CA1120835A - Multiple analysis hematology reference control reagent and method of making the same - Google Patents
Multiple analysis hematology reference control reagent and method of making the sameInfo
- Publication number
- CA1120835A CA1120835A CA000329726A CA329726A CA1120835A CA 1120835 A CA1120835 A CA 1120835A CA 000329726 A CA000329726 A CA 000329726A CA 329726 A CA329726 A CA 329726A CA 1120835 A CA1120835 A CA 1120835A
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- CA
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- Prior art keywords
- reference control
- urea
- control
- platelet
- suspension
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 239000013643 reference control Substances 0.000 title claims abstract description 52
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 4
- 238000004458 analytical method Methods 0.000 title claims abstract 4
- 239000003153 chemical reaction reagent Substances 0.000 title abstract description 21
- 210000001772 blood platelet Anatomy 0.000 claims abstract description 98
- 210000003743 erythrocyte Anatomy 0.000 claims abstract description 54
- 210000004369 blood Anatomy 0.000 claims abstract description 50
- 239000008280 blood Substances 0.000 claims abstract description 50
- 238000000034 method Methods 0.000 claims abstract description 18
- 238000005259 measurement Methods 0.000 claims abstract description 13
- 238000012544 monitoring process Methods 0.000 claims abstract description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 71
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 55
- 239000004202 carbamide Substances 0.000 claims description 55
- 239000000725 suspension Substances 0.000 claims description 44
- 239000011780 sodium chloride Substances 0.000 claims description 37
- 241001465754 Metazoa Species 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 230000001627 detrimental effect Effects 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 7
- 238000012360 testing method Methods 0.000 claims description 5
- 235000021120 animal protein Nutrition 0.000 claims description 4
- 230000002939 deleterious effect Effects 0.000 claims description 4
- 239000012460 protein solution Substances 0.000 claims description 4
- 230000002489 hematologic effect Effects 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 150000003841 chloride salts Chemical class 0.000 claims 5
- 210000002381 plasma Anatomy 0.000 claims 2
- 210000004027 cell Anatomy 0.000 abstract description 23
- 210000000265 leukocyte Anatomy 0.000 abstract description 16
- 102000001554 Hemoglobins Human genes 0.000 abstract description 14
- 108010054147 Hemoglobins Proteins 0.000 abstract description 14
- 238000004820 blood count Methods 0.000 abstract description 9
- 238000009826 distribution Methods 0.000 abstract description 9
- 238000005534 hematocrit Methods 0.000 abstract description 9
- 238000002405 diagnostic procedure Methods 0.000 abstract description 4
- 239000004615 ingredient Substances 0.000 abstract description 2
- 230000002452 interceptive effect Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000006285 cell suspension Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 3
- 230000002934 lysing effect Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000010836 blood and blood product Substances 0.000 description 2
- 210000000601 blood cell Anatomy 0.000 description 2
- 229940125691 blood product Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000834 fixative Substances 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 206010018910 Haemolysis Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- COQLPRJCUIATTQ-UHFFFAOYSA-N Uranyl acetate Chemical compound O.O.O=[U]=O.CC(O)=O.CC(O)=O COQLPRJCUIATTQ-UHFFFAOYSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 238000004159 blood analysis Methods 0.000 description 1
- 239000012503 blood component Substances 0.000 description 1
- 210000001217 buttock Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 102000018146 globin Human genes 0.000 description 1
- 108060003196 globin Proteins 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/96—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood or serum control standard
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2496/00—Reference solutions for assays of biological material
- G01N2496/05—Reference solutions for assays of biological material containing blood cells or plasma
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Urology & Nephrology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Cell Biology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A single diagnostic test reagent for use as a multiple analysis hematology reference control for monitoring the precision and accuracy of measurements or determinations of red blood cell, white blood cell and platelet blood cell counting, hemoglobin content, hematocrit, mean cell volume and mean platelet volume determination, red cell distribution width and platelet distribution width determination, and determination of mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and thrombocytocrit. The control reagent includes ingredients for monitoring platelet parameters also notwithstanding that potential interfering effects of red blood cells normally observed in blood specimens also are present in the control reagent. The control reagent is suitable for use in automated or semi-automated hematology instruments and by users of manual methodologies.
The invention includes a method of making said control reagent.
A single diagnostic test reagent for use as a multiple analysis hematology reference control for monitoring the precision and accuracy of measurements or determinations of red blood cell, white blood cell and platelet blood cell counting, hemoglobin content, hematocrit, mean cell volume and mean platelet volume determination, red cell distribution width and platelet distribution width determination, and determination of mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and thrombocytocrit. The control reagent includes ingredients for monitoring platelet parameters also notwithstanding that potential interfering effects of red blood cells normally observed in blood specimens also are present in the control reagent. The control reagent is suitable for use in automated or semi-automated hematology instruments and by users of manual methodologies.
The invention includes a method of making said control reagent.
Description
l~LZV83~
BACKGROUND OF THE INVENTION
This invention concerns a stable hematology reference control reagent suitable for use in common medical diagnostic procedures to analyze and test a patient's blood sample for making classic determinations with respect to the blood sample and more particularly, provides a novel diagnostic test control reagent which lncludes ingredients providing the control reagent with the capability of monitorlng the desired platelet parameters of the patient's blood sample as well as the seven classic determinations or parameters with respect to the blood sample. In other words, the invention provides a single hematology reference control reagent which can be used for monitoring the precision and accuracy of the classic hematology measurements or determinations i.e. red blood cell count (RBC), white blood cell count (W~C), hematocrit (HCT), the hemoglobin (HGB), the mean corpuscular he globin (MCH), ~he mean cor-puscular volu~e (MCV) and the mean corpuscular hemoglobin concentration (MCHC) and as a control also for monitoring the accuracy and precision of the measure-ment and determination of platelet parameters such as platelet~count, mean platelet volume, platelet volume fraction (thrombocytocrit) and platelet distribution width using the same whole blood product that is conventionally used for the control for the previously mentioned classical hematology para-meters.
