The reality of laboratory diagnostics and hemostasis testing is evolving with new paradigms of efficiency. The driving forces of healthcare and laboratory diagnostics in the third millennium are mainly represented by macro- and microeconomics. In a world with limited resources shattered by an unprecedented economic crisis, laboratory diagnostics is undergoing a substantial reorganization, with emergence of new models under the imperative of terms, such as bedside testing, consolidation, and networking. The paradigms under which these changes are being developed include a variety of environment, pre-analytical, technological, professional, and healthcare aspects. The maintenance of continued quality is indeed the major challenge to be faced in the foreseeable future. In fact, some challenges pre-potently emerge during a consolidation process, which basically involve delayed testing, centrifugation, transportation, and stability of the specimens, as well as the potential mismatch of the sample matrix.

Significant advances have been made in the capability and flexibility of coagulation instrumentation. Instruments previously required manual pipetting, recording, and calculation of results, which necessitated significant operator expertise, intervention, and time. Current technology allows a walk-away environment in which the operator can move on to perform other tasks, after specimens and reagents are loaded and the testing sequence is initiated. Immunoassay technology became available on coagulometers and is used to measure a growing number of coagulation factors and proteins, expanding the diagnostic capabilities of the laboratory. Coagulation protein testing, which used to take hours or days to perform using traditional antigen-antibody detection methodologies such as enzyme-linked immunosorbent assay or electrophoresis, now can be done in minutes on an automated analyzer. The introduction of new coagulation methodologies has improved testing capabilities in the coagulation laboratory. Refinement of these methodologies has allowed the use of synthetic substrates and measurements of single proenzymes, enzymes, and monoclonal antibodies, which increases the ability to recognize the causes of disorders of hemostasis and thrombosis.

Indian Market Dynamics

Indian Coagulation Instruments and Reagents Market The Indian market for coagulation and instruments in 2014 saw 11 percent growth over 2013. The market is estimated at Rs.102 crore, with reagents dominating at Rs.71.5 crore.

The instruments at Rs.30.5 crore, continue to have a contribution of Rs.18.1 crore from fully automated instruments. The market for semi-automated instruments constituting single-channel, 2-channel and 4-channel is estimated at Rs.12.4 crore in 2014.

Stago, including Trinity Biotech (which sold its worldwide coagulation business to the Stago Group in 2010, and its products in India are marketed by Rapid Diagnostics), leads the segment. Werfen Medical India and Sysmex are aggressive in this segment. 2014 saw the entry of Abbot in this segment in India.

In 2015, there has been some churn at the vendor front. Stago, which had set up its own office in India in 2013, has parted ways with Suyog Diagnostics in July 2015. Suyog represents Werfen Medical India, which is focused on the fully automated range of instruments, reagents, and services. Sysmex, earlier represented by Transasia, is entering the market on its own (only for coagulation) for all new contracts. Roche, having launched its coagulation products in Europe is expected to launch in India in 2016.

Coagulation testing, which encompasses both laboratory and point of care (POC) testing, continues to be one of the most important segments of in vitro diagnostics market. New models of laboratory coagulation testing devices and reagents, which are dominated by prothrombin time (PT) and activated partial thromboplastin time (aPTT), and include upgrades such as greater automation and the integration of more esoteric coagulation tests such as D-dimer and antiphospholipid assays are being introduced.

2014 saw fresh offerings from coagulation analyzer manufacturers, of which at least two have launched entirely new testing systems. Werfen Medical India's ACL AcuStar hemostasis system has been met with great enthusiasm for its speed, accuracy, and comprehensive line of high performance chemiluminescent assays. The system is perhaps the first hemostasis analyzer to incorporate chemiluminescence technology, and features the HemosIL AcuStar anticardiolipin (IgG and IgM) and anti-2GP-I (IgG and IgM) assays for antiphospholipid syndrome.

Also new from the company are the HemosIL protein S activity and factor VIII assays. The first, a second-generation assay, offers increased onboard stability of eight hours on ACL TOP systems, while the second is a factor VIII-deficient plasma that features 24-hour stability.

