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Coagulation Instruments and Reagents

Future prospects for the coagulation laboratory

The future landscape will include a more varied test menu, tailored toward monitoring or testing of a broader group of anticoagulants, including but not limited to heparin, VKAs, Dabigatran, and Rivaroxaban.

Over the past decade, the introduction of new coagulation analyzer tests has led to an increase in the quality and efficiency of hemostasis laboratories.

Some of the modern complex coagulators also possess high throughput, flexibility, and reliability. Other than this, they provide improved accuracy and precision, and easy-to-use advanced software, provided with in-built graphs and calibration curves.

Moreover, there has been a significant rise in the prevalence of cardiac diseases and blood disorders, which has created the need for improved coagulation analyzers across the globe. Besides this, the sales of coagulation analyzers are positively being influenced by the increasing number of hospitals, diagnostic centers, and research institutes established worldwide.

Covid-19 has had a favorable impact on the global coagulation testing market. There was a high demand for coagulation-related parameters, such as D-dimer; in fact, the increase in D-dimer was the most significant change in coagulation parameters, such as prothrombin time (PT) or aPTT. Also, serious novel Covid-19 pneumonia patients have thrombosis (blood clot), and this requires continuous monitoring of patients during treatment. This aspect is eventually fueling the demand for coagulation testing procedures, which is expected to accelerate the market growth in coming years.

Indian market dynamics
The Indian coagulation instruments and reagents market in 2021 is estimated at ₹311.25 crore. The value of the fully automated instruments that were sold, mostly to the government, is ₹2.4 crore, estimated at 20 units. The sales of semi-automated instruments is estimated at 1200 units, valued at ₹12.85 crore. All government centers, up to the district level have now procured the instruments, and moving forward as the budgets are sanctioned, they are planning to upgrade to fully automated instruments. In 2021, large orders were placed by the Tamil Nadu and Uttar Pradesh governments for semi-automated instruments and by Madhya Pradesh government for automated instruments.

An additional 165 fully automated systems were placed. The leading players remain Stago, followed by Werfen and Sysmex. Transasia, a recent entrant in this segment, had good success with a couple of bulk orders for instruments from the government in 2021.

Indian coagulation instruments market*
Tier I Tier II Tier III Others
Stago (including Trinity) Werfen India and Sysmex Transasia Tulip, Agappe, Compact Diagnostics, CPC Diagnostics, HUMAN, Meril Diagnostics, Roche, and Trivitron
*Vendors are placed in different tiers on the basis of their sales contribution to the overall revenues of the Indian coagulation instruments market.

ADI Media Research

As a trend, the three leading brands reported that while they were not able to sell a large number of fully automated instruments, average unit prices not only declined, but there was also a huge variation between the final prices. Additionally, the manufacturers’ exposure has increased in 2020 and 2021 as more analyzers have been placed, and that is expected to give better return over the next few years.

High-quality results at all times
Srinivas Naidu
Senior Product Manager – Coagulation,
Sysmex India Pvt. Ltd.

In hemostasis, test results can point out major clinical issues, some of which may be life-threatening, if not dealt with swiftly and accurately. For instance, cardiovascular disease (CVD) is one of the leading causes of death and disability in the world. And this is not likely to change any time soon, considering the demographics and lifestyle we see today. Like all patients, people with CVD have the best chance of survival when their illness is detected early.

Labs offering hemostasis testing can really support clinicians with patient diagnosis. Since confidence in the subsequent clinical decision making is essential, you need equipment that performs reliably and produces results of consistent high quality at all times. You need to meet TAT demands and help patients as soon as possible, so the tests have to be performed fast – even with complex samples that require precise pre-analytical treatment. And as the industry evolves, the spectrum of test requests is increasing too. It is a challenging situation.

Unlike other areas of testing, the sample integrity plays a vital role on the quality of results in hemostasis testing. So, if an analyzer is able to identify erroneous samples then that would be an ideal analyzer for the respective laboratory.

Sysmex, one of the leading global players in hemostasis instrumentation and reagents addresses these concerns with their latest analyzer, Sysmex CN-series. CN-series, takes the reliability and performance of CS-series and takes it up to a whole new level.