It is a co~mon medical diagnostic procedure to analyze and test ablood sample of a patlent in order to make certaln classic determinations wlth respect to the blood sample. This procedure is an important diagnostic tool for the physician. As a result of modern technological advances, there have been automated instruments developed which will accept a patient's blood sample and process the sample automatically and continuously to provide the parameters or determinations described above as the seven classic parameters X ~
1120~35 of a blood ~ample. An instrument which will accept a patient's blood sample and process same automatically and continuously to provide the6e seven classic parameters or determinations enumerated is described and claimed in U.S. Patent No. 3,549,994. Said U.S. Patent 3,549,994 provides acceptable definitions of such parameters and illuminates the problems to be solved in handling of the blood sample as it is drawn through the fluid system of said patented apparatus.
Coulter Electronics, Inc. of Hialeah, Florida, the assignee of this patent application, also manufacturers and sells other blood cell counting and analyzing instruments which are less sophisticated than the apparatus of said U.S. Patent 3,549,994 but which are operated to determine red blood cell and white blood cell counts, hemoglobin concentration and their collected indices such as HCT, MCV, MCH and MCHC.
In the use of such an instrument which may be referred to herein, at times, by the registered trademark "COULTER COUNTER" owned by Coulter Electronics, Inc., there is required to be employed a multi-purpose diluent comprising an electrolyte which enables electronic measurements to be made by the COULTER
COUNTE ~ instrument. A suitable multi-purpose diluent for use in blood analysis by an electronic instrument such as the COULTER COUNTE ~ is described and claimed in U.S. Patent 3,962,125.
A suitable reagent for determing leukocytes and hemoglobin in the blood sample by means of a high speed automated hematology instrument such AS
the COULTER COUNTE ~ is described in U.S. Patent 3,874,852 lssued April 1, 1975.
The reagent described and claimed in said patent i9 a lysing reagent for con-verting hemoglobin to a chromogen for making the desired deter~inations.
Coulter Electronics, Inc. has heretofore provided a hematology reference control for accuracy in electronic estimatlon of blood cell values capable of functioning with the diluent and lysing reagents discussed above.
X
'., ~
' 112(~3S
One such reference control has been sold by Coulter Electronics under its registered Trademark 4C which comprised a modified whole blood hematology reference control prepared from fresh human blood. Fixed erythrocytes were added to simulate leukocytes. This reference control had seven known blood values which were stable for a desired period of time. The reference control was prepared for use with the COULTER COUNTE ~ and accessory mean corpuscular volume hematacrit computers and hemoglobinominators. When used with the blood diluent identified above, it served as a check on accuracy of dilution, red blood cell counts, and MCV-Hematocrit computer calibration. After addltion of a lysing reagent~ the reference control served as a check on white blood cell counts. Thus, the so-called 4C~ hematology reference control was utilized in the COULTER COUNTE ~ for electronic estimation of red and white blood cells, hematocrit, mean corpuscular volume, hemoglobin, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration. Other hematology reference controls also were available for use with the COULTER COUNTE ~ which comprise stabilized human red blood cell suspensions such as the product known as Baker Haem ~ of J. P. Baker Chemical Corporation or the product known as CH-6 of the Dade Reagent Company of Hialeah, Florida. However, none of these mentioned hematology control reagents were capable of being used for testing accuracy of measurements of platelet parameters. Consequently, for making such determinations, a separate control had to be employed for monitoring the platelet parameters. In other words, a separate control had to be employed for making the platelet determinations and the hematology control reagents for making the seven classical measurements or parameter determinations could not be employed for platelet control functions.
Further, prior art platelet counting has been inadequate because of the lack of stable platelet controls containing other blood components, namely, , i X~
red blood cells. Thus, the increasing availability of instrumentation for distinguishing platelets from red blood cellq and automatically performing platelet counts has created a great need for stable control products which contain both platelets and red blood cells.
The single hematology control of this invention includes the capability of monitoring platelet parameterg as well as the seven classic para-meters of hematology measurements. This hematology control has the advantage in that it elim~nates the need for a separate control material for monitoring platelet parameters and provides a more meaningful determination of platelet parameters in that the potential interfering red blood cells, red blood cell metabolities, etc., normally observed in patient blood specimen~ are present in the control material of the invention. This is especially important for platelet counts performed with manual methodologies using light microscopy or phase microscopy, where great skills on the part of laboratory technologists is required to adequately differentiate blood platelets from red blood cells and other cellular materials. The sub~ect invention also provides a means for monitoring these measurements using manual methodology or automated or semi-automated hematology instruments for hematology measurements along with a means for tes~ing accuracg of platele~ count, mean platelet volume, platelet volume fraction (thrombocytocrit) and platelet distribution based on the use in the reference control of the present invention of the same whole blood product which is conventionally used for control of the classic seven hema- !
tology parameters.
SUMMARY OF THE INVENTION
This invention consists of a stable whole blood co~trol containing ; platelets prepared by adding freshly procured human blood platelets or animal blood platelets either natively drawn or preserved through chemical or physical , fixation to a conventional, commercially available whole blood hematology control, such as said 4 ~. Baker Haem- ~ or Dade CH-6 ~. Such heretofore conventional, commercially available whole blood hematology control reagents are conditioned in accordance with the invention by adding sodium chloride and urea. The sodium chloride and urea may be added direc~ly to the whole blood control or may be dissolved first in water and then added to the whole blood control. The components are present and/or are added ln proportion such that the values for WBC, RBC, ~GB, HCT, MCV, MCH, MCHC, red cell distribution width, platelet count, mean platelet volume, thrombocytocrit and platelet volume width distribution approximate those found in normally occurring human blood specimens and which can be measured by using a variety of known manual or automatic instrumentation methodologies. The suspension medium can comprise an artificial medium, human or animal plasma or animal protein solutions.
The 4 ~ product of Coulter Electronics, Inc. is a stable reference control which was especially suitable for use with the COULTER COUNTE ~ I
instrument when establishing standards of quality control for the performance of the instrument. A correctly calibrated and functioning instrument is utilized to provide the seven measured or calculated parameters within a range of expected results when the 4 ~ is used.
