CN116410258A - Factor XI deficiency plasma protective agent and application thereof - Google Patents
Factor XI deficiency plasma protective agent and application thereof Download PDFInfo
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- CN116410258A CN116410258A CN202310392199.6A CN202310392199A CN116410258A CN 116410258 A CN116410258 A CN 116410258A CN 202310392199 A CN202310392199 A CN 202310392199A CN 116410258 A CN116410258 A CN 116410258A
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to the technical field of in-vitro diagnostic reagents, in particular to a factor XI deficiency plasma protective agent and application thereof. The invention provides a protective agent comprising a buffer solution, a freeze-drying protective agent, a surfactant, a preservative and inorganic salt, factor XI deficient plasma comprising human factor XI plasma and the protective agent, and application of the factor XI deficient plasma in preparing a blood coagulation factor activity detection reagent or a kit. The protective agent provided by the invention can effectively ensure the stability and activity of the protein in human factor XI blood plasma, protect the protein in blood plasma from inactivation caused by the freeze-drying process, and further improve the product performance of the blood plasma containing human factor XI. The factor XI deficient plasma provided by the invention is suitable for most of the common full-automatic coagulation analyzers in the market.
Description
Technical Field
The invention relates to the technical field of in-vitro diagnostic reagents, in particular to a factor XI deficiency plasma protective agent and application thereof.
Background
The molecular mechanism of hemostasis is the process of sequential activation by a series of clotting factors, from the activation of coagulation to the formation of a plasma clot, which is dependent on both the extrinsic and intrinsic coagulation pathways (including the common pathway of coagulation).
Factor XI (F XI) is a serine protease zymogen, once known as plasma thromboplastin precursor (Plasma Thromboplastin Antecedent, PTA), a plasma coagulation factor involved in contact in the intrinsic coagulation pathway. Factor XI is essential for maintaining the endogenous pathway and plays a key role in the amplification of the coagulation cascade. During the clotting process, a deficiency in factor XI (either due to genetic factors or due to acquired factors) will affect the balance of the entire clotting system. Congenital defects in coagulation factor XI are associated with typical hemophilia a and other hemorrhagic diseases such as christmas disease, PTA deficiency, hageman-trait and hypoprothrombinemia, etc. Acquired coagulation disorders may involve the deficiency of multiple coagulation factors. They are often associated with trauma, liver disease, vitamin K deficiency or anticoagulant therapy. For the monitoring of these diseases, accurate diagnosis of the activity of coagulation factor XI and other coagulation factors and other factors responsible for the disease is required.
For the detection of the blood coagulation factor XI, two main products are mainly used in the market at present, one is mainly used for detecting the protein content of the blood coagulation factor, and the other is mainly used for detecting the activity of the blood coagulation factor, namely a clotting method, and the principle is based on the correction capability of detecting the clotting time (APTT) extension of the blood plasma of the blood deficiency factor caused by the to-be-detected sample. The coagulation method has the advantages of simple operation, accurate result, capability of truly reflecting the activity of the coagulation factors which actually play a role in the coagulation process, and the like, and is widely applied.
During plasma clotting, the absence of any clotting factor will affect the overall clotting response, and thus the status of the clotting factor will directly affect the stability of factor XI deficient plasma. In order to ensure the stability of factor XI lacking plasma, the factor XI is usually prepared into a freeze-dried product or frozen plasma is stored in an ultralow temperature environment, but the activity of the blood coagulation factors is extremely easy to be reduced in the processes of freeze-drying, storing and the like, so that the activity of each blood coagulation factor in the plasma is ensured to be a precondition for the stability of the plasma.
In recent years, due to the strong popularization and use of the full-automatic coagulation analyzer, the factor XI activity measurement is automated, so that the operation threshold of the factor XI measurement is reduced, and the accuracy of the detection result is greatly improved. Thus, the demand for reagents related to factor XI assays is increasing. At present, a plurality of manufacturers produce kits for measuring the factor XI, but the kits are foreign products, have high price and long purchase period, are easily influenced by factors such as external environment and the like in the transportation and storage process, and lead to the inactivation of the blood coagulation factors, so that the stability of the kits is reduced.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a factor XI-deficient plasma protective agent and application thereof, which can effectively protect the activity of factor XI-deficient plasma before and after lyophilization, and has the advantages of simple preparation method, low cost and strong stability.
