US3293134A - Diagnostic reagent composition for determining blood coagulation factors and method of use - Google Patents
Diagnostic reagent composition for determining blood coagulation factors and method of use Download PDFInfo
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- US3293134A US3293134A US136724A US13672461A US3293134A US 3293134 A US3293134 A US 3293134A US 136724 A US136724 A US 136724A US 13672461 A US13672461 A US 13672461A US 3293134 A US3293134 A US 3293134A
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen
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- This invention relates to a diagnostic reagent composition for use in determining blood coagulant factors reduced by treatment with anti-coagulants, particularly oral anti-coagulants used in the treatments of humans, and to methods of blood plasma coagulation factor determination therewith.
- An object of the present invention is to provide a composite diagnostic reagent composition which is adapted for use without modification, other than aqueous reconstitution.
- a further object of the invention is to provide such a diagnostic reagent composition and method which may be employed on patient plasma stored up to forty-eight hours or more.
- Another object of the invention is to provide such a diagnostic reagent composition in admixed composite form as opposed ta the employment of separate individual components not in admixture prior to their admixture with patient plasma.
- Still another object of the invention is to provide a diagnostic reagent composition for controlling anti-coagulant therapy which will enable detection in reduction of platelet factors in the blood plasma of patients under anti-coagulant therapy and simultaneously under treatment with other drugs, such as quinidine, which cause such reduction.
- the present invention provides a novel composite diagnostic reagent composition and method for determining blood coagulant factors.
- the present composition and method are sensitive to the extrinsic coagulation system as well as to the usual intrinsic system, as measured by standard techniques for controlling anticoagulant therapy, and may be employed to test stored patient plasma.
- a tissue thromboplastin preferably comprising aqueous extract -of acetone, treated horse brain, having weak activity toward human plasma is employed.
- Adsorbed bovine plasma treated to have undetectable concentrations of the factors which are known to be reduced in anti-coagulant treatment; namely, proconveitin (in the extrinsic system), Stuart factor (in both the extrinsic and intrinsic system), prothrombin, is employed.
- This adsorbed bovine plasma is selected and treated to contain high, stabilizing concentrations of proaccelerin and fibrinogen.
- the mixture of the thromboplastin and the plasma are buffered to a pH of 7.2 to 7.6 to avoid variations in clotting activity due to departure from optimal pH.
- the mixture also includes calcium ion in sufficient amount for optimal activity.
- the present diagnostic reagent composition which is prepared to be free of added platelet factors, such as cephalin or substitute, provides sensitivity in the intrinsic system to the reduction of platelet factors by drugs, such as quinidine, simultaneously given with anti-coagulants, which characteristic is not known to be heretofor available in any diagnostic reagent composition for controlling anti-coagulant therapy.
- a number of drugs used in the treatment of heart disease may include as a side effect, thrombocytopenic purpura, a hemorrhagic condition caused by reduction in the number of blood platelets, which are the source for the platelet factor, an essential constituent of the intrinsic system of blood coagulation (Hunt J. C., et al., Proceedings of the Staff Meeting of the Mayo Clinic, vol. 33, No. 4, p. 87 (February 1958). It is also recognized that treatment with such drugs, when the patient is on simultaneous anti-coagulation therapy, can result in reduction of platelet factors which do not manifest themselves as purpura, but which are clinically similar to the results of overdosage with anti-coagulants (Sussman, L. N., et al., JAMA, vol. 156, No. 7, p. 702, October 15, 1954).
- composite reagent comprising thromboplastin from bovine, horse or swine brain having a low activity toward human plasma; adsorbed bovine plasma; cephalin and calcium chloride, buffered to a pH of 6 to 8.
- Such composite diagnostic reagent composition is available in frozen-dried ampoule form. The employment of this composition is stated to permit a quantitative measure of the reduction of the plasma thromboplastin component (Christmas factor) by virtue of the inclusion of the cephalin component.
- this reagent composition enables simultaneous and combined determination of the coagulability of the blood with a single test which is stated to proceed at the same rate for the specific factors proconvertin, prothrombin, Stuart factor and Christmas factor.
- cephalin is known to contribute total insensitivity of the diagnostic reagent composition to reduction in platelet factors for which cephalin, by definition is a substitute.