BACKGROUND OF THE INVENTION
This invention concerns a stable hematology reference control reagent suitable for use in common medical diagnostic procedures to analyze and test a patient's blood sample for making classic determinations with respect to the blood sample and more particularly, provides a novel diagnostic test control reagent which lncludes ingredients providing the control reagent with the capability of monitorlng the desired platelet parameters of the patient's blood sample as well as the seven classic determinations or parameters with respect to the blood sample. In other words, the invention provides a single hematology reference control reagent which can be used for monitoring the precision and accuracy of the classic hematology measurements or determinations i.e. red blood cell count (RBC), white blood cell count (W~C), hematocrit (HCT), the hemoglobin (HGB), the mean corpuscular he globin (MCH), ~he mean cor-puscular volu~e (MCV) and the mean corpuscular hemoglobin concentration (MCHC) and as a control also for monitoring the accuracy and precision of the measure-ment and determination of platelet parameters such as platelet~count, mean platelet volume, platelet volume fraction (thrombocytocrit) and platelet distribution width using the same whole blood product that is conventionally used for the control for the previously mentioned classical hematology para-meters.
It is a co~mon medical diagnostic procedure to analyze and test ablood sample of a patlent in order to make certaln classic determinations wlth respect to the blood sample. This procedure is an important diagnostic tool for the physician. As a result of modern technological advances, there have been automated instruments developed which will accept a patient's blood sample and process the sample automatically and continuously to provide the parameters or determinations described above as the seven classic parameters X ~
1120~35 of a blood ~ample. An instrument which will accept a patient's blood sample and process same automatically and continuously to provide the6e seven classic parameters or determinations enumerated is described and claimed in U.S. Patent No. 3,549,994. Said U.S. Patent 3,549,994 provides acceptable definitions of such parameters and illuminates the problems to be solved in handling of the blood sample as it is drawn through the fluid system of said patented apparatus.
Coulter Electronics, Inc. of Hialeah, Florida, the assignee of this patent application, also manufacturers and sells other blood cell counting and analyzing instruments which are less sophisticated than the apparatus of said U.S. Patent 3,549,994 but which are operated to determine red blood cell and white blood cell counts, hemoglobin concentration and their collected indices such as HCT, MCV, MCH and MCHC.
In the use of such an instrument which may be referred to herein, at times, by the registered trademark "COULTER COUNTER" owned by Coulter Electronics, Inc., there is required to be employed a multi-purpose diluent comprising an electrolyte which enables electronic measurements to be made by the COULTER
COUNTE ~ instrument. A suitable multi-purpose diluent for use in blood analysis by an electronic instrument such as the COULTER COUNTE ~ is described and claimed in U.S. Patent 3,962,125.
A suitable reagent for determing leukocytes and hemoglobin in the blood sample by means of a high speed automated hematology instrument such AS
the COULTER COUNTE ~ is described in U.S. Patent 3,874,852 lssued April 1, 1975.
The reagent described and claimed in said patent i9 a lysing reagent for con-verting hemoglobin to a chromogen for making the desired deter~inations.
Coulter Electronics, Inc. has heretofore provided a hematology reference control for accuracy in electronic estimatlon of blood cell values capable of functioning with the diluent and lysing reagents discussed above.
X
'., ~
' 112(~3S
One such reference control has been sold by Coulter Electronics under its registered Trademark 4C which comprised a modified whole blood hematology reference control prepared from fresh human blood. Fixed erythrocytes were added to simulate leukocytes. This reference control had seven known blood values which were stable for a desired period of time. The reference control was prepared for use with the COULTER COUNTE ~ and accessory mean corpuscular volume hematacrit computers and hemoglobinominators. When used with the blood diluent identified above, it served as a check on accuracy of dilution, red blood cell counts, and MCV-Hematocrit computer calibration. After addltion of a lysing reagent~ the reference control served as a check on white blood cell counts. Thus, the so-called 4C~ hematology reference control was utilized in the COULTER COUNTE ~ for electronic estimation of red and white blood cells, hematocrit, mean corpuscular volume, hemoglobin, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration. Other hematology reference controls also were available for use with the COULTER COUNTE ~ which comprise stabilized human red blood cell suspensions such as the product known as Baker Haem ~ of J. P. Baker Chemical Corporation or the product known as CH-6 of the Dade Reagent Company of Hialeah, Florida. However, none of these mentioned hematology control reagents were capable of being used for testing accuracy of measurements of platelet parameters. Consequently, for making such determinations, a separate control had to be employed for monitoring the platelet parameters. In other words, a separate control had to be employed for making the platelet determinations and the hematology control reagents for making the seven classical measurements or parameter determinations could not be employed for platelet control functions.
Further, prior art platelet counting has been inadequate because of the lack of stable platelet controls containing other blood components, namely, , i X~
red blood cells. Thus, the increasing availability of instrumentation for distinguishing platelets from red blood cellq and automatically performing platelet counts has created a great need for stable control products which contain both platelets and red blood cells.
The single hematology control of this invention includes the capability of monitoring platelet parameterg as well as the seven classic para-meters of hematology measurements. This hematology control has the advantage in that it elim~nates the need for a separate control material for monitoring platelet parameters and provides a more meaningful determination of platelet parameters in that the potential interfering red blood cells, red blood cell metabolities, etc., normally observed in patient blood specimen~ are present in the control material of the invention. This is especially important for platelet counts performed with manual methodologies using light microscopy or phase microscopy, where great skills on the part of laboratory technologists is required to adequately differentiate blood platelets from red blood cells and other cellular materials. The sub~ect invention also provides a means for monitoring these measurements using manual methodology or automated or semi-automated hematology instruments for hematology measurements along with a means for tes~ing accuracg of platele~ count, mean platelet volume, platelet volume fraction (thrombocytocrit) and platelet distribution based on the use in the reference control of the present invention of the same whole blood product which is conventionally used for control of the classic seven hema- !
tology parameters.
