Researchers at Organon Teknika, the manufacturer of the MDA series of automated, photo-optical coagulation analyzers, are hoping that analysis of clot waveform patterns can be to Hemostasis testing what the electrocardiogram (EKG) is to cardiac function analysis. The beauty of tests like the EKG is that they present detailed information on several components of a biological process. In the case of the EKG, the process is the beating of our hearts. In the case of waveform analysis, the process is the dynamics of clot formation. Just as EKGs do now, clot waveform analysis soon may provide clinicians with valuable diagnostic information.
The most commonly used methods to test for clotting abnormalities are Prothrombin Time (PT) and activated Partial Thromboplastin Time (aPTT). Performing PT and aPTT tests is relatively simple and consequently has been automated for decades.
“Most standard methods of PT and aPTT testing provide information only on clotting time, not on the clotting process,” said Ginny Meihaus, Organon Teknika marketing director. However, complete optical analysis of the waveform profile can provide data on the time, acceleration, rate and magnitude of fibrin polymerization, and, therefore, may provide technologists and clinicians with much more information about the presence, etiology and course of clotting abnormalities.
Researchers have been interested in the dynamic nature of the clotting process for some time. As early as the 1940s, Hartert used thrombelastographs (TEG) to track aspects of clot formation. TEGs are still used today, although primarily for research because they are slow and not easily automated. However, TEGs do provide information on the time required for fibrin to form and the rate and extent of clot formation. Despite this 50-year-old awareness of clot formation dynamics and the existence of TEG, a practical means of using this information in a routine clinical setting has not been available.
Organon Teknika’s MDA series of hemostasis analyzers can scrutinize clot waveforms during routine PT and aPTT tests. The system first blanks each well for background turbidity, then looks at 10 parameters of the clot formation process and uses intelligent algorithms to develop a waveform pattern. Unlike other optical coagulation analyzers that read absorbance, the MDA series systems read transmittance. Using transmittance makes it possible to critically analyze the precoagulation phase of the clotting reaction.
Figure A.
Under normal conditions, the precoagulation phase is uneventful with light absorbance or transmittance only changing with clot formation (Figure A). Researchers have known for some time, however, that an abnormality, called a “biphasic” waveform, could occur during this phase in critically ill patients (Figure “B”). “In fact, early photo-optical systems were prone to “false trips” (falsely short clotting times) because the systems would read the first phase of a biphasic response as the clot and never see the second phase, which is the actual clot reaction,” said Meihaus.
Figure B.
In an effort to avoid false trips, some manufacturers of photo-optical systems developed more sophisticated algorithms. Nevertheless, it was not until persistent investigators in the United Kingdom used an MDA analyzer to demonstrate an association between this anomalous waveform pattern and specific clinical conditions that the full potential for a clinical application of waveform analysis became apparent.
In 1997 Dr. Cheng Hock Toh, Colin Downey and their colleagues at the Royal Liverpool University Hospital reported on 29 patients in the intensive care unit who, by standard laboratory and clinical criteria, had Disseminated Intravascular Coagulation (DIC). Using the MDA to evaluate the coagulation waveform patterns for these patients, they found that all 29 also had an atypical “biphasic” waveform in their aPTT. Moreover, the gradient of the initial slope of the biphasic waveforms correlated with the severity or the progression of the clinical conditions of these DIC patients.
DIC is a serious clinical condition with causes ranging from obstetrical catastrophes, to metastatic malignancies, to massive trauma and bacterial sepsis. Clinically, DIC may be relatively mild, or it may be acute or fulminant. The mortality rate for patients with fulminant DIC is 70 percent. In addition to PT and aPTT, other coagulation screening tests used to diagnose DIC include thrombin time, fibrinogen, FDP and/or D-dimer and platelet count. However, whether they are used solo or in combination, standard tests have low specificity and sensitivity for diagnosing DIC. What is needed is a simple, single, sensitive and rapid test. The report on the DIC patients in the UK indicated waveform analysis could be such a test.
In additional studies, the same Royal Liverpool investigators confirmed that the biphasic waveform was highly sensitive and specific for DIC. Although a biphasic waveform was seen in other conditions that did not fit the standard diagnostic criteria for DIC, all the conditions exhibited evidence of coagulopathies. These studies established the biphasic waveform as a quick and reliable marker for DIC. Furthermore, one of the 10 parameters used in the MDA waveform analysis can be used to estimate the severity of the biphasic slope. Research presented at a recent thrombosis conference in The Netherlands showed a strong correlation between the severity of the biphasic slope and clinical outcome. Therefore, it may be possible to monitor patients’ responses to treatment by tracking changes in the coagulation waveform.
Another valuable finding is that the biphasic waveform may occur up to 48 hours before a diagnosis of DIC can be made by traditional criteria. The MDA systems can recognize these atypical “biphasic” waveforms and notify the system operator. Called the “A2 flag”, this feature identifies the presence of a biphasic waveform while running routine aPTTs. Thus, in addition to the potential for helping to identify and monitor patients with DIC, waveform analysis also may identify patients with non-overt and probably unsuspected DIC — patients who perhaps are the most likely to benefit from early treatment.
Studies published by Organon Teknika scientists and clinical investigators have demonstrated that waveform analysis of routine screening assaid has the potential to provide both laboratorians and clinicians with important additional information beyond clot time alone. For patients with DIC, such information could be invaluable. “As valuable as it is,” Meihaus concluded, “identification and quantification of the biphasic waveform is only the first application of waveform analysis technology that we are likely to see.”