Sysmex was one of the first companies worldwide to incorporate pre-analytical sample testing and platelet aggregometry testing in a hemostasis analyzer, and our commitment remains the same with the CN-series also, which provides all these and much more.

Sysmex CN-series comes with a higher throughput, thereby lessening the turnaround time and even with the higher throughput the space requirement is very low.

The dead volumes of samples are very low so that means there are more analyses from lesser volumes.

Sysmex CN-series identifies sub-optimal samples by employing HIL testing and sample volume check, clot waveform analysis to assess comprehensive hemostasis functions. CN-series inhibitor testing is more convenient with the cross-mixing functions.

Global market dynamics
The global coagulation analyzers market size is expected to be valued at USD 7.8 billion in 2032 and exhibit growth at a CAGR of 11.3 percent from 2022 to 2032. It is expected to grow at a steady pace and reach USD 5.1 billion in 2022. The rising prevalence of blood disorders and cardiovascular diseases among the geriatric population is projected to spur the sales of coagulation analyzers over the next 8 years.

Over the past decade, rapid advancements in technology and the introduction of new coagulation analyzer tests have led to an increase in the quality and efficiency of hemostasis laboratories. Some of the modern complex coagulators also possess high throughput, flexibility, and reliability. Other than this, they provide improved accuracy and precision, and easy-to-use advanced software provided with in-built graphs and calibration curves. Moreover, there has been a significant rise in the prevalence of cardiac diseases and blood disorders, which has created the need for improved coagulation analyzers across the globe. Besides this, the sales of coagulation analyzers are positively being influenced by the increasing number of hospitals, diagnostic centers, and research institutes established worldwide.

In addition, the growing usage of PTTs for measuring the total time taken for the blood to clot in healthcare facilities is set to drive the market. These are estimated to be extensively used in hospitals for monitoring patients implanted with ventricular-assist devices or mechanical heart valves. The rising number of patients suffering from pulmonary embolism, chronic atrial fibrillation, deep venous thrombosis, and venous embolism is also likely to propel the market.

There has been a presence of a considerable number of companies that are significantly contributing to the market growth. Product innovation and ongoing R&D activities to develop advanced technologies have helped in boosting the growth of the market. The competition is fierce due to the consolidated nature of the market with top companies reporting to occupy major share in the market. The key players in the market are adopting various strategic moves to sustain the intense competition. Some of the major key players in the market include F. Hoffmann-La Roche Ltd., Sysmex Corporation, Siemens Healthineers AG, Helena Laboratories, Meril Life Sciences Pvt. Ltd., and Trivitron Healthcare, among others.

Future of hemostasis laboratory testing
Anticoagulant therapy monitoring represents the main purpose of most routine coagulation laboratories, along with preoperative screening. Anticoagulants are alternatively referred to as anti-thrombotics, given their intended clinical therapeutic efficacy. The main current anticoagulant armamentarium comprises heparin and vitamin K antagonists (VKAs) (also known as coumarins), such as warfarin or acenocoumarol. The main new anticoagulant agents include, but do not exclusively comprise, Dabigatran etexilate, Rivaroxaban, and Apixaban. VKAs and heparin are typically monitored because they exhibit a narrow therapeutic window and largely unpredictable behavior in treated individuals. In contrast, the newer agents have been clinically developed and evaluated as requiring little to null laboratory monitoring. Laboratory testing of these agents will, however, be required in select cases, and laboratories should become proactive in recognizing the in-vitro behavior of these agents, developing appropriate strategies for any required testing, as well as establishing appropriate policies for post-test counseling on test results and expected outcomes.

