CN104459165A - Method for detecting anticoagulant capacity of human prothrombin complex - Google Patents
Method for detecting anticoagulant capacity of human prothrombin complex Download PDFInfo
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- CN104459165A CN104459165A CN201410757119.3A CN201410757119A CN104459165A CN 104459165 A CN104459165 A CN 104459165A CN 201410757119 A CN201410757119 A CN 201410757119A CN 104459165 A CN104459165 A CN 104459165A
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- 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
Abstract
The invention discloses a method for detecting anticoagulant capacity of a human prothrombin complex. The method comprises the following steps: (1) taking the human prothrombin complex, diluting until a blood coagulation factor IX is 0.8-1.3IU/ml, adding a human prothrombin solution with the isovolumetric concentration being 4-6IU/ml, mixing evenly, and standing at room temperature for 1-2 minutes; (2) adding a thrombin chromogenic substrate solution which is isovolumetric to the human prothrombin solution, mixing evenly, and incubating at 22-28 DEG C for 4-6 minutes, wherein the concentration of the chromogenic substrate solution is 0.5-0.7mg/ml; (3) determining a light absorption value at the wavelength of 405nm, and determining once 30-50 seconds for 5-8 times in all; and (4) drawing the time changing trend along with the light absorption value by taking the determined light absorption value as a longitudinal coordinate (y) and time (s) as a cross coordinate (x), building a linear equation y=kx+a, wherein k is slope, and calculating the value of 1/k. The method for detecting the anticoagulant capacity of the human prothrombin complex is simple and convenient to operate and good in repeatability; the comprehensive anticoagulant ability of the PCCs product can be quantitatively detected; and the safety of the PCCs product can be evaluated.
Description
Technical field
The present invention relates to a kind of method detecting Human Factor Ⅸ Complex's anticoagulant capacity.
Background technology
Human Factor Ⅸ Complex (prothrombin complex concentrates, PCCs) be a kind of plasma protein products being separated preparation from human normal plasma, mainly comprise four kinds of clotting factor (coagulation factor, F), be respectively FII, FVII, FIX, FX, these four kinds of clotting factor have similar physicochemical property, all need vitamin K dependent to synthesize simultaneously; In addition, three kinds of anticoagulant proteins also containing PROTEIN C (proteinC, PC), Protein S (protein S, PS), the same vitamin K dependent synthesis of albumen Z (protein Z, PZ).Since the sixties in last century, these goods were used for the clinical prevention of hemophilia B, because its composition is comparatively complicated, its clinical indication constantly expands, also can be used for congenital or acquired FII, FVII, FX, PC, PS to lack, Coagulation Dysfunction disease caused by liver diseases, chronic infusion F VIII body produces the treatment lost blood seriously that the hemophilia A of anti-F VIII antibody and wound cause, and is extended to again in recent years and takes the excessive and treatment of the haemorrhage caused of bicoumarin anticoagulant.China's large population base, hepatopath crowd's ratio is high, and add high-purity FII, FVII, FX, PC, PS preparation and lack, therefore PCCs clinical practice is more extensive.
From PCCs goods be used for clinical since, have many about the report causing thrombosis complication, in order to reduce its thrombotic risk, the nineties in last century, many scholars think add heparin and antithrombase (antithrombin in PCCs, AT) anticoagulation preparation can reduce the thrombogenicity of PCCs, but a rigid unified standard is not had to the concrete addition of heparin in PCCs and AT, and, domestic and international producer adopts DEAE-sephadex A50 gel to carry out PCCs separation mostly, but concrete technology condition is not identical, cause the PC that it contains, PS, PZ is also inconsistent, in addition heparin and AT addition neither one unified standard, cause anti-freezing composition (PC in PCCs, PS, PZ, heparin and AT) content has very big-difference, thus cause the anticoagulant capacity of PCCs also to have a great difference.
At present, the anticoagulant capacity of biological products is weighed by the active quantities detecting anticoagulant substances usually.But because the shortage of different process and unified standard makes anti-freezing composition in different PCCs (PC, PS, PZ, heparin and AT) content inconsistent, and it is mixed in together with short congeal into point FII, FVII, FIX, FX.Therefore, the anticoagulant capacity of PCCs goods detects very complicated, and comprehensive anticoagulant capacity is difficult to evaluate, and then cannot determine the thrombus occurrence risk of PCCs goods.
