The coagulation laboratory is an ever-changing environment populated by automated analyzers that offer advances in both volume and variety of tests. Hardware and software innovations provide for random access testing with multi-test profiles. In the past, the routine coagulation test menu consisted of prothrombin time (PT) with international normalized ratio (INR); partial thromboplastin time (PTT), also referred to as the activated partial thromboplastin time (APTT); fibrinogen; thrombin time; and D-dimer assays. More specialized testing was performed in tertiary care institutions or reference laboratories employing medical laboratory scientists with specialized training. With the introduction of new instrumentation and test methodologies, coagulation testing capabilities have expanded significantly; so, many formerly specialized tests can now be performed easily by general medical laboratory staff. New instrumentation has made coagulation testing more standardized, consistent, and cost effective. Automation has not advanced, however, to the point of making coagulation testing foolproof or an exact science. Operators must develop expertise in correlating critical test results with the patient's diagnosis, and when monitoring antithrombotic therapy. Good method validation of procedures, cognitive ability, and theoretical understanding of the hemostatic mechanisms are still required to ensure the accuracy and validity of test results so that the physician can make an informed decision about patient care.

Indian Market Dynamics

Indian Coagulation Instruments and Reagents Market Value-WiseThe Indian market for coagulation and instruments in 2015 was valued at Rs.122 crore, with reagents dominating at Rs.107.36 crore. This includes 16 percent customs duty and 10 percent freight.

The instruments at Rs.14.64 crore, have a contribution of Rs.9.66 crore from fully automated instruments. The market for semi-automated instruments constituting single-channel, 2-channel, and 4-channel was valued at Rs.4.98 crore in 2015.

Stago is represented by five distributors - Syndicate Diagnostic P Ltd, Bio Medica, Nisha Sales, Labex, and Imperial Biotech. 2015 was a good year for the company. Metropolis awarded its exclusive order to the vendor and it replaced most of the instruments in the Apollo Group.

Werfen India was not far behind. Its major customers included SRL Diagnostics, Dr Lal Pathlabs, CMC, Max, Gangaram, PGI Chandigarh, AIIMS, SGPGI, the Global Group, the Care Group and St Johns, and the Indian Army.

In August 2016, Sysmex Corporation received the 14th Annual Merit Award for Collaborative Achievement between Industry, Academia, and Government of Japan for the practical realization of a system for diagnosing hepatic fibrosis using glycosylation, developed in collaboration with the National Institute of Advanced Industrial Science and Technology.

Global Market

Indian Coagulation Instruments Market Value-WiseThe global coagulation analyzers market is expected to reach USD 3.58 billion by 2019 from USD 2.6 billion in 2015, growing at a CAGR of 8.3 percent from 2015 to 2020, owing to factors such as increasing geriatric population and rising prevalence of blood-related disorders.

Furthermore, key factors driving the market growth include high-throughput results from hemostasis analyzers, increasing adoption of automated hemostasis instruments, and development of high sensitivity and specificity of coagulation analyzers. Additionally, high throughput obtained from clinical diagnostic procedures, which are driven by multitasking of coagulation analyzers devices that provide information about patient's blood clotting status, and monitoring the effect of drugs such as heparin and anticoagulants are expected to boost usage rates over the forecast period.

Additionally, the effects of blood component therapy contribute to growth of coagulation analyzers market. Improved clinical diagnostic procedures and favorable initiatives conducted by organizations such as the World Health Organization (WHO) pertaining to the development of novel products are expected to have a positive impact on the coagulation analyzers market over the next 5 years. Increasing prevalence of diseases such as heart attack-inducing blood clots, impaired liver function, hemophilia, Von Willebrand disease, thrombocytopenia, cancer, and hypercoagulability are anticipated to provide growth opportunities to the coagulation analyzers market in the coming years. However, relatively low adoption and high cost of advanced coagulation analyzers in emerging economies can hamper the growth of this market.

The global coagulation analyzers market is segmented on the basis of product, test type, and technology. On the basis of product, the market is segmented as clinical laboratory analyzers, instruments, automated and semi-automated analyzers, consumables, reagents, and analyzers for point-of-care (POC) testing. Furthermore, on the basis of test type, the market is segmented into various testing kits such as prothrombin time (PT), activated clotting time, D dimer, and fibrinogen (FIB). Technologically, market segmentation includes mechanical, optical, and electrochemical devices.

