JP6747491B2 - Blood state analysis device, blood state analysis system, blood state analysis method, and blood state analysis program for realizing the method on a computer - Google Patents

Description

The present technology relates to a blood condition analyzer. More specifically, in a state in which one or more drugs selected from the group consisting of anticoagulant treatment release agents, coagulation activators, anticoagulants, platelet activators and antiplatelet agents are added to a blood sample, The present invention relates to an apparatus for analyzing the state of a blood sample, a blood state analysis system, a blood state analysis method, and a program for causing a computer to realize the method.

As a method for obtaining the volume fraction of cells in a cell suspension, a low frequency electric conductivity of the suspension (a frequency of 100 kHz or less) and a low frequency electric conductivity of a solvent containing no cells (a frequency of 100 kHz or less) A method using is known (Non-Patent Document 1). For example, in a suspension in which spherical cells are diluted, the volume fraction of cells can be obtained by the following mathematical formula (1).

On the other hand, when the shape of the suspended cells is not spherical, it is also necessary to consider the shape of the cells.For example, in a suspension in which the cells of the spheroid are diluted, the volume fraction of the cells is It can be obtained by the following formula (2).

Further, in the case of a concentrated suspension, which has a high cell density and cannot be treated as a dilute dispersion system, it is necessary to use another equation considering the interaction between cells.

However, in these conventional methods, it is necessary to use the electric conductivity of a solvent that does not contain cells, and the volume fraction of cells cannot be obtained from the data of only the suspension. Further, the cells need to be dispersed in the solvent without being aggregated. For this reason, for example, in the case of blood containing a plasma component, red blood cell corpuscles, agglutination, and the like generally occur, and thus the volume fraction of red blood cells and the like cannot be obtained by a conventional method. Moreover, the degree of change or aggregation changes variously depending on the flow of blood and the time after being allowed to stand, so it is difficult to obtain a formula that takes into account the degree of change or aggregation. No such formula is known.

By the way, as a general blood coagulation test, a blood coagulation test represented by prothrombin time (PT) and activated partial thromboplastin time (APTT) is known. These methods are methods for analyzing proteins involved in coagulation reaction, which are contained in plasma obtained by centrifuging a blood sample. This field has been technically established, and it has been considered that the needs in the medical field are almost satisfied.

However, in the perioperative (acute phase) treatment or the like, which requires promptness, the above method is insufficient to meet the needs of accurately and simply examining comprehensive coagulation pathology of patients. Specifically, for example, in large-scale surgery such as heart surgery involving extracorporeal circulation with an artificial heart-lung machine, treatment of severe trauma, and liver transplant surgery, not only surgical bleeding but bleeding due to abnormal coagulation may persist. is there. Nevertheless, in conventional coagulation tests, cell components such as platelets and erythrocytes, which play an important role in the coagulation reaction in the body, are removed by centrifugation, so the test results are inconsistent with the actual clinical condition. There are also many.

In addition, the coagulation pathology of patients varies greatly throughout the perioperative period and often changes from a bleeding tendency to a thrombosis tendency. However, PT and APTT are tests for a bleeding tendency, and a highly sensitive test method for a thrombosis tendency has not yet been achieved. Not established.

As a comprehensive coagulation test in the acute phase, thromboelastometry, which dynamically measures viscoelastic changes associated with blood coagulation processes, has been commercialized by Western companies as TEG (registered trademark) and ROTEM (registered trademark). However, in these, (1) the measurement is not automated, the inspection result depends on the operator's procedure, (2) is easily affected by vibration, (3) the quality control (QC) procedure is complicated, The reason why the reagent for QC is expensive and (4) the skill of interpreting the output signal (thromboelastogram) is required are considered to be the first reason for preventing the sufficient spread. Therefore, for patients who do not need blood transfusion if a comprehensive coagulation test is performed, blood products are often used preventively and empirically at present, which not only increases the risk of infections, but also wastes blood products. And bring increased medical costs.