- the variable pH range of this material namely, from pH 6 to pH 8, which is employed with a weak thromboplastin for human plasma, renders the results subject to variability, due to departure from the optimal pH of the blood clotting reaction which is established to be in the immediate range of 7.2 to 7.6. It is believed that such a condition may cause results which simulate the action of the therapy when, in fact, such results are due entirely to deficiencies in the reagent system.
- use of a diagnostic reagent composition of the type having added cephalin can result in a masking of conditions caused by simultaneous therapy (in addition to anti-coagulant therapy). Due to the masking of these conditions, simultaneous therapy may be continued,-
- compositions including cephalin as a component, cannot be employed to detect reduction in platelet factors; on the other hand, the composition of the instant invention is adapted for use in detecting reduction of all those components effectively measured by the commercially available composition.
- the present invention provides a novel composite diagnostic reagent composition
- tissue thromboplastin having weak activity toward human plasma, adsorbed bovine plasma and calcium ion, buffered to a pH of 7.2 to 7.6, which is sensitive to changes in the extrinsic coagulation system, which also is sensitive to changes in the intrinsic coagulation system, as measured by standard methods, and which also is sensitive to components of the intrinsic system, such as platelet factors, which may be reduced during anti-coagulant therapy by simultaneous treatment with quinidine or other drugs.
- Other drugs which exhibit thrombocytopenic purpura as side effects, when given to patients under anti-coagulant therapy, may cause reduction in the platelet factors which are detectable by virtue of the present invention.
- one of the primary features of the present composition is the detection of reduction in platelet factors during anti-coagulant therapy treatment where the patient is additionally subjected to supplemental drug treatment, as with quinidine, by means of a unitary one-stage test procedure.
- Example 11 METHOD OF USE Patient blood is obtained by veni-puncture and oxalated, the plasma being obtained by centrifuging. The sample then is immediately transferred to a silicone-coated tube. Adequate portions of the reagent of Example I and the patient plasma are separately warmed to 37 C. for three to five minutes, following which 0.05 ml. of patient plasma to be tested is added to 0.25 ml. of the reagent and the time for fibrin formation is noted. The fibrin formation time is compared with a curve plotted by diluting normal plasma to various levels with physiological saline or water and the activity of the patient plasma as a percentage of normal activity is calculated by reference to the plotted curve.
- Therapeutic range -30 Patient blood plasma obtained and stored as above and an adequate portion of the reagent of Example II are separately warmed at 37 C. for three to five minutes. 0.1 ml. of-the patient plasma to be tested is added to 0.5 ml. of the reagent and the time for fibrin formation is noted. The fibrin formation time is compared with a curve plotted by diluting normal plasma to various levels with physiological saline or water and the activity of the patient plasma as a percentage of normal activity is calculated by reference to the plotted curve.
- a cephalin free diagnostic reagent composition for use in determining blood coagulation factors in both extrinsic and intrinsic coagulation systems having a pH of 7 .2-7.-6 and consisting essentially of (1) tissue thromboplastin having weak activity toward human plasma;
- the diagnostic reagent composition of claim 1 wherein the weak tissue thromboplastin is an aqueous extract of acetone dried horse brain.
- the method of determining blood plasma coagulation factor levels which comprises admixing patient plasma with the diagnostic reagent composition of claim 1 and measuring the length of time required to form fibrin.
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Description
United States Patent Ofifice 3,293,134 Patented Dec. 20, 1966 DIAGNOSTIC REAGENT COMPOSITION FOR DE- TERMINING BLOOD COAGULATION FACTORS AND METHOD OF USE Jane G. Lenahan, Florham Park, and Monroe L. Miller and Raphael Cohen, Morristown, N.J., assignors to Warner-Lambert Pharmaceutical Company, Morris Plains, N.J., a corporation of Delaware N Drawing. Filed Sept. 8, 1961, Ser. No. 136,724
3 Claims. (Cl. 167-845) This invention relates to a diagnostic reagent composition for use in determining blood coagulant factors reduced by treatment with anti-coagulants, particularly oral anti-coagulants used in the treatments of humans, and to methods of blood plasma coagulation factor determination therewith.
An object of the present invention is to provide a composite diagnostic reagent composition which is adapted for use without modification, other than aqueous reconstitution.
A further object of the invention is to provide such a diagnostic reagent composition and method which may be employed on patient plasma stored up to forty-eight hours or more.