SUMMARY OF THE INVENTION
This invention consists of a stable whole blood co~trol containing ; platelets prepared by adding freshly procured human blood platelets or animal blood platelets either natively drawn or preserved through chemical or physical , fixation to a conventional, commercially available whole blood hematology control, such as said 4 ~. Baker Haem- ~ or Dade CH-6 ~. Such heretofore conventional, commercially available whole blood hematology control reagents are conditioned in accordance with the invention by adding sodium chloride and urea. The sodium chloride and urea may be added direc~ly to the whole blood control or may be dissolved first in water and then added to the whole blood control. The components are present and/or are added ln proportion such that the values for WBC, RBC, ~GB, HCT, MCV, MCH, MCHC, red cell distribution width, platelet count, mean platelet volume, thrombocytocrit and platelet volume width distribution approximate those found in normally occurring human blood specimens and which can be measured by using a variety of known manual or automatic instrumentation methodologies. The suspension medium can comprise an artificial medium, human or animal plasma or animal protein solutions.
The 4 ~ product of Coulter Electronics, Inc. is a stable reference control which was especially suitable for use with the COULTER COUNTE ~ I
instrument when establishing standards of quality control for the performance of the instrument. A correctly calibrated and functioning instrument is utilized to provide the seven measured or calculated parameters within a range of expected results when the 4 ~ is used.
2~ Also, the invention encompasses the disclosed method of making the stable reference control.
DETAILED DESCRIPTION OF THE INVENTION
This invention utilizes a combination of urea and sodium chloride as (1) a stabilizing agent for use with whole blood controls that include platelets and ~2) an inhibitor of the detrimental effects of animal and human red blood cell metabolites, by-products, and chemicals inherent to tile red blood cell and white blood cell on animal and human platelets.
i X
~ 77 ~,al7~7 ~ 71' 7 .. ~ `.7'_~
Urea alone previously has been employed as a stabilizing agent in pure suspensions of human blood platelets prepared as a control material to be used in connection with performing platelet counts. The human blood platelets prepared in this manner have been essentially in pure suspensions;
no residual red blood cells or white blood cells have been allowed to be present in such controls. The function of the added urea in such control suspensions simply has been to prevent the gradual disintegration of the platelets during subsequent storage over a period of time equaling several months. The overall effect has been to provide a suspension of platelets that remains relatively constant (+ 20%) in the number of blood platelets per unit volume. If the urea were not added, the number of particles per unit volume would gradually increase as the platelets began to disintegrate usually within several days.
Heretofore, red blood cells and white blood cells have not been allowed to be present in platelet controls. The reason is believed to be that these cells almost immediately cause platelets to aggregate and disintegrate, thereby destroying the effectiveness of the mixed control materialO In addition, urea in high concentrations was known to be detrimental to the stability and integrity of red blood cells, ~hereby apparently precluding its use as a preservative in suspensions containing red blood cells. As a result, prior known platelet controls have consisted simply of pure suspensions of human platelets in the presence of urea as a preservative, no red blood cells L
or other formed elements of the blood having been allowed to be present, there-by dimlnishing their effectiveness as control materials.
Until the present invention, there have been no known successful combinations of whole blood reference controls that contain preserved human platelets stabilized with two molar urea. In fact, present art teaches that . .
~.
~; ' ' ' :
:
~ZV83~
when two molar ures employed in this invention i9 added to human blood cells, the red blood cells are destroyed (Owen, J.D., "Computer Simulated Urea Reflection Coefficients in Human Red Blood Cellg", Biochem. et Biophys. Acta 443, 306-310, 1976; Saunders, A.M., Scott, F., "Hematologic Automation by Use of Continuous Flow Systems", J. Histochem. Cytochem. 22, 707-710, 1974).
We have discovered that urea in the presence of sodium chloride serves to prevent the deleterious effect of autologous red blood cells and white blood cells on blood platelets in the guspension. Consequently, we provide a stable blood platelet suspension that contains red blood cells and approximates the composition of human blood. There is provided a single stable suspension which contains both blood platelets and red blood cells, made possible through the use of a combination of urea and sodium chloride which is added to previously stabilized human red blood cell suspensions, such as Coulter 4C ~ Baker Haem-C ~, or Dade CH-60 ~ which can easily tolerate the otherwise detrimental effects of urea. The combination of urea, saline and the previously pre~erved red blood cell suspension is itself uniquely 6tuble and provides a compatible medium in which either native blood platelets or blood platelets that have been fixed using formaldehyde, glutaraldehyde, osmic acid or other chemical fixative agents can coexist in stable form.
Another derived benefit of this invention is that the combination of urea, saline and previously fixed red blood cell suspensions provides an environment in which the cell volume of individual blood platelets remain un- !
changed. By use of a combination blood platelet and red blood cell control suspension, it is now possible for laboratories to monitor the accuracy f platelet count, mean platelet volume (MPV) and platelet volume distribution (PDW~ measurements, so that effective patient measurements may be performed on a routine basis.
llZV83S
A whole blood control containing platelets according to the inveneion was prepared by mixing conventional, commercially available whole blood control products such as Coulter 4C ~ Baker Haem-C ~ or Dade CH-60 ~ with freshly collected or chemically preserved human blood platelets or animal blood plate-lets and a mlxture of urea and sodium chloride. After stabilizing for several days, the suspension was found to have stable values for the hematology para-meters WBC, RBC, HGB, MCV, HCT, MCH, MCHC, red cell distribution width, platelet count, mean platelet volume, thrombocytocrit and platelet volume distribution width. The detrimental effects of the red blood cells and white cell analogs present in the whole blood controls used as substrate was prevented by the addition of sodium chloride and urea and the material could be used as a stable control for several months.
MET~OD OF PREPARING CONTROL REAGENT
The first step, in one mode of preparing a whole blood platelet control of this invention was to procure a volume of conventionally manufactured whole blood hematology reference control material such as Coulter 4C-~, Baker Haem-C ~ or Dade CH-60 ~ or any other commercially manufactured or other suitable whole blood hematology control material comprising treated erythrocytes in an artificial medium. Then human or animal blood platelets were procured through venipuncture or other bleeding procedure of the donor human or animal subject. The human or animal blood platelets can then be used in any manner whatsoever either as freshly obtained or after any of the chemical or physical fixative procedures have been applied to the platelets.