In recent years, a technique for easily and accurately evaluating the degree of blood coagulation is being developed. For example, Patent Document 1 discloses a technique for acquiring information on blood coagulation from the permittivity of blood, which is "a pair of electrodes and an alternating voltage is applied to the pair of electrodes at predetermined time intervals. Applying means, measuring means for measuring the permittivity of blood disposed between the pair of electrodes, and permittivity of blood measured at the above-mentioned time intervals after the action of the anticoagulant acting on the blood is released. Is used to analyze the degree of action of the blood coagulation system, and a blood coagulation system analyzer having the analyzing means.

As a blood sample in this method, a blood sample collected from a vein using citric acid or the like as an anticoagulant is generally used. Immediately before the start of the measurement, the anticoagulant is released by using an anticoagulant treatment releasing agent such as an aqueous solution of calcium chloride, and the measurement is performed in a state where the blood coagulation reaction is allowed to proceed.

JP, 2010-181400, A

Phys. Med. Biol. 54 (2009) 2395-2405

As mentioned above, the technique for assessing blood coagulation ability continues to progress day by day, but on the other hand, in addition to the clinical condition of the patient, some other factor causes an artifact in recent years. Has come to be understood.

Therefore, the main purpose of the present technology is to provide a technology capable of easily and accurately evaluating blood coagulation ability.

In order to solve the above-mentioned problems, the present inventors have earnestly studied the cause of the artifacts generated in the blood coagulation ability evaluation results. As a result, it was found that the blood coagulation ability evaluation result is greatly affected by the fact that the drug used for measurement is concentrated in plasma due to the excluded volume effect of blood cell components in blood, and to complete the present technology. I arrived.
That is, in the present technology, first, in a state in which a drug is added to a blood sample, a device for analyzing the state of the blood sample based on the electrical characteristics of the blood sample,
Correlation of the blood coagulation evaluation result of the blood sample from the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result based on electrical characteristics, in correspondence with the concentration of the drug present in plasma in the blood sample. Provided is a blood condition analyzer including a correction unit for correcting.
In the blood state analysis device according to the present technology, the correlation may be a predetermined one, or the correlation detection unit may be provided in the device to determine the correlation at the time of analysis. Above, it is also possible to perform the correction by the correction unit.
The blood coagulation evaluation result used in the blood state analysis device according to the present technology may be a result obtained by a known method in advance, or the device may evaluate the degree of blood coagulation based on the electrical characteristics of the blood sample. By providing a blood coagulation evaluation unit that obtains the blood coagulation evaluation result, it is possible to obtain the blood coagulation evaluation result in the same device.
In the present technology, the method for calculating the concentration of the drug present in plasma in the blood sample is not particularly limited, and can be determined by a general calculation method. For example, the hematocrit value of the blood sample and/or It is possible to calculate the concentration of the drug present in plasma in the blood sample based on the amount of hemoglobin. At this time, the device is provided with a plasma drug concentration calculating unit that calculates the concentration of the drug present in the plasma of the blood sample based on the hematocrit value and/or the hemoglobin amount of the blood sample. It is also possible to determine the concentration of the drug present in the plasma in the blood sample in the device.
Further, the hematocrit value and/or the amount of hemoglobin at this time may be a value obtained by a known method in advance, or the device may use the hematocrit value of the blood sample based on the electrical characteristics of the blood sample. It is also possible to determine the hematocrit value and/or the hemoglobin amount in the same device by providing a red blood cell quantitative evaluation unit that determines the hemoglobin amount and/or the hemoglobin amount.
The blood condition analyzer according to the present technology can also include a measurement unit that measures the electrical characteristics of the blood sample.
In addition, the blood state analysis device according to the present technology may include both the blood coagulation evaluation unit and the red blood cell quantitative evaluation unit. In this case, the electrical characteristics used in the evaluations of both the evaluation units may be the electrical characteristics of the same frequency, but in the blood coagulation evaluation unit, the electrical characteristics based on the electrical characteristics of the blood sample at the first frequency are used. Then, the degree of blood coagulation is evaluated, and the red blood cell quantitative evaluation unit determines the hematocrit value and/or the hemoglobin amount based on the electrical characteristics of the blood sample at a second frequency different from the first frequency. It is also possible to ask.
The drug can be selected from any one or more of an anticoagulant release agent, a coagulation activator, an anticoagulant, a platelet activator, and an antiplatelet agent.
The correlation between the concentration of the drug in plasma and the blood coagulation evaluation result can be determined from two or more different concentrations of the drug present in the plasma in the blood sample.
The blood condition analyzer according to the present technology can perform analysis based on the electrical characteristics of a blood sample at a frequency of 1 kHz to 50 MHz.