Be badly in need of finding a kind of method that can measure the comprehensive anticoagulant capacity of PCCs.
Summary of the invention
In order to solve the problem, the invention provides a kind of method detecting Human Factor Ⅸ Complex's anticoagulant capacity, the comprehensive anticoagulant capacity of PCCs can be measured.
The present invention detects the method for Human Factor Ⅸ Complex's anticoagulant capacity, and it comprises the steps:
(1) get Human Factor Ⅸ Complex, being diluted to FIX is 0.8-1.3IU/ml, adds the human thrombin solution that equal-volume concentration is 4-6IU/ml, mixing, and room temperature places 1-2min;
(2) add isopyknic fibrin ferment chromophoric substrate solution with human thrombin again, mixing, hatch 4-6min under 22-28 DEG C of water bath condition, the concentration of described chromophoric substrate solution is 0.5-0.7mg/ml;
(3) measure light absorption value at 405nm wavelength condition, every 30-50s measures 1 time, measures 5-8 time altogether;
(4) with the light absorption value of said determination for ordinate (y), with the time (s) for horizontal ordinate (x), draw light absorption value time dependent trend, and set up linear equation y=kx+a, wherein k is slope, calculates the value of 1/k.
Room temperature: 25 DEG C ± 5 DEG C.
Preferably, in step (1), clotting factor 1-1.2IU/ml is diluted to.
Preferably, in step (1), the concentration of human thrombin solution is 5IU/ml.
Preferably, in step (1), the time that room temperature is placed is 2min.
Preferably, in step (2), described fibrin ferment chromophoric substrate is CS-01 (38), and its molecular formula is H-D-Phe-Pip-Arg-pNa2HCl.
Preferably, in step (2), described in the temperature of hatching be 26 DEG C.
Preferably, in step (2), described in time of hatching be 6min.
Preferably, in step (2), the concentration of described chromophoric substrate solution is 0.6mg/ml.
Preferably, in step (3), every 40-50s measures 1 time.
Preferably, in step (3), measure 5-6 time altogether.
In order to accurately weigh the anticoagulant capacity of Human Factor Ⅸ Complex, researchist is devoted to the single-activity assay of its anti-freezing composition (as PC, PS, PZ, heparin, AT) at present, but its overall anticoagulant capacity but cannot be evaluated.
But the present inventor finds unexpectedly, adopt the inventive method can the overall anticoagulant capacity of direct-detection Human Factor Ⅸ Complex, and without the need to detecting the active quantities of each anticoagulant substances, achieve unexpected technique effect.
Inventor finds in research process, adopt the inventive method, Human Factor Ⅸ Complex and fibrin ferment and substrate thereof are reacted under specified conditions of the present invention, within the specific time period, the change speed of light absorption value (OD value) and the anticoagulant capacity linearly negative correlation of Human Factor Ⅸ Complex, and the slope in the linear equation of light absorption value and time is exactly the parameter of the change speed reacting light absorption value, thus by calculating the inverse of this slope, the anticoagulant capacity of Human Factor Ⅸ Complex can just be determined.
The method that the present invention detects Human Factor Ⅸ Complex is easy and simple to handle, reproducible, can the comprehensive anticoagulant capacity of quantitative measurement PCCs goods, thus can evaluate the security of different PCCs goods and compare.
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
Accompanying drawing explanation
OD value (s) change curve and the linear equation in time of the PCCs goods mensuration of the different heparin of Fig. 1 and AT content
OD value (s) change curve and the linear equation in time that the domestic and international four kinds of PCCs goods of Fig. 2 measure
Embodiment
Prothrombin complex (PCCs), purchased from domestic and international goods company;
Human thrombin, purchased from sigma company, lot number: SLBK7230V;
Fibrin ferment chromophoric substrate CS-01 (38), purchased from HYPEN-biomed company, lot number: 30401-1.Embodiment 1 detection method
1. the dilution of Human Factor Ⅸ Complex (PCCs) goods
PCCs goods pure water is diluted to 0.8IU FIX/ml, gets 40 μ l and add in microwell plate.