The next step was to prepare a solution of urea and sodium chloride in water or other vehicle for subsequent mixing with the whole blood control and the platelets. In the solution, the urea and sodium chloride are added in the following relationship, generally, to 1000 ml of medium, e.g. water, `
iizv~3s Urea 120 gms Sodium Chloride 9 gms Variations in urea used in one liter of medium range between 100 and 140 gms and sodium chloride, between 8 and 10 gms. ~he urea and sodium chloride were either mixed with each other and subsequently added to the control suspension or were dissolved in approximately one liter of medium, e.g. water, and the resulting solution added at that time to the control material in amounts ~o be discussed hereinafter. A salt equivalent ~o sodium chloride may be utilized.
The final step was to simply mix the commercially or lndividually prepared whole blood hematology reference control, untreated, unstabili~ed or previously stabilized platelet suspension and the solution of urea and sodium chloride together. After mixing for approximately 30 minutes, and allowing the cell suspension to stabilize for approximately 48 hours, the control material was stable for complete hematology parameters, as stated. A selective suspension of red blood cells and platelets i8 realized. The suspen6ion medium can be artificial, or a human or animal plasma or human or animal protein solutions.
The following examples show how suspension~ of treated red blood cells, platelets and solutions of sodium chloride and urea can be mixed together to ~20 provide the whole blood control of the present invention, as described:
(I) A solution containing 24 grams of urea and 1.8 grams of sodium chloride in 200 ml of distilled water is added to 1000 ml of a treated whole blood suspension such as Coulter 4C.
A solution containing 2.4 grams of urea and 0.18 grams of sodium chloride in 20 ml of distilled water is added to 100 ml of a hu~an platelet suspension.
Each resulting suspenslon is mixed for several minutes and then the treated red blood cell suspension and platelet suspension, both containing urea, _ 9 _ 1~2V~
are mixed with each other thoroughly for approximately thirty minutes and allowed to subsequently stabilize for approximately 48 hours to provide the reference control of this invention.
(2) 20.0 grams of urea and 1.5 grams of sodium chloride are directly added to 1000 ml of a treated whole blood suspension such as Coulter 4C.
100 ml of a human platelet suspension is then directly added to the treated whole blood control suspension containing urea and sodium chloride. The suspension is mixed for approximately 30 minutes and allowed to stabilize for 48 hours to provide the reference control of this invention. It will be noted from this embodiment that it i8 not required to solublize the urea and sodium chlorlde prior to admixture with the treated whole blood suspension.
DETAILED DESCRIPTION OF THE INVENTION
This invention utilizes a combination of urea and sodium chloride as (1) a stabilizing agent for use with whole blood controls that include platelets and ~2) an inhibitor of the detrimental effects of animal and human red blood cell metabolites, by-products, and chemicals inherent to tile red blood cell and white blood cell on animal and human platelets.
i X
~ 77 ~,al7~7 ~ 71' 7 .. ~ `.7'_~
Urea alone previously has been employed as a stabilizing agent in pure suspensions of human blood platelets prepared as a control material to be used in connection with performing platelet counts. The human blood platelets prepared in this manner have been essentially in pure suspensions;
no residual red blood cells or white blood cells have been allowed to be present in such controls. The function of the added urea in such control suspensions simply has been to prevent the gradual disintegration of the platelets during subsequent storage over a period of time equaling several months. The overall effect has been to provide a suspension of platelets that remains relatively constant (+ 20%) in the number of blood platelets per unit volume. If the urea were not added, the number of particles per unit volume would gradually increase as the platelets began to disintegrate usually within several days.
Heretofore, red blood cells and white blood cells have not been allowed to be present in platelet controls. The reason is believed to be that these cells almost immediately cause platelets to aggregate and disintegrate, thereby destroying the effectiveness of the mixed control materialO In addition, urea in high concentrations was known to be detrimental to the stability and integrity of red blood cells, ~hereby apparently precluding its use as a preservative in suspensions containing red blood cells. As a result, prior known platelet controls have consisted simply of pure suspensions of human platelets in the presence of urea as a preservative, no red blood cells L
or other formed elements of the blood having been allowed to be present, there-by dimlnishing their effectiveness as control materials.
Until the present invention, there have been no known successful combinations of whole blood reference controls that contain preserved human platelets stabilized with two molar urea. In fact, present art teaches that . .
~.
~; ' ' ' :
:
~ZV83~
when two molar ures employed in this invention i9 added to human blood cells, the red blood cells are destroyed (Owen, J.D., "Computer Simulated Urea Reflection Coefficients in Human Red Blood Cellg", Biochem. et Biophys. Acta 443, 306-310, 1976; Saunders, A.M., Scott, F., "Hematologic Automation by Use of Continuous Flow Systems", J. Histochem. Cytochem. 22, 707-710, 1974).
We have discovered that urea in the presence of sodium chloride serves to prevent the deleterious effect of autologous red blood cells and white blood cells on blood platelets in the guspension. Consequently, we provide a stable blood platelet suspension that contains red blood cells and approximates the composition of human blood. There is provided a single stable suspension which contains both blood platelets and red blood cells, made possible through the use of a combination of urea and sodium chloride which is added to previously stabilized human red blood cell suspensions, such as Coulter 4C ~ Baker Haem-C ~, or Dade CH-60 ~ which can easily tolerate the otherwise detrimental effects of urea. The combination of urea, saline and the previously pre~erved red blood cell suspension is itself uniquely 6tuble and provides a compatible medium in which either native blood platelets or blood platelets that have been fixed using formaldehyde, glutaraldehyde, osmic acid or other chemical fixative agents can coexist in stable form.
Another derived benefit of this invention is that the combination of urea, saline and previously fixed red blood cell suspensions provides an environment in which the cell volume of individual blood platelets remain un- !
changed. By use of a combination blood platelet and red blood cell control suspension, it is now possible for laboratories to monitor the accuracy f platelet count, mean platelet volume (MPV) and platelet volume distribution (PDW~ measurements, so that effective patient measurements may be performed on a routine basis.
llZV83S
A whole blood control containing platelets according to the inveneion was prepared by mixing conventional, commercially available whole blood control products such as Coulter 4C ~ Baker Haem-C ~ or Dade CH-60 ~ with freshly collected or chemically preserved human blood platelets or animal blood plate-lets and a mlxture of urea and sodium chloride. After stabilizing for several days, the suspension was found to have stable values for the hematology para-meters WBC, RBC, HGB, MCV, HCT, MCH, MCHC, red cell distribution width, platelet count, mean platelet volume, thrombocytocrit and platelet volume distribution width. The detrimental effects of the red blood cells and white cell analogs present in the whole blood controls used as substrate was prevented by the addition of sodium chloride and urea and the material could be used as a stable control for several months.