In the present technology, next, an electrical characteristic measuring device including a measuring unit that measures the electrical characteristic of a blood sample,
A device for analyzing the state of the blood sample based on the electrical characteristics of the blood sample in the state where a drug is added to the blood sample, the blood coagulation evaluation based on the concentration and electrical characteristics of the drug in plasma. A blood state analysis device comprising a correction unit that corrects the blood coagulation evaluation result of the blood sample from the correlation with the result in accordance with the concentration of the drug present in the plasma in the blood sample,
A blood condition analysis system having the following.
The blood state analysis system according to the present technology may include a server including an information storage unit that stores the measurement result of the electrical characteristic measuring device and/or the analysis result of the blood state analyzing device.
In this case, the server can also be connected to the electrical characteristic measuring device and/or the blood condition analyzing device via a network.

In the present technology, further, in a state in which a drug is added to a blood sample, a method of analyzing the state of the blood sample based on the electrical characteristics of the blood sample,
Correlation of the blood coagulation evaluation result of the blood sample from the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result based on electrical characteristics, in correspondence with the concentration of the drug present in plasma in the blood sample. Provided is a blood state analysis method for performing a correction step of correcting.

In the present technology, in addition, in a state where a drug is added to a blood sample, a program used for analyzing the state of the blood sample based on the electrical characteristics of the blood sample,
Correlation of the blood coagulation evaluation result of the blood sample from the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result based on electrical characteristics, in correspondence with the concentration of the drug present in plasma in the blood sample. Provide a blood condition analysis program for causing a computer to realize a correction function for correction.

According to the present technology, it is possible to easily and accurately evaluate blood coagulation ability.
Note that the effects described here are not necessarily limited and may be any effects described in the present technology.

It is a schematic conceptual diagram which shows typically the concept of the blood state analysis apparatus 1 which concerns on this technique. It is a schematic conceptual diagram which shows typically the concept of the blood state analysis system 10 which concerns on this technique. It is a flow chart of the blood state analysis method concerning this art. 8 is a drawing-substitute graph showing a correlation between a blood coagulation time (CFT100) obtained by measurement of a dielectric constant and a hematocrit value in Example 1. FIG. 8 is a drawing-substitute graph showing a correlation between hematocrit values and various parameters indicating blood coagulation ability obtained by measurement of dielectric constant in Example 1. FIG. 8 is a drawing-substitute graph showing a correlation between blood coagulation time (CFT100) obtained by measurement of dielectric constant and calcium concentration in Example 2. FIG. 8 is a drawing-substitute graph showing a correlation between various parameters indicating blood coagulation ability obtained by measurement of dielectric constant and calcium concentration in Example 2. FIG.

Hereinafter, a suitable mode for carrying out the present technology will be described with reference to the drawings. The embodiments described below are examples of typical embodiments of the present technology, and the scope of the present technology should not be construed narrowly. The description will be given in the following order.
1. Blood condition analyzer 1
(1) Correction unit 11
(2) Correlation detector 12
(3) Blood coagulation evaluation unit 13
(4) Plasma drug concentration calculation unit 14
(5) Red blood cell quantitative evaluation unit 15
(6) Measuring unit 16
(7) Storage unit 17
(8) Blood sample 2. Blood condition analysis system 10
(1) Electrical characteristic measuring device 101
(2) Blood condition analyzer 1
(3) Server 102
(4) Display unit 103
(5) User interface 104
3. Blood Condition Analysis Method (1) Correction Step I
(2) Correlation detection step II
(3) Blood coagulation evaluation step III
(4) Plasma drug concentration calculation step IV
(5) Red blood cell quantitative evaluation step V
(6) Measurement process VI
(7) Storage process VII
4. Blood condition analysis program

