WO1991008460A1 - Direct fibrinogen assay - Google Patents

Direct fibrinogen assay Download PDF

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Publication number
WO1991008460A1
WO1991008460A1 PCT/US1990/006988 US9006988W WO9108460A1 WO 1991008460 A1 WO1991008460 A1 WO 1991008460A1 US 9006988 W US9006988 W US 9006988W WO 9108460 A1 WO9108460 A1 WO 9108460A1
Authority
WO
WIPO (PCT)
Prior art keywords
plasma
fibrinogen
sample
concentration
delta value
Prior art date
Application number
PCT/US1990/006988
Other languages
French (fr)
Inventor
Julie Frances Hoffman
Janet Black Callahan
Charles Hermas Swope
Original Assignee
Akzo N.V.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Akzo N.V. filed Critical Akzo N.V.
Priority to KR1019920701275A priority Critical patent/KR920704117A/en
Publication of WO1991008460A1 publication Critical patent/WO1991008460A1/en
Priority to FI922312A priority patent/FI922312A/en

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/84—Systems specially adapted for particular applications
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • 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
    • G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/745—Assays involving non-enzymic blood coagulation factors
    • G01N2333/75—Fibrin; Fibrinogen

Definitions

  • the invention relates to a method for determining the concentration of fibrinogen in blood plasma using thrombin as a reagent.
  • Prior methods of using thrombin to measure fibrinogen concentration include the Clauss method which is based on measuring the time it takes for a plasma-thrombin reaction to occur (clotting time) and the ACL3 fibrinogen assay.
  • the Clauss method is described in Manual of Hemostasis and Thrombosis, ed. 3, by Arthur R. Thompson and Laurence A. Harker, Appendix A, p. 179 (1983) and in Gerrinnunqs physioloqische neglected Methode zur Bestimmunq des Fibrinogens by A. Clauss, Acta Haematol, 17:237 (1957).
  • the ACL3 method is described in Method for the Determina ⁇ tion of Functional (Clottable) Fibrinogen by the New Family of ACL Coagulometers by E. Rossi, P. Mondonico, A. Lo abar- di, L. Preda, Thrombosis Research 52; 453-469 (1988). These methods rely on the measurement of a relevant parameter such as clotting time or changes in optical transmission and on multiple dilutions of a calibrator plasma to compensate conditions of the instrument and reagent at a given time. Using calibrator plasmas (i.e. plasma having known fibrinogen concentrations) "standard lines" or "calibration curves" must be constructed repeatedly whenever conditions warrant.
  • calibrator plasmas i.e. plasma having known fibrinogen concentrations
  • the relevant quantity such as clotting time
  • concentration is then "read" from the standard curve.
  • This process can involve considerable calculation, and is often tedious and time consuming.
  • the relevant quantity being measured is often instrument depen ⁇ dent, as well as reaction dependent.
  • the instrument used to measure the relevant parameter employs an electro-optical system in which scattered or transmitted light is detected
  • the value obtained from the measurement will depend on the signal level measured by the optical sensor, which in turn depends on the amount of light incident on the reaction vessel as well as the electronic gains used in association with the optical sensor.
  • the values of these quantities do not remain constant in time, nor do they remain constant from channel to channel or instrument to instrument.
  • the present invention provides a method for measuring the concentration of fibrinogen in a blood plasma sample.
  • a sample of plasma containing fibrinogen is provided in a container.
  • Thrombin is added to the sample and mixed with the sample to form a reaction mixture.
  • An initial optical transmit- tance is measured for the reaction mixture.
  • the thrombin and fibrinogen are allowed to react with each other in the reaction mixture.
  • a final optical transmittance is measured for the reaction mixture.