MET~OD OF PREPARING CONTROL REAGENT
The first step, in one mode of preparing a whole blood platelet control of this invention was to procure a volume of conventionally manufactured whole blood hematology reference control material such as Coulter 4C-~, Baker Haem-C ~ or Dade CH-60 ~ or any other commercially manufactured or other suitable whole blood hematology control material comprising treated erythrocytes in an artificial medium. Then human or animal blood platelets were procured through venipuncture or other bleeding procedure of the donor human or animal subject. The human or animal blood platelets can then be used in any manner whatsoever either as freshly obtained or after any of the chemical or physical fixative procedures have been applied to the platelets.
The next step was to prepare a solution of urea and sodium chloride in water or other vehicle for subsequent mixing with the whole blood control and the platelets. In the solution, the urea and sodium chloride are added in the following relationship, generally, to 1000 ml of medium, e.g. water, `
iizv~3s Urea 120 gms Sodium Chloride 9 gms Variations in urea used in one liter of medium range between 100 and 140 gms and sodium chloride, between 8 and 10 gms. ~he urea and sodium chloride were either mixed with each other and subsequently added to the control suspension or were dissolved in approximately one liter of medium, e.g. water, and the resulting solution added at that time to the control material in amounts ~o be discussed hereinafter. A salt equivalent ~o sodium chloride may be utilized.
The final step was to simply mix the commercially or lndividually prepared whole blood hematology reference control, untreated, unstabili~ed or previously stabilized platelet suspension and the solution of urea and sodium chloride together. After mixing for approximately 30 minutes, and allowing the cell suspension to stabilize for approximately 48 hours, the control material was stable for complete hematology parameters, as stated. A selective suspension of red blood cells and platelets i8 realized. The suspen6ion medium can be artificial, or a human or animal plasma or human or animal protein solutions.
The following examples show how suspension~ of treated red blood cells, platelets and solutions of sodium chloride and urea can be mixed together to ~20 provide the whole blood control of the present invention, as described:
(I) A solution containing 24 grams of urea and 1.8 grams of sodium chloride in 200 ml of distilled water is added to 1000 ml of a treated whole blood suspension such as Coulter 4C.
A solution containing 2.4 grams of urea and 0.18 grams of sodium chloride in 20 ml of distilled water is added to 100 ml of a hu~an platelet suspension.
Each resulting suspenslon is mixed for several minutes and then the treated red blood cell suspension and platelet suspension, both containing urea, _ 9 _ 1~2V~
are mixed with each other thoroughly for approximately thirty minutes and allowed to subsequently stabilize for approximately 48 hours to provide the reference control of this invention.
(2) 20.0 grams of urea and 1.5 grams of sodium chloride are directly added to 1000 ml of a treated whole blood suspension such as Coulter 4C.
100 ml of a human platelet suspension is then directly added to the treated whole blood control suspension containing urea and sodium chloride. The suspension is mixed for approximately 30 minutes and allowed to stabilize for 48 hours to provide the reference control of this invention. It will be noted from this embodiment that it i8 not required to solublize the urea and sodium chlorlde prior to admixture with the treated whole blood suspension.
(3) A solution containing 26.6 grams of urea and 1.98 grams of sodium chloride in 220 ml of distilled water is directly added to 1000 ml of a treated whole blood control suspension such as Coulter 4C. 100 ml of a human platelet suspension is then added. The resulting suspension i8 mixed for approximately 30 minutes and allowed to stabilize for 48 hours to provide the refe-rence control of this invention.
In the reference control of the present invention, urea is present ; in the relationship of between about 16.7 to about 23.3 grams in approximately one liter of the control of the invention.
Also, in the reference control of the invention, sodium chloride is added, in relation to the urea concentration, i.e., 1.33 to 1.67 grams sodium chloride to each liter of reference control containing the aforementioned 16.7 to 23.3 grams of urea.
It is to be understood that this added amount of sodium chloride is - additional to the residual salinity of the treated whole blood suspension or platelet suspension to which same is added. It will further be understood that X
1~5 the significant factor in accordance with the lnvention, i8 the relationship between the urea and the added sodium chloride, not the total sallnity of the reference control.
It is this relationghip between the urea and the added sodium chloride that enables the preparation of a stable reference control containing at least both red blood cells and platelets.
The following will be noted with respect to the effect and importance of added sodium chloride. Most Rtarting materials used in the present sus-pension, stabilized blood controls and platelet suspensions contain previously added sodium chloride. The invention describes adding a mixture of urea and sodium chloride to these materials so that they may co-exist. The purpose of the added sodium chloride is to maintain the osmotic and ionic balance when urea is added.
One should consider that there exists an independence of cell count (platelets, red blood cells and white blood cells) and cell characteristics (mean cell volume, and cell morphology) from chemical composition of the reference control of the invention. The chemical composition of the reference control of the invention consisting of previously stabilized red blood cells and fixed red blood cells, platelets, and added urea and added sodium chloride, 20~ is independent of the desired cell count and cell characteri~tics. For ;;
example, the invention allows approximately lOO ml of a suspension containing either very many platelets or very few platelets to be added to approximately lOOO ml of an existing whole blood control such a~ Coulter 4C havlng a high or low red blood count in white blood count value, in the high or low mean cell line value so that the resulting approximate volume of 1100 ml of cell sus-pension has relatively few or =any platelets, red blood cells and white blood cells, depending upon the levels desired.
i 112~83S .
As used in the art and in this specification, the terms "stsbilized"
and "treated" as applied to blood cell9, are synonymous and are contrasted with the term "fixed cells". Both the initial starting materials described in this invention (the previously stabilized cell control and the platelets) can consist of either stabilized or treated cells, chemically fixed cells or native untreated cells.
