CN104459165B - A kind of method detecting Human Factor Ⅸ Complex's anticoagulant capacity - Google Patents
A kind of method detecting Human Factor Ⅸ Complex's anticoagulant capacity Download PDFInfo
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Abstract
The invention discloses a kind of method detecting Human Factor Ⅸ Complex's anticoagulant capacity, step is as follows: (1) takes Human Factor Ⅸ Complex, being diluted to plasma thromboplastin component is 0.8-1.3IU/ml, add the human thrombin solution that equal-volume concentration is 4-6IU/ml, mixing, room temperature places 1-2min；(2) thrombin chromophoric substrate solution isopyknic with human thrombin solution is added, mixing, hatch 4-6min under 22-28 DEG C of condition, the concentration of described chromophoric substrate solution is 0.5-0.7mg/ml；(3) measuring light absorption value at 405nm wavelength condition, every 30s-50s measures 1 time, measures 5-8 time altogether；(4) with the light absorption value of mensuration for vertical coordinate (y), with the time (s) for abscissa (x), the time dependent trend of light absorption value is drawn, and set up linear equation y=kx+a, wherein k is slope, calculates the value of 1/k,.The method that the present invention detects Human Factor Ⅸ Complex's anticoagulant capacity is easy and simple to handle, reproducible, can the comprehensive anticoagulant capacity of detection by quantitative PCCs goods, evaluate the safety of PCCs goods.
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 (prothrombincomplexconcentrates, PCCs) it is a kind of plasma protein products separating preparation from human normal plasma, mainly comprise four kinds of thrombin (coagulationfactor, F), respectively FII, FVII, FIX, FX, these four kinds of thrombins have similar physicochemical property, are both needed to vitamin K dependent synthesis simultaneously；Additionally, the three kinds of anticoagulant proteins synthesized possibly together with PROTEIN C (proteinC, PC), Protein S (proteinS, PS), the same vitamin K dependent of albumen Z (proteinZ, PZ).From the sixties in last century these goods for hemophilia B clinical prevention since, owing to its composition is complex, its clinical indication constantly expands, can be additionally used in congenital or acquired FII, FVII, FX, PC, PS to lack, Coagulation Dysfunction disease caused by hepatic disease, the treatment lost blood seriously that chronic infusion F VIII body produces the hemophilia A of anti-F VIII antibody and wound causes, is extended to again in recent years and takes that dicoumarol anticoagulant is excessive and the treatment of hemorrhage that causes.China's large population base, hepatopath crowd's ratio is high, adds high-purity FII, FVII, FX, PC, PS preparation and lacks, and therefore PCCs clinical practice is more extensive.
nullFrom PCCs goods for since clinic，Have many about the report causing thrombosis complication，In order to reduce its thrombotic risk，The nineties in last century，Many scholars think and add heparin and antithrombase (antithrombin in PCCs，AT) anticoagulation preparation can reduce the thrombogenicity of PCCs，But the concrete addition of heparin in PCCs and AT is not had a rigid unified standard，And，Domestic and international producer adopts DEAE-sephadexA50 gel to carry out PCCs separation mostly，But concrete technology condition also differs，Cause the PC that it contains、PS、PZ is also inconsistent，In addition heparin and AT addition neither one unified standard，Cause anticoagulant composition (PC in PCCs、PS、PZ、Heparin and AT) content has very big-difference，Thus causing the anticoagulant capacity of PCCs also to have a great difference.
At present, the anticoagulant capacity of biological product is weighed usually by the active quantities of detection anticoagulant substances.But, owing to the shortage of different process and unified standard makes anticoagulant composition (PC, PS, PZ, heparin and AT) content in different PCCs inconsistent, and itself and coagulant composition FII, FVII, FIX, FX are mixed in together.Therefore, the anticoagulant capacity detection of PCCs goods is extremely complex, and comprehensive anticoagulant capacity is difficult to evaluate, and then cannot determine the thrombosis occurrence risk of PCCs goods.
It is 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 problems referred to above, the invention provides a kind of method detecting Human Factor Ⅸ Complex's anticoagulant capacity, it is possible to measure the comprehensive anticoagulant capacity of PCCs.
The present invention detects the method for Human Factor Ⅸ Complex's anticoagulant capacity, and it comprises the steps:
(1) taking 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) thrombin chromophoric substrate solution isopyknic with human thrombin is added, 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) measuring 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 vertical coordinate (y), with the time (s) for abscissa (x), the time dependent trend of light absorption value is drawn, 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), it is diluted to thrombin 1-1.2IU/ml.