Indian Coagulation Instruments Market 2015In 2015, consumables segment accounted for the highest share in the coagulation analyzers market in terms of revenue. Clinical laboratory analyzers is one of the fastest growing segment over the forecast period of 5 years due to technological advancements such as dual- and four-channel system simultaneously useful for testing of PT, APTT (activated partial thromboplastin test), FIB, and TT (thrombin time). Technological advancements in POC procedures such as outpatient anticoagulation, cardiac surgery units, and dialysis units along with quality assurance to overcome adverse reaction caused due to anticoagulation therapy, and home testing services is anticipated to gear up the market growth over the next 5 years. Additionally, lower testing volumes, improved patient care, and analyzation of more parameters are anticipated to boost the demand for coagulation analyzers.

The key regional segments include North America, Europe, Asia-Pacific, Latin America, and MEA. In 2015, North America held the largest share of coagulation analyzers market, followed by Europe. Key factors attributing to its large share include increasing prevalence of blood-related disorders, constant technological advancements, high disposable income, and improved healthcare infrastructure. Furthermore, increasing number of mergers and acquisitions, high R&D expenditure, and favorable government initiatives for new product development are expected to propel market growth in this region. Asia-pacific is expected to be the fastest-growing regional market over the forecast period as a consequence of significant factors such as increasing need of coagulation diagnostic procedures and increasing patient awareness about technological developments integrated with improving healthcare infrastructure. Furthermore, new market entrants owing to less competition are expected to play vital role in providing growth to the coagulation analyzers market in this region over the next 5 years.

Emerging Trends

Technological advances are leading to the development of innovative equipment such as miniaturized point-of-care testing devices. This small-size device offers certain advantages such as rapid analysis with small sample size, reduced quantity of reagents required, and functional integration of multiple devices. Also, vendors are striving to provide minimally invasive and non-invasive testing systems that are easy to handle. The top three emerging trends driving the point-of-care coagulation testing market are decentralized testing, increase in online marketing, and growing popularity of disposable coagulation testing products.

Increase in Online Marketing

Online marketing has led to a rapid increase in sales of POC devices and services. In 2015, a research study estimated that about 70 percent of the population in the US relies on online shopping portals for purchasing various items. Online marketing websites offer a wide selection of branded POCT devices and consumables, together with the convenience of shopping from the comfort of home. Online selling of POC coagulation testing devices and consumables can, therefore, significantly increase the revenue of vendors.

Growing Popularity of Disposable Products

Disposable POC diagnostic products are preferred as they are more hygienic. Therefore, manufacturers are introducing technologically advanced portable POC products with single-license owners. Some POC coagulation testing devices comprise a test-specific disposable cartridge containing the necessary reagents to perform the test. These disposable cartridges are easy to use and are inexpensive.

Advances in Coagulation Technology

Significant advances have been made in the capability and flexibility of coagulation instrumentation. Instruments previously required manual pipetting, recording, and calculating the results, which necessitated significant operator expertise, intervention, and time. Current technology allows a walkaway environment in which, after specimens and reagents are loaded and the testing sequence is initiated, the operator can move on to perform other tasks.

Clot detection methods have remained consistent but with the advent of chromogenic- and immunologic-based assays, other instrumentation needed to be incorporated into the coagulation laboratory. Multiple methodologies became incorporated into single analyzers to expand their test menu options. From instruments that performed only clot-based assays, clinical laboratory instruments were developed that could perform both clot-based and chromogenic-based assays on one platform. The next step was the development of a single instrument that could perform clotting and chromogenic and immunologic assays. Additional advances have included improved specimen and reagent storage and processing, increased throughput, and enhanced data management and result traceability.

Improved Accuracy and Precision

In the days of visual methods, coagulation assays were performed in duplicate to reduce the coefficient of variation, which generally exceeded 20 percent. Semi-automated instruments have improved upon precision, but the requirement for manual pipetting of plasma and reagents continues to necessitate duplicate testing. With the advent of fully automated instruments, precision has improved to the extent that single testing can be performed with confidence, halving material and reagent costs. Coefficients of variation of less than 5 percent, and even less than 1 percent for some tests, have been achieved. Initial accuracy and precision are established by in-lab method validation for all instrument and reagent combinations.

Random Access Testing

Automated coagulometers now provide random access testing. Through simple programming, a variety of tests can be run in any order on single or multiple specimens within a testing sequence. Previous automated analyzers were capable of running only one or two assays at a time, so batching was necessary. The disadvantage was that specimens with multiple orders had to be handled multiple times. For current automated analyzers, the ability to run multiple tests is limited only by the number of reagents that can be stored in the analyzer and the instrument's ability to interweave tests requiring different end-point detection methodologies simultaneously, such as clot-based, chromogenic, and immunologic methods. Random access promotes profiling.