Fresh from Diagnostica Stago, the STA Compact Max benchtop analyzer is suitable for use in routine and specialty hemostasis testing. It combines powerful and proven viscosity-based clot-detection technology with easy-to-use expert module software. Innovative features of this new instrument's software, are multi-dilution management for factor assays; electronic lot conversion; autoverification rules; automatic management of dilutions, reruns, and reflex testing; advanced USB export capabilities; and customizable database queries.

Global Market

The global coagulation instruments and reagents market is expected to reach USD 3.58 billion by 2019 from USD 2.4 billion in 2015, growing at a CAGR of 8.3 percent. In the past ten years, the global coagulation market has witnessed challenging and dynamic market conditions with the presence of high competition among market players, development of technologically advanced instruments and reagents, and increasing healthcare awareness among the population globally.

The growth of the global coagulation market is driven by factors such as increasing development of high-throughput coagulation analyzers and focus of key players on the development of technologically advanced coagulation analyzers. Moreover, the rising trend of laboratory automation and development of high-sensitivity coagulation analyzers for point-of-care testing (POCT) has also provided the much needed impetus to this market.

However, the relatively low adoption rate of advanced coagulation instruments in emerging countries and high cost of coagulation analyzers are restraining the growth of the global coagulation market. North America dominated the global hemostasis analyzers market, with the United States accounting for a major market share in 2014. However, the Asia-Pacific region is expected to witness the highest growth in the forecast period with the rising focus of prominent players on emerging Asian countries. An increasing number of general surgeries and organ transplantations are also major drivers for this market.

Technology Trends

Indian Coagulation Instruments and Reagents Market The traditional coagulation tests (aPTT and PT/INR) have been developed while discovering the coagulation cascade and these tests have been standardized for monitoring therapy including vitamin K antagonist-INR and heparin-aPTT. Moreover, they have a longstanding position in diagnosis and management of factor deficiencies including hemophilia and are licensed by many authorities for this purpose.

Although these tests are recommended for management of acute hemorrhage, they need some laboratory turnaround time and may not reflect the complexity of the hemostatic impairment. On one hand, these tests were neither developed nor evaluated for predicting bleeding risk and treatment of acute bleeding patients. The use of global hemostatic coagulation tests in managing acute hemorrhage yields better results as the traditional tests inform on the initiation of clotting but not the hemostatic capacity in terms of clot formation and maximal thrombin generation.

POCT. Recent research in the management of hemorrhage has led to several changes in clinical practice. Evidence is accumulating that POCT results in fewer transfusions, improved patient outcomes, and reduced hospital costs. However, there is still insufficient high quality evidence to support transfusion guidelines and algorithms based on POCTs alone, and more robust studies are needed.

The implementation of POCT requires institutional support and senior clinical leadership to realise the benefits, with educational programmes, audit, and feedback regarding transfusion practice. A change in philosophy is required from performing testing only when there is an obvious bleeding problem, toward the concept of routinely monitoring high-risk patients throughout the surgical procedure.

This informs clinical practice, establishes normal ranges for that population, identifies patients at risk, and allows early identification and treatment of evolving coagulopathy. POCT testing within hemostasis is an expanding field, with the most widely used test being POCT international normalized ratio (INR). Many of these devices are being used in a non-laboratory setting by staff with no laboratory training.

The effort of translating the different platelet function tests as diagnostic tools for evaluating bleeding disorders and monitoring antiplatelet therapies is in progress. Actually, the available platelet function POCT is making possible the institution of platelet tests in laboratories and intensive care units, allowing their use in different clinical settings such as inherited bleeding disorders, cardiovascular intensive care, trauma coagulopathy, liver transplantation, and obstetric care for the prediction of bleeding.

Similarly, the use of these tests could be extended not only at the bedside in critical areas outside of the specialized laboratory, but also in centralized and satellite laboratories. Indeed, the upgrading of the WB test, such as MEA, or platelet mapping or the new ROTEM platelet device, may guide clinicians in making the correct diagnosis of bleeding risk or in properly tailoring the antiplatelet therapy directly in pre- or post-operative care.