1. Blood condition analyzer 1
FIG. 1 is a schematic conceptual diagram schematically showing the concept of a blood state analysis device 1 (hereinafter, also referred to as “device 1”) according to the present technology. The blood state analysis device 1 according to the present technology includes at least one drug selected from the group consisting of an anticoagulant release agent, a coagulation activator, an anticoagulant, a platelet activator, and an antiplatelet agent (hereinafter, “ A device for analyzing the state of the blood sample in a state in which the “drug” is added), and includes at least a correction unit 11. In addition, the correlation detection unit 12, the blood coagulation evaluation unit 13, the plasma drug concentration calculation unit 14, the red blood cell quantitative evaluation unit 15, the measurement unit 16, the storage unit 17, and the like may be provided as necessary.

Examples of the drug include anticoagulants such as calcium chloride, calcium sulfate, calcium carbonate, calcium acetate, etc. (that is, these are calcium salts); tissue factor, contact factor, ellagic acid, kaolin, celite, Coagulation activators such as thrombin and batroxobin; anticoagulants such as citric acid, heparin, hirudin, EDTA, direct thrombin inhibitors, activated factor X inhibitors; platelet activation such as collagen, arachidonic acid, ADP, thrombin Agents: acetylsalicylic acid (aspirin), prostaglandins, thromboxane synthase inhibitors, thienopyridine derivatives (ticlopidine hydrochloride, clopidogrel, prasugrel, etc.), PDE3 inhibitors, 5-serotonin receptor 2 antagonists, GPIIb/IIIa inhibitors, etc. One or more selected from the group consisting of the above antiplatelet agents can be freely selected and used.

Hereinafter, each part will be described in detail.

(1) Correction unit 11
The correction unit 11 converts the blood coagulation evaluation result of the blood sample into the concentration of the drug present in the plasma of the blood sample based on the correlation between the drug concentration in plasma and the blood coagulation evaluation result. Correct accordingly.

In the present technology, as shown in Examples described later, it was found that even when the same blood sample is used, the parameter indicating blood coagulation ability changes depending on the concentration of the drug to be added in plasma. That is, it was found that an error occurs in the blood coagulation evaluation result depending on the amount of the drug to be added, the proportion of plasma in the blood sample, and the like. Therefore, by correcting the blood coagulation evaluation result in accordance with the concentration of the drug present in plasma, the artifact caused by the change in the concentration of the drug in plasma is eliminated, and a more accurate evaluation can be performed. It can be carried out.

In the correction unit 11, the concentration dependency of the test value obtained by the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result, a correction function using a correction constant determined by the correlation, and the like, Correct to the test value at the reference drug concentration.

The correlation used in the correction in the correction unit 11 may be a predetermined one, or the device 1 may be provided with a correlation detection unit 12 to be described later to obtain the correlation at the time of analysis and then correct the correlation. It is also possible to perform the correction by the unit 11.

(2) Correlation detector 12
The correlation detector 12 obtains the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result. In the blood state analyzer 1 according to the present technology, the correlation detection unit 12 is not essential, and as described above, a predetermined correlation can be used. However, by providing the correlation detection unit 12, the correlation The detection and correction can be performed in one device. The method of obtaining the blood correlation is not particularly limited and can be obtained by using a general statistical method. For example, the following method can be mentioned.

(A) Method of Obtaining Correlation Coefficient The correlation detection unit 12 employs, for example, a method of obtaining a correlation coefficient from the concentration dependence of test values at two or more different plasma drug concentrations, and obtains the correlation. You can Then, based on the obtained correlation coefficient, the corrector 11 corrects the test value at the reference drug concentration to obtain an accurate evaluation result.

In this method, since the correlation coefficient is obtained for each sample, it is possible to make a correction suitable for each sample.

(B) Method of Obtaining Correction Constant In the correlation detection unit 12, for example, a regression equation showing the concentration dependence of the test value at two or more different plasma drug concentrations per sample is obtained for each sample. Find each one, find the coefficient of each regression equation or mathematical combination of multiple coefficients that has a substantially constant value regardless of the sample, and find the correction constant that can be used for almost all samples A method may be employed to determine the correlation.

In this method, once the correction constant is obtained, the following analysis has an advantage that the correction can be performed by measurement at one plasma drug concentration per sample.