These two basic coagulation tests are typically supplemented in many laboratories by fibrinogen assays, D-dimer tests, and occasionally thrombin time (TT) assays. Together, these five assays may be used to assess the hemostasis status in patients, including the potential for disseminated intravascular coagulation, as well in differential diagnosis strategies, or to assess for potential preanalytical issues. For example, TT is very sensitive to UH, whereas fibrinogen assays tend to be less sensitive or are insensitive. Thus, the TT and fibrinogen testing may play a role in evaluating for a differential diagnosis of fibrinogen deficiency or heparin excess, which may be important in assessing for inappropriate sample collection, sample clotting, or heparin contamination. Otherwise, the TT, fibrinogen, and D-dimer tests do not normally play a big part in anticoagulant testing or antithrombotic therapy, except when the latter is used to assist decisions on the duration of anticoagulant therapy in patients with recent episodes of venous thrombosis.

Non-routine anticoagulant monitoring tests. A small selection of additional tests is sometimes used to assess the anticoagulant status of patients undergoing anticoagulant therapy. The most commonly applied is the chromogenic anti-Xa assay, which is sensitive to the presence of UH, but which is most typically utilized – as required – to monitor LMWH.

The classical approach. The post-thrombotic therapy is typically initiated using UH, since this agent exerts an immediate anticoagulant effect. UH provides a varied clinical responsiveness in different people, only in part related to body mass index and adiposity, and hence requires monitoring to ensure that a sufficient anticoagulant effect is maintained, as well as to prevent administration of excessive anticoagulant that may lead to undesired bleeding. The narrow therapeutic window of anticoagulant effect is typically reflected by an APTT range of around 1.5–2.5x baseline values. UH is administered parenterally, and although this is acceptable for short-term hospital stays, it is uncomfortable for the patient. Other complications of UH therapy include the rare but potentially life-threatening condition known as heparin-induced thrombocytopenia (HIT), which can also be associated with massive and life-threatening thrombosis (HITT).

Factors to consider for coagulation testing
Afser Shariff
Operon Biotech and Healthcare

It was baseball’s Yogi Berra who said, with the unique slant that was his hallmark, “In theory, there is no difference between theory and practice. In practice, there is.” More vividly, boxer Mike Tyson once summed up the same reality when asked to comment on an opponent’s strategy in an upcoming match, “Everybody has a plan – until they get hit.”

In this short discussion, let us confine to the few challenges a typical lab faces in coagulation testing, and what could be done in overcoming them. Coagulation as a subject is often complicated to understand and at times mysterious, and so is its laboratory testing.

Let us outline a few of the important aspects:

Basics first
Hemostatic screening and frequently asked tests, e.g., prothrombin time (PT) and the activated partial thromboplastin time (APTT), which are often undertaken to establish a risk of bleeding, at times can be misleading and can generate normal results even in individuals with significant derangements of hemostasis. The most important screening test in hemostasis is the patient’s personal bleeding history (if this can be considered a test), their current medications, and any family history suggestive of an inherited bleeding disorder.

Lab’s quality assurance
In my career spanning 20 years, working with products and solutions in hemostasis, It is evident how many labs do not pay attention to basic standardization and quality testing practices as basic as not deriving mean normal for each batch of reagents, or a wrong calculation of a PT result in INR format, and even a laboratory fails to recognize a new batch of reagents and the ISI change.

Bottom line
Develop stringent SOPs for parameter wise testing; Effective sample and reagents handling; Establish IQA (internal quality assurance), EQA (external quality assurance); Understand and work to mitigate the effects of (pre) pre-analytical – pre-analytical – analytical – post-analytical – (post) post-analytical errors; Inculcate continuous improvements in the existing testing like mixing studies, and inhibitor assay testing; Do not shy to have a calibrated, tested whole blood POC coagulation device at the lab; and choose the reagents, instruments and, most importantly, the vendor wisely

And quality is achieved by sustained practice and best outcomes come only from quality.

Patients suffering thrombosis are thereby switched from UH to VKAs for long-term management. The normal post-thrombosis therapy lasts approximately 3-6 months, but in some cases can be extended or indefinite. VKAs are not immediate acting, taking several days to initiate effective anticoagulation. The dose-response is variable for several known and some unknown reasons, including compliance, pharmacogenetics, drug, and food interactions. VKAs are also characterized by a narrow therapeutic window, typically reflected by an INR around 2.0–3.0 or 2.5–3.5, depending on the clinical indication. The risk of bleeding might be worse than that with UH since the only effective therapeutic management is factor-replacement therapy or administration of by-passing agents, such as recombinant activated FVII or anti-inhibitor coagulant complex.

