 700 nm), Sanderink and van Rijn,15 and Harboe.16 The automatic measurement of plasma indices adapted for use on laboratory instrumentation is also based on multiwavelength scanning (e.g., most frequently at 570 and 600 nm for cell-free hemoglobin) as part of a preanalytical check screen for interfering substances. The plasma indices are already available on instrumentation of the Sysmex CS-series (Sysmex Co., Kobe, Japan),17,18 and will also be available soon on the Instrumentation Laboratory ACL-series (Instrumentation Laboratory, Bedford, MA).19 It is also worthwhile mentioning here that additional instrumentation tools exist—especially developed for hemocytometers—for establishing whether hemolysis may or may not be present in whole blood specimens (i.e., specific flags for the presence of cellular debris, erythrocyte ghosts, or fragments),20 or whether loss of function has occurred for platelets (i.e., mean platelet component, recognition of discoid, and less functional platelets).21 As noted earlier, an additional feature of contemporary automated coagulation analyzers is the use of a broad spectrum of wavelengths (e.g., 340, 405, 575, 660, and 800 nm), which would enable to the selection of the optimal absorbance according to the specific type of interference.

Failure Patterns Sensors Contemporary automated coagulation analyzers are equipped with sample fluid aspirating and dispensing systems, which are adapted to aspirate biological samples from blood tubes or cuvettes contained within sample containers, and subsequently to dispense the plasma into an instrument reaction cuvette. The aspirating and dispensing systems are based on sample probes mounted on moveable arms, which perform aspiration and dispensing functions guided by robotic controllers. During aspiration, the moveable arm settles the sample probe above the sample container and lowers the probe until it is partially immersed in plasma. A pump, syringe, or alternate less common devices are then activated to aspirate a portion of sample, and the probe is then retracted to allow dispensing of plasma into one or more reaction cuvettes. Something may go wrong in this process

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during plasma aspiration, possibly due to an instrument malfunction or latent conditions of the samples (e.g., sample clot). Basically, an insufficient volume of plasma may be aspirated, a small clot or clotted fluid may be pulled off the sample onto the probe and then dispensed into the reaction cuvette, or an air bubble may replace part of the sample volume during aspiration (►Fig. 2). Regardless of the specific circumstances, the final effect is that the volume of plasma in the reaction cuvette may be lower than predicated and the test result would hence be unreliable. To overcome these various types of problems, the modern laboratory instrumentation has been equipped with “failure patterns” devices, which basically include “liquid level” and “clot” sensors typically placed inside the needle assembly of the sampling arm. Some basic approaches have been developed to reliably identify the presence of clotted plasma in the sample. A former method entails descending the probe into the sample, measuring a first capacitance reading (including also radio frequency admittance or impedance monitoring) as the probe first contacts a surface of the fluid, ascending the sample probe, measuring a second capacitance reading during the ascending, and finally assessing the potential presence of a clot carryout condition based on the first and second capacitance readings. An alternative strategy encompasses descending the probe into the sample, measuring a first-level reading, ascending the sample probe, measuring a secondlevel reading, and finally determining the presence of a potential clot based on the difference between descending and ascending liquid levels. The volume and bubble sensors both work in similar ways, that is, by using capacitance or pressure sensors. In general, the failure pattern sensors systematically compare the profile of a normal aspiration pressure or capacitance curve with the actual profile of aspiration and when the difference between these exceeds a predetermined satisfactory limit, the sample is flagged as either containing clots or known to be less than a desired aspiration volume. Liquid level is usually sensed by determining the height at which a change in capacitance or pressure occurs, whereas clots are detected by determining the change in capacitance or pressure as the tip moves up after aspiration. Additional approaches entail the use of sonic and ultrasonic sensors, conductance monitoring, or vibrating fork fluid level sensors, which measure the existence, nonexistence, increase, or reduction of a particular vibration.