For example, Coulter 4C consists of stabilized (treated) red blood cells and chemically fixed red blood cells.
Stabilized (treated) cells consist of human or non-human cells to which various preservatives have been added to prolong their life.
Chemically fixed cells consist of human or non-human cells which have been chemically hardened, i.e. tanned, usually by chemicals such as glutaraldehyde, formaldehyde, osmic acid or uranyl acetate.
Stabilized cells are generally susceptable to hemolysis or disruption in the precense of surfactants or low osmolality~ while chemically fixed cells retain thelr morphology under such environments.
As explained, the hematology reference control embodying the invention was suitable for use in making manual determinations as well.
Persons skilled in the art know the methodologies used for manual determina-tions of RBC, WBC, HGB and HCT using such control reagents. It is believedunnecessary to explain in detail these manual methodologies, it being suffi-cient to appreciate that the reference control of the invention can be used both for instrumentation and manual methodologies, a~ de~cribed herein.
In the reference control of the present invention, urea is present ; in the relationship of between about 16.7 to about 23.3 grams in approximately one liter of the control of the invention.
Also, in the reference control of the invention, sodium chloride is added, in relation to the urea concentration, i.e., 1.33 to 1.67 grams sodium chloride to each liter of reference control containing the aforementioned 16.7 to 23.3 grams of urea.
It is to be understood that this added amount of sodium chloride is - additional to the residual salinity of the treated whole blood suspension or platelet suspension to which same is added. It will further be understood that X
1~5 the significant factor in accordance with the lnvention, i8 the relationship between the urea and the added sodium chloride, not the total sallnity of the reference control.
It is this relationghip between the urea and the added sodium chloride that enables the preparation of a stable reference control containing at least both red blood cells and platelets.
The following will be noted with respect to the effect and importance of added sodium chloride. Most Rtarting materials used in the present sus-pension, stabilized blood controls and platelet suspensions contain previously added sodium chloride. The invention describes adding a mixture of urea and sodium chloride to these materials so that they may co-exist. The purpose of the added sodium chloride is to maintain the osmotic and ionic balance when urea is added.
One should consider that there exists an independence of cell count (platelets, red blood cells and white blood cells) and cell characteristics (mean cell volume, and cell morphology) from chemical composition of the reference control of the invention. The chemical composition of the reference control of the invention consisting of previously stabilized red blood cells and fixed red blood cells, platelets, and added urea and added sodium chloride, 20~ is independent of the desired cell count and cell characteri~tics. For ;;
example, the invention allows approximately lOO ml of a suspension containing either very many platelets or very few platelets to be added to approximately lOOO ml of an existing whole blood control such a~ Coulter 4C havlng a high or low red blood count in white blood count value, in the high or low mean cell line value so that the resulting approximate volume of 1100 ml of cell sus-pension has relatively few or =any platelets, red blood cells and white blood cells, depending upon the levels desired.
i 112~83S .
As used in the art and in this specification, the terms "stsbilized"
and "treated" as applied to blood cell9, are synonymous and are contrasted with the term "fixed cells". Both the initial starting materials described in this invention (the previously stabilized cell control and the platelets) can consist of either stabilized or treated cells, chemically fixed cells or native untreated cells.
For example, Coulter 4C consists of stabilized (treated) red blood cells and chemically fixed red blood cells.
Stabilized (treated) cells consist of human or non-human cells to which various preservatives have been added to prolong their life.
Chemically fixed cells consist of human or non-human cells which have been chemically hardened, i.e. tanned, usually by chemicals such as glutaraldehyde, formaldehyde, osmic acid or uranyl acetate.
Stabilized cells are generally susceptable to hemolysis or disruption in the precense of surfactants or low osmolality~ while chemically fixed cells retain thelr morphology under such environments.
As explained, the hematology reference control embodying the invention was suitable for use in making manual determinations as well.
Persons skilled in the art know the methodologies used for manual determina-tions of RBC, WBC, HGB and HCT using such control reagents. It is believedunnecessary to explain in detail these manual methodologies, it being suffi-cient to appreciate that the reference control of the invention can be used both for instrumentation and manual methodologies, a~ de~cribed herein.
Claims (21)
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A multiple analysis hematology reference control comprising a suspension of red blood cells and platelets in a saline medium which includes urea, said urea being present in at least a concentration normally detrimental to stability and integrity of red blood cells, said urea concentration not causing deleterious effects such that red blood cell and platelet parameters are generally stable and approximate those occuring in mammalian blood speci-mens, wherein said control is capable of being used for testing and the accuracy and precision of classical red blood cell and platelet parameters.
2. A reference control as described in claim 1 in which said medium is an artificial one.
3. A reference control as described in claim 1 in which said medium is a human or animal blood plasma.
4. A reference control as described in claim 1 in which said medium is a human or animal protein solution.
5. A reference control as described in claim 1 in which said plate-lets are of human or animal origin.
6. A reference control as described in claim 1 in which the urea is present in the ratio of between about 16.7 to 23.3 grams in approximately 1 liter of the reference control.
7. A reference control as described in claim 6 in which sodium chloride is added in the ratio of between 1.33 and 1.67 grams to approximately one liter of the reference control.
8. A multiple analysis hematology reference control comprising a single suspension of red blood cells and platelets, said suspension including urea and sodium chloride in a selected suspension medium which enables use of the control for monitoring the accuracy and precision of measurements or determinations of classical hematology parameters and platelet parameters of blood sample, said urea being present in at least a concentration normally detrimental to stability and integrity of red blood cells, said urea con-centration not causing deleterious effects such that red blood cell and platelet parameters are generally stable and approximate those occuring in mannalian blood specimens, wherein said reference control is capable of being used for testing the accuracy and precision of classical red blood cell and platelet parameters.
9. A reference control as described in claim 8 in which said medium is an artificial one.
10. A reference control as described in claim 8 in which said medium is a human or animal blood plasma.
11. A reference control as described in claim 8 in which said medium is a human or animal protein solution.
12. A reference control as described in claim 8 in which said plate-lets are of human or animal origin.
13. A reference control as described in claim 8 in which the urea is present in the ratio of between 16.7 and 23.3 grams in approximately one liter of the reference control.
