CN113174425A - Heparin quantitative detection kit and application thereof - Google Patents

Heparin quantitative detection kit and application thereof Download PDF

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Publication number
CN113174425A
CN113174425A CN202110423725.1A CN202110423725A CN113174425A CN 113174425 A CN113174425 A CN 113174425A CN 202110423725 A CN202110423725 A CN 202110423725A CN 113174425 A CN113174425 A CN 113174425A
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reagent
heparin
kit according
coagulation factor
low molecular
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CN202110423725.1A
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田茹
耿强
黄改荣
余占江
陈永强
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Pro Med Beijing Technology Co ltd
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Pro Med Beijing Technology Co ltd
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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
    • 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
    • G01N2333/7456—Factor V
    • 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
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/95—Proteinases, i.e. endopeptidases (3.4.21-3.4.99)
    • G01N2333/964—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue
    • G01N2333/96425—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals
    • G01N2333/96427—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general
    • G01N2333/9643—Proteinases, i.e. endopeptidases (3.4.21-3.4.99) derived from animal tissue from mammals in general with EC number
    • G01N2333/96433—Serine endopeptidases (3.4.21)
    • G01N2333/96441—Serine endopeptidases (3.4.21) with definite EC number
    • G01N2333/96444—Factor X (3.4.21.6)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2400/00—Assays, e.g. immunoassays or enzyme assays, involving carbohydrates
    • G01N2400/10—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • G01N2400/38—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence, e.g. gluco- or galactomannans, e.g. Konjac gum, Locust bean gum, Guar gum
    • G01N2400/40—Glycosaminoglycans, i.e. GAG or mucopolysaccharides, e.g. chondroitin sulfate, dermatan sulfate, hyaluronic acid, heparin, heparan sulfate, and related sulfated polysaccharides

Abstract

The invention provides a heparin quantitative detection kit and application thereof, wherein the kit comprises a reagent R1, a reagent R2, a reagent L1 and a reagent L2; the reagent R1 comprises composite phospholipid, coagulation factor Xa and coagulation factor activator RVV-V; the reagent R2 comprises calcium chloride; the reagent L1 is a common heparin quality control product comprising mammal plasma and common heparin; the reagent L2 is a low molecular heparin quality control product comprising mammalian plasma and low molecular heparin. The kit provided by the invention forms a prothrombinase complex, directly activates prothrombin, does not need to pretreat a sample, is convenient to operate, has shorter detection time, and is not influenced by the integrity of contact pathway and tissue factor pathway proteins; meanwhile, the method is suitable for various types of samples to be detected and different operating environments, and accurate and rapid quantitative determination of heparin in the samples is realized.