Sample Mixers Sample mixing is a critical issue, especially in hematological and hemostasis testing, wherein the anticoagulants in the tube (i.e., EDTA in the former case and buffered sodium citrate in the latter)22,23 need to be adequately mixed with blood to ensure appropriate anticoagulation, at least until the analysis has been concluded.24 The Clinical and Laboratory Standards Institute (CLSI) guideline,25 along with other widespread recommendations,26,27 or manufacturers’ instructions, specifies that blood samples for coagulation testing should be mixed immediately after collection, by three to six times delicate inversion. This indication is based on the assumption Seminars in Thrombosis & Hemostasis

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Fig. 2 Analytical errors merging from the presence of clots or air bubbles in the sample and for inefficient aspiration of plasma.

that insufficient mixing may not enable appropriate anticoagulation,28 whereas vigorous mixing might cause spurious hemolysis or activation of primary and secondary hemostasis.29 Regardless of immediate management of samples, another important aspect is the appropriate mixing of the blood tubes immediately before analysis. This must necessarily be avoided when using plasma for clotting assays, but is instead essential for hematological testing, which also includes platelet count and derived parameters, wherein all corpuscular elements should be adequately resuspended in the surrounding plasma to enable reliable enumeration and sizing. This critical aspect can now be automatically performed by the vast majority of modern hemocytometers, which are equipped with sample mixers before whole blood is aspirated by the sample probe. It is also important to mention here that it has been shown that a plasma layer stratification may occur in primary blood tubes after traditional centrifugation, thus causing a bias in the measurements of prothrombin time (PT) and fibrinogen (increased concentration) in the lower than in the upper part of the tube.30 This phenomenon cannot be prevented with the use of modern coagulation analyzers.

or might catch a gloved finger in the tube. The obvious benefits of closed-tube sampling by mean of the so-called cap-piercing are hence represented by lower risk of biohazard exposure, reduced stress, and less risk of carpal tunnel syndrome, as well as enhanced quality of test results.31 In some instruments, the cap piercer also detects whether or not the cap is present and the blade does not descend when the tube is opened or the cap is already pierced. Instrument carryover may also be minimized using cap-piercing. Additional features of the new generation of sophisticated fully automated coagulation analyzer include potentiality for automatic reflex testing, repetition, reanalysis, and automatic (internal) redilution of samples, along with advanced samples and reagents management by laser barcode readers and compatibility with automated sample tracking systems. The positive identification of reagents by barcode reading is particularly attractive, as it permits gathering of continuously updated information about batch numbers, expiration date, and residual number of tests.

Cap-Piercing and Additional Tools

It is now unquestionable that collection of blood specimens is the most vulnerable step throughout the diagnostic process,32–35 wherein the vast majority of nonconformities affecting the quality of the diagnostic sample originates from inappropriate or mishandling procedures during36–38 or immediately after venipuncture.24,29 Along with the presence of interfering substances—that is, cell-free hemoglobin, hypertriglyceridemia, and hyperbilirubinemia—additional and important sources of preanalytical variability exist in the diagnostic sample, which may

Open-tube sampling has been the standard of laboratory testing for decades, as it was recognized that this process poses several risks to sample integrity and operator(s) safety. First, open tubes can be subjected to accidental splashes or aerosol leaks, with loss of sample and potential contamination of operators by infectious biological material. The recapping of blood tubes, which may also be required after analysis has been completed to prevent evaporation, is also a tedious and frustrating process, where caps may be affixed too tightly Seminars in Thrombosis & Hemostasis

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Phlebotomy Tools

Technological Advances in the Hemostasis Laboratory frequently go undetected due to the latent difficulty of establishing an appropriate interception pathway, or for the lack of reliable tools for their standard identification.39,40 These basically include misidentification, with latent potential of attributing correct laboratory data to the wrong patient and thus impairing the diagnostic and therapeutic decision making,41,42 along with venous stasis. In particular, a clinically significant bias in the values of PT, activated partial thromboplastin time, fibrinogen, and D-dimer (and presumably also additional hemostasis test parameters) systematically occurs after prolonged (i.e.,  3 minutes) tourniquet placing.43

Positive Patient Identification Systems Although the overall frequency of identification errors is reported to be as low as 1 to 2% in clinical practice, this figure suffers from clear underestimation due to the simple fact that most cases of misidentification typically go undetected.40 Moreover, the consequences of identification errors are reported to be far more serious than other types of preanalytical and analytical errors. Positive patient identification thus provides the essential tool for reducing the likelihood of these errors, and is based on several potential approaches, including the use of traditional barcodes, radio frequency identification, biometrics, magnetic strips, optical character recognition, smart cards, and voice recognition.41 Whatever the approach being implemented, the leading aspect remains the appropriate labeling of primary blood tubes. The Joint Commission still includes appropriate patient identification in the first place of the elements of performance (i.e., National Patient Safety Goal 01.01.01, effective January 1, 2013), where it is recommended that at least two patient’s identifiers should be used when collecting blood samples and other specimens for clinical testing, while blood tubes and other containers should be labeled in the presence of the patient.44 It is, however, surprising—and almost disappointing—that the CLSI guideline H3-A6 currently recommends that tubes must be positively identified after filling, and not before.25 Postcollection labeling of blood tubes poses a substantial risk of misidentification, simply because events may occur that disrupt the continuity of the collection and labeling process; instead, the use of automatic systems for tube(s) labeling should be encouraged, either in phlebotomy services or at the bedside.45,46