Platelet function assay. Laboratory tests of platelet function, such as bleeding time, light transmission platelet aggregation, lumiaggregometry, impedance aggregometry on whole blood, and platelet activation investigated by flow cytometry, are traditionally utilized for diagnosing hemostatic disorders and managing patients with platelet and hemostatic defects, but their use is still limited to specialized laboratories.

POCT dedicated to platelet function, using pertinent devices much simpler to use, has now become available. POCT includes new methodologies which may be used in critical clinical settings and also in general laboratories because they are rapid and easy to use, employing whole blood without the necessity of sample processing.

The rapid platelet function assay (RPFA) measures platelet function using a small, undiluted sample of anticoagulated whole blood. The advantages of RPFA over other methods of assessing platelet function are the speed with which results can be obtained, the need for only a small sample of blood, the semi-automated format in which processing of the blood is not required, the microprocessor-controlled digital readout, and it is compatibility with a variety of anticoagulants and platelet agonists. The results from the RPFA can be reported as a percentage of baseline aggregation or as an absolute rate of aggregation.

Advances in anticoagulants. Evaluation of new anticoagulants resulted in recent advances in the development of novel oral anticoagulants (NOA). Major advances in the development of NOA progressed well, with the goal of developing safe and effective oral anticoagulants that do not require frequent monitoring or dose adjustment along with minimal food/drug interactions.

Indirect inhibitors such as low-molecular-weight heparin (LMWH) and the pentasaccharide fondaparinux represent improvements over traditional drugs such as unfractionated heparin for acute treatment of venous thromboembolism (VTE) with more targeted anticoagulant approaches, predictable pharmacokinetic profiles, and lack of need for monitoring.

Vitamin K antagonist, with its inherent limitations of multiple food and drug interactions and frequent need for monitoring, remains the only oral anticoagulant approved for long-term secondary thromboprophylaxis in VTE. Newer anticoagulant drugs such as injectables (fondaparinux, idraparinux), oral direct thrombin inhibitors (dabigatran), oral direct factor Xa inhibitors (rivaroxaban, apixaban, and others), and tissue factor/factor VIIa complex inhibitors are tailor-made to target specific procoagulant complexes and have the potential to greatly expand oral antithrombotic targets for both acute and long-term treatment of VTE, acute coronary syndromes, and prevention of stroke in atrial fibrillation patients.

Industry Speak
Identifying Unmet Customers' Needs

The need for coagulation testing has considerably increased in view of growth in the number of cardiovascular surgeries being performed and an increase in number of patients using anticoagulants. Prevention of conditions such as deep venous thrombosis, strokes, pulmonary embolisms, and myocardial infarctions are also contributing to growth. With the need to normalize anticoagulation therapy, it has become imperative to continuously monitor coagulation factors, thus further driving the market for coagulation.

Within the IVD sector, coagulation still remains an area of relatively limited understanding and expertise among lab scientists. This, coupled with the dearth of clinical hematologists in Indian hospitals, is preventing the market from realizing its full potential. From the demand side, the Indian coagulation market is highly fragmented with a large number of small laboratories and complete lack of standardization. Lack of knowhow and insufficient test load makes them resort to unreliable methods of testing. In large labs, on the other hand, the increase in the type and number of specialized tests, coupled with a shortage in laboratory staff, is pushing them to go for a greater level of automation.

The need of the hour is for the companies to come up with new business models serve the unmet needs of the customers. Moreover, companies need to invest more time and efforts with clinicians because the demand for all the tests lies with them. A win-win model needs to be created for all three stakeholders - the company, the user, and the patients. Perhaps, we can borrow some ideas from other unrelated industries to consolidate the needs of smaller hospitals and create some pay-per-use model of engagement. It goes without saying that the future potential lies in tier-II and tier-III cities and their needs must be addressed. This means more R&D budget needs to be allotted for developing more stable reagents. The organized segment should explore the opportunities of expanding to semi-urban and rural areas and new partnerships and realignment of distribution network would be the way to go.