More recently, the use of UH is being significantly reduced, and in some cases abandoned, in several countries, because LMWH has taken its place also in the initial phase of venous thromboembolism (VTE) treatment. This later pharmacological agents consist of chains of polysaccharides obtained with different approach to fractionation or depolymerization of polymeric heparin, which exhibits an average molecular weight of less than 8 kDa, and containing not less than 60 percent of chains with molecular weight lower than 8 kDa. LMWH provides some theoretical advantages over UH in terms of reduced need to monitor, and lower risk of complications, such as HIT. LMWH is administered by subcutaneous injection, but different commercial products may differ substantially, and laboratory monitoring, if performed, is still plagued by substantial inter-laboratory variation.

Quality assurance in testing at point of care
Gabriel Alias
Biomedical Scientist, Senior Applied Hematologist,
Boule Diagnostics AB

Diagnostic testing at the point of care brings many advantages for the patient. Analysis report is prompt, and the patient is available for immediate re-testing or follow-up testing, if required. The short time from testing to result increases the patient’s ability to recover from illness by allowing early diagnosis and initiation of treatment.

However, implementing a point-of-care (POC) program can be a challenge. Hospital POC coordinators need to monitor multiple operators and devices that are used at many locations outside of the clinical laboratory for regulatory compliance. Generally, satellite test facilities are considered extensions of the central laboratory; however, their location in proximity to the patient does not affect the regulatory standards that they need to adhere to. Diagnostic equipment providers, therefore, look to solutions to facilitate this work.

Historically, POC devices were mostly strip-based, with low complexity and limited data management capabilities. Today, testing at the point of care is performed also with moderately complex bench-top instruments, allowing device data to be monitored for quality assurance.

A range of data-management software is available to offer POC coordinators oversight of instruments and operators. Open-access software provides the opportunity to connect equipment from several manufacturers, however, with a limited functionality. Although a brand-specific software is manufacturer-dependent, such a software can be tailored to a specific instrument to better meet the needs.

Software solutions that allow remote access to instrument and operator data provide POC coordinators the possibility to, for example, track device status and service history; manage software updates; ensure quality control limits and frequency intervals are met; manage operator access, competence, and authorization; monitor performance qualification data to ensure instruments meet specifications; and track workload to manage inventory of consumables. With web-based solutions, data management applications can be accessed from virtually anywhere.

Instrument availability is a prerequisite for diagnostic testing at the point of care. To ensure instrument uptime, manufacturers establish local service teams that can provide quick support, if necessary. Many manufacturers also establish local consumable manufacturing to ensure availability on demand – all to help caregivers catch patients early, contributing to a greater patient safety and quality of care.

New anticoagulants. The new and emerging oral anticoagulants are primarily direct inhibitors of either factor Xa or thrombin (FIIa). These agents do not (in theory) require laboratory monitoring, since they have been largely developed and clinically investigated without laboratory testing. The two agents most advanced in terms of global release, and currently licensed clinical use, are Dabigatran Etexilate and Rivaroxaban, respectively, reflecting anti-IIa and anti-Xa agents. Another agent in an advanced stage is apixaban, another anti-Xa agent.

As with the development of most new anticoagulants, initial evaluation and clearance for clinical use tends to be in well-defined at-risk groups, such as primary prophylaxis for VTE prevention in orthopedic surgery, followed by medical applications of post-VTE treatment and secondary prevention, and the holy grail of anticoagulant drug treatment, namely AF, and prevention of stroke or systemic thrombosis. Stroke prevention in AF is the underlying indication for approximately 50 percent of all patients treated with VKAs, and is thus a major target of new anticoagulants, which is, therefore, expected to reflect the clinical indication that will mostly affect the role and organization of anticoagulant centers worldwide. Current approved indications for Dabigatran, Etexilate, and Rivaroxaban are similar, and based on extensive trials showing either non-inferiority or superiority to alternate therapies, typically the LMWH enoxaparin, 40 mg once daily for prevention of VTE or VKA for prevention of systemic embolism in patients with AF.