Another object of the invention is to provide such a diagnostic reagent composition in admixed composite form as opposed ta the employment of separate individual components not in admixture prior to their admixture with patient plasma.
Still another object of the invention is to provide a diagnostic reagent composition for controlling anti-coagulant therapy which will enable detection in reduction of platelet factors in the blood plasma of patients under anti-coagulant therapy and simultaneously under treatment with other drugs, such as quinidine, which cause such reduction.
The present invention provides a novel composite diagnostic reagent composition and method for determining blood coagulant factors. The present composition and method are sensitive to the extrinsic coagulation system as well as to the usual intrinsic system, as measured by standard techniques for controlling anticoagulant therapy, and may be employed to test stored patient plasma. A tissue thromboplastin, preferably comprising aqueous extract -of acetone, treated horse brain, having weak activity toward human plasma is employed.
Adsorbed bovine plasma, treated to have undetectable concentrations of the factors which are known to be reduced in anti-coagulant treatment; namely, proconveitin (in the extrinsic system), Stuart factor (in both the extrinsic and intrinsic system), prothrombin, is employed. This adsorbed bovine plasma is selected and treated to contain high, stabilizing concentrations of proaccelerin and fibrinogen. The mixture of the thromboplastin and the plasma are buffered to a pH of 7.2 to 7.6 to avoid variations in clotting activity due to departure from optimal pH. The mixture also includes calcium ion in sufficient amount for optimal activity.
It has been discovered that the present diagnostic reagent composition, which is prepared to be free of added platelet factors, such as cephalin or substitute, provides sensitivity in the intrinsic system to the reduction of platelet factors by drugs, such as quinidine, simultaneously given with anti-coagulants, which characteristic is not known to be heretofor available in any diagnostic reagent composition for controlling anti-coagulant therapy.
It is well recognized that a number of drugs used in the treatment of heart disease may include as a side effect, thrombocytopenic purpura, a hemorrhagic condition caused by reduction in the number of blood platelets, which are the source for the platelet factor, an essential constituent of the intrinsic system of blood coagulation (Hunt J. C., et al., Proceedings of the Staff Meeting of the Mayo Clinic, vol. 33, No. 4, p. 87 (February 1958). It is also recognized that treatment with such drugs, when the patient is on simultaneous anti-coagulation therapy, can result in reduction of platelet factors which do not manifest themselves as purpura, but which are clinically similar to the results of overdosage with anti-coagulants (Sussman, L. N., et al., JAMA, vol. 156, No. 7, p. 702, October 15, 1954).
There is commercially available a composite reagent comprising thromboplastin from bovine, horse or swine brain having a low activity toward human plasma; adsorbed bovine plasma; cephalin and calcium chloride, buffered to a pH of 6 to 8. Such composite diagnostic reagent composition is available in frozen-dried ampoule form. The employment of this composition is stated to permit a quantitative measure of the reduction of the plasma thromboplastin component (Christmas factor) by virtue of the inclusion of the cephalin component. Thus, it has been advanced that this reagent composition enables simultaneous and combined determination of the coagulability of the blood with a single test which is stated to proceed at the same rate for the specific factors proconvertin, prothrombin, Stuart factor and Christmas factor.
However, it has not been established that reduction of the Christmas factor is measurable at critically low levels of the order of 10% and below. On the other hand, the inclusion of cephalin is known to contribute total insensitivity of the diagnostic reagent composition to reduction in platelet factors for which cephalin, by definition is a substitute. The variable pH range of this material; namely, from pH 6 to pH 8, which is employed with a weak thromboplastin for human plasma, renders the results subject to variability, due to departure from the optimal pH of the blood clotting reaction which is established to be in the immediate range of 7.2 to 7.6. It is believed that such a condition may cause results which simulate the action of the therapy when, in fact, such results are due entirely to deficiencies in the reagent system. Thus, in effect, use of a diagnostic reagent composition of the type having added cephalin can result in a masking of conditions caused by simultaneous therapy (in addition to anti-coagulant therapy). Due to the masking of these conditions, simultaneous therapy may be continued,-
which in turn may give rise to hemorrhagic conditions, or the masked condition itself already may be hemorrhagic.