Description

Heparin quantitative detection kit and application thereof
Technical Field
The invention belongs to the technical field of medical detection, in particular to clinical blood coagulation detection, and particularly relates to a heparin quantitative detection kit and application thereof.
Background
Heparin was first discovered by the liver and is named after it, and is widely found in tissues such as liver, lung, blood vessel wall, intestinal mucosa and the like of mammals as a natural anticoagulant substance. Currently, heparin is widely used in clinical anticoagulant therapy as an anticoagulant drug, and mainly comprises common heparin, low-molecular heparin, heparin derivatives (such as fondaparinux sodium) and the like. The common heparin is used as a mixture, the molecular weight range is 3000-30000 KD, and the average molecular weight is about 15000 KD. The low molecular weight heparin is an amino dextran sulfate fragment obtained after cracking common heparin, is also a mixture, and has a molecular weight range of 3000-5000 KD. Fondaparinux sodium, also known as fondaparinux, is a chemically synthesized pentosan methyl derivative with a molecular weight of about 1700 KD. The common heparin, the low molecular heparin and the fondaparinux can be combined with the antithrombin III, so that the affinity of the antithrombin III and the blood coagulation factor Xa is improved, and the effect of the antithrombin Xa is enhanced. The molecular weight of the common heparin can be simultaneously combined with antithrombin III and blood coagulation factor IIa to play the role of the blood coagulation factor IIa. The common heparin can inhibit the coagulation factors IIa and Xa at the same time, and the ratio is 1: 1; the low molecular weight heparin can inhibit coagulation factors Xa and IIa at a ratio of 2-4: 1; fondaparinux can only inhibit coagulation factor Xa.
Heparin is used for preventing and treating thrombosis or embolism diseases (such as myocardial infarction, thrombophlebitis, pulmonary embolism and the like); disseminated Intravascular Coagulation (DIC) due to various causes; also used for the anticoagulation treatment of certain blood samples or instruments in operations such as hemodialysis, extracorporeal circulation, catheterization, microvascular surgery and the like. Heparin can be cleared and degraded by the reticuloendothelial system, and a small amount of heparin is excreted by the kidney; low molecular weight heparin and fondaparinux are mainly excreted from the body through the kidneys. Excessive heparin dosage or heparin residue in vivo can cause spontaneous hemorrhage which is usually manifested as cerebral hemorrhage, postpartum hemorrhage and the like of skin, nasal cavity, oral mucosa and even internal organs, and serious patients can cause cerebral hemorrhage, postpartum hemorrhage and the like, so that monitoring the heparin dosage and evaluating the heparin residue in vivo are particularly important.
Currently, methods clinically used for detecting the heparin content mainly include APTT detection, anti-Xa detection, ACT detection and the like. The APTT test is suitable for monitoring the normal heparin with medium and low dose, and the standardization cannot be realized due to excessive influencing factors. ACT detection is useful for monitoring high doses of heparin, and the results are not correlated with APTT and anti-Xa detection.
Therefore, how to adapt to a multi-platform operating environment and accurately and quickly quantitatively determine heparin in a sample is a problem to be solved.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a heparin quantitative detection kit and application thereof, which are suitable for various types of samples to be detected and different operating environments and can realize accurate and rapid quantitative determination of heparin in the samples.
The purpose of the invention is realized by the following technical scheme:
a heparin quantitative detection kit comprises a reagent R1, a reagent R2, a reagent L1 and a reagent L2;
the reagent R1 comprises composite phospholipid, coagulation factor Xa and coagulation factor activator RVV-V;
the reagent R2 comprises calcium chloride;
the reagent L1 is a common heparin quality control product comprising mammal plasma and common heparin;
the reagent L2 is a low molecular heparin quality control product comprising mammal plasma and low molecular heparin;
wherein the heparin comprises low molecular heparin, heparin derivatives, etc.
Further, the reagent R1 also comprises a buffer, a protective agent and a preservative.
Further, the complex phospholipid in the reagent R1 is a mixture of phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine; the concentration of the composite phospholipid is 1-200 mug/ml, preferably 10-30 mug/ml, and more preferably 20 mug/ml; wherein the weight portion ratio of phosphatidylcholine (lecithin), phosphatidylethanolamine (cephalin) and phosphatidylserine is (1-2): (3-5): 1-3).
Further, the coagulation factor Xa in the reagent R1 is activated coagulation factor Xa, and is derived from mammals, preferably bovine coagulation factor, and more preferably human coagulation factor; the concentration of the reagent in the reagent R1 is 0.01-10 nkat/ml, preferably 0.5-2 nkat/ml, and more preferably 0.8 nkat/ml.
Further, the coagulation factor activator RVV-V in the reagent R1 is extracted from viper venom, and the concentration of the coagulation factor activator RVV-V in the reagent R1 is 0.1-10U/ml, preferably 0.8-5U/ml, and more preferably 2.5U/ml.
