Chemistry: analytical and immunological testing – Composition for standardization – calibration – simulation,... – Particle count or volume standard or control
Reexamination Certificate
1999-10-12
2002-01-29
Wallenhorst, Maureen M. (Department: 1748)
Chemistry: analytical and immunological testing
Composition for standardization, calibration, simulation,...
Particle count or volume standard or control
C436S008000, C436S016000, C436S070000, C252S408100
Reexamination Certificate
active
06342391
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the measurement of erythrocyte sedimentation rate (ESR), and more particularly to a blood control standard for the quality control of the measurement of ESR.
BACKGROUND OF THE INVENTION
The ESR test measures the sedimentation rate of aggregated erythrocytes in plasma. The rate of sedimentation is an indirect means of quantitating Rouleaux formation as well as red cell aggregation. Sedimentation occurs because the apparent surface/volume ratio of the red cells decreases and the denser Rouleaux overcome the buoyant forces of the plasma and sink. Erythrocyte sedimentation depends upon an interrelationship of a number of inherent biologic variables. Anything that increases the tendency to form Rouleaux or red cell aggregation will accelerate the sedimentation rate. In vivo, the plasma concentrations of proteins and globulins as well as the shape of the red blood cells are the most important factors contributing to the ESR.
In most normal persons, sedimentation takes place slowly, but in a variety of disease states the rate is rapid and in some cases proportional to the severity of the disease. The ESR test has been utilized as an indirect measure of these disease states. However, the test is very non-specific in that values for “normal” ESR may be influenced by local conditions as well as the age and sex of the patient. Nonetheless, the ESR test is an extremely common test which plays a significant role in contemporary medical practice.
Westergren developed the technique of performing an ESR determination as described in a paper published in 1924. See Alf Westergren, “Die senkungscreaktion”, Ergegn. Inn. Med. Kinderheilk., 26:577 (1924). In the Westergren method, a blood sample is obtained by venepuncture and is thoroughly mixed with a suitable anticoagulant. Because the proteins and globulins in blood are unstable in vitro, at room temperature the test must be set up within 2 hours, or at 4
E
C within 6 hours. The blood-anticoagulant is thoroughly mixed by gentle repeated inversion and a clean dry standard Westergren-Katz tube is filled and adjusted to the ‘0’ mark. The tube is then placed in a strictly vertical position under room temperature conditions (18-25
E
C), not exposed to direct sunlight and free from vibrations and drafts. After a time period, usually 1 hour, the distance (x) from the bottom of the surface meniscus to the top of the column of sedimenting red cells (where the full density is apparent), is read in mm and recorded as the ESR value. The result is expressed as follows: ‘ESR (Westergren 1 hr)=×mm’. Variations in the materials and methods are known, however, the basic technique is relatively unchanged since its introduction.
One variation of the Westergren method is a result of the substantial recent efforts directed to ways of decreasing the time involved in conducting the ESR test. Several ESR test apparatus manufacturers have developed methods of conducting ESR tests in less than one hour, e.g., 20 minutes or 30 minutes. These methods generally involve measuring the sedimentation distance after 20 or 30 minutes and converting that measurement to a one hour equivalent. Because the rate of sedimentation of a patient sample is generally exponential (i.e., nonlinear), this conversion involves something more than simply dividing the result by the fraction of one hour within which the measurement was made. Instead, these manufacturers have developed proprietary empirical conversion factors for converting a 20 or 30 minute measured value to a one hour standard value.
Due to the manner in which ESR is measured, in addition to the biologic variables certain identifiable environmental and technical factors may influence the ESR test in misleading ways. For example, the following factors may affect the measurement of ESR:
Environmental Factors:
1. Temperature. The room temperature during the test could lead to a misleadingly high ESR (higher temperatures) or low ESR (lower temperatures). Further, a variation of temperature during the test will also lead to misleading results.
2. Vibration. Vibration or movement of the testing apparatus during the test will result in misleading results.
Procedural Factors:
1. Positioning of tube. The correct or incorrect positioning of the tube at a perpendicular angle will affect test results.
2. Delay prior to test. A delay in performing the test beyond 2 hours of drawing the blood sample will create ambiguous results.
3. Insertion of tube in reservoir (for modified Westergren procedures). Failure to fully insert the tube to the bottom of the reservoir in certain modified Westergren procedures will affect the test results.
4. Unfamiliarity or failing to follow manufacturer's directions will affect test results.
Testing Materials Factors
1. Tube. Variations of the composition and/or length of the measurement tube will affect test results. For example, the use of glass vs. plastic tubes in either a Wintrobe or Westergren procedure will lead to variations in the observed sedimentation rate.
2. Anticoagulant. The anticoagulant used will affect test results.
3. Plasma. Changes in the plasma composition is a significant factor determining the measured ESR.
Before the commercial introduction in the mid-1990s of an ESR control product manufactured by Hycor Biomedical, Inc. of Garden Grove, Calif., there was no known commercial control by which the foregoing, and other, factors could be eliminated as sources affecting test results. Accordingly, a given ESR measurement could only be accepted as within a relatively large range of error. This decreased the significance of the ESR test.
Hycor's commercial ESR control product allowed users to monitor and verify the accuracy of their ESR test method and apparatus. However, it was found that chemical agents used in certain commercial ESR testing apparatus raised compatibility issues with the Hycor commercial product. In particular, in the presence of citrate, red blood cells in the Hycor ESR control were found to change their morphologies such that their sedimentation velocities were inhibited. A similar observation was made when the cells were in the presence of normal saline solution. These effects are significant because citrate and saline solution are commonly present in many commercially available ESR test apparatuses. It is therefore desirable to obtain an ESR control having the desirable properties described herein and which is compatible with citrate and/or saline.
Moreover, and as discussed above, many current commercially available ESR test apparatuses measure sedimentation rates over a time period of less than one hour, which is a departure from the standard Westergren technique. For example, the Ves-matic system (manufactured by Diesse Diagnostica Senese, Monteriggioni, Italy) and Sedimatic system (Analys Instrument AB, Stockholm, Sweden) measure ESR over periods of 20 minutes and 30 minutes, respectively, rather than one hour. Because of this, it is also desirable to obtain an ESR control that is capable of providing consistent and reproducible results for ESR test apparatuses that operate over measurement periods other than one hour.
SUMMARY OF THE INVENTION
The present invention is a reference control designed to monitor the accuracy and precision of analytical methods for determining the sedimentation rate of human erythrocytes in whole blood specimens.
In a first aspect, the ESR control comprises a three component colloidal/emulsion suspension: (1) a synthetic plasma base, (2) a polymer having a high molecular weight in the range of between 15,000-500,000, and (3) mammalian red blood cells. In the preferred embodiment, the polymer used is Dextran, a polysaccharide. Dextran is known for its use as a plasma expander used for cell separation, but is used for a different purpose in the ESR control of the present invention. Here, the addition of Dextran to the synthetic plasma base serves the function of behaving similar to an abnormal increase of large plasma proteins such as Fibrinogen and Alpha 2 macro-globuli
Chen Roulhwai
Zaidi Azra S.
Dobrusin & Thennisch PC
Streck Laboratories Inc.
Wallenhorst Maureen M.
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