,As above mentioned, unitary compositions, including cephalin as a component, cannot be employed to detect reduction in platelet factors; on the other hand, the composition of the instant invention is adapted for use in detecting reduction of all those components effectively measured by the commercially available composition.
Accordingly, the present invention provides a novel composite diagnostic reagent composition comprising tissue thromboplastin having weak activity toward human plasma, adsorbed bovine plasma and calcium ion, buffered to a pH of 7.2 to 7.6, which is sensitive to changes in the extrinsic coagulation system, which also is sensitive to changes in the intrinsic coagulation system, as measured by standard methods, and which also is sensitive to components of the intrinsic system, such as platelet factors, which may be reduced during anti-coagulant therapy by simultaneous treatment with quinidine or other drugs. Other drugs which exhibit thrombocytopenic purpura as side effects, when given to patients under anti-coagulant therapy, may cause reduction in the platelet factors which are detectable by virtue of the present invention.
Thus, one of the primary features of the present composition is the detection of reduction in platelet factors during anti-coagulant therapy treatment where the patient is additionally subjected to supplemental drug treatment, as with quinidine, by means of a unitary one-stage test procedure.
PREPARATION OF DIAGNOSTIC REAGENT COMPOSITION Example I 1 volume of barium sulfate adsorbed oxalated bovine plasma is added to 1 volume of distilled water, plus 1 volume of a solution which is 0.15 m. in respect to sodium chloride, and 0.25 m. with respect to calcium chloride, plus 1 volume of aqueous extract of acetone treated horse brain tissue, which has been rendered 0.05 m. in respect to calcium chloride; plus, butter to bring the complete admixture to a pH of 7.2 to 7.6.
Example 11 METHOD OF USE Patient blood is obtained by veni-puncture and oxalated, the plasma being obtained by centrifuging. The sample then is immediately transferred to a silicone-coated tube. Adequate portions of the reagent of Example I and the patient plasma are separately warmed to 37 C. for three to five minutes, following which 0.05 ml. of patient plasma to be tested is added to 0.25 ml. of the reagent and the time for fibrin formation is noted. The fibrin formation time is compared with a curve plotted by diluting normal plasma to various levels with physiological saline or water and the activity of the patient plasma as a percentage of normal activity is calculated by reference to the plotted curve.
' Percent activity Normal range 100 Therapeutic range -30 Patient blood plasma obtained and stored as above and an adequate portion of the reagent of Example II are separately warmed at 37 C. for three to five minutes. 0.1 ml. of-the patient plasma to be tested is added to 0.5 ml. of the reagent and the time for fibrin formation is noted. The fibrin formation time is compared with a curve plotted by diluting normal plasma to various levels with physiological saline or water and the activity of the patient plasma as a percentage of normal activity is calculated by reference to the plotted curve.
Percent activity From the foregoing, it will be apparent that the invention provides a novel composition and method for use in determining blood coagulation factors and it will be apparent to those skilled in the art that various changes may be made without departing from the spirit of the invention and therefore the invention is not limited to what is described in the specification but only as indicated in the appended claims.
We claim:
1. A cephalin free diagnostic reagent composition for use in determining blood coagulation factors in both extrinsic and intrinsic coagulation systems having a pH of 7 .2-7.-6 and consisting essentially of (1) tissue thromboplastin having weak activity toward human plasma;
(2) adsorbed bovine plasma, free from Stuart factor, prothrombin, proconvertin and Christmas factor and containing proaccelerin and fibrinogen.
2. The diagnostic reagent composition of claim 1 wherein the weak tissue thromboplastin is an aqueous extract of acetone dried horse brain.
3. The method of determining blood plasma coagulation factor levels which comprises admixing patient plasma with the diagnostic reagent composition of claim 1 and measuring the length of time required to form fibrin.
Normal range Therapeutic range References Cited by the Examiner UNITED STATES PATENTS 4/ 1965 Owren 167--84.5
- OTHER REFERENCES Chemical Abst., vol. 46, 1952, p. 5168.
Dede: Am. J. Med. Tech., vol. 21, No. 4, 1955, pp. 222-231.
Hunt: Proceed. Staif Meeting of the Mayo Clinic, 3314, February 1958, pp. 87-92.
Langdell: The J. of Lab. and Clin. Med. 41:4, April 1953, pp. 637-647.
Mann: PSEBM, vol. 66, 1947, pp. 33-35.