  • the measurements are manipulated in the manner described below and concentration of fibrinogen is determined from a previously established standard curve.
  • the standard curve is constructed in such a manner that it remains unchanged by variations in instrument, reagent or sample. Therefore, once established, it is not necessary to repeatedly reconstruct it.
  • the present method is preferably used in conjunction with an optical monitoring system such as that disclosed in concurrently filed and copending U.S. Patent Application Serial No. 07/443,952 to Swope et al., entitled “Multichan ⁇ nel Optical Monitoring System", assigned to the assignee of the present application, the disclosure of which is incorporated herein by reference, or in conjunction with commercially available hemostasis instruments such as the assignee's model Coag-A-Mate XC or model Coag-A-Mate XM. Approximate reagent/plasma concentrations that are suitable for the method of the invention are known from the Clauss fibrinogen method noted above.
  • the thrombin con ⁇ centration is preferably about 100 NIH units (a strong thrombin concentration) and the plasma sample is preferably diluted in a 1:10 ratio (a weak plasma concentration) with Owren *s Veronal Buffer (sodium barbital) .
  • Owren *s Veronal Buffer sodium barbital
  • the formation of fibrinogen is photo-optically monitored for total change between the optical transmittance before the onset of the reaction and the optical transmittance at the conclusion of the reac ⁇ tion.
  • reagent is added to plasma and, after a time which allows for complete sample-reagent mixing, an initial transmittance signal (Ti) is recorded.
  • Ti initial transmittance signal
  • Tf final transmittance signal
  • the relevant parameter, delta or D is computed the initial and final transmittance measurements by normalizing the difference in the readings to the initial value plus any offset using the following equation:
  • D is the normalized digital value of delta
  • Ti is the digital value of the transmitted light prior to the onset of the clot
  • Tf is the digital value of the transmitted light subsequent to the formation of the clot
  • SQ is the digital offset that may have been imposed as part of the instrument design
  • K is an arbitrary constant chosen for convenience. It should be noted that in prior methods, D was defined as the difference (Ti ⁇ Tf) only. The denominator in the above expression represents the normalization of D to the initial value of the transmittance.
  • the next step in determining the concentration of fibrinogen of an unknown sample is to refer the above determined value of D to the concentration by the use of a standard curve. This is done by first computing the quantity
  • D c is the previously determined delta for a calibrator plasma of known fibrinogen concentra- tion.
  • Measurements of D c are performed relatively infrequently as changes in test conditions warrant.
  • the next step is to use a previously determined correlation equation which describes the relationship between R and fibrinogen concentration to determine the fibrinogen concentration of the sample. It has been discovered that the correlation equation relating R and fibrinogen concentration does not change significantly with different designated reagents and calibrator plasmas. Therefore, it can be permanently stored as part of the computational software and does not require periodic recomputation.
  • the correlation equation is preferably derived as follows: Various standard plasmas of known fibrinogen concentration are prepared and a delta value D s is deter- mined for each standard plasma. Next, a value R s is calculated for each standard plasma based on the following equation:
  • R s is the R value for a standard plasma
  • D s is the measured delta value for the standard plasma
  • D c is the previously determined delta for the calibrator plasma.
  • the correlation equation is then derived by plotting R s versus log(C s /C c ) for the various standard plasmas where C s is the fibrinogen concentration of a standard plasma and C c is the fibrinogen concentration of the calibrator plasma.