The invention provides a protective agent, which comprises buffer solution, freeze-drying protective agent, surfactant, preservative and inorganic salt, wherein,
the buffer solution comprises at least one of HEPES buffer solution, tris buffer solution and phosphate buffer solution;
the protective agent comprises at least one of sucrose, mannitol, sorbitol, glycine, dextran-40 and trehalose;
the surfactant comprises at least one of poloxamer 188 and sodium cholate;
the preservative comprises NaN 3 At least one of thimerosal and ciprofloxacin;
the inorganic salt includes at least one of sodium chloride and potassium chloride.
Compared with the selection of other components, the components in the protective agent provided by the invention are matched with each other, so that a more stable freeze-drying system is provided for preparing freeze-dried blood plasma, the activities of blood coagulation factors and fibrinogen in the blood plasma can be protected to the greatest extent, the blood plasma is effectively stabilized, and a more accurate technical effect is obtained.
In some embodiments, the buffer is HEPES buffer, the protectant is glycine, dextran-40, and trehalose, the surfactant is poloxamer 188, the preservative is ciprofloxacin, and the inorganic salt is sodium chloride. Compared with other reagents, the components are tightly matched with each other, so that the compatibility is strong, the preparation of freeze-dried blood plasma can be more effectively matched, and meanwhile, the activities and the stability of each coagulation factor and fibrinogen in the blood plasma are taken into consideration, so that more accurate technical effects are obtained.
Preferably, the protective agent consists of water, 123.6-357.5 g/L HEPES buffer solution, 10-50g/L trehalose, 10-100g/L glycine, 10-50g/L dextran-40, 1-5g/L poloxamer 188, 1-5g/L ciprofloxacin and 0.1-1 g/L sodium chloride, and the pH value of the protective agent is 7.8.
A comparison experiment is carried out on the freeze-dried plasma prepared by the components and the protective agent with the concentration range and a commercial product, and repeated detection is carried out on the normal range fixed value plasma and the pathological range fixed value plasma, so that the result shows that the variation Coefficient (CV) of the normal range fixed value plasma and the pathological range fixed value plasma measured by the plasma provided by the invention is smaller than that of the commercial product, the repeatability is better, and a more accurate technical effect is obtained.
Further preferably, the protective agent consists of water, 240g/L HEPES buffer solution, 20g/L trehalose, 50g/L glycine, 20g/L dextran-40, 2g/L poloxamer 188, 2.5g/L ciprofloxacin and 0.2g/L sodium chloride, and the pH value of the protective agent is 7.8.
Experiments show that at the concentration, the freeze-dried plasma prepared by the protectant has the best effect and the best experimental repeatability.
The invention also provides application of the protective agent in preparing blood coagulation factor deficient plasma or a kit containing the blood coagulation factor deficient plasma.
Preferably, the clotting factor deficient plasma comprises factor XI deficient plasma.
Further preferably, the factor XI deficient plasma is human blood plasma lacking XI, in particular human negative blood plasma, from which blood coagulation factor XI is removed to a level of less than or equal to 1%.
The invention provides factor XI deficient plasma or a kit comprising factor XI deficient plasma, including human factor XI deficient plasma and said protective agent.
Preferably, the volume ratio of the protective agent to the human factor XI-deficient plasma is (1-3): 7-9.
Further preferred, the volume ratio of the protective agent to the human factor XI-deficient plasma is 2:8.
The invention also provides application of the factor XI deficient plasma in preparing a blood coagulation factor activity detection reagent or a kit.
The invention provides a method for detecting factor XI activity in human blood plasma by using a blood coagulation factor activity detection kit, which comprises the following specific steps:
(1) diluting the plasma sample with the diluent in a ratio of 1:5 (returning to room temperature of 15-25 ℃), pipetting into a test tube, pre-warming at 37 ℃, and simultaneously adding CaCl (sodium carbonate) 2 Pre-heating at 37 ℃;
(2) mixing the factor XI measuring reagent and the diluted plasma sample in a volume ratio of 1:1, mixing at 37 ℃ and incubating for 0.5-2 minutes;
(3) adding APTT reagent, mixing with diluted plasma sample in a volume ratio of 1:1, mixing at 37 ℃ and incubating for 0.5-2 minutes;
(4) adding CaCl 2 Mixing the reagent and the diluted plasma sample in a volume ratio of 1:1, and reading the absorbance value of the sample at 405nm after 2 minutes of action at 37 ℃;
(5) the activity of factor XI in plasma samples was calculated from known standard curves.