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 thrombin chromophoric substrate is CS-01 (38), and its molecular formula is H-D-Phe-Pip-Arg-pNa 2HCl.
Preferably, in step (2), described in the temperature hatched 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 enable accurately to weigh the anticoagulant capacity of Human Factor Ⅸ Complex, research worker is devoted to the single-activity assay of its anticoagulant composition (such as PC, PS, PZ, heparin, AT) at present, but its overall anticoagulant capacity but cannot be evaluated.
But, the present inventor is found surprisingly that, and adopts the inventive method can directly detect the overall anticoagulant capacity of Human Factor Ⅸ Complex, without the active quantities detecting each anticoagulant substances, achieves unexpected technique effect.
Inventor finds in research process, adopt the inventive method, Human Factor Ⅸ Complex is reacted under specified conditions of the present invention with thrombin and substrate thereof, 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 light absorption value and the slope in the linear equation of time are exactly the parameter of the change speed reacting light absorption value, thereby through the inverse calculating this slope, it is possible to determine the anticoagulant capacity of Human Factor Ⅸ Complex.
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 assay PCCs goods, thus the safety of different PCCs goods can be evaluated and compares.
The detailed description of the invention of form by the following examples, is described in further detail the foregoing of the present invention.But this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to below example.All technology realized based on foregoing of the present invention belong to the scope of the present invention.
Accompanying drawing explanation
OD value (s) change curve and the linear equation in time that the PCCs goods of Fig. 1 difference heparin and AT content measure
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
Detailed description of the invention
Prothrombin complex (PCCs), purchased from domestic and international goods company；
Human thrombin, purchased from sigma company, lot number: SLBK7230V；
Thrombin 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 0.8IUFIX/ml, takes 40 μ l and add in microwell plate.
2.PCCs mixes with human thrombin
Take 40 μ l concentration be 4IU/ml human thrombin, add in above-mentioned microwell plate, slightly shake, mix homogeneously, room temperature place 1min.
3. chromogenic reaction
Above-mentioned microwell plate adds chromophoric substrate CS-01 (38) (molecular formula: the H-D-Phe-Pip-Arg-pNa 2HCl) solution that 40 μ l concentration are 0.5mg/ml, mix homogeneously, under 22 DEG C of water bath condition, hatches 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 vertical coordinate (y), with the time (s) for abscissa (x), drawing the time dependent trend of OD value, and set up linear equation y=kx+a, wherein k is slope.
6. the quantitative Analysis 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 0.8-1.0IUFIX/ml, takes 60 μ l and add in microwell plate.
2.PCCs mixes with human thrombin
Take 60 μ l concentration be 5IU/ml human thrombin, add in above-mentioned microwell plate, slightly shake, mix homogeneously, room temperature place 1.5min.
3. chromogenic reaction
Above-mentioned microwell plate adds chromophoric substrate CS-01 (38) (molecular formula: the H-D-Phe-Pip-Arg-pNa 2HCl) solution that 60 μ l concentration are 0.6mg/ml, mix homogeneously, under 25 DEG C of water bath condition, hatches 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 vertical coordinate (y), with the time (s) for abscissa (x), drawing the time dependent trend of OD value, and set up linear equation y=kx+a, wherein k is slope.
6. the quantitative Analysis 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 1.3IUFIX/ml, takes 80 μ l and add in microwell plate.
2.PCCs mixes with human thrombin
Take 80 μ l concentration be 6IU/ml human thrombin, add in above-mentioned microwell plate, slightly shake, mix homogeneously, room temperature place 2min.
3. chromogenic reaction
Above-mentioned microwell plate adds chromophoric substrate CS-01 (38) (molecular formula: the H-D-Phe-Pip-Arg-pNa 2HCl) solution that 80 μ l concentration are 0.7mg/ml, mix homogeneously, under 28 DEG C of water bath condition, hatches 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 vertical coordinate (y), with the time (s) for abscissa (x), drawing the time dependent trend of OD value, and set up linear equation y=kx+a, wherein k is slope.
6. the quantitative Analysis of comprehensive anticoagulant capacity
Calculate 1/k value, be the comprehensive anticoagulant capacity of PCCs.
By the mode of experimental example, beneficial effects of the present invention is described below:
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) taking commercially available PCCs concentrate, measure FIX active quantities, it is 1.2IU/ml that ultra-pure water is diluted to FIX active quantities, subpackage 200 μ l mono-.Appropriate AT (antithrombase) (50IU/ml) and heparin (1000IU/ml) solution is added respectively in equivalent PCCs concentrate diluent, the PCCs goods of the different heparin of preparation and AT active quantities, because of the volume differences adding different AT and heparin volume causes, adding appropriate ultra-pure water to make up, final volume is 250 μ l.The PCCs goods of the different heparin of preparation and AT active quantities are individually identified as A, B, C, D, as shown in table 1.Take the PCCs goods 50 μ l of prepared different AT and heparin activity content respectively, add in 96 orifice plates.More than operation all carries 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, mix homogeneously, 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, take OD value meansigma methods.