Abstract

An endpoint assay for measuring fibrinogen utilizing strong thrombin and weak plasma. In a preferred embodiment the assay is based on the direct conversion of a normalized signal from a sensor to fibrinogen concentration.

Description

DIRECT FIBRINOGEN ASSAY
BACKGROUND OF THE INVENTION The invention relates to a method for determining the concentration of fibrinogen in blood plasma using thrombin as a reagent.
Prior methods of using thrombin to measure fibrinogen concentration, include the Clauss method which is based on measuring the time it takes for a plasma-thrombin reaction to occur (clotting time) and the ACL3 fibrinogen assay. The Clauss method is described in Manual of Hemostasis and Thrombosis, ed. 3, by Arthur R. Thompson and Laurence A. Harker, Appendix A, p. 179 (1983) and in Gerrinnunqs physioloqische schnell Methode zur Bestimmunq des Fibrinogens by A. Clauss, Acta Haematol, 17:237 (1957). The ACL3 method is described in Method for the Determina¬ tion of Functional (Clottable) Fibrinogen by the New Family of ACL Coagulometers by E. Rossi, P. Mondonico, A. Lo abar- di, L. Preda, Thrombosis Research 52; 453-469 (1988). These methods rely on the measurement of a relevant parameter such as clotting time or changes in optical transmission and on multiple dilutions of a calibrator plasma to compensate conditions of the instrument and reagent at a given time. Using calibrator plasmas (i.e. plasma having known fibrinogen concentrations) "standard lines" or "calibration curves" must be constructed repeatedly whenever conditions warrant. In the determina- tion of fibrinogen concentration of an unknown sample, the relevant quantity, such as clotting time, is measured and the concentration is then "read" from the standard curve. This process can involve considerable calculation, and is often tedious and time consuming. Another deficiency of these prior methods is that the relevant quantity being measured is often instrument depen¬ dent, as well as reaction dependent. For example, if the instrument used to measure the relevant parameter employs an electro-optical system in which scattered or transmitted light is detected, the value obtained from the measurement will depend on the signal level measured by the optical sensor, which in turn depends on the amount of light incident on the reaction vessel as well as the electronic gains used in association with the optical sensor. The values of these quantities do not remain constant in time, nor do they remain constant from channel to channel or instrument to instrument.
SUMMARY OF THE INVENTION Therefore, it is an object of the invention to provide a method for measuring the concentration of fibrinogen in a blood sample that is more efficient and efficacious manner than prior methods.
It is another object of the invention to eliminate the effects of instrument variation and channel variation in measuring the changes in optical transmission, which are the basis for determining fibrinogen concentration.
It is also an object of the invention to employ measured quantities in a manner that eliminates the need to repeatedly establish a standard curve. The present invention provides a method for measuring the concentration of fibrinogen in a blood plasma sample. According to the method of the invention, a sample of plasma containing fibrinogen is provided in a container. Thrombin is added to the sample and mixed with the sample to form a reaction mixture. An initial optical transmit- tance is measured for the reaction mixture. The thrombin and fibrinogen are allowed to react with each other in the reaction mixture. A final optical transmittance is measured for the reaction mixture. The measurements are manipulated in the manner described below and concentration of fibrinogen is determined from a previously established standard curve.
It is an aspect of the invention that the standard curve is constructed in such a manner that it remains unchanged by variations in instrument, reagent or sample. Therefore, once established, it is not necessary to repeatedly reconstruct it.
DESCRIPTION OF THE PREFERRED EMBODIMENTS The present method is preferably used in conjunction with an optical monitoring system such as that disclosed in concurrently filed and copending U.S. Patent Application Serial No. 07/443,952 to Swope et al., entitled "Multichan¬ nel Optical Monitoring System", assigned to the assignee of the present application, the disclosure of which is incorporated herein by reference, or in conjunction with commercially available hemostasis instruments such as the assignee's model Coag-A-Mate XC or model Coag-A-Mate XM. Approximate reagent/plasma concentrations that are suitable for the method of the invention are known from the Clauss fibrinogen method noted above. The thrombin con¬ centration is preferably about 100 NIH units (a strong thrombin concentration) and the plasma sample is preferably diluted in a 1:10 ratio (a weak plasma concentration) with Owren *s Veronal Buffer (sodium barbital) . Other suitable diluents for the plasma are described in Clauss.
In the present invention the formation of fibrinogen is photo-optically monitored for total change between the optical transmittance before the onset of the reaction and the optical transmittance at the conclusion of the reac¬ tion. According to the method, reagent is added to plasma and, after a time which allows for complete sample-reagent mixing, an initial transmittance signal (Ti) is recorded. When the clot is fully formed, the final transmittance signal (Tf) is processed as described below.