The invention provides a protective agent comprising a buffer solution, a freeze-drying protective agent, a surfactant, a preservative and inorganic salt, factor XI deficient plasma comprising human factor XI plasma and the protective agent, and application of the factor XI deficient plasma in preparing a blood coagulation factor activity detection reagent or a kit. Compared with the prior art, the protective agent provided by the invention can effectively ensure the stability and activity of the protein in human factor XI blood plasma, and further improve the product performance of the human factor XI blood plasma. The protective agent disclosed by the invention is prepared from trehalose, glycine and dextran-40 which are used as freeze-drying protective agents, so that the stability of plasma proteins in plasma in a freeze-drying process and the stability of freeze-dried products after re-dissolution can be effectively protected; poloxamer 188 is used as a surfactant to further protect the proteins in the plasma from inactivation by the lyophilization process. The factor XI deficient plasma provided by the invention is suitable for most of the common full-automatic coagulation analyzers in the market.
Drawings
FIG. 1 changes in clotting factor II activity in matrix plasma;
FIG. 2 shows the variation of clotting factor V activity in matrix plasma;
FIG. 3 shows the change in clotting factor VII activity in matrix plasma;
FIG. 4 shows the change in clotting factor VIII activity in matrix plasma;
FIG. 5 shows the change in clotting factor IX activity in matrix plasma;
FIG. 6 shows the variation of clotting factor X activity in matrix plasma;
FIG. 7 shows the change in coagulation factor XII activity in matrix plasma;
FIG. 8 shows the variation of the clotting factor FIB content in the matrix plasma;
FIG. 9 shows a correlation analysis of the detection results of the kit of the present invention with the Siemens kit at CS 2400;
FIG. 10 shows analysis of correlation of detection results of the inventive kit and STAGO kit on STA-R event;
fig. 11 shows the correlation analysis of the detection results of the kit of the invention and the IL kit on acltop 750.
Detailed Description
The invention provides factor XI deficiency plasma protectant and application thereof, and one skilled in the art can properly improve the process parameters by referring to the content of the text. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that the invention can be practiced and practiced with modification and alteration and combination of the methods and applications herein without departing from the spirit and scope of the invention.
The invention provides a protective agent, which comprises buffer solution, freeze-drying protective agent, surfactant, preservative and inorganic salt, wherein,
the buffer solution is at least one selected from HEPES buffer solution, tris buffer solution and phosphate buffer solution;
the protective agent is at least one selected from sucrose, mannitol, sorbitol, glycine, dextran-40 and trehalose;
the surfactant is at least one selected from poloxamer 188 and sodium cholate;
the preservative is selected from NaN 3 At least one of thimerosal and ciprofloxacin;
the inorganic salt is at least one selected from sodium chloride and potassium chloride.
The test materials adopted by the invention are all common commercial products and can be purchased in the market. The invention is further illustrated by the following examples:
EXAMPLE 1 preparation of the kit of the invention for factor XI deficient plasma
The invention provides a formula for preparing a factor XI assay kit by using human factor XI-deficient plasma, which adopts the following technical scheme:
the manufacturer of the human factor XI blood plasma used in the research and development process of the kit is Biomex GmbH in Germany, and the pH value of the protective agent is regulated to 7.8 and then added into the human factor XI blood plasma to be fully and uniformly mixed. The formulation of the protective agent of the kit is shown in table 1, and the volume ratio of the protective agent to plasma is 2:8.
TABLE 1 protectant formulation table (Experimental group)
Table 2 protective agent formulation table (control group)
EXAMPLE 2 investigation of the ratio of the protective agent to plasma of the kit of the invention
The ratio of the protective agent to the plasma in the kit is mainly set to 3 gradients, namely 1:9, 2:8 and 3:7, so as to explore the influence of the ratio of the protective agent to the plasma on the accuracy of the measurement value of the kit. The standard human plasma (target value: 91%) of Siemens is accurately detected by taking commercial products and freeze-dried products of each experimental group, and the detection results are summarized and the relative deviation between the detection results and the standard human plasma target value is calculated. The results are shown in Table 3, and the relative deviation of the activity values from the target values for the standard human plasma measured by all experimental groups was smaller than that of the commercial kit. Experimental results show that the ratio of the protective agent to the blood plasma has little influence on the accuracy of the measured value of the blood plasma, but when the ratio is 2:8, the relative deviation between the measured value and the target value is the smallest, and the ratio of the protective agent to the blood plasma in the kit is (1-3) (7-9), preferably 2:8.