Siddhartha Shivam
Business Unit Manager-Haemostasis,
Instrumentation Laboratory India Private Limited

Industry Speak
Expectations from Entry Level Automated Systems

Today, with technological advancement, entry level automated (ELA) clinical chemistry analyzers have reached to a different height to cater to the needs of not only as the main system in the medium segment of laboratories, but also as the back-up system in the premium segment of laboratories.

We have always observed, for a medium segment laboratory, the primary reason of procuring an ELA system is empowering their laboratories to meet their requirements of speed, flexibility, reliability, and economy. However, the expectation and benefit of ELA systems are beyond that. With the present socioeconomic conditions, the basic requirement of a medium segment laboratory is to have an ELA system with minimum running time and maintenance cost. Till today, there is typical fear of hidden cost factors for maintaining a fully automated analyzer, which generally led the prospective buyers to have more expectations from one ELA system. The expectations from this segment of prospective buyers include - The ELA system should be reliable and sturdy in terms of hardware and less service prone model; should use minimum amount of water; should not use proprietary detergents or wash solutions; should use minimum amount of reagents in performing each tests; and should be able to perform a wide range of biochemistry and immunoturbidimetry assays.

If we evaluate the details of the above expectations, we learn more.

As there is no proper index to judge the sturdiness of the system, the prospective buyers rely on the quality of the materials and parts used to manufacture the model and they expect that the model should go through reliable and stringent accreditation processes, e.g., US FDA.

As a certain quality of water is required, ELA systems are not so economical. The users always prefer to have a system which consumes minimum amount of water. Even more, they prefer the systems where the cuvette wash station is external and consumes minimum amount of water.

The proprietary detergents are another important factor which is considered by the prospective buyers. They always prefer to have a non-proprietary wash solution with minimum consumption without compromising on reliability. In this case, the material of the probe and the engineering behind washing the probe plays a vital role. They are well aware that with their medium workload, the expenses for the proprietary wash solutions or detergents may be heavy for them.

Another common expectation is to have the ELA system which consumes less amount of reagents, viz., 200 µL with proportionate minimum amount of sample like 2 µL, which ensures no compromise in linearity and sensitivity of the assay.

The last but not the least preference is to have a system which can do multitasking. Today, there are various ELA systems in the IVD industry. But few extra features like on-board mixing facility in few of the models made them unique.

Prasenjit Das
Group Product Manager,
CPC Diagnostics

Industry Speak
Selection of the Apt Semi-Automated Hemostasis System

Hemostasis testing is routinely conducted in laboratories. The labs opt for a system based on specific requirements such as need for a fully automated analyzer, type of tests, and availability of service in a remote area.

Some of the end-users and their requirements:

Small system for standalone labs. Of the more than 45,000 labs in India, 30,000 are standalone catering to smaller cities and towns. Such labs offer basic test parameters and outsource the specific ones. The most common coagulation tests performed are PT and APTT. A coagulation system for a standalone lab needs to meet basic requirements such as easy reagent availability, accessible technical support, easy to use consumables, small reagent pack size, and reasonable cost per test. A small affordable system with the above features is most suited, since these labs are situated mostly in remote areas.

While choosing a single channel coagulation system, it is advisable to choose one with only cuvettes since stirrers/steel balls are not available easily. A single channel system is recommended since it can perform Factors, Lupus, and D-dimer. An added feature is the presence of an in-built printer, for easy operations.

Standby system for accredited centers. Most accredited centers have a complete 4 channel automated system. In order to ensure smooth functioning, a back-up system with identical features is preferred. The standby system should comply with some basic requirements - Ability to do all tests, including D-dimer and special tests; multi-standard graphs on display and printout; QC charts for each test with at least three controls; and ability to input reagent lot and other features like expiry management, data storage and interface for export of results.

Nowadays, such systems are easily available offering additional benefits of single cuvettes and with reasonable reagent usage.

