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Coagulation testing

Part 2: The quest to optimize near-patient analyzers

A healthy and competitive market can bring out industry's best. Here's how some diagnostics firms are answering the challenge to move hemostasis testing closer to the patient. Note: this is the second part of a two-part article. If you haven't already done so, you might like to read part I before continuing.

To capitalize on the growing market for hemostasis analysis, many companies are now competing fiercely to develop instruments that meet the characteristics of the ideal near-patient analyzer.^1,2 However, developing such an instrument to assess the extremely complex physiological process of coagulation is no small order. Such systems must provide utility in multiple clinical settings and be capable of monitoring a variety of patient conditions. Achieving the right balance among sensitivity, precision, and cost-effectiveness is a complicated endeavor.

From a hemostasis perspective, today's patients are considerably more complicated than those of years past. In part, this is because therapeutic intervention with oral anticoagulants generally begins earlier and continues longer, with prophylactic treatment occurring on an outpatient basis.^3–5 Such intervention has been demonstrated to result in improved clinical outcomes, and may also have the potential to reduce overall costs to both the patient and the institution.

Many new and improved analyzers (and other devices) have emerged on the market in recent years.^2,6,7 These analyzers have been developed by companies with a long established presence in hematology and hemostasis as well as by smaller emerging companies. The most successful players will be those that offer the most innovative approaches to optimizing the management of hemostatically compromised patients, which should include a means for monitoring patients throughout the course of their illness.

Hemostasis Management

Healthcare professionals have shown that early intervention and rigorous control of patients' hemostatic status can improve clinical outcomes and reduce overall healthcare costs. To make such hemostasis management possible, manufacturers have developed not only new therapeutic agents, but also new technologies that permit near-patient hemostasis testing. The challenge for such new technologies is to reduce the cost and improve the efficiency of clinical diagnosis and monitoring without sacrificing diagnostic accuracy or quality control. In short, the results of near-patient hemostasis tests must correlate well with similar tests conducted in a central laboratory. One complicating factor for all such tests is the character of the therapeutic agents commonly used in hemostasis management.

Despite the recent appearance in the marketplace of newer therapeutic agents, heparin remains the most widely used anticoagulant. Indeed, among prescribed natural pharmaceuticals, heparin is second in use only to insulin. Its mode of action is to significantly enhance the action of antithrombin III (ATIII) by forming a heparin–ATIII complex that inhibits the serine proteases of the coagulation cascade. There are two commercial sources of heparin: porcine intestinal mucosa and bovine lung. These inexpensive preparations are heterogeneous in nature, and are now available in both high- (HMW) and low-molecular-weight (LMW) forms, with a molecular weight that ranges between 9 and 30 Kd.⁴

Although heparin has been widely used in the management of thrombotic patients for decades, it has remained a somewhat controversial agent.^8–10 A major reason for this controversy is the extreme variation of patients' responses to heparin during interventional procedures (up to a 12-fold variation). Both the source and the ratio of fractions in heparin preparations are known to affect its potency; thus, manufacturers must label the drug with the activity of the preparation in units according to the United States Pharmacopeia. Such variations also cause difficulties for the diagnostic systems used to monitor such patients. Traditionally, the activated partial thromboplastin time test (APTT) has been used to monitor patients who are undergoing heparin therapy. But variations in sampling technique for this test can significantly affect the sensitivity of the test system.⁹

Significant intervariation in patient responses to heparin has also been demonstrated. For example, the amount of heparin required to achieve a particular target level of anticoagulation during cardiopulmonary bypass (CPB) procedures may vary threefold between patients, and the time required for blood clearance may vary fourfold. Moreover, these factors do not correlate with the extent of surgery; the patient's age, weight, or body surface; or one another. It has therefore been suggested that the use of empiric dosing for heparin therapy is likely to result in inaccurate coagulation management for many patients.^10,11 Taken together, these variables have complicated the screening of at-risk patients, and subsequent therapeutic intervention using heparin.