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lishing a network according to the typical “hub and spoke” model,50 is continuously being driven by large economic pressures and increasing shortage of experienced laboratory personnel. This paradigm shift in local organization of laboratory diagnostics has been accomplished with two apparently opposite and paradoxical circumstances, which comprise gradual centralization of “specialized” testing (i.e., those tests with high complexity and low volumes), counterbalanced by broad introduction of point-of-care testing for routine analyses (e.g., those characterized by low complexity, intermediate volumes, and need for reduced turnaround time). As for the former aspect, the need for sample(s) transportation from peripheral facilities to the reference laboratory, and even from distant wards to the core laboratory within large hospitals, requires that strict quality criteria are fulfilled, to prevent deterioration of samples. Such deterioration may be substantially magnified in those specimens being referred for coagulation testing because the stability of coagulation and fibrinolytic proteins is much lower than that of other common clinical chemistry analytes.

Pneumatic Tube Systems Pneumatic tube systems represent a fast and effective method for transport of biological samples to the core laboratory, an increasing paradigm in modern healthcare facilities. Previous reports have raised concern regarding possible samples deterioration during transportation, due to high transport speeds (up to 7.6 m/s), combined with rapid acceleration and deceleration.51 Several recent studies have now convincingly shown that no significant differences can be observed for routine coagulation testing or select markers of platelet activation (e.g., the mean platelet component) during transportation.52–54 It is noteworthy, however, that transportation of whole blood samples via tube systems may affect the results of platelet function studies, especially in patients undergoing antiplatelet therapy or with primary platelet dysfunctions,55–57 as well as those of thromboelastographic techniques53,58 so that a different path of transportation should be advisable in these circumstances.

Integrated Systems for Long-Distance Transportation Transillumination Devices The application of venous stasis, typically by means of the tourniquet, is a widespread practice during sample collection, and is still recognized as an important source of preanalytical variability.47 Several lines of evidence now attest that the use of transillumination devices, which are based on cold, near-infrared light-emitting diodes whose lights are absorbed by intraerythrocyte hemoglobin, is effective to enable complete abolishment of the bias due to extravasation of small molecules and hemoconcentration in routine coagulation testing,48 while also increasing the likelihood of a successful venipuncture.

Postphlebotomy Tools Local reorganization, obtained either by consolidation of small peripheral laboratories into larger factories49 or estab-

Due to the well-established assumption that sample quality should be preserved during transportation, integrated systems that enable prevention of or limiting the deleterious effects of inappropriate transport conditions (i.e., trauma, long duration, extremes of temperature, and humidity) are highly advisable. These basically entail the use of transport boxes suitable to preserve integrity of the specimens and maintain stable internal conditions,59 as well as the use of reliable monitoring systems based on data loggers for registering time and temperature at predetermined intervals throughout transportation, mission starters, and system managers (i.e., decoders of transport conditions which allow reading, visualization, and validation of data). 60 The use of these systems was proven effective to remarkably decrease the number of unsuitable specimens in a recent study.61 Seminars in Thrombosis & Hemostasis

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Conclusions Technological advancements have undeniably resulted in increased quality and efficiency in laboratory medicine, including the hemostasis laboratory. However, coagulation testing is much more complex than other “simpler” test systems involving discrete analytes in a simpler matrix such as serum (e.g., clinical chemistry tests). Coagulation/ hemostasis testing also requires additional technical and clinical expertise, not only in terms of measurement procedures but also for interpreting and then appropriately utilizing the derived information. Thus, additional and special caution has to be used when designing projects of TLA that include coagulation/hemostasis testing because peculiar and particular requirements must be taken into account.

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40 Preston FE, Lippi G, Favaloro EJ, Jayandharan GR, Edison ES,

51 Pragay DA, Fan P, Brinkley S, Chilcote ME. A computer directed

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