TABLE 3 accuracy test results
Note that: relative deviation = (test value-calibrator target value)/calibrator target value x 100%
EXAMPLE 3 stability study of the Components of the kit of the invention
The substrate plasma was subjected to coagulation factor assay (II, V, VII, VIII, IX, X, XII) and FIB content assay, and after plasma was prepared as in example 1, stability assay was performed. Blood coagulation factor and FIB detection were performed on factor XI deficient plasma before and after lyophilization, respectively, and the average value was taken three times for each detection, and the statistical analysis (t-test) was performed on the detected data, and the results are shown in tables 4 to 11. The results show that the activity and the FIB content of each blood coagulation factor in the blood plasma of the control group are reduced to different degrees, and the activity and the FIB content of each blood coagulation factor in the blood plasma before and after freeze-drying of the kit (experimental group) have no obvious change, so that the components of the kit (experimental group) can effectively protect the blood coagulation factors in the blood plasma from the influence of the freeze-drying process; after the freeze-dried product of the kit (experimental group) is redissolved, the activity of each blood coagulation factor has no obvious change in the continuous 5-day test, which indicates that the combination of the components of the protective agent of the kit can effectively stabilize the enzyme activities of each blood coagulation factor and FIB after the plasma is redissolved. The comparison of the experimental group and the control group 1-8 shows that any one of the components of the trehalose, the glycine and the dextran-40 is deleted or replaced, the freeze-drying protection effect is reduced to different degrees, which indicates that the trehalose, the glycine and the dextran-40 are used as the protecting agent together, and the stability of plasma proteins in plasma in the freeze-drying process and the stability of the freeze-dried product after re-dissolution can be effectively protected. Comparison of the experimental group with the control group 9 shows that the addition of poloxamer 188 can further protect the proteins in the plasma from inactivation caused by the lyophilization process.
TABLE 4 measurement of coagulation factor II Activity
TABLE 5 measurement of coagulation factor V Activity
TABLE 6 measurement of factor VII Activity
TABLE 7 measurement of factor VIII Activity
TABLE 8 measurement of factor IX Activity
TABLE 9 measurement of coagulation factor X Activity
TABLE 10 measurement of factor XII Activity
TABLE 11 FIB content determination results
Example 4 concentration of major components of protective agent in the kit of the present invention the major components of the protective agent were set to 3 concentrations, respectively, and the set was set by an orthogonal method (as in table 12) to investigate the effect of the concentration of each component of the protective agent on the reproducibility of the kit. And repeatedly detecting the normal range fixed value Plasma (Control Plasma N) and the pathological range fixed value Plasma (Control Plasma P) by taking commercially available products and freeze-dried products of each experimental group. The measurement results were collected and the Coefficient of Variation (CV) was calculated. The results are shown in Table 12, and the Coefficient of Variation (CV) of the normal range and pathological range plasma was smaller than that of the commercial kit (5.18%, 8.42%). Meanwhile, the experimental results of experimental group 5 are superior to other experimental groups. In summary, the kit has good repeatability of detection results when the concentration of trehalose in the kit protective agent component is 10-50g/L, the concentration of glycine is 10-100g/L, the concentration of dextran-40 is 10-50g/L, the concentration of poloxamer 188 is 1-5g/L, and the kit is most preferable when the concentration of trehalose is 20g/L, the concentration of glycine is 50g/L, the concentration of dextran-40 is 20g/L, and the concentration of poloxamer 188 is 2 g/L.
TABLE 12 repeatability test results
Example 5 applicability of the kit of the present invention to a coagulation analyzer which is mainstream in the market
(1) Application of the kit of the invention to CS2400
A total of 57 blood samples were randomly drawn from hospitalization and outpatient clinics at the Shanghai university of transportation medical institute affiliated Ruijin Hospital and at the Shanghai university of traditional Chinese medicine affiliated Longhua Hospital. Uniformly mixing blood with 0.109mol/L sodium citrate anticoagulation solution according to the ratio of 9:1, centrifuging at 2500r/min for 15 minutes, and separating to obtain plasma. The samples were measured on CS2400 using the kit of the present invention obtained in example 1 and the Siemens factor XI activity measurement kit (clotting method), respectively, and correlation coefficients of the two were calculated and subjected to linear regression. The results show that the correlation coefficient of the two kits, γ= 0.9955, and the linear regression equation is y= -0.1139+1.0231x, see fig. 9.
According to the requirements of the American Clinical Laboratory Standardization Institute (CLSI) document (gamma > 0.975), the detection data of the kit provided by the invention and the French STAGO company import kit have good consistency.