2.PCCs mixes with human thrombin
Get 40 μ l concentration be 4IU/ml human thrombin, add in above-mentioned microwell plate, slightly shake, mix, room temperature place 1min.
3. chromogenic reaction
Add chromophoric substrate CS-01 (38) (molecular formula: the H-D-Phe-Pip-Arg-pNa2HCl) solution that 40 μ l concentration are 0.5mg/ml in above-mentioned microwell plate, mix, under 22 DEG C of water bath condition, hatch 4min.
4. absorbance measurement
405nm wavelength condition measures light absorption value (OD value), and every 30s measures 1 time, measures 5 times, altogether 150s.
5. linear equation is set up
With the OD value of said determination for ordinate (y), with the time (s) for horizontal ordinate (x), draw the time dependent trend of OD value, and set up linear equation y=kx+a, wherein k is slope.
6. the quantitative calculating of comprehensive anticoagulant capacity
Calculate 1/k value, be the comprehensive anticoagulant capacity of PCCs.
Embodiment 2 detection method
1. the dilution of Human Factor Ⅸ Complex (PCCs) goods
PCCs goods pure water is diluted to 0.8-1.0IU FIX/ml, gets 60 μ l and add in microwell plate.
2.PCCs mixes with human thrombin
Get 60 μ l concentration be 5IU/ml human thrombin, add in above-mentioned microwell plate, slightly shake, mix, room temperature place 1.5min.
3. chromogenic reaction
Add chromophoric substrate CS-01 (38) (molecular formula: the H-D-Phe-Pip-Arg-pNa2HCl) solution that 60 μ l concentration are 0.6mg/ml in above-mentioned microwell plate, mix, under 25 DEG C of water bath condition, hatch 5min.
4. absorbance measurement
405nm wavelength condition measures light absorption value (OD value), and every 40s measures 1 time, measures 7 times, altogether 280s.
5. linear equation is set up
With the OD value of said determination for ordinate (y), with the time (s) for horizontal ordinate (x), draw the time dependent trend of OD value, and set up linear equation y=kx+a, wherein k is slope.
6. the quantitative calculating of comprehensive anticoagulant capacity
Calculate 1/k value, be the comprehensive anticoagulant capacity of PCCs.
Embodiment 3 detection method
1. the dilution of Human Factor Ⅸ Complex (PCCs) goods
PCCs goods pure water is diluted to 1.3IU FIX/ml, gets 80 μ l and add in microwell plate.
2.PCCs mixes with human thrombin
Get 80 μ l concentration be 6IU/ml human thrombin, add in above-mentioned microwell plate, slightly shake, mix, room temperature place 2min.
3. chromogenic reaction
Add chromophoric substrate CS-01 (38) (molecular formula: the H-D-Phe-Pip-Arg-pNa2HCl) solution that 80 μ l concentration are 0.7mg/ml in above-mentioned microwell plate, mix, under 28 DEG C of water bath condition, hatch 6min.
4. absorbance measurement
405nm wavelength condition measures light absorption value (OD value), and every 50s measures 1 time, measures 8 times, altogether 400s.
5. linear equation is set up
With the OD value of said determination for ordinate (y), with the time (s) for horizontal ordinate (x), draw the time dependent trend of OD value, and set up linear equation y=kx+a, wherein k is slope.
6. the quantitative calculating of comprehensive anticoagulant capacity
Calculate 1/k value, be the comprehensive anticoagulant capacity of PCCs.
Below by the mode of experimental example, beneficial effect of the present invention is described:
The mensuration of the comprehensive anticoagulant capacity of PCCs of the different heparin of experimental example 1 and AT content and comparing
1. experimental technique
(1) get commercially available PCCs concentrate, measure FIX active quantities, it is 1.2IU/ml that ultrapure water is diluted to FIX active quantities, packing 200 μ l mono-.Appropriate AT (antithrombase) (50IU/ml) and heparin (1000IU/ml) solution is added respectively in equivalent PCCs concentrate dilution, prepare the PCCs goods of different heparin and AT active quantities, because adding the volume differences that different AT and heparin volume cause, add appropriate ultrapure water to make up, final volume is 250 μ l.The PCCs goods preparing different heparin and AT active quantities are designated A, B, C, D respectively, as shown in table 1.Get the PCCs goods 50 μ l of prepared different AT and heparin activity content respectively, add in 96 orifice plates.More than operation is all carried out under 2-4 DEG C of condition.
