Chemistry: analytical and immunological testing – Composition for standardization – calibration – simulation,... – Particle count or volume standard or control
Reexamination Certificate
1999-10-18
2002-09-03
Wallenhorst, Maureen M. (Department: 1743)
Chemistry: analytical and immunological testing
Composition for standardization, calibration, simulation,...
Particle count or volume standard or control
C436S008000, C436S063000, C436S176000, C435S002000, C435S029000, C435S810000, C422S067000, C252S408100
Reexamination Certificate
active
06444471
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the field of hematology, and in particular, to assays for determining the number or presence of the formed elements of blood such as red blood cells, white blood cells, platelets and reticulocytes. More specifically, the invention relates to control compositions used in performing such assays, and to processes for preparing, and methods of using such control compositions.
BACKGROUND OF THE INVENTION
The field of hematology involves the study of blood, including the discrete cell populations that make up the blood and blood forming organs. The ability to reliably and accurately distinguish and count cells is one important tool in this field. Clinical significance can be attributed to abnormal levels, in both relative and absolute terms, of most cell populations.
The study of the dynamics of blood cell production and destruction depends upon the enumeration of new cells being delivered to the circulation per unit time. New immature red blood cells (known as reticulocytes) are easily identified and can be quantified as a percentage of total red blood cells (“RBCs”).
A reticulocyte is created during the final stages of erythroid development, resulting from the enucleation of RNA-rich, orthochromatic normoblasts. The feature of reticulocytes most frequently used to distinguish them from mature RBCs is their stainable RNA. Reticulocytes most recently released into blood from the bone marrow compartment contain the highest levels of cellular RNA. As reticulocytes mature, the cells gradually lose RNA, and this biochemical change can be used to determine not only the presence of reticulocytes, but also can serve as an indicator of reticulocyte maturational stages. Within 1 to 2 days from being released from the bone marrow compartment, the reticulocytes lose RNA to a point where the cells become indistinguishable from mature RBCs.
As a result of the foregoing, reticulocytes can be distinguished from mature red blood cells by the presence in reticulocytes of cellular RNA. Other less prevalent methods of identifying reticulocytes involve staining of mitochondria, ribosomes, and other cytoplasmic organelles (with so-called supravital dyes, such as new methylene blue, brilliant cresyl blue, and acridine orange), as well as methods involving recognition of cell surface markers unique to reticulocytes. The reticulocyte percentage is then multiplied by the red cell count in order to provide the number of reticulocytes per microliter.
Reticulocytes require 3 to 4 days to mature into non-stainable red blood cells, with about 2 to 3 days of this period being spent in the bone marrow and about 1 to 2 days being spent in the peripheral blood. The reticulocyte count can be clinically significant, if accurately measured. Levels approaching 3% of the total number of circulating red cells may indicate increased marrow activity, e.g., when blood synthesis is stimulated with erythropoietin. In contrast, levels below about 0.5% can be an indication of bone marrow incompetence. Hence, a reticulocyte count is an effective measure of marrow erythroid output.
Many approaches have been described for determining absolute and/or relative reticulocyte levels. Although such approaches have traditionally been performed manually, automated procedures are being used with increasing frequency. An increasing number of manufacturers of automated cell counting instruments have added the ability to count reticulocytes to their systems. Additionally, some instruments provide the ability to measure the relative maturity of reticulocytes, which is inversely proportional to the amount of stainable matter (e.g., RNA) within the cell. This indicates the relative age of the reticulocyte leaving the bone marrow. Such values may be referred to as the immature reticulocyte fraction (“IRF”), the reticulocyte maturation index (“RMI”), and other such terms commonly used to describe this measurement.
The newest of the cell counting instruments include the reticulocyte count, complete blood count (“CBC”), and the white blood cell (“WBC”) differential count. However, current controls for such instruments are separate products (i.e., separate CBC/WBC differential control and separate reticulocyte control) that must be run on these instruments in two distinct steps. In general, a CBC plus differential control critiques the ability of a diagnostic instrument to correctly determine the total white cell count and the percentage of the five major classes of white blood cells (leukocytes) commonly found in circulation which comprise this total, namely, lymphocytes, neutrophils, monocytes, eosinophils, and basophils, as well as total RBCs and platelets in the sample. When using these latest counting instruments, the CBC/WBC differential control is run and recovered values for this control are compared with expected values. Thereafter, the reticulocyte only control is run and recoveries are compared with the expected values.
Thus, the present inventors believe it would be advantageous to provide a single hematology control that allows measurement of the formed elements of blood, including reticulocytes, red blood cells, white blood cells, (and subpopulations thereof) and platelets. Such a unitary control would avoid the necessity of performing separate counts to obtain values for the components of whole blood.
Each reticulocyte counting method relies upon a standardized reticulocyte control to assess the accuracy and reliability of the results. Reticulocyte-only controls have been provided in a number of different forms. Human blood is generally considered a poor source of reticulocytes for controls, because it is typically too low in reticulocyte count to be useful for the preparation of a wide range of control levels.
A control composition known as Retic-C™ is available in three control levels from Beckman/Coulter Corporation (Miami, Fla.). This product includes avian red blood cells as reticulocyte analogues. Avian RBCs are significantly larger than human reticulocytes and, in contrast to reticulocytes, also contain a nucleus. Because these cells are not true reticulocytes, they do not stain in the manner common to reticulocytes. As a result, the composition is limited to use on Coulter automated instruments such as the Coulter STKS™.
Another reticulocyte-only control composition is a reticulocyte analogue product available as the Retic-CHEX™ from Streck Laboratories (Omaha, Nebr.). This control contains a reticulocyte analogue that suffers from poor staining intensity and displays characteristics only somewhat like that of true reticulocytes. Yet other control compositions, both of which are manufactured by Streck Laboratories, include the Test Point™ product (available in 2% and 5% levels for use with Bayer instruments), and a 2% and 5% level control available for instruments manufactured by Sysmex. Both compositions are limited in that they provide only two reticulocyte levels, with the upper level being significantly lower than desired.
The present inventors previously described a reticulocyte-only control composition comprising stabilized, maturation-arrested porcine reticulocytes in a red blood cell base, wherein the red blood cell base comprises mature erythrocytes. The present inventors have also described methods of preparing and methods of using such a reticulocyte control. See U.S. Pat. Nos. 5,858,789 and 5,736,402, and 5,945,340 (all of which are commonly owned by the assignee of the present application, and the disclosure of each is incorporated by reference). Unlike the controls described above, this reticulocyte control contains true reticulocytes, obtained from pigs. By avoiding the use of reticulocyte analogs as described above in connection with other commercially available products, this control provides a more accurate reticulocyte count. As described in the cited patents, mature erythrocytes for the control can be provided from porcine, human, or other mammalian sources.
The above reticulocyte controls provide stand-alone controls that measure the levels of only reticulocy
Fredrikson & Byron PA
Research & Diagnostic Systems, Inc.
Wallenhorst Maureen M.
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