Blood bank system. Around 500 blood banks in India offer blood components. The main tests of Fibrinogen and Factor VIII are part of the QC protocol. Since both these are multi-standard tests, the analyzer must have the ability to display and store calibration charts. Most importantly, these systems must be affordable to the user along with reagent, availability.

Transasia recognizes the need of different laboratories, and offers two advanced coagulation analyzers, ECL 105 single channel and ECL 412 four channel. Both these analyzers use an innovative technology thereby giving most accurate results at affordable costs.

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

Industry Speak
Mechanical Detection, Optical Detection

Hemostasis is dependent on several interacting delicate systems. Various assays like prothrombin time, activated protrombin time, thrombin time, fibrinogen, factor assays, and the like are performed in laboratories to determine the effectiveness of the coagulation system thereby ensuring clinical interpretation and prophylaxis. The tests are relatively easy to perform and offer high degree of accuracy for clinical relevance.

The coagulation analyzer market is bifurcated into fully automated systems, single-channel, 2-channel, and 4-channel analyzers. Single to double channels contribute approximately 44 percent of the analyzers market. The semi-automated systems are available with two different technologies namely mechanical and scattered light principle or optical measurement. The debate on effectiveness of both these technologies has been evident over the years with many leading companies offering either.

Mechanical Detection

Electro-mechanical - based on completion of an electrical circuit by a fibrin strand. A probe with two electrodes that have a current passing between them drops into a cup with plasma and reagents. When fibrin is sensed between the electrodes, a detection circuit will sense the completed circuit which is the endpoint (Fibrometer).

Electromagnetic mechanical - based on an increase in plasma viscosity as fibrin forms. The oscillation of a steel ball within a cuvette in an electromagnetic field is monitored. As the plasma sample clots, ball movement slows down which is used to determine the endpoint.

Optical Detection

Photo-optical-based on the phenomenon that light will be scattered by fibrin strand formation. As the plasma sample clots, it becomes more optically dense and the amount of light falling on a photo-sensitive detector decreases (i.e., transmitted light decreases). The drop or change in light is determined as the endpoint.

Photometric-based on absorbency (optical density) of monochromatic light (uses filter) passing through the cuvette as the reaction being measured occurs. Transmitted light is measured and converted to absorbance which is proportional to concentration of the substance being measured.

We offer two models of semi-automated coagulation analyzers in 2-channel and 4-channel formats. The analyzers are based on advanced scattered light principle and come equipped with electronic pipette. The analyzers have an inbuilt stop watch that ensures accurate and precise results that are critical for patients.

Rajesh M Patel
Head- Business Operations,
Meril Diagnostics

Second Opinion
Coagulation Profile through Latest Machines

Coagulation test forms a very important part in the diagnostics field. Till now, it was a much neglected area in terms of machinery and automation because the stress was more on automation in the field of cell counter. For a long time, most of the tests in the field of coagulation were done manually. Manual methods are crude and are not reliable as they are very much dependent on the skills of the person doing the tests, both in terms of expertise in performing the tests and the ability to judge the final results, which tend to vary from person to person. Thus came the need for automation. With automation the test results were more reliable, dependable, took less time and could be reproduced to get same results time and again.

Nowadays, a variety of semi-automated and automated machines are available. The choice of the machine depends on estimated workload of the lab and cost implications.The purchase of any instrument is very complicated and time consuming process.

The following points need to be considered before purchasing any instrument:

  • Speed, accuracy, and precision
  • Single machine performing multiple tests or multitasking machines
  • The facility of cap piercing in closed vials, which saves a lot of time
  • Stability of the reagents over a large range of temperature with less fuss in handling them
  • Easy supply of reagents Able to detect errors, i.e., flagging
  • The sample throughput time of the machine should match the workload
  • Storage of data should be largeGood after-sales service and support and easy availability of spare parts
  • Least maintenance in terms of time and money.

Dr Nishi Upadhyay
Consultant Pathologist,
Upadhyay Clinic, New Delhi

Second Opinion
Need for Accurate Results

coagulation testing is useful in assessing the risk of excessive bleeding or developing clot (thrombosis) somewhere in the blood vessels. Coagulation tests measure the ability of the blood to clot and the time taken for blood to clot.