(3) Blood coagulation evaluation unit 13
The blood coagulation evaluation unit 13 evaluates the degree of blood coagulation based on the electrical characteristics of the blood sample to obtain the blood coagulation evaluation result. The blood coagulation evaluation unit 13 is not essential in the blood state analysis device 1 according to the present technology, and it is also possible to obtain the blood coagulation evaluation result by, for example, another device or method in advance.

The electrical characteristics of the blood sample are measured by the external electrical characteristics measuring apparatus, or the blood state analyzing apparatus 1 according to the present technology, when the measuring section 16 described below is provided. The data of can be used as it is. Alternatively, data obtained by removing noise from raw data can be used.

Examples of the electrical characteristics of blood that can be used in the blood coagulation evaluation unit 13 include dielectric constant, impedance, admittance, capacitance, conductance, conductivity, phase angle, and the like. These electrical characteristics can be converted into each other by the mathematical formulas shown in Table 1 below. Therefore, for example, the evaluation result of evaluating the degree of blood coagulation using the result of the dielectric constant measurement of the blood sample is the same as the evaluation result when the result of the impedance measurement of the same blood sample is used. Many of these electric quantities and physical property values can be described by using complex numbers, and thus the conversion formula can be simplified.

The electrical characteristic used for the evaluation in the blood coagulation evaluation unit 13 may be an electrical characteristic at an arbitrary frequency, but in particular, the degree of blood coagulation is evaluated from the electrical characteristic of the blood sample at a frequency of 1 kHz to 50 MHz. It is preferable to evaluate the degree of blood coagulation from the electrical characteristics of the blood sample at a frequency of 3 MHz to 15 MHz. This is because changes in electrical characteristics due to blood coagulation are observed at frequencies of 1 kHz to 50 MHz, and changes in electrical characteristics are more prominent at frequencies of 3 MHz to 15 MHz.

(4) Plasma drug concentration calculation unit 14
The plasma drug concentration calculating unit 14 calculates the concentration of the drug present in the plasma in the blood sample. The plasma drug concentration calculating unit 14 is not essential in the blood state analyzing apparatus 1 according to the present technology, and measures the concentration of the drug existing in plasma in the blood sample by, for example, another device or method in advance. It is also possible.

The plasma drug concentration calculating unit 14 is characterized by calculating the plasma drug concentration based on the hematocrit value and/or the hemoglobin amount of the blood sample. A blood sample having a high hematocrit value and/or a hemoglobin amount has a relatively low plasma amount, and conversely, a blood sample having a low hematocrit value and/or a hemoglobin amount has a relatively high plasma amount. That is, the plasma amount shows a negative correlation with the hematocrit value and/or the hemoglobin amount in the blood sample.

Then, when the same amount of the drug is added, a blood sample having a large hematocrit value and/or hemoglobin amount has a relatively low plasma amount, so that the drug concentration in plasma is high, and conversely, the hematocrit value and/or Alternatively, a blood sample having a small amount of hemoglobin has a relatively large amount of plasma, and thus the drug concentration in plasma is low. That is, when the same amount of the drug is added, the concentration of the drug present in plasma shows a positive correlation with the hematocrit value and/or the hemoglobin amount in the blood sample. Using this correlation, the plasma drug concentration calculating unit 14 calculates the plasma drug concentration based on the hematocrit value and/or the hemoglobin amount of the blood sample.

As the hematocrit value and/or the hemoglobin amount of the blood sample, it is possible to use a measured value obtained by another device or method in advance, or the device 1 is provided with a red blood cell quantitative evaluation unit 15 described later, It is also possible to use the hematocrit value and/or the amount of hemoglobin obtained in the evaluation unit 15.

(5) Red blood cell quantitative evaluation unit 15
The red blood cell quantitative evaluation unit 15 evaluates the hematocrit value and/or the hemoglobin amount based on the electrical characteristics of the blood sample. The erythrocyte quantitative evaluation unit 15 is not essential in the blood state analysis device 1 according to the present technology, and it is also possible to measure the hematocrit value and/or the hemoglobin amount in a blood sample by another device or method in advance, for example. Is.