14. A reference control as described in claim 13 in which sodium chloride is added in the relationship of between 1.33 and 1.67 grams in approximately one liter of said reference control.
15. A method of making a single hematological reference control for monitoring the accuracy of measurements of both conventional hematology para-meters and platelet parameters comprising:
A) preparing a stabilized suspension of human or animal blood platelets;
B) procuring a conventional whole blood hematology reference control comprising erythrcytes in a suspension medium;
C) mixing the stabilized platelet suspension and the reference control with a mixture of urea and sodium chloride or the like salt selected to be compatible with the hematology components of the mixture for a pre-selected period of time; and D) allowing the resultant suspension to stabilize for approximately 48 hours, said urea being present in at least a concentration normally detri-mental to stability and integrity of erythrocytes, said urea concentration not causing deleterious effects such that erythrocyte and platelet parameters are generally stable and approximate those occuring in mammalian blood specimens.
A) preparing a stabilized suspension of human or animal blood platelets;
B) procuring a conventional whole blood hematology reference control comprising erythrcytes in a suspension medium;
C) mixing the stabilized platelet suspension and the reference control with a mixture of urea and sodium chloride or the like salt selected to be compatible with the hematology components of the mixture for a pre-selected period of time; and D) allowing the resultant suspension to stabilize for approximately 48 hours, said urea being present in at least a concentration normally detri-mental to stability and integrity of erythrocytes, said urea concentration not causing deleterious effects such that erythrocyte and platelet parameters are generally stable and approximate those occuring in mammalian blood specimens.
16. The method as described in claim 15 in which the urea and chloride salt are mixed together and added to the control of paragraph (B) initially.
17. The method as described in claim 15 in which the urea and chloride salt are dissolved in a reasonable volume of water and then added to the control of paragraph (B).
18. The method as described in claim 15 in which a suspension medium is employed which is artificial or of a natural biological character.
19. The method as described in claim 15 in which the urea and chloride salt are dissolved in a reasonable volume of water and then added to the control of paragraph (B) and then the platelet suspension of paragraph (A) added thereto.
20. The method as described in claim 15 in which the urea and chloride salt are added respectively to the control of paragraph (B) and to the platelet suspension of paragraph (A) and the resulting suspensions admixed.
21. The method as described in claim 20 in which the urea and chloride salt are solublized before addition to said control of paragraph (B) and platelet suspension of paragraph (A).
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US91576178A | 1978-06-15 | 1978-06-15 | |
| US915,761 | 1978-06-15 | ||
| US44,841 | 1979-06-06 | ||
| US06/044,841 US4219440A (en) | 1979-06-06 | 1979-06-06 | Multiple analysis hematology reference control reagent and method of making the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1120835A true CA1120835A (en) | 1982-03-30 |
Family
ID=26722060
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000329726A Expired CA1120835A (en) | 1978-06-15 | 1979-06-14 | Multiple analysis hematology reference control reagent and method of making the same |
Country Status (11)
| Country | Link |
|---|---|
| AU (1) | AU525932B2 (en) |
| CA (1) | CA1120835A (en) |
| DE (1) | DE2923957A1 (en) |
| DK (1) | DK248679A (en) |
| ES (1) | ES481548A1 (en) |
| FR (1) | FR2432172A1 (en) |
| GB (1) | GB2023287B (en) |
| IL (1) | IL57562A0 (en) |
| IT (1) | IT1117245B (en) |
| NL (1) | NL7904656A (en) |
| SE (1) | SE7905238L (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4264470A (en) * | 1979-05-07 | 1981-04-28 | Coulter Electronics, Inc. | Selecting goat erythrocytes to simulate human platelets in hematologic reference controls |
| US6174728B1 (en) | 1998-04-03 | 2001-01-16 | Avl Medical Instruments Ag | Control or calibration standard for use with instruments for optical measurement of hemoglobin concentration in blood samples |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3558522A (en) * | 1969-03-05 | 1971-01-26 | Baxter Laboratories Inc | Hematology control standard comprising washed red blood cells and synthetic latex particles |
| US3640896A (en) * | 1970-04-13 | 1972-02-08 | Pfizer | Process for stabilizing fowl red blood cells |
| US3873467A (en) * | 1974-02-01 | 1975-03-25 | United Medical Lab Inc | Hematologic reference control |
| US4160644A (en) * | 1977-06-13 | 1979-07-10 | Streck Laboratories, Inc. | Platelet reference control and method of preparation |
-
1979
- 1979-06-13 DE DE19792923957 patent/DE2923957A1/en not_active Withdrawn
- 1979-06-13 ES ES481548A patent/ES481548A1/en not_active Expired
- 1979-06-14 IT IT49424/79A patent/IT1117245B/en active
- 1979-06-14 DK DK248679A patent/DK248679A/en not_active Application Discontinuation
- 1979-06-14 FR FR7915259A patent/FR2432172A1/en not_active Withdrawn
- 1979-06-14 NL NL7904656A patent/NL7904656A/en not_active Application Discontinuation
- 1979-06-14 GB GB7920790A patent/GB2023287B/en not_active Expired
- 1979-06-14 SE SE7905238A patent/SE7905238L/en not_active Application Discontinuation
- 1979-06-14 AU AU48067/79A patent/AU525932B2/en not_active Ceased
- 1979-06-14 CA CA000329726A patent/CA1120835A/en not_active Expired
- 1979-06-14 IL IL57562A patent/IL57562A0/en unknown
Also Published As
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| DK248679A (en) | 1979-12-16 |
| IT1117245B (en) | 1986-02-17 |
| NL7904656A (en) | 1979-12-18 |
| AU525932B2 (en) | 1982-12-09 |
| GB2023287B (en) | 1982-12-15 |
| GB2023287A (en) | 1979-12-28 |
| ES481548A1 (en) | 1980-07-01 |
| FR2432172A1 (en) | 1980-02-22 |
| SE7905238L (en) | 1979-12-16 |
| IL57562A0 (en) | 1979-10-31 |
| AU4806779A (en) | 1979-12-20 |
| IT7949424A0 (en) | 1979-06-14 |
| DE2923957A1 (en) | 1980-01-03 |
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