Clotting presents excessive bleeding when there is a cut. However, blood moving through blood vessels should not clot, as such clots can travel through blood stream to the heart, lungs, or brain causing heart attack or stroke.

Coagulation mechanism is carried out by coagulation factors, coagulation inhibitory, or fibrinolysis system. Coagulation tests are carried out in labs as common blood tests using whole blood citrated plasma; conditions that can cause coagulation problems are liver diseases, thrombophilia, and hemophilia. People take medications that can effect clotting. Coagulation profile is adverse in the above cases and even before surgery. It is a screening test for abnormal blood clotting which includes clotting line (CT) PT/INR, aPTT, platelets, thrombin test, and fibrinogen. There are also special tests like factor assays. PT/INR measures a part of the clotting pathway, i.e., extrinsic pathway. It is increased by warfarin therapy, liver dysfunction, or DIC. Activated partial thromboplastin time (aPTT) measures a part of the clotting pathway, i.e., intrinsic pathway. It is increased in therapy with IV heparin, hemophilia, or DIC. Platelets count measures the number of platelets in a blood stream, a routine component of complete blood count (CBC). Thrombin time is a screening coagulation test designed to assess fibrin formation from fibrinogen in plasma. Fibrinogen test is used to determine the level of fibrinogen in the blood. Fibrinogen is a blood plasma protein that is made in the liver. It is consumed in DIC and snake envenomation. Decreased levels result in increased bleeding tendency. Abnormal results may be sign of hemorrhage, fibrinolysis, or placental abruption. A d-dimer test is a blood test that measures a substance that is released when a blood clot breaks up. D-dimer is a fibrin degradation product (FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is increased in conditions of increased clotting activity in body. It is often eluted with different reasons.

Modern coulometers observe development of blood clots in blood or blood plasma. Primary patient care in hospitals demand accurate results of PT/INR in patients on OCT (oral anticoagulant therapy).

Dr Madhubala Talwar
Sanjeevani Dwarka Path Labs,
New Delhi

 

Road Ahead

Technological advancements in POCT procedures such as outpatient anticoagulation, cardiac surgery units, and dialysis units along with quality assurance to overcome adverse reaction caused with anticoagulation therapy and home testing services is anticipated to change the dimensions of coagulation testing laboratories. Additionally, lower testing volumes, improved patient care, and analyzation of more parameters is anticipated to boost the demand for coagulation analyzers.

The coagulation laboratory is an ever-changing environment populated by automated analyzers that offer advances in both volume and a variety of tests. Hardware and software innovations provide for random access testing with multitest profiles.

In the past, the routine coagulation test menu consisted of prothrombin time (PT) with INR, partial thromboplastin time (PTT, activated partial thromboplastin time), fibrinogen, thrombin time, and D-dimer assays. More specialized testing was performed in tertiary care institutions or reference laboratories, employing medical laboratory scientists with specialised training.

With the introduction of new instrumentation and test methodologies, coagulation testing capabilities have expanded significantly, so that many formerly specialized tests can 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 or condition when monitoring antithrombotic therapy. Good method validation of procedures, cognitive ability, and theoretical understanding of the hemostatic mechanism are still required to ensure the accuracy and validity of test results so that the physician can make an informed decision about patient care.

Thrombosis and hemorrhage are major contributors to morbidity and mortality. The traditional laboratory tests do not supply enough information to diagnose and treat patients timely according to their phenotype. Global hemostasis tests might improve these circumstances.

The viscoelastic tests (ROTEM/TEG) demonstrated to ameliorate treatment of acute hemorrhage in terms of decreased amount of transfusion and lowered costs. Thrombin generation measurement is indicative of thrombosis and might also become an important tool in managing hemorrhage.

While the clot waveform analysis is less well known it could be of worth in staging sepsis patients, early detection of DIC, and also in diagnosis and treatment monitoring of hemophiliac patients. Although in different degree all three methods still need more background, standardization, and acceptance before a wide clinical application.


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