The electrical characteristics of the blood that can be used by the red blood cell quantitative evaluation unit 15 are the same as the electrical characteristics that can be used by the blood coagulation evaluation unit 13, so a description thereof will be omitted here.

The electrical characteristics used for the evaluation in the red blood cell quantitative evaluation unit 15 may be the electrical characteristics of an arbitrary frequency, but in the present invention, in particular, from the electrical characteristics of the blood sample at the frequency of 2 to 25 MHz, the hematocrit value and the It is preferable to evaluate the hemoglobin amount, and it is more preferable to evaluate the hematocrit value and/or the hemoglobin amount from the electrical characteristics of the blood sample at a frequency of 2 to 10 MHz. The electrical characteristics of a blood sample at a frequency of 2 to 25 MHz are not easily affected by red blood cell change, and the fluctuation is small until the blood coagulation reaction reaches a certain level, which is obtained by a general conventional blood test. This is because it correlates with the hematocrit value and the amount of hemoglobin. Further, at a frequency higher than 10 MHz, the electrical response of blood becomes weak and the influence of noise becomes relatively strong. Therefore, by using the electrical characteristics of 10 MHz or less, more accurate evaluation can be performed.

It is preferable that the electrical characteristics of the blood used in the red blood cell quantitative evaluation unit 15 be as early as possible after the start of measurement. Specifically, it is preferable to use the electrical characteristics within 3 minutes after releasing the anticoagulation by the anticoagulant. This is because if the anticoagulation is released within 3 minutes, the influence of blood change and coagulation can be minimized. In addition, in the case of the measurement performed by adding a coagulation activator, since the time until the start of blood coagulation is short, it is preferable to use the electrical characteristics within 1 minute after the release of anticoagulation.

The blood state analysis device 1 according to the present technology may include the blood coagulation evaluation unit 13, the plasma drug concentration calculation unit 14, and the red blood cell quantitative evaluation unit 15 in addition to the correction unit 11. By including these, from the electrical characteristics obtained in one measurement, blood coagulation ability and hematocrit value and/or hemoglobin amount is evaluated, and the obtained hematocrit value and/or hemoglobin amount gives the drug concentration in plasma. Can be performed in a single device, and a series of processes of correcting the obtained blood coagulation ability evaluation result in accordance with the calculated plasma drug concentration can be performed. As a result, it is possible to reduce the analysis cost and the analysis time.

When the blood state analysis device 1 according to the present technology includes both the blood coagulation evaluation unit 13 and the erythrocyte quantitative evaluation unit 15, the electrical characteristics used for evaluation in both evaluation units are the electrical characteristics of the same frequency. Can be used, the blood coagulation evaluation unit 13 evaluates the degree of blood coagulation based on the electrical characteristics of the blood sample at the first frequency, and the red blood cell quantitative evaluation unit 15 evaluates the blood sample to the first frequency. It is also possible to obtain the hematocrit value and/or the amount of hemoglobin based on the electrical characteristics at the second frequency different from the first frequency. For example, as described above, the blood coagulation evaluation unit 13 and the erythrocyte quantitative evaluation unit 15 have different preferable frequencies of the electric characteristics used for the evaluation. Therefore, by using the electric characteristics of more suitable frequency bands, An accurate evaluation can be done.

(6) Measuring unit 16
The measuring unit 16 measures the electrical characteristics of the blood sample. In the blood state analysis device 1 according to the present technology, the measurement unit 16 is not essential, and it is possible to use data measured using an external electrical characteristic measurement device.

The measurement unit 16 can include one or more blood sample holding units. In the blood condition analyzer 1, the blood sample holding unit is not essential, and the measuring unit 16 can be designed in such a manner that a known cartridge type measuring container or the like can be installed.

When the measurement unit 16 is provided with a blood sample holding unit, the form of the blood sample holding unit is not particularly limited as long as the blood sample to be measured can be held in the measurement unit 16, and it can be designed in a free form. it can. For example, one or a plurality of cells provided on the substrate can function as a blood sample holding unit, or one or a plurality of containers can function as a blood sample holding unit.