Furthermore, the buffer solution in the reagent R1 is a Tris-HCl buffer system, and the concentration is 10-200 mM, preferably 40 mM.
Further, the protective agent in the reagent R1 comprises Ethylene Diamine Tetraacetic Acid (EDTA) (the concentration is 10-200 mM), sodium chloride (the concentration is 0.5-1.5% (W/V)), mannitol (the concentration is 0.1-6% (W/V)), bovine serum albumin (the concentration is 0.5-5% (W/V)) and trehalose (the concentration is 0.5-10% (W/V)); the preservative is Proclin300, and the concentration of the preservative is 0.02-0.05%. The pH value of the reagent R1 is adjusted to 6.0-9.0, preferably 7.0-8.0.
Furthermore, the concentration of calcium chloride in the reagent R2 is 20-100 mM, preferably 50 mM.
Further, a reagent L1 is a common heparin quality control product, and two heparin levels are set, wherein the two heparin levels are 0.5 IU/ml and 2.0 IU/ml respectively; the reagent L2 is a low molecular heparin quality control product, and the content of the low molecular heparin is 0.8 IU/ml and 2.2 IU/ml respectively. The mammalian plasma in the reagents L1 and L2 is preferably porcine plasma or bovine plasma.
Another aspect of the invention:
the kit is applied to the quantitative detection of heparin, and is suitable for a plurality of detection platforms including a blood coagulation analyzer platform and a thrombelastogram platform.
Further, suitable test subjects include human whole blood and plasma.
Compared with the prior art, the invention has the beneficial effects that:
1. the heparin quantitative detection kit is suitable for various types of samples to be detected, can comprise human body fluids such as human whole blood, plasma and the like, and does not need to pretreat the samples; and the detection is not influenced by hemolysis, lipemia, lupus anticoagulant and the like of the sample to be detected;
2. the method used by the heparin quantitative detection kit is viscoelastic methodology, can be used for different detection platforms, including a blood coagulation analyzer platform and a thrombus elastogram platform, has wide application range and is suitable for bedside detection;
3. the kit can be used for quantitatively detecting the heparin content in a sample, and provides composite phospholipid, coagulation factor Xa, a coagulation factor activator RVV-V and calcium chloride, wherein the composite phospholipid provides a reaction site for coagulation, the RVV-V activates the coagulation factor V in a sample, and the coagulation factor Xa and the activated coagulation factor V Va form a prothrombinase complex to directly activate prothrombin without pretreating the sample, so that the kit is convenient to operate and short in detection time, is beneficial to determining the using dosage of an anticoagulant drug, avoids the waste of drugs and large clinical hemorrhage, and is not influenced by the integrity of proteins of a contact pathway and a tissue factor pathway; meanwhile, the quality control products (reagent L1 and reagent L2) matched with the kit can be monitored regularly, so that the accuracy of a detection result is ensured.
Drawings
The technical scheme provided by the invention is further explained in detail by combining the drawings and the embodiment:
FIG. 1 is a graph of a calibration curve for a common heparin-ACT value;
FIG. 2 is a graph of the low molecular heparin-ACT calibration curve;
FIG. 3 is a graph showing the correlation between ACT values and anti-Xa activities;
FIG. 4 is a graph showing the correlation between clotting time and anti-Xa activity.
Detailed Description
Example 1 configuration of reagents R1, R2
The embodiment provides a heparin quantitative detection reagent R1, which comprises the following specific components in part by weight:
0.4844 g of tris (hydroxymethyl) aminomethane, 0.9 g of sodium chloride, 0.8 g of mannitol, 2.0 g of bovine serum albumin, 4.5 g of trehalose and 0.3722 g of EDTA are accurately weighed and added into a beaker, an appropriate amount of purified water is added and stirred until the materials are completely dissolved, and the solution is transferred into a volumetric flask and is calibrated to 100 ml. The pH of the obtained solution is adjusted to 7.4 by hydrochloric acid, and a reagent R1 buffer protection solution is obtained.
Accurately weighing 2.25 g of sodium chloride, adding the sodium chloride into a beaker, adding a proper amount of purified sodium chloride, stirring the sodium chloride until the sodium chloride is completely dissolved, and transferring the solution into a volumetric flask to calibrate the volume to 250 ml, thereby obtaining the physiological saline solution.
Respectively weighing phosphatidylcholine (lecithin), phosphatidylethanolamine (cephalin) and phosphatidylserine according to the weight part ratio of 1:3:2, adding physiological saline, and accelerating diffusion at 37 ℃ to obtain 2 mg/ml composite phospholipid suspension.
Accurately measuring physiological saline by a pipettor, dissolving the Xa freeze-dried powder, and preparing the blood coagulation factor Xa stock solution with the concentration of 100U/ml.
Accurately measuring physiological saline solution by a liquid transfer machine, dissolving the coagulation factor activator RVV-V, and preparing the coagulation factor activator RVV-V stock solution with the concentration of 40 nkat/ml.
And accurately measuring 500 mu L of the prepared composite phospholipid suspension, 12.5 mu L of the blood coagulation factor Xa stock solution and 15 mu L of the blood coagulation factor activator RVV-V stock solution 10 mu L, Proclin300 preservative, adding the compound phospholipid suspension into 50 ml of reagent R1 buffer protection solution, and uniformly stirring by using a magnetic stirrer to obtain the reagent R1 stock solution.