The PCCs goods of the different AT of table 1 and heparin activity content
| Goods are numbered | AT active quantities (IU/ml) | Heparin activity content (IU/ml) |
| A | 0 | 0 |
| B | 0.4 | 5 |
| C | 0.8 | 0 |
| D | 0.8 | 2.5 |
(2) every hole adds 6IU/ml human thrombin 50 μ l, Homogeneous phase mixing, and room temperature places 2min.
(3) every hole adds chromophoric substrate CS-01 (38) the solution 50 μ l of 0.6mg/ml, mixes, hatches 6min under 26 DEG C of water bath condition.
(4) microplate reader 405nm wavelength reads light absorption value (OD value), and 40s measures 1 time, totally 5 times, 200s.3 duplicate detection, get OD value mean value.
(5) with the OD value measured for ordinate (y), with the time (s) for horizontal ordinate (x), draw OD value change curve in time, and set up linear equation y=kx+a.
(6) calculate 1/k value respectively, be the comprehensive anticoagulant capacity of different heparin and AT content PCCs.
2. experimental result
As shown in Figure 1, anticoagulant capacity result is as shown in table 2 below for linear equation:
The mensuration of the comprehensive anticoagulant capacity of PCCs of the different heparin of table 2 and AT content
| Goods are numbered | Linear equation k value | Comprehensive anticoagulant capacity (1/k value) |
| A | 0.04 | 25.0000 |
| B | 0.0271 | 36.9004 |
| C | 0.0344 | 29.0698 |
| D | 0.0305 | 32.7869 |
Contrasted as can be seen from Fig. 1 and table 2:
1.A group PCCs does not add AT and heparin, and B, C, D group PCCs all with the addition of AT and/or heparin, and their anticoagulant capacity is better than A group PCCs.
Use detection method to detect to find, the anticoagulant capacity of A group PCCs is 25.0000, and B, C, D group PCCs anticoagulant capacity is respectively 36.9004,29.0698 and 32.7869, is all greater than A group PCCs, illustrate that the anticoagulant capacity of B, C, D group PCCs is better than A group PCCs, consistent with expected results.
2.D group PCCs is than C group PCCs and many heparin of 2.5IU/ml, and its anticoagulant capacity is better than C group PCCs.
Use detection method to detect to find, D group PCCs anticoagulant capacity is respectively 32.7869, and the anticoagulant capacity of C group PCCs is 29.0698, illustrates that the anticoagulant capacity of D group PCCs is better than C group PCCs, consistent with expected results.
Experimental result illustrates, the inventive method accurately can detect the anticoagulant capacity of PCCs goods.
The mensuration of the comprehensive anticoagulant capacity of the domestic and international different PCCs goods of experimental example 2 and comparing
1. experimental technique
(1) get the PCCs goods of 4 kinds of domestic and international different manufacturers, be labeled as A, B, C, D.By specification fully dissolves 4 kinds of goods respectively, and 2-4 DEG C of placement, gets 1ml, and diluting FIX active concentration with ultrapure water in 30min is 1IU/ml.Get the PCCs after 70 μ l dilutions respectively, add in 96 orifice plates.
(2) every hole adds 5IU/ml human thrombin 70 μ l, Homogeneous phase mixing, and room temperature places 1.5min.
(3) every hole adds chromophoric substrate CS-01 (38) the solution 70 μ l of 0.55mg/ml, mixes, hatches 5min under 25 DEG C of water bath condition.
(4) microplate reader 405nm wavelength reads light absorption value (OD value), and 50s measures 1 time, totally 6 times, 300s.3 duplicate detection, get OD value mean value.