No monitoring required? Although most of these novel anticoagulant agents have been developed on the premise of not requiring any monitoring, the reality is proving to be quite different. Overall, there will be many occasions in which clinicians will like to know whether or not an anticoagulant effect is evident. As specifically regards assessing compliance, the half-life of most of the new oral anticoagulants is comprised between 10 and 14 hours, with anticoagulant effects spanning from 24 to 36 hours. As such, compliance may be virtually assessed only within ~12 hours from ingestion of the last tablet. It is also noteworthy that test results may be highly different when the blood sample is collected 2 hours after the last tablet intake (which roughly corresponds to the peak) as compared with 12 or 24 hours afterwards in cases of twice or once daily intake, respectively.

However, as these agents have been developed and assessed in clinical trials without any monitoring of anticoagulant effect, there are no standardized or well-established tests for their effective assessment. As the new agents are either directed against FIIa or FXa, the tests that are sensitive to these agents are those most likely to be used for their laboratory assessment.

Can these agents be monitored using other laboratory tests? Other tests evaluated for sensitivity to these two agents, as well as many other agents in development, include the dilute PT, the reptilase time, thrombin generation, thromboelastography, HepTest (a clot-based anti-Xa assay), the prothrombinase-induced clotting time (PICT), the dilute Russell Viper Venom Time assay, and a chromogenic anti-FIIa assay. The behaviour of some of these tests was as expected, and on other occasions appears paradoxical (e.g., low doses of Rivaroxaban showed an unexpected shortening of the PICT), thus suggesting that some test refinements would be necessary before such tests could be utilized for assessment of anticoagulant activity with these agents. Unlike the standard routine assays, some of these tests are unavailable (and likely to remain as such) to most laboratories and, therefore, unlikely to be initiated for routine assessment of these agents. For example, the thrombin-generation assay is affected by both Dabigatran and Rivaroxaban, and may be useful not only for detecting over-coagulation, but also for monitoring anticoagulation reversal. However, it is unlikely that many laboratories could implement the thrombin-generation assay in practice, as it cannot be performed using standard coagulation equipment.

Future perspectives. The development of new anticoagulants that in theory do not require monitoring would predict the demise of the current anticoagulants (i.e., heparin and VKAs), and thus the potential doom of routine coagulation tests, given that these tests are primarily used for this purpose. Indeed, even should occasional testing be required for the new anticoagulants, the standard tests (PT/INR, APTT, TT) as currently performed in laboratories would not be suitable, due to poor sensitivity, over sensitivity, and/or the lack of an optimal dose-response relationship.

Since these routine tests reflect the core business of hemostasis testing, the obvious question arises of whether this marks the inevitable doom of routine haemostasis laboratories.

Do not close up shop just yet. Despite the optimistic predictions about the superior clinical utility of the new anticoagulants as antithrombotic agents, the existing anticoagulants (i.e., VKAs, heparin/heparinoids) are likely to remain in use for some time to come.

The new anticoagulants appear from clinical trials to have a favorable safety profile. Nevertheless, the high specificity (i.e., either anti-IIa or anti-Xa) of these agents would indicate limited utility for some applications. For example, these agents may not be able to replace the conventional anticoagulant drugs in polytherapeutic approaches (e.g., management of coronary syndrome, thrombotic stroke, and malignancy-associated thrombosis).

The current lack of reversal or antidote for most agents also means general unsuitability for some during surgery indications, such as on-pump coronary bypass, where heparin and anti-aggregant agents are still the cornerstones of therapy. Cost is another issue.

Heparin and VKAs are cheap drugs compared to the new anticoagulants. Patients in developing countries as well as sections of the population in developed countries may remain on VKA therapy simply because of affordability, which is also linked to compliance. With the expense of the new drugs, some patients are tempted to skip or reduce doses, with potentially devastating consequences, and so may be more safely managed on VKAs.

