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COMMENTARY
Opportunities for point-of-care hemostasis monitoring
Craig M. Jackson
Greater numbers of cardiovascular surgical procedures and increased use of anticoagulant therapy have expanded the need for hemostasis monitoring. New anticoagulant agents are contributing to this need, because the classic mature tests of hemostatic function are inadequate for monitoring therapy with the new agents. Therefore, a completely new generation of tests is needed. Such tests must not only be geared toward point-of-care (POC) use but also incorporate scientific breakthroughs to overcome the limitations of currently available tests.
The Growing Need for Hemostatic Function Monitoring
Monitoring patient hemostatic function to ensure an appropriate balance between risk of thrombosis and risk of hemorrhage is necessary in two common situations: short-term anticoagulant use in the operating room and long-term anticoagulant therapy.
In the operating room, heparin is administered and monitored during surgical procedures with a high risk of thrombotic complications. The use of tests for activated clotting time (ACT) and activated partial thromboplastin time (aPTT) in operating room monitoring is an archetypal example of POC testing in hemostasis. Instrumentation for measuring ACT has been available for several years.
Monitoring is also required for the hemodilution and hypothermia that occur during extracorporeal circulation and cause increases in clotting times unrelated to any anticoagulant in use.
Similarly, the monitoring of oral anticoagulant therapy is necessary to adjust the anticoagulant dose to balance the risk of thrombosis against the risk of excessive bleeding. Several small, convenient, simple-to-use devices have been developed and marketed for monitoring oral anticoagulant therapy.
The use of POC instruments for monitoring anticoagulant therapy in physicians' offices is rapidly gaining acceptance. In Germany, self-testing at home by patients on oral anticoagulant therapy has been introduced. The published studies indicate that better control of anticoagulation is achieved with self-testing than with laboratory testing, and at a reduced overall cost.1–3
Limitations of Tried-and-True Tests
New antithrombotic drugs that are promising alternatives to heparin and the vitamin K–antagonists have been developed and are being used. Examples include low-molecular-weight heparin derivatives, heparin-like glycosaminoglycans, recombinant hirudin (the anticoagulant derived from the medicinal leech), inhibitors of Factor Xa (derived from the medicinal leech and other organisms), synthetic active site-directed inhibitors of thrombin, abciximab (a monoclonal antibody against the platelet fibrinogen receptor), and aprotinin.
When only conventional heparin was available, the ACT test used with whole blood during cardiovascular surgery was generally satisfactory. However, the ACT and aPTT tests have been found to be of almost no utility for monitoring low-molecular-weight heparins and hirudin, and are inaccurate when abciximab is used in conjunction with heparin. The ACT and aPTT tests are insensitive to low-molecular-weight heparin but are too sensitive to hirudin.
These are not problems associated with instrumentation. Rather, they reflect the fact that all the components of these coagulation function tests—except for a reagent that initiates the series of reactions that culminate in clotting (fibrin gelation)—are provided by the patient's blood or plasma sample. Because of this intrinsic limitation, the inadequacies of these tests for monitoring new anticoagulant drugs are unlikely to be eliminated by "tweaking" the initiating reagent or by simple electronic compensation.
Similar problems are associated with oral anticoagulant therapy monitoring. The classic prothrombin time (PT) test is performed using citrate-anticoagulated plasma. The plasma has been freed from platelets, the cellular elements responsible for primary hemostasis in vivo, thus preventing them from contributing to the classic PT. However, platelets are present in the whole blood samples used in POC devices that measure a prothrombin time. A bias between PTs that use plasma and those that use whole blood has been observed, but bias can be compensated for; thus this concern may be unimportant.
There is at least one offsetting advantage of POC aPTT testing over conventional testing. The short time between blood sample collection and POC testing reduces the time for platelet fragmentation, a common cause of misleading results in aPTT tests.
There are fundamental limitations associated with POC PT testing in addition to the plasma versus whole blood bias. One limitation is that for the PT test, as for the ACT and aPTT tests, all reactants of the clotting process except the initiating reagent, thromboplastin, are derived from the patient sample. The second is the variability of the initiating reagent, thromboplastin itself. Composition and formulation differences between manufacturers create inconsistencies among lots of thromboplastin from different manufacturers, but even lots from the same manufacturer are variable because of the complexity of the raw material. These limitations apply to both the POC PT test and the classic plasma PT test.
One limitation, however, is specific to the POC test. The convenient test cassettes, cartridges, or strips that have the thromboplastin associated with them cannot be as comprehensively calibrated as classic PT tests. This is an inherent limitation of the single-use cassette, cartridge, or strip. Manufactured lots can be calibrated, but device-to-device variability can only be estimated from statistical sampling of the lot or batch of finished devices. A similar situation exists with the aPTT test when it is performed with POC devices, but the problems are fewer because of the simpler composition of the reagents for the aPTT.
Computational adjustment for bias differences among lots can provide the physician or surgeon with a consistent and informative result. However, the results obtained with POC devices are not necessarily comparable to the classic laboratory methods for PTs and aPTTs, nor are the results from different POC devices. When POC PT testing becomes more widespread, it is possible that this lack of comparability might contribute to errors in treatment.