(5) with the OD value of mensuration for vertical coordinate (y), with the time (s) for abscissa (x), draw OD value and change over curve, 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
Linear equation is as it is shown in figure 1, anticoagulant capacity result is as shown in table 2 below:
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 by Fig. 1 and Biao 2 it can be seen that
1.A group PCCs is not added with 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.
Detection method detection is used to find, the anticoagulant capacity of A group PCCs is 25.0000, and B, C, D group PCCs anticoagulant capacity respectively 36.9004,29.0698 and 32.7869, it is all higher 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.
Detection method detection is used to find, D group PCCs anticoagulant capacity 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 can accurately detect the anticoagulant capacity of PCCs goods.
The mensuration of the experimental example 2 different comprehensive anticoagulant capacity of PCCs goods both at home and abroad and comparing
1. experimental technique
(1) take 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, 2-4 DEG C of placement, and taking the interior ultra-pure water dilution FIX active concentration of 1ml, 30min is 1IU/ml.Take 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, mix homogeneously, 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, take OD value meansigma methods.
(5) with the OD value of mensuration for vertical coordinate (y), with the time (s) for abscissa (x), draw OD value and change over curve, 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.The comprehensive anticoagulant capacity of A, B, C, D4 kind PCCs is as shown in table 3.
2. experimental result
The mensuration of the domestic and international 4 kinds of different comprehensive anticoagulant capacity of 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 |
Due to domestic and international producer, to prepare the technique of PCCs variant, and coagulant composition and anticoagulant composition that it contains differ, and its comprehensive anticoagulant capacity should differ.Shown in experimental result table 3, the comprehensive anticoagulant capacity of A, B, C, D is respectively as follows: 25.3165,16.3399,18.2815,27.1739.
Experimental result illustrates, the inventive method can effectively detect the anticoagulant capacity of PCCs goods.
To sum up, the inventive method can effectively 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. the method detecting Human Factor Ⅸ Complex's anticoagulant capacity, it is characterised in that: it comprises the steps:
(1) taking 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) thrombin chromophoric substrate solution isopyknic with human thrombin solution is added, mixing, hatch 4-6min under 22-28 DEG C of condition, the concentration of described chromophoric substrate solution is 0.5-0.7mg/ml；
(3) measuring light absorption value under 405nm wavelength condition, every 30s-50s measures 1 time, measures 5-8 time altogether；
(4) with the light absorption value of mensuration for vertical coordinate (y), with the time (s) for abscissa (x), the time dependent trend of light absorption value is drawn, and set up linear equation y=kx+a, wherein k is slope, calculates the value of 1/k,.
2. method according to claim 1, it is characterised in that: in step (1), being diluted to plasma thromboplastin component is 1-1.2IU/ml.
3. method according to claim 1, it is characterised in that: in step (1), the concentration of human thrombin solution is 5IU/ml.
4. method according to claim 1, it is characterised in that: in step (1), the time that room temperature is placed is 2min.
5. method according to claim 1, it is characterised in that: in step (2), described thrombin chromophoric substrate is CS-01 (38), and its molecular formula is H-D-Phe-Pip-Arg-pNa 2HCl.
6. method according to claim 1, it is characterised in that: in step (2), described in the temperature hatched be 26 DEG C.
7. method according to claim 1, it is characterised in that: in step (2), described in time of hatching be 6min.
8. method according to claim 1, it is characterised in that: in step (2), the concentration of described chromophoric substrate solution is 0.6mg/ml.
9. method according to claim 1, it is characterised in that: in step (3), every 40-50s measures 1 time.
10. method according to claim 1, it is characterised in that: in step (3), measure 5-6 time altogether.
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| CN103884662A (en) * | 2014-02-24 | 2014-06-25 | 辽宁诺康生物制药有限责任公司 | Method for determining thrombin-like enzyme activity |
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| CN101171519A (en) * | 2005-04-29 | 2008-04-30 | 瑟纳普斯有限责任公司 | Measuring thrombin activity in whole blood |
| CN103884662A (en) * | 2014-02-24 | 2014-06-25 | 辽宁诺康生物制药有限责任公司 | Method for determining thrombin-like enzyme activity |
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