(5) with the OD value measured for ordinate (y), with the time (s) for horizontal ordinate (x), draw OD value change curve in time, and set up linear equation y=kx+a, as shown in Figure 2.
(6) calculate 1/k value respectively, be the comprehensive anticoagulant capacity of PCCs.A, B, C, D 4 kinds of comprehensive anticoagulant capacity of PCCs are as shown in table 3.
2. experimental result
The mensuration of the domestic and international 4 kinds of comprehensive anticoagulant capacity of different PCCs goods of table 3
| Goods are numbered | Linear equation k value | Comprehensive anticoagulant capacity (1/k value) |
| A | 0.0395 | 25.3165 |
| B | 0.0612 | 16.3399 |
| C | 0.0547 | 18.2815 |
| D | 0.0368 | 27.1739 |
The technique preparing PCCs due to domestic and international producer is variant, its contain short to congeal into point and anti-freezing composition not identical, its comprehensive anticoagulant capacity should not be identical.Shown in experimental result table 3, the comprehensive anticoagulant capacity of A, B, C, D is respectively: 25.3165,16.3399,18.2815,27.1739.
Experimental result illustrates, the inventive method effectively can detect the anticoagulant capacity of PCCs goods.
To sum up, the inventive method effectively can detect the anticoagulant capacity of Human Factor Ⅸ Complex, and easy and simple to handle, with low cost, application prospect is good.
Claims (10)
1. detect a method for Human Factor Ⅸ Complex's anticoagulant capacity, it is characterized in that: it comprises the steps:
(1) get Human Factor Ⅸ Complex, being diluted to plasma thromboplastin component is 0.8-1.3IU/ml, adds the human thrombin solution that equal-volume concentration is 4-6IU/ml, mixing, and room temperature places 1-2min;
(2) add and human thrombin solution isopyknic fibrin ferment chromophoric substrate solution, mixing, hatch 4-6min under 22-28 DEG C of condition, the concentration of described chromophoric substrate solution is 0.5-0.7mg/ml again;
(3) under 405nm wavelength condition, measure light absorption value, every 30s-50s measures 1 time, measures 5-8 time altogether;
(4) with the light absorption value measured for ordinate (y), with the time (s) for horizontal ordinate (x), draw light absorption value time dependent trend, and set up linear equation y=kx+a, wherein k is slope, calculates the value of 1/k.
2. method according to claim 1, is characterized in that: in step (1), be diluted to clotting factor 1-1.2IU/ml.
3. method according to claim 1, is characterized in that: in step (1), and the concentration of human thrombin solution is 5IU/ml.
4. method according to claim 1, is characterized in that: in step (1), and the time that room temperature is placed is 2min.
5. method according to claim 1, is characterized in that: in step (2), and described fibrin ferment chromophoric substrate is CS-01 (38), and its molecular formula is H-D-Phe-Pip-Arg-pNa2HCl.
6. method according to claim 1, is characterized in that: in step (2), described in the temperature of hatching be 26 DEG C.
7. method according to claim 1, is characterized in that: in step (2), described in time of hatching be 6min.
8. method according to claim 1, is characterized in that: in step (2), and the concentration of described chromophoric substrate solution is 0.6mg/ml.
9. method according to claim 1, is characterized in that: in step (3), every 40-50s measures 1 time.
10. method according to claim 1, is characterized in that: in step (3), measures 5-6 time altogether.
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| CN104805171A (en) * | 2015-04-10 | 2015-07-29 | 中国农业科学院植物保护研究所 | Novel method for activity evaluation of active substances |
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| CN107255622A (en) * | 2017-06-30 | 2017-10-17 | 上海贞元诊断用品科技有限公司 | A kind of kit that dabigatran content is detected based on fibrin ferment Chromogenic assay |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107167439A (en) * | 2017-06-30 | 2017-09-15 | 上海贞元诊断用品科技有限公司 | A kind of kit that dabigatran content is detected based on Chromogenic assay |
| CN107255622A (en) * | 2017-06-30 | 2017-10-17 | 上海贞元诊断用品科技有限公司 | A kind of kit that dabigatran content is detected based on fibrin ferment Chromogenic assay |
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