Standardization of POC devices for coagulation testing is a concern of FDA. At an August meeting in Washington, DC, sponsored jointly by FDA and the College of American Pathologists (CAP), several proposals for addressing the standardization problem were discussed. Unfortunately, the meeting was announced only 11 days before it was held.4 Proposals for standardization of POC and conventional laboratory testing were solicited, and several were received. Some of the proposals can be read in the CDRH section of FDA's Web site.5–6
Barriers to Innovation
The widely used procedures discussed above have changed little since the late 1930s in the case of the classic PT, or since the 1950s to 1960s for the aPTT and its variants. These tests are showing their age. So why aren't there new and better tests? For some of the newer therapeutics, there are new and better tests. One of the deterrents to the acceptance of new tests, however, is almost certainly the comfort that 40 to 60 years of experience with the old tests engenders, in spite of their recognized shortcomings. Moreover, the old tests are inexpensive, an obvious attraction given current cost-cutting pressures.
In addition to these appealing factors, the standardization of thromboplastins by manufacturers through use of the International Standardization Index (ISI), which took many years to achieve, has simplified the lives of technologists doing coagulation testing with PT when they change lots of reagents. The International Normalized Ratio (INR) for determining the extent of anticoagulation has enabled administration of oral anticoagulants with fewer complications and has made data from different laboratories around the world comparable. Although comparability among INR values for different thromboplastins and different instruments is far from perfect, it is such a marked improvement over the situation that prevailed before adoption of the INR that it must be considered a milestone for administering and monitoring oral anticoagulant therapy.
Change from the classic PT test to a test that isn't "PT-like"—as opposed to tests like the POC PTs that offer only incremental increases in convenience and cost reduction—is likely to be resisted. So, where are the opportunities?
A Window of Opportunity
The new therapeutic agents have created a definite need for additional new tests and test technologies. Specialized tests that are more sensitive to low-molecular-weight heparins have been developed and are being used. Variations on Factor Xa inactivation use clotting time measurement; other variations use chromogenic substrate hydrolysis. These innovative tests can be run on existing laboratory analyzers.
In at least one of the currently available tests, coagulation components are supplemented to reduce dependence on the patient's coagulation factors. This modification removes the limitation intrinsic to the aPTT test for heparin monitoring and also ensures sensitivity to low-molecular-weight heparins. POC versions of this test are under development for use in the operating room.
Several companies have tests for hirudin under evaluation. Tests for abciximab, at least one of which uses a small POC device, are available.
Another test that removes the limitations of the aPTT test is a test for the mutation in clotting Factor V (Factor V mutation R506Q [Factor VLeiden]). The basic format of the test is similar to that of the classic aPTT test, but with the use of a Factor V–deficient plasma and selective activation of protein C, or provision of protein C in a preactivated form.7 With this formulation, the test for activated protein C resistance, the phenotypic expression of the mutation in Factor V, is more than 98% sensitive and 98% specific.
Interestingly, FDA deemed one commercial version of this test to be substantially equivalent to an aPTT test and cleared the manufacturer's 510(k) application. Simpler clearance for marketing may be a trend for these devices.8
Another test with promise is a chromogenic substrate–based variation on another classic coagulation test, the thromboplastin generation test (TGT). Evidence presented at a recent congress of the International Society on Thrombosis and Haemostasis (Washington, DC, August 14–21, 1999) suggests that this modernized form of the TGT is sensitive to anticoagulant substances that the two classic tests are not.
These innovative tests represent some opportunities that have already been seized. More opportunities are available, but to capitalize on them researchers and developers will need to focus not so much on instrumentation but more on understanding the hemostasis system and the complex relationships among its components.
References
1. S Morsdorf et al., "Training of Patients for Self Management of Oral Anticoagulant Therapy: Standards, Patient Suitability, and Clinical Aspects, "Seminars in Thrombosis and Hemostasis 25, no. 1 (1999): 109–115.
2. U Taborski, FJ Wittstamm, and A Bernardo, "Cost-Effectiveness of Self-Managed Anticoagulant Therapy in Germany," Seminars in Thrombosis and Hemostasis 25, no. 1 (1999): 103–107.
3. U Taborski and G Muller-Berghaus, "State-of-the-Art Patient Self Management for Control of Oral Anticoagulation," Seminars in Thrombosis and Hemostasis 25, no. 1 (1999): 43–47.
4. Federal Register, 64 FR:41939–41940 (August 2, 1999).
5. "Whole Blood Coagulation Workshop—Draft Standardization Proposal," in CDRH Home Page [on-line] (Rockville, MD: FDA, Center for Devices and Radiological Health, 1999 [cited 7 October 1999]); available from Internet: http://www.fda.gov/cdrh/meetings/wbcwproposal.html.
6. "International Workshop on the Standardization of Whole Blood Coagulation Devices," in CDRH Home Page [on-line] (Rockville, MD: FDA, Center for Devices and Radiological Health, 1999 [cited 14 October 1999]); available from Internet: http://www.fda.gov/cdrh/ode/wbcw-transcript.pdf.
7. C Hall et al., "Evaluation of a Modified aPTT-Based Method for Determination of APC Resistance in Plasma from Patients on Heparin or Oral Anticoagulant Therapy," Thrombosis Research 89 (1999): 203–209.
8. TM Tsakeris, "Point-of-Care IVDs: Overcoming the Hurdles to Market," IVD Technology 5, no. 3 (1999): 22–25.
Craig M. Jackson is an industry consultant based in San Diego and a member of the IVD Technology editorial advisory board. He is also chairman of the joint committee on standardization of coagulation tests of the International Federation of Clinical Chemistry, and the scientific and standardization committee of the International Society on Thrombosis and Haemostasis.
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