(2) Application of the kit in STA-R Evolution
Blood samples were randomly drawn from hospitalization and outpatient clinics at the Shanghai university of transportation medical institute affiliated Ruijin Hospital and the Shanghai university of traditional Chinese medicine affiliated Longhua Hospital for 50 copies. Uniformly mixing blood with 0.109mol/L sodium citrate anticoagulation solution according to the ratio of 9:1, centrifuging at 2500r/min for 15 minutes, and separating to obtain plasma. The correlation coefficients of the kit of the present invention obtained in example 1 and the Factor XI (FXI) measurement kit (clotting method) from STAGO were calculated by measuring the samples on STA-R Evolution, respectively, and performing linear regression. The results show the correlation coefficient γ= 0.9936 for both kits, with a linear regression equation of y=0.2994+0.9818 x, see fig. 10.
According to the requirements of the American Clinical Laboratory Standardization Institute (CLSI) document (gamma > 0.975), the detection data of the kit provided by the invention and the detection data of the STAGO company imported kit are in good consistency.
(3) Application of the kit of the invention to ACL TOP 750
Blood samples were randomly drawn from hospitalization and outpatient clinics at the Shanghai university of transportation medical institute affiliated Ruijin Hospital and the Shanghai university of traditional Chinese medicine affiliated Longhua Hospital for a total of 85. Uniformly mixing blood with 0.109mol/L sodium citrate anticoagulation solution according to the ratio of 9:1, centrifuging at 2500r/min for 15 minutes, and separating to obtain plasma. The correlation coefficients of the test samples obtained in example 1 and the IL company Factor XI deficient piasma test kit were calculated by measuring the test samples on ACL TOP 750, respectively, and performing linear regression. The results show the correlation coefficient γ= 0.9921 for both kits, with a linear regression equation of y= -0.9793+1.0233x, see fig. 11.
The test data of the kit of the invention and the imported kit of the US IL company have good consistency according to the requirements of the American Clinical Laboratory Standardization Institute (CLSI) document (gamma > 0.975).
In conclusion, the kit disclosed by the invention can be suitable for most of full-automatic coagulation analyzers commonly used in the market.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (10)
1. The protective agent is characterized by comprising buffer solution, freeze-drying protective agent, surfactant, preservative and inorganic salt, wherein,
the buffer solution comprises at least one of HEPES buffer solution, tris buffer solution and phosphate buffer solution;
the protective agent comprises at least one of sucrose, mannitol, sorbitol, glycine, dextran-40 and trehalose;
the surfactant comprises at least one of poloxamer 188 and sodium cholate;
the preservative comprises NaN 3 At least one of thimerosal and ciprofloxacin;
the inorganic salt includes at least one of sodium chloride and potassium chloride.
2. The protectant of claim 1, wherein the buffer is HEPES buffer, the protectant is glycine, dextran-40, and trehalose, the surfactant is poloxamer 188, the preservative is ciprofloxacin, and the inorganic salt is sodium chloride.
3. The protective agent according to claim 2, characterized in that the protective agent consists of water, 123.6-357.5 g/L HEPES buffer, 10-50g/L trehalose, 10-100g/L glycine, 10-50g/L dextran-40, 1-5g/L poloxamer 188, 1-5g/L ciprofloxacin and 0.1-1 g/L sodium chloride, the pH of the protective agent being 7.8.
4. A protective agent according to claim 3, characterized in that it consists of water, 240g/LHEPES buffer, 20g/L trehalose, 50g/L glycine, 20g/L dextran-40, 2g/L poloxamer 188, 2.5g/L ciprofloxacin and 0.2g/L sodium chloride, the pH of the protective agent being 7.8.
5. Use of a protective agent according to any one of claims 1 to 4 for the preparation of clotting factor deficient plasma or a kit comprising clotting factor deficient plasma.
6. The use of claim 5, wherein the clotting factor deficient plasma comprises factor XI deficient plasma.
7. Factor XI deficient plasma or a kit comprising factor XI deficient plasma, characterized by comprising human factor XI plasma and a protective agent according to any one of claims 1 to 4.
8. The factor XI deficient plasma according to claim 7 wherein the volume ratio of the protective agent to the human factor XI plasma is (1-3): 7-9.
9. The factor XI deficient plasma according to claim 8 wherein the volume ratio of the protective agent to the human factor XI plasma is 2:8.
10. Use of factor XI deficient plasma according to any one of claims 7 to 9 for the preparation of a clotting factor activity detection reagent or kit.
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