Open Reagent Systems

A variety of reagents from numerous distributors are available for coagulation testing, and laboratory directors want the flexibility of selecting the reagents that best suit their needs without being restricted in their choices by the analyzers being used. Recognizing that the ability to select reagents independently of the test system is a high priority, instrument manufacturers have responded by developing systems that provide optimal performance with alternative manufacturers' reagents, provided that the reagents are compatible with the instrument's methodology.

Reagent Tracking

Many automated instruments keep record of reagent lot numbers and expiration dates, which makes it easier for the laboratory to maintain reagent integrity and comply with regulatory requirements. Additional features often include on-board monitoring of reagent volumes with flagging systems to alert the operator when an insufficient volume of reagent is present in relation to the number of specimens programmed to be run. Reagent barcoding supports record keeping because it tracks reagent properties and enables the operator to load coagulometers without stopping specimen analyses.

Expanded Computer Capabilities

The computer circuitry of analyzers now incorporates internal data storage and retrieval systems. Hundreds of results can be stored, retrieved, and compiled into cumulative reports. Multiple calibration curves can be stored and accessed. Quality control files can be stored, which eliminates the time-consuming task of manually logging and graphing quality-control values. Westgard rules can be applied, and failures are automatically flagged. Some analyzers feature automatic repeat testing when failures occur on the initial run. The quality control files can be reviewed or printed on a regular basis to meet regulatory requirements.

The programming flexibility of modern analyzers has enhanced the laboratory's opportunities to provide expanded test menus. Most advanced analyzers are preprogrammed with several routine test protocols ready for use. Specimen and reagent volumes, incubation times, and other testing parameters do not need to be predetermined by the operator but can be changed easily, when necessary. Additional tests can be programmed into the analyzer by the user, whenever needed, which allows for enhanced flexibility of the analyzer and reduces the need for laboratories to have multiple instruments.

Instrument interfacing to laboratory information systems and specimen bar coding capabilities have become a priority as facilities of all sizes endeavor to reduce dependence on manual record keeping. Bidirectional interfaces improve efficiency through the ability of the instrument to send specimen bar code information to the laboratory information systems and receive a response listing the tests that have been ordered. This eliminates the need for the operator to program each specimen and test.

The Road Ahead

Since the early history of hemostasis laboratory, coagulation analyzers have been mostly designed for running clotting tests. In recent decades, however, these instruments have become increasingly equipped with additional technical tools to perform a broader test menu for investigation of bleeding and thrombotic disorders.

An important arena that is currently inaccessible to most coagulation analyzers is the exploration of platelet function. The current armamentarium of diagnostic tests in this field includes impedance platelet aggregometry on platelet-poor plasma (PPP), which is performed using traditional optical lumi-aggregometers, and innovative platelet function analyzers on whole blood, which generally simulate platelet adhesion/aggregation under high shear conditions, and after stimulation with a number of platelet agonists.

In regard to technical perspectives, the integration of these techniques within a next-generation hemostasis instrumentation is theoretically feasible, and has been explored in a limited manner in a newer hemostasis instrument, the Siemens CS-2100s.

Post-analytical sample management may be seen as critical as the pre-analytical and analytical management in some circumstances. This specifically refers to repeated or reflex testing. Re-run of samples may be necessary when the analysis is to be repeated with suspicion of an analytical error or interference, or when the observation of abnormal values may trigger forward automatic testing. Reflex tests are those that automatically result in the order of one or more secondary analyses based on predefined criteria applied to the initial test. A typical example in hemostasis is lupus anticoagulant (LAC) testing. The second-line tests are manually activated in most laboratories.

The future of hemostasis laboratory is currently unwritten and no crystal ball can accurately predict it. The challenge of coagulation analysis in the context of the widespread use of novel anticoagulants is a paradigmatic example.

According to ongoing reorganization of laboratory diagnostics around the globe, continuous technological innovations, and predictable trends of disease prevalence, some basic ideas can be proposed to envisage how a next-generation coagulation analyzer might be.

Shivadas Pokkalath, Product Manager-Coagulation, Transasia Bio-Medicals Limited
Industry Speak
Five Check-Points while Choosing Fully Automated Coagulation Analyzers

Coagulation tests are an important part of diagnosis and hence there is a need to identify a system based on precision of reporting. Most laboratories regularly perform PT and APTT tests and occasionally other tests. For laboratories with a workload of 25 PT and APTT per day, it is essential to choose an automated system over a manual one. Automation minimizes human error in pipetting and other complex protocol requirements.