Another common oral anticoagulant, warfarin, is often prescribed for home use by ambulatory patients following hospital discharge.^3,4 Warfarin and other oral anticoagulants exert their activity by interfering with the synthesis of the vitamin K–dependent clotting zymogens (factors II, VII, IX, X, protein C, and protein S). Monitoring of these oral anticoagulants is traditionally performed using modifications of the prothrombin time test.^3,4,12–14

Newly developed methods for near-patient testing can help physicians to improve their use of such anticoagulant therapies by providing the information necessary to keep a patient's clotting mechanisms in check while avoiding the adverse effects of hemorrhaging. Now, manufacturers that have entered the near-patient hemostasis analyzer market are attempting to optimize their instruments in order to achieve all the characteristics of the ideal analyzer.

Optimizing Hemostasis Analyzers

In their quest to develop the optimal near-patient hemostasis instrument, manufacturers must address a multitude of testing considerations. The ultimate challenge is to provide reliable, laboratory-quality results that can facilitate timely, appropriate intervention in all near-patient settings, but most importantly in acute-care environments. Although many new instruments have become available, none can boast all the characteristics suggested as necessary to meet this goal. Nevertheless, a number of the commercially available instruments offer major improvements in hemostasis testing. Such improvements include the use of whole blood in a closed-tube system that requires minimal sample preparation (or none at all), and onboard data management systems.

Most of the newly developed hemostasis analyzers are targeted for specific near-patient settings. For use in cardiac catheterization and bypass suites, for instance, the primary instruments are those for performing the activated clotting time (ACT) test. For intensive care units, manufacturers offer APTT analyzers. And for home use by patients who have been discharged from the hospital, diagnostics companies are now making available modified analyzers for performing the prothrombin time (PT) test. Certain analyzers, however, provide multiple hemostasis tests on the same near-patient instrument (see Table I).

Table I. Major features of commercially available near-patient hemostasis analyzers.

Feature	ITC Hemachron 8000	ITC Hemachron 801	CDI TAS	Medtronic ACT	Actalyke A2P
Portability	Handle	Handle	(n/a)	Handle	Handle
Size (H x W x D; cm)	25 x 30.5 x 40.6	38 x 63.5 x 71	9.9 x 15 x 27	16.5 x 20.3 x 24.1	25 x 15 x 28
Weight (Kg)	5.44	1.9	1.9	3.6	4.2
Temperature range to 37°C	Yes	Yes	(n/a)	Yes	Yes
CLIA complexity	Moderate	Moderate	Moderate	Moderate	Moderate
Time to test results (min.)	< 5	< 5	(n/a)	Test- dependent	Test- dependent
Data format	Quantitative	Quantitative	Quantitative	Quantitative	Quantitative
Provides printed copy	Yes	No	Yes	No	Yes
Sample type	Whole blood	Whole blood	Fresh or citrated whole blood, plasma	Fresh or citrated whole blood, plasma (test-dependent)	Whole blood
Sample volume (µl)	400–2000	400–2000	30	10–40	400–2000
Reagent type	Test tube	Test tube	Test card	Cartridge	Test tube
Tests performed	ACT, APTT, PT	ACT, APTT, PT	ACT, APTT, PT	ACT, APTT, PT	ACT

In-Hospital Near-Patient Coagulation Analyzers. The activated clotting time test (ACT) has been accepted as a point-of-care hemostasis assay for more than 20 years.^15,16 The test's widespread adoption is due in part to the fact that it is simple to perform, uses whole blood as a sample, and provides results within seconds. From a clinical perspective, it is the most suitable test for short-duration procedures such as CPB, during which patients commonly receive large quantities of heparin (up to 8 units/ml of blood).