And (3) subpackaging the obtained solution into penicillin bottles, wherein the volume of each bottle is 30 mu l, and freeze-drying to obtain the heparin quantitative detection reagent R1 component.
The main component of the reagent R2 is calcium chloride, and the concentration of the calcium chloride is 50 mM.
Example 2 arrangement of reagents L1 and L2
Preparation of reagent L1 (plain heparin quality control):
the plasma used in the quality control product is normal mammal plasma, which does not contain heparin, low molecular heparin and other heparin substances. Preparing freeze-drying protective solution, weighing 20 g of trehalose, 5.0 g of mannitol and 150 mu L of Proclin300 preservative, adding into 500 ml of blood plasma, and uniformly stirring by a magnetic stirrer. The obtained solution is divided into two parts, each part is 250 ml, 125 IU common heparin and 500 IU common heparin are respectively added into the solution, the mixture is stirred uniformly and subpackaged, and the subpackaging volume is 1 ml/bottle. Freeze-drying to obtain the common heparin quality control product.
Preparation of reagent L2 (low molecular heparin quality control product):
the plasma used in the quality control product is normal mammal plasma, which does not contain heparin, low molecular weight heparin and heparinoid. Preparing freeze-drying protective solution, weighing 20 g of trehalose, 5.0 g of mannitol and 150 mu L of Proclin300 preservative, adding into 500 ml of blood plasma, and uniformly stirring by a magnetic stirrer. The obtained solution is divided into two parts, each part is 250 ml, 100 IU low molecular heparin and 550 IU low molecular heparin are respectively added into the solution, the mixture is stirred uniformly and subpackaged, and the subpackaged volume is 1 ml/bottle. Freeze-drying to obtain the low molecular heparin quality control product.
Example 3 application of the kit to the elastogram platform
500 mu L of sample to be tested is added into the reagent R1 prepared in the embodiment 1 until R1 is completely dissolved and mixed evenly, and the concentration of heparin in the sample is 1.0 IU/ml.
Figure DEST_PATH_IMAGE001
The R1 stock solution in example 1 is dispensed into sample cups, the dispensing amount is 20 mu L/cup, and the reagent R1 cup is obtained by freeze-drying. The sample used in the table below had a heparin content of 1.0 IU/ml.
Figure 762746DEST_PATH_IMAGE002
In summary, the reagent R1 is preferably a reagent R1 cup, the loading method is preferably the scheme 5 in the above table, 350. mu.L of the sample is directly loaded into the reagent R1 cup, 50. mu.L of the reagent R2 prepared in example 1 is loaded, and the mixture is mixed and absorbed 3 times for detection.
69 samples of the test were tested according to the above test system, and the results were compared with heparin-detecting gold standard-Anti-Xa, and the correlation r = 0.979.
Example 4
Establishing a mathematical model of the coagulation time and the heparin content:
the method of the embodiment 2 is used for establishing the ordinary heparin and the low molecular heparin gradient quality control products, and the concentrations of the ordinary heparin quality control products are 0, 0.2, 0.5, 1.0, 1.5, 2.0, 3.0 and 4.0 IU/ml respectively. The concentrations of the low molecular weight heparin quality control substances are respectively 0, 0.2, 0.5, 1.0, 1.5, 2.0, 3.0 and 4.0 IU/ml.
The assay was performed as described in example 3, with 2 replicates per concentration averaged. The calibration curves obtained in fig. 1 and fig. 2 are y =0.007x-0.5462 for the general heparin activity-ACT value calibration curve equation and y =0.0067x-0.5446 for the low molecular heparin activity-ACT value calibration curve equation, where y is heparin activity and x is ACT value.
Example 5 application of the kit to the hemagglutination Meter platform
The kit can be adapted to various mainstream hemagglutination instruments such as Stago, Siemens, Sysmex and IL, and the ACL TOP 700 hemagglutination instrument is selected as detection equipment in the embodiment.
The reaction system is as follows: the reagent R1 was completely dissolved in 100. mu.l of purified water, 50. mu.l of the reagent was mixed with the plasma to be tested at 1:1, and incubated at 37 ℃ for 180 seconds, and then 50. mu.l of the reagent R2 prepared in example 1 was added to start the assay. The correlation between the detection result and the detection result of heparin detection gold standard-Anti-Xa is shown in FIG. 4, and the correlation coefficient r = 0.96. A heparin-coagulation time calibration curve was established according to the method described in example 4.
In conclusion, the kit can quantitatively detect the content of heparin in a sample, and the sample can be whole blood or plasma and can be used for a thromboelastogram platform and a hemagglutination instrument platform. The detection range of both the common heparin and the low molecular heparin can reach 0.1-4.0 IU/ml.
Finally, it should be noted that the above only illustrates the technical solution of the present invention, but not limited thereto, and although the present invention has been described in detail with reference to the preferred arrangement, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made thereto without departing from the spirit and scope of the technical solution of the present invention.