Drug evaluation studies are also performed with selected patient cohorts, in many respects ideal patients, with many other subjects (non-ideal patients) excluded for various reasons. Typically excluded are patients with renal and liver dysfunctions, pregnant women, pediatric populations, individuals at extremes of body weight, and individuals with complex disease and multiple morbidities. Notably, there was a high exclusion rate in the clinical trials evaluating both Dabigatran and Rivaroxaban.

However, when these drugs are eventually released and approved for selective indications in the real world, non-ideal patients, including those excluded by clinical trial criteria, will also need to be managed by anticoagulation therapy. There has also been much recent publicity about adverse events including death whilst on the new agents, and possibly related to selection of inappropriate patients to treat (e.g., renal dysfunction).

Naturally, the old anticoagulants are also not without significant risk of bleeding or other serious adverse outcomes, as previously highlighted.

The future anticoagulation of patients with complex diseases is again worth raising here. Clinical trials that aim to include such patients will be delayed by drug developers, given the possibility of adverse comparative findings against the classical agents, and thus potential negative influence on approvals for other indications.

Another interesting consideration is the potential role of anticoagulant therapy in modulating cancer spread, given the reported bidirectional relationship of cancer and haemostasis. At the current time, heparins – especially LMWH – appear to provide the best potential option in this regard, believed due to their anti-thrombin activity, which targets the protease-activated receptor (PAR) pathway, and thus, the potential role of the new anticoagulants in this area of treatment remains an academic point.

Way forward
In conclusion, new oral anticoagulants cannot completely replace older ones (heparin and VKAs). Therefore, for the foreseeable future, these will continue to be important anticoagulants. As these will still require laboratory monitoring, the routine coagulation tests (PT/INR and APTT) will similarly remain a part of this foreseeable future as well. These tests will also still have value in assessing for hemostasis-related defects, potentially related to both bleeding and thrombosis. Moreover, renal failure, liver dysfunction, extremes of body weight and even genetic polymorphisms may influence adsorption, clearance, metabolism, and excretion of some of the new and emerging anticoagulants. Combined with the current lack of ideal anticoagulant antidotes, the need or clinical desire for laboratory testing (in lieu of monitoring) of the new anticoagulants is predictable. Additional reasons for laboratory testing include to assess compliance or therapy failure (unexpected thrombosis or bleeding), to establish whether co-medication effects may be affecting drug efficacy, when bridging from one anticoagulant to another, and in unconscious patients (e.g., trauma) undergoing surgery.

Routine laboratory testing of the new anticoagulants will also develop over time. Evaluations into which tests might be useful for monitoring these have started, with the diluted TT or ECT, and the chromogenic anti-Xa assays currently emerging as clear leaders for potential clinical utility of Dabigatran and Rivaroxaban testing respectively. However, the common tests, including the PT and APTT, might be found to be suitable in time, albeit in modified form (e.g., dilute PT). A chromogenic anti-IIa or chromogenic ecarin assay would also be feasible contenders for assessment of Dabigatran, particularly for laboratories already running a chromogenic anti-Xa assay.

Finally, the dRVVT remains under-investigated but represents another potential opportunity, in theory permitting dual assessment of both Dabigatran and Rivaroxaban. Nevertheless, performance of any of these assays for assessment of the anticoagulant effects of Dabigatran and Rivaroxaban in the absence of adequate standards and adequate test standardization would suggest current limited or questionable clinical utility. There will also be a clear need to develop appropriate quality control and external quality-assurance processes for these tests when used in these settings, which is anything but ancillary.

Specific laboratory counseling on the most appropriate test to be ordered according to the drug being administered, as well as on the best way to interpret test results, will also be necessary, at least for the initial period of utilization of these novel anticoagulant agents.

In summary, the imminent demise of the routine coagulation laboratory, and of the PT/INR and APTT, appears a little premature. The future landscape will include a more varied test menu, tailored toward monitoring or testing of a broader group of anticoagulants, including but not limited to heparin, VKAs, Dabigatran, and Rivaroxaban. The classical five test (i.e., PT/INR, APTT, TT, Fibrinogen, and D-dimer) panels used by many laboratories will also broaden. So, be prepared, instead, for a larger workload!

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