Nature, vol. 186, April 9, 1960, pp. 173-174.
Owren: The Lancet, Nov. 7, 1959, pp. 754-758.
Rodman: Am. J. Clin. Path, vol 29, 1958, pp. 525-538. Stormorken: Acta Physiol. Scand., vol. 41, 1957, pp. 301-305.
Sussmanr J.A.M.A., vol. 156, Oct. 15, 1954, pp. 702- 705.
Waaler: Scand. J. Clin. and Lab. Investigation, vol. 9, 1957, pp. 322-330.
SAM ROSEN, Primary Examiner.
ANNA P. FAGELSON, Assistant Examiner.
Claims (1)
1. A CEPHALIN FREE DIAGNOSTIC REAGENT COMPOSITION FOR USE IN DETERMINING BLOOD COAGULATION FACTORS IN BOTH EXTRINSIC AND INTRISIC COAGULATION SYSTEMS HAVING A PH OF 7.2-7.6 AND CONSISTING ESSENTIALLY OF (1) TISSUE THROMBOPLASTIN HAVING WEAK ACTIVITY TOWARD HUMAN PLASMA; (2) ADSORBED BOVINE PLASMA, FREE FROM STAUART FACTOR, PROTHROMBIN, PROCONVERTIN AND CHRISTMAS FACTOR AND CONTAING PROCCELERIN AND FIGRINOGEN.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US136724A US3293134A (en) | 1961-09-08 | 1961-09-08 | Diagnostic reagent composition for determining blood coagulation factors and method of use |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US136724A US3293134A (en) | 1961-09-08 | 1961-09-08 | Diagnostic reagent composition for determining blood coagulation factors and method of use |
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| US3293134A true US3293134A (en) | 1966-12-20 |
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| US136724A Expired - Lifetime US3293134A (en) | 1961-09-08 | 1961-09-08 | Diagnostic reagent composition for determining blood coagulation factors and method of use |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3947378A (en) * | 1974-12-23 | 1976-03-30 | Warner-Lambert Company | Adsorbed plasma |
| US4363633A (en) * | 1979-06-28 | 1982-12-14 | Radiometer A/S | Reference liquid |
| WO1983004105A1 (en) * | 1982-05-07 | 1983-11-24 | Cooper Laboratories, Inc. | Clotting assay and reagent therefor |
| US4851336A (en) * | 1985-09-05 | 1989-07-25 | Yin E Thye | Composition, kit, and method for assaying heparinano a method for making the composition |
| US4946775A (en) * | 1985-09-05 | 1990-08-07 | Yin E Thye | Composition, kit and method for assaying heparin and a method for making the composition |
| US4948724A (en) * | 1985-09-05 | 1990-08-14 | Yin E Thye | Composition, kit and method for assaying heparin and a method for making the composition |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3179567A (en) * | 1958-05-16 | 1965-04-20 | Owren Paul Arnor | Reagent and method for determining the coagulability of blood |
-
1961
- 1961-09-08 US US136724A patent/US3293134A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3179567A (en) * | 1958-05-16 | 1965-04-20 | Owren Paul Arnor | Reagent and method for determining the coagulability of blood |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3947378A (en) * | 1974-12-23 | 1976-03-30 | Warner-Lambert Company | Adsorbed plasma |
| US4363633A (en) * | 1979-06-28 | 1982-12-14 | Radiometer A/S | Reference liquid |
| US4935373A (en) * | 1979-06-28 | 1990-06-19 | Radiometer A/S | Reference liquid |
| WO1983004105A1 (en) * | 1982-05-07 | 1983-11-24 | Cooper Laboratories, Inc. | Clotting assay and reagent therefor |
| US4455377A (en) * | 1982-05-07 | 1984-06-19 | Cooper Laboratories, Inc. | Clotting assay and reagent therefor |
| US4851336A (en) * | 1985-09-05 | 1989-07-25 | Yin E Thye | Composition, kit, and method for assaying heparinano a method for making the composition |
| US4946775A (en) * | 1985-09-05 | 1990-08-07 | Yin E Thye | Composition, kit and method for assaying heparin and a method for making the composition |
| US4948724A (en) * | 1985-09-05 | 1990-08-14 | Yin E Thye | Composition, kit and method for assaying heparin and a method for making the composition |
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