Claims (10)

1. The heparin quantitative detection kit is characterized by comprising a reagent R1, a reagent R2, a reagent L1 and a reagent L2;
the reagent R1 comprises composite phospholipid, coagulation factor Xa and coagulation factor activator RVV-V;
the reagent R2 comprises calcium chloride;
the reagent L1 is a common heparin quality control product comprising mammal plasma and common heparin;
the reagent L2 is a low molecular heparin quality control product comprising mammal plasma and low molecular heparin.
2. The heparin quantitative detection kit according to claim 1, wherein the reagent R1 further comprises a buffer, a protective agent and a preservative.
3. The heparin quantitative determination kit according to claim 1, wherein, the complex phospholipid in the reagent R1 is a mixture of phosphatidylcholine, phosphatidylethanolamine and phosphatidylserine; the concentration of the compound phospholipid in the reagent R1 is 1-200 mu g/ml, wherein the weight part ratio of phosphatidylcholine to phosphatidylethanolamine to phosphatidylserine is (1-2) - (3-5) - (1-3).
4. The heparin quantitative determination kit according to claim 1, wherein the blood coagulation factor Xa in the reagent R1 is activated blood coagulation factor Xa, and the concentration thereof in the reagent R1 is 0.01-10 nkat/ml.
5. The heparin quantitative determination kit according to claim 1, wherein the coagulation factor activator RVV-V in the reagent R1 is extracted from viper venom, and the concentration of the coagulation factor activator RVV-V in the reagent R1 is 0.1-10U/ml.
6. The heparin quantitative determination kit according to claim 2, wherein the buffer solution in the reagent R1 is Tris-HCl buffer system.
7. The heparin quantitative determination kit according to claim 2, wherein the components of the protective agent in the reagent R1 comprise Ethylene Diamine Tetraacetic Acid (EDTA), sodium chloride, mannitol, bovine serum albumin and trehalose.
8. The heparin quantitative determination kit according to claim 1, wherein the concentration of calcium chloride in the reagent R2 is 20-100 mM.
9. Use of a kit according to any one of claims 1 to 8 for the quantitative detection of heparin using a kit according to any one of claims 1 to 8 in a plurality of detection platforms including a hemagglutination and thromboelastography platform.
10. The use of the kit according to claim 9, wherein the test subjects to be tested include human whole blood and plasma.
CN202110423725.1A 2021-04-20 2021-04-20 Heparin quantitative detection kit and application thereof Pending CN113174425A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107727872A (en) * 2017-09-01 2018-02-23 上海太阳生物技术有限公司 A kind of kit of heparin determination
CN108982865A (en) * 2018-08-16 2018-12-11 上海原科实业发展有限公司 A kind of thrombelastogram method heparin immue quantitative detection reagent box and preparation method thereof
CN109082458A (en) * 2018-08-16 2018-12-25 上海原科实业发展有限公司 A kind of thrombelastogram standard measure detects oral coagulation factor xa inhibitors kit and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107727872A (en) * 2017-09-01 2018-02-23 上海太阳生物技术有限公司 A kind of kit of heparin determination
CN108982865A (en) * 2018-08-16 2018-12-11 上海原科实业发展有限公司 A kind of thrombelastogram method heparin immue quantitative detection reagent box and preparation method thereof
CN109082458A (en) * 2018-08-16 2018-12-25 上海原科实业发展有限公司 A kind of thrombelastogram standard measure detects oral coagulation factor xa inhibitors kit and preparation method thereof

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* Cited by examiner, † Cited by third party
Title
ROBERT CG等: "Heparin-calibrated chromogenic anti-Xa activity measurements in patients receiving rivaroxaban:can this test be used to quantify drug level", 《ANN PHARMACOTHER》 *

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