Manufacturers of commercially available analyzers for ACT testing include Array Medical (Somerville, NJ), Cardiovascular Diagnostics, Inc. (CDI; Raleigh, NC), International Technidyne Corp. (ITC; Edison, NJ), and Medtronic (Minneapolis). On some of their ACT instruments, CDI, ITC, and Medtronic have added the APTT test as a menu item (see Figure 1). Most of these analyzers are readily portable (either by hand or with a cart), with the largest measuring approximately 38 x 64 x 71 cm and the heaviest weighing approximately 6 kg (see Table I). In support of their portability, these analyzers operate on either 110 or 220 V ac, and in many instances operate on rechargeable batteries.

Figure 1. The current generation of ACT analyzers offers a wide range of features to simplify near-patient testing. Models shown are the Actalyke (Array Medical), the Hemochron 8000 multiple hemostasis analyzer (International Technidyne Corp.), and the Thrombolytic Assessment System (TAS; Cardiovascular Dynamics, Inc.).

To simplify operation, many of these instruments possess onboard quality control systems. These usually operate either by means of software algorithms, or by an electronic quality control device that automatically simulates test performance to permit accurate validation of the test system.

Among their other features, many of these ACT analyzers incorporate onboard printers, enabling the clinician to obtain a hard copy of the test results for inclusion in the patient's medical record. Most of the instruments are capable of monitoring temperatures to 37°C. In addition, all offer rapid turnaround, providing immediate test results that permit the physician to use test data as the initial basis for appropriate intervention.

In addition to these characteristics of the optimal analyzer, some companies' instruments offer features that can increase end-user acceptance and help to reduce overall costs. For example, some of the instruments feature bar code recognition systems that automatically read the labels on blood-collection tubes, thereby aiding in data management. Other instruments offer data storage, and some have RS-232 ports to facilitate communication with computer networks. In addition, some offer dual-well capabilities, making it possible to perform duplicate sample analysis.

But perhaps the biggest difference among the various systems for near-patient hemostasis testing is in the purchase prices of the instrumentation and related disposables, which vary by as much as 70% for ACT instruments (see Table II). When estimating the costs involved in purchasing and operating an ACT test system, purchasers should remember to evaluate each system's pricing structure.

Although all of the ACT analyzers described here offer results in a timely fashion, there is room for improvement in the manner in which clot formation time is detected and reported. Traditionally, ACT analyzers have used a functional end-point detection method; that is, they determine the time to clot formation by physically detecting the clot. By contrast, the operating principle of both the Array and ITC systems is that of electromagnetic clot detection. Formation of a clot displaces the magnet in a disposable test tube containing the patient sample. When the magnet is no longer sensed by the instrument's detector, the system provides the ACT result as the time (in seconds) required for clot formation. To improve on this single-point clot detection system, Array Medical has developed a two-point clot detection system that senses the magnet from two independent locations (see Figure 2). This method of clot detection is less affected by clot stability than the other systems, thereby improving the reliability of test results in clinical settings. A study comparing the performance of five commercially available ACT analyzers on CPB patients found that the two-point detection system was consistently more sensitive, detecting clot initiation more quickly than the methods used by other instruments.¹⁶

Figure 2. The two-point clot-detection mechanism offered on the Actalyke ACT analyzer (Array Medical); (a) two sensors are located at 0 and 90°; (b) formation of a clot displaces the magnet in the disposable test tube; (c) when the magnet reaches a fixed distance between detectors 1 and 2 (approximately 46° away from detector 1, or 1° closer to detector 2) the system provides the ACT result as the time (in seconds) required for clot formation. The two-point system can detect clots at an earlier stage of fibrin formation, and is less affected by clot stability than other systems.

Recent Developments in Near-Patient Coagulation Assays. Although APTT and PT tests have traditionally been performed in the central laboratory, a number of manufacturers have recently developed or adapted analyzers for performing these tests in near-patient settings. Such companies include CDI, ITC, and Medtronic (see Table I).

In contrast to the near-patient ACT analyzers described above, these APTT and PT assays and analyzers compete for a different portion of the near-patient hemostasis testing market. Targeted at the intensive care unit rather than the surgical suite, their primary functions are to monitor patient levels of heparin (via APTT testing), or to provide information that will enable a physician to decide whether the patient must undergo transfusion (via APTT and PT testing).