An automated system needs to be selected based on these five check points.

Reaction cuvette

Cuvettes of different kinds such as cartridge, centrifugal disc, rolls, and single cuvettes are available. Systems that use single cuvettes are recommended as those with multiple cartridges run the risk of breakdown due to the cartridges getting stuck within the system. In case of rolls, a few blank cuvettes are wasted every time the system performs initialization, resulting in greater consumption.

Use of emulsion and other system solutions

In order to maintain accuracy of reporting, probe cleaning is a must between dispensing reagents and samples. Emulsions, DSorb, etc., increase the cost per reportable test and hence should be avoided.

Sample barcode and manual entry

Systems that have a provision for both manual and barcode entry of samples should be selected. This is essential to avoid instances where the barcode is not read by the system, resulting in samples getting missed.

Principle of detection

Coagulation systems are based on indirect and direct methods of clot detection. In the indirect method, the clot formation is decided based on the movement of a metal ball or bar. In the direct, optical method, the clot formation is displayed as a clot curve. Seventy-five percent of coagulation analyzers available today are based on the direct method, as it is found to be the most acceptable method.

After-sales support

Prompt customer service is a very important criterion while choosing a system. It is vital to know whether the instrument provider has a strong after-sales support network. This is especially true for remote locations as accessibility is a big concern. Lack of availability of personnel with troubleshooting expertise, is another challenge.

Transasia Bio-Medicals Ltd. recognizes the needs of laboratories and offers an advanced fully automated coagulation analyzer, ECL 760. This analyzer uses an innovative technology to give accurate results and is backed by a strong pan-India service network.

Shivadas Pokkalath
Product Manager-Coagulation,
Transasia Bio-Medicals Limited

Rishi Chadha, Country Manager, Stago India Private Limited

"Over the last decades, Indian coagulation market has significantly innovated and now it is time for consolidation of all its segments. There is need for continuous education of customers not only in the metro cities but also in B/C/D class cities. Also there is need for education to improve the level of coagulation testing to the level of A Class cities; this will reduce the TAT for better and timely patient care.

The market is moving toward smart automation instruments for bigger labs. However, entry-level semi-automatic instruments that are smart and easy to use have raised the level of coagulation testing in small labs with standardization of testing."

Rishi Chadha
Country Manager,
Stago India Private Limited

 

 

 

Dr Vanajakshi S, HOD & Sr. Consultant, Department of Hematology & Clinical Pathology, Apollo Health City, Hyderabad
Second Opinion
Validation of APTT for Heparin Sensitivity

Intravenous/subcutaneous unfractionated heparin (UFH) is widely used for treatment of venous thromboembolism, APTT being frequently used for monitoring heparin dosage. Inadequate/excess heparinization leads to recurrent thrombosis/bleeding respectively; hence a sensitive and accurate method for heparin monitoring is very essential.

UFH therapy is monitored by a variety of methods, including APTT, thrombin time-related assays, heparin assay by protamine neutralization or factor Xa inhibition assay and activated clotting time test, and most frequently used test is the APTT.

The response of APTT to heparin varies with different reagents, instruments, patient response to heparin, and the heparin itself. This emphasizes the need for each laboratory to determine the sensitivity of APTT to heparin each time there is a change in the method.

Methods to determine heparin sensitivity include:

  • Validation of heparin sensitivity of the APTT using an assay of heparin: This can be done by simultaneously determining the APTT (seconds) and heparin concentration (U/mL) using samples from patients receiving UFH for treatment of thromboembolism. A dose-response curve can be calculated from the data using regression analysis and the APTT corresponding to a heparin concentration of 0.3-0.7U/mL (by F.Xa inhibition assay) can be derived.
  • Validation of heparin sensitivity of APTT using ex vivo heparin specimens: Comparison with an existing, validated APTT reagent.
  • Validation of heparin sensitivity of APTT using instrument recalibration.

To conclude, all laboratories that do APTT for monitoring heparin therapy must determine the sensitivity of the method to heparin, inform the clinicians of the sensitivity, and recommend a therapeutic interval. This must be done each time there is a change in the method.

Dr Vanajakshi S
HOD & Sr. Consultant,Department of Hematology & Clinical Pathology,
Apollo Health City, Hyderabad

 

 


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