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
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.
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 coagulationÂ 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.
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.
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.