The relevant parameter, delta or D, is computed the initial and final transmittance measurements by normalizing the difference in the readings to the initial value plus any offset using the following equation:
Ti - Tf
D = x K
T± + S0
where D is the normalized digital value of delta;
Ti is the digital value of the transmitted light prior to the onset of the clot; Tf is the digital value of the transmitted light subsequent to the formation of the clot; SQ is the digital offset that may have been imposed as part of the instrument design; and K is an arbitrary constant chosen for convenience. It should be noted that in prior methods, D was defined as the difference (Ti~Tf) only. The denominator in the above expression represents the normalization of D to the initial value of the transmittance.
The next step in determining the concentration of fibrinogen of an unknown sample is to refer the above determined value of D to the concentration by the use of a standard curve. This is done by first computing the quantity
D
R = log( ) Dc
where
Dc is the previously determined delta for a calibrator plasma of known fibrinogen concentra- tion.
Measurements of Dc are performed relatively infrequently as changes in test conditions warrant. The next step is to use a previously determined correlation equation which describes the relationship between R and fibrinogen concentration to determine the fibrinogen concentration of the sample. It has been discovered that the correlation equation relating R and fibrinogen concentration does not change significantly with different designated reagents and calibrator plasmas. Therefore, it can be permanently stored as part of the computational software and does not require periodic recomputation.
The correlation equation is preferably derived as follows: Various standard plasmas of known fibrinogen concentration are prepared and a delta value Ds is deter- mined for each standard plasma. Next, a value Rs is calculated for each standard plasma based on the following equation:
Ds Rs = log( ) Dc
where
Rs is the R value for a standard plasma; Ds is the measured delta value for the standard plasma; and
Dc is the previously determined delta for the calibrator plasma. The correlation equation is then derived by plotting Rs versus log(Cs/Cc) for the various standard plasmas where Cs is the fibrinogen concentration of a standard plasma and Cc is the fibrinogen concentration of the calibrator plasma. It will be understood that the above description of the present invention is susceptible to various modifica¬ tions, changes and adaptations, and the same are intended to be comprehended within the meaning and range of e- quivalents of the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A method for optically measuring a concentration of fibrinogen in a blood plasma sample, said method compris¬ ing: providing a sample of plasma containing fibrinogen in a container; adding thrombin to the sample; mixing the thrombin with the sample to form a reaction mixture; measuring an initial optical transmittance for the reaction mixture; allowing the thrombin and fibrinogen to react with each other in the reaction mixture; measuring a final optical transmittance for the reaction mixture; comparing the final transmittance measurement to the initial transmittance measurement to compute a delta value; and determining the concentration of fibrinogen based on the delta value.
2. The method of claim 1, wherein the thrombin is at a concentration of about 100 NIH units and the plasma sample is diluted in about a 1:10 ratio with sodium barbital.
3. The method of claim 1, wherein the delta value is computed according to the equation:
Ti - Tf
D = x K
Ti + s0 where
D is a normalized value of delta;
Ti is the initial optical transmittance of the sample; Tf is the final optical transmittance of the sample; SQ is an offset which is dependent on the device used to perform said method; and K is a predetermined constant.
4. The method of claim 1, wherein said step of determining fibrinogen concentration further comprises: deriving a correlation equation which allows fibrinogen concentration of a sample to be determined from a value R, where R is computed from the equation
D R = log( )
Dc where
D is the delta value of the sample plasma; and Dc is a delta value of a calibrator plasma; and determining the fibrinogen concentration of the plasma sample based on the derived correlation equation.
5. The method of claim 4, wherein the correlation equation is derived by: measuring a delta value for a plurality of standard plasmas of different known concentrations; measuring a delta value for a calibrator plasma of known concentration; and plotting Rs versus the log(Cs/Cc) for the plurality of standard plasmas where
Ds Rs = log( )
Dc where
Rs is the R value for a standard plasma;
Ds is a measured delta value for the standard plasma; Dc is a measured delta value for a calibrator plasma; Cs is the concentration of fibrinogen in the standard plasma; and Cc is the concentration of fibrinogen in the calibrator plasma.
PCT/US1990/006988 1989-12-01 1990-11-30 Direct fibrinogen assay WO1991008460A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
KR1019920701275A KR920704117A (en) 1989-12-01 1990-11-30 Fibrinogen Direct Analysis Method
FI922312A FI922312A (en) 1989-12-01 1992-05-21 DIRECTIVE OF CONSTRUCTION.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US44394889A 1989-12-01 1989-12-01
US443,948 1989-12-01