Each of these systems attempts to meet the characteristics of the ideal near-patient instrument by offering simple use, a whole-blood format, and data management capabilities. Although all have been shown to correlate reasonably well with clinical laboratory results, companies are currently striving to improve these correlations. To ensure that the results from such near-patient analyzers can be interpreted accurately, it has been suggested that they should harmonize within a coefficient of variance (CV) of less than 5% with those from the central laboratory.¹⁷

Although none of these instruments achieve all of the desired features, all are suitable for near-patient testing. The portability of these near-patient analyzers allows for easy transport within the clinical environment. This feature is particularly important in acute-care settings, where sequential monitoring is essential to ensure optimal therapeutic intervention.^1,2,14

CDI, ITC, and Medtronic have adapted their ACT analyzers to perform APTT tests and other hemostasis assays (see Table I). Although such flexibility is a desirable feature of the optimal near-patient analyzer, it remains to be seen whether purchasers will be attracted by such units. In some settings, for instance, the current costs of the instrument and associated disposables could prove an obstacle to increased sales (see Table II).

Home-Use Coagulation Assays. Both Boehringer Mannheim (Indianapolis) and ITC have developed handheld devices that make it possible for patients to accomplish PT self-monitoring in their own homes (see Figure 3). Other companies are expected to enter this market in the near future.

Figure 3. Portability and convenience are key features of commercially available PT monitors designed for home use by patients on oral anticoagulant therapy. Models shown are the Coaguchek (Boehringer Mannheim) and the Protime (International Technidyne Corp.).

The ultimate in portability, these devices are targeted for patients who remain on oral anticoagulant therapy after discharge and who require frequent monitoring of their hemostatic status. Such patients include those who have artificial heart valves, and those suffering from atrial fibrillation (and are therefore at risk of stroke).^18,19 For these patients, the benefits of such PT microanalyzers include convenience, increased testing frequency, and potentially tighter control of their anticoagulant therapy—with associated positive clinical outcomes.^18–20

A number of published studies have demonstrated an acceptable correlation (CV less than 10%) between the coagulation data that can be obtained from home-use microanalyzers and those derived from central laboratory testing.^20–22 However, the vast majority of these studies were performed in central laboratory settings by personnel specifically trained in coagulation testing. It is therefore uncertain to what degree the results of such studies can be considered representative of actual home use by patients involved in self-management of anticoagulant prophylaxis.^20–22

To ensure that the beneficial attributes of home-use analyzers are achieved, patients must be first identified as suitable for self-testing, and then be adequately trained. Attention must be paid to screening out those patients not suitable for home testing, such as those with poor eyesight, those having difficulties with motor coordination or manual dexterity, and those who are memory impaired. In a 10-year study, it was reported that only 40% of patients initially identified as suitable for self PT testing actually adopted home testing. Moreover, it was concluded that additional studies are required to confirm both the cost-effectiveness and expected advantages to the patient.^21,22

With the increasing use of oral anticoagulants for many clinical conditions where thrombosis is considered a risk, home-use PT analyzers are here to stay. However, it is unlikely that any of the other traditional hemostasis assays will be developed for self-testing platforms.

Complex Tests. As indicated in the first installment of this article, complex tests of hemostatic dysfunction use the principles of existing end-point assays—such as the APTT, PT, and thrombin clotting time (TCT) tests—to assess deficiencies among the blood factors associated with coagulation. Examples of these assays include those for deficiencies of factors VIII or IX, which are initially diagnosed when a patient's APTT result is prolonged. Since a longer than normal APTT can indicate the presence of von Willebrand's disease, hemophilia, and other conditions, additional testing is necessary to provide the physician with further information. The patient sample is diluted with a normal sample containing different levels of the factor that is suspected of being deficient, in order to obtain a level that produces a normal APTT result. Such testing provides a more accurate diagnosis as to the nature of the dysfunction.^23,24

Although such complex tests are useful in certain clinical settings, it is unlikely that any of them will be considered suitable additions to the menus of near-patient analyzers. At least for the foreseeable future, the singular nature of complex tests means that they will most likely remain as specific assays performed in the central laboratory.