Publications (1)

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WO1991008460A1 true WO1991008460A1 (en) 1991-06-13

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EP (1) EP0502103A4 (en)
JP (1) JPH05503008A (en)
KR (1) KR920704117A (en)
AU (1) AU641459B2 (en)
CA (1) CA2068221A1 (en)
FI (1) FI922312A (en)
IE (1) IE904244A1 (en)
WO (1) WO1991008460A1 (en)
ZA (1) ZA909564B (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6101449A (en) * 1995-06-07 2000-08-08 Akzo Nobel N.V. Method for predicting the presence of congenital and therapeutic conditions from coagulation screening assays
US6321164B1 (en) 1995-06-07 2001-11-20 Akzo Nobel N.V. Method and apparatus for predicting the presence of an abnormal level of one or more proteins in the clotting cascade
US6429017B1 (en) 1999-02-04 2002-08-06 Biomerieux Method for predicting the presence of haemostatic dysfunction in a patient sample
US6502040B2 (en) 1997-12-31 2002-12-31 Biomerieux, Inc. Method for presenting thrombosis and hemostasis assay data
US6898532B1 (en) 1995-06-07 2005-05-24 Biomerieux, Inc. Method and apparatus for predicting the presence of haemostatic dysfunction in a patient sample
US7179612B2 (en) 2000-06-09 2007-02-20 Biomerieux, Inc. Method for detecting a lipoprotein-acute phase protein complex and predicting an increased risk of system failure or mortality
US7211438B2 (en) 1999-02-04 2007-05-01 Biomerieux, Inc. Method and apparatus for predicting the presence of haemostatic dysfunction in a patient sample
CN110257475A (en) * 2019-06-28 2019-09-20 深圳市国赛生物技术有限公司 Fibrinogen detection reagent and preparation method thereof and detection reagent product

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US3658480A (en) * 1970-04-13 1972-04-25 Bio Data Corp Coagulation timing apparatus, and method
US3833864A (en) * 1972-11-30 1974-09-03 R Kiess Digital direct reading colorimeter
US3861877A (en) * 1974-01-21 1975-01-21 Clinical Technology Inc Optical analysis of fluids
US3989382A (en) * 1975-01-22 1976-11-02 Bio-Data Corporation Platelet aggregation monitoring device
US4659550A (en) * 1981-06-16 1987-04-21 Hoffmann-La Roche Inc. Method and apparatus for measuring blood coagulation time
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6101449A (en) * 1995-06-07 2000-08-08 Akzo Nobel N.V. Method for predicting the presence of congenital and therapeutic conditions from coagulation screening assays
US6269313B1 (en) 1995-06-07 2001-07-31 Akzo Nobel N.V. Method for predicting the presence of congenital and therapeutic conditions from coagulation screening assays
US6321164B1 (en) 1995-06-07 2001-11-20 Akzo Nobel N.V. Method and apparatus for predicting the presence of an abnormal level of one or more proteins in the clotting cascade
US6564153B2 (en) 1995-06-07 2003-05-13 Biomerieux Method and apparatus for predicting the presence of an abnormal level of one or more proteins in the clotting cascade
US6898532B1 (en) 1995-06-07 2005-05-24 Biomerieux, Inc. Method and apparatus for predicting the presence of haemostatic dysfunction in a patient sample
US6502040B2 (en) 1997-12-31 2002-12-31 Biomerieux, Inc. Method for presenting thrombosis and hemostasis assay data
US6429017B1 (en) 1999-02-04 2002-08-06 Biomerieux Method for predicting the presence of haemostatic dysfunction in a patient sample
US7211438B2 (en) 1999-02-04 2007-05-01 Biomerieux, Inc. Method and apparatus for predicting the presence of haemostatic dysfunction in a patient sample
US7179612B2 (en) 2000-06-09 2007-02-20 Biomerieux, Inc. Method for detecting a lipoprotein-acute phase protein complex and predicting an increased risk of system failure or mortality
CN110257475A (en) * 2019-06-28 2019-09-20 深圳市国赛生物技术有限公司 Fibrinogen detection reagent and preparation method thereof and detection reagent product
CN110257475B (en) * 2019-06-28 2023-05-02 深圳市国赛生物技术有限公司 Fibrinogen detection reagent, preparation method thereof and detection reagent product

Also Published As

Publication number Publication date
EP0502103A1 (en) 1992-09-09
ZA909564B (en) 1992-11-25
AU641459B2 (en) 1993-09-23
FI922312A0 (en) 1992-05-21
KR920704117A (en) 1992-12-19
IE904244A1 (en) 1991-06-05
JPH05503008A (en) 1993-05-27
CA2068221A1 (en) 1991-06-02
AU6898391A (en) 1991-06-26
EP0502103A4 (en) 1993-05-05
FI922312A (en) 1992-05-21

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