Immunoassays. In an effort to accurately quantitate the level of specific peptides, proteins, and factors of the coagulation cascade, researchers have developed a number of immunodiagnostic assays. Many companies believe that such assays may be the future of both testing and management in cases of hemostatic dysfunction. Examples of immunoassays that are currently in either diagnostic kit or research-use-only formats include tests for factors VIIa, IX, X, XIIa, prothrombin fragment F1.2, soluble fibrin polymers, and fibrin D-dimer.^2,25 Clinical Hemostasis Review publishes an annual list of such tests and their current development status.

None of the available immunoassays are now in widespread use. However, it has been suggested that appropriately designed clinical studies could demonstrate the clinical utility of these tests for identifying patients who are at risk of developing hemostatic complications (either thrombosis or hemorrhage). In turn, the results of such tests would permit clinicians to intervene with the appropriate therapy.^2,25

Commonly performed by trained personnel in a centralized laboratory setting, a number of these immunodiagnostic assays are currently in development for the near-patient environment. However, as with the traditional tests for hemostatic dysfunction, care will need to be taken to ensure that results from the near-patient setting correlate well with those from the laboratory. Only then will the utility of such near-patient immunoassays be accepted.

The Future of Coagulation Testing

In addition to the factors of the coagulation cascade, platelets play an extremely important role in hemostasis. Indeed, there have been a considerable number of antiplatelet agents developed that are indicated for use in conjunction with anticoagulants. It is now realized that monitoring antiplatelet therapy is of major interest in most (if not all) clinical settings where invasive procedures are performed. Some of the more common antiplatelet agents include aspirin (a weak antiplatelet agent that affects cyclooxygenase activity during the life of the platelet), and the various glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists. The latter group of compounds include ReoPro (Centocor and Eli Lilly), Integrilin (Cor Therapeutics), and Aggrastat (Merck). Numerous other compounds (including oral ones) are currently under development.

These agents are now recognized as having an extremely important role in the prevention of thromboembolic processes, and require careful dosing and monitoring to avoid the adverse side effect of hemorrhagic complications. Unfortunately, there are currently no available near-patient assays capable of accurate and timely platelet-function testing. This void has precipitated a race by a number of companies—including both established firms and newcomers—for the development of platelet function analyzers for use in near-patient settings.

Some of these companies—including Dade Behring (Deerfield, IL) and Medtronic—have already received approval for their platelet-function testing platforms. Others planning to enter the market include Array Medical and Accumetrics (San Diego). The instruments developed by these companies will address the issues associated with near-patient platelet-function testing, and offer to provide enhanced management of hemostatically compromised patients.

Conclusion

Thrombotic disease afflicts millions of patients, and its manifestations cause significant morbidity and mortality. New antithrombins and antiplatelet agents are on the horizon to better manage these complex conditions and more efficiently control the thrombotic process. Nevertheless, a complication of these treatments is often bleeding, which can be severe. As a result, patient monitoring is critical to ensure appropriate treatment regimens.

For these sickest of patients, laboratory monitoring may not be ideal for a variety of reasons. As a result, near-patient hemostasis testing technologies have evolved to provide rapid results in both clinical and outpatient settings. These technologies can provide significant benefit in therapeutic intervention and patient management. Near-patient technologies have yet to evolve to meet each and every criterion of the ideal instrument. No doubt manufacturers will continue to strive to meet these criteria since the market opportunity is a healthy, growing one.

References

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25. Bauer KA, "New Markers for In Vivo Coagulation," Current Opinion in Haematology, 1:341–346, 1994. David G. M. Carville, PhD, is vice president for new product development, and Kirk E. Guyer, BS, is manager of the research and development laboratory, at Array Medical Laboratories (South Bend, IN).