When one or a plurality of containers are used as the blood sample holding unit, the form thereof is not particularly limited, and if the blood sample to be measured can be held, a cylindrical body, a polygonal cross section (triangle, square or more). Cylinders, cones, polygonal cones with a polygonal cross section (triangle, square or more), or a combination of one or more of these can be freely designed according to the condition of the blood sample and the measurement method. can do.

The material forming the container is also not particularly limited, and can be freely selected within the range that does not affect the state of the blood sample to be measured, the purpose of measurement, or the like. In the present technology, it is particularly preferable to form the container using a resin from the viewpoint of ease of processing and molding. In the present technology, the type of resin that can be used is not particularly limited, and one type or two or more types of resins applicable for holding a blood sample can be freely selected and used. Examples thereof include hydrophobic and insulating polymers and copolymers such as polypropylene, polymethylmethacrylate, polystyrene, acrylic, polysulfone, and polytetrafluoroethylene, and blend polymers. In the present technology, it is particularly preferable to form the blood sample holding portion with one or more resins selected from polypropylene, polystyrene, acrylic, and polysulfone, among these. This is because these resins have the property of having low coagulation activity on blood.

It is preferable that the blood sample holder be configured to be hermetically sealed while holding the blood sample. However, as long as the time required to measure the electrical characteristics of the blood sample can be stagnant and the measurement is not affected, the airtight configuration is not required.

The specific method for introducing and sealing the blood sample into the blood sample holding section is not particularly limited, and the blood sample can be introduced by any method depending on the form of the blood sample holding section. For example, a method in which a blood sample holding part is provided with a lid and a blood sample is introduced using a pipette or the like, and then the lid is closed and hermetically closed, or an injection needle is inserted from the outer surface of the blood sample holding part to remove the blood sample After injecting, the method of sealing by sealing the penetrating portion of the injection needle with grease or the like can be mentioned.

The measuring unit 16 can include one or a plurality of applying units. In the blood state analyzing apparatus 1, this applying section is not essential, and an external applying apparatus can be used by designing, for example, an electrode to be inserted into the blood sample holding section from the outside.

The application unit applies a predetermined voltage to the blood sample at each set measurement interval, starting from the time when the command to start the measurement is received or the time when the power of the blood condition analyzer 1 is turned on. Apply.

The number of electrodes used as a part of the application unit and the material forming the electrodes are not particularly limited as long as the effects of the present technology are not impaired, and any number of electrodes can be formed using free materials. For example, titanium, aluminum, stainless steel, platinum, gold, copper, graphite, etc. may be mentioned. In the present technology, it is particularly preferable to form the electrode with an electrically conductive material containing titanium. This is because titanium has the property of having low coagulation activity on blood.

The measurement unit 16 can also perform a plurality of measurements. As a method for performing a plurality of measurements, for example, a method for simultaneously performing a plurality of measurements by providing a plurality of measurement units 16, a method for performing a plurality of measurements by scanning one measurement unit 16, and moving a blood sample holding unit By doing so, a method of performing a plurality of measurements, a method of providing a plurality of measurement units 16 and selecting one or a plurality of measurement units 16 to perform actual measurement by switching can be cited.

(7) Storage unit 17
In the blood state analysis device 1 according to the present technology, the correction result corrected by the correction unit 11, the correlation obtained by the correlation detection unit 12, each evaluation evaluated by the blood coagulation evaluation unit 13 and/or the red blood cell quantitative evaluation unit 15 As a result, the storage unit 17 that stores the plasma drug concentration calculated by the plasma drug concentration calculating unit 14, the measurement result measured by the measuring unit 16, and the like can be provided. In the blood state analysis device 1 according to the present technology, the storage unit 17 is not essential, and an external storage device may be connected to store each result.

In the blood state analysis device 1 according to the present technology, the storage unit 17 may be provided separately for each unit, or one storage unit 17 may be designed to store various results obtained by each unit. Is also possible.

(8) Blood sample In the blood state analysis device 1 according to the present technology, the blood sample that can be the measurement target is not particularly limited as long as it is a sample containing blood, and can be freely selected. Specific examples of the blood sample include whole blood or a diluted solution thereof, a blood sample to which a drug other than the above drug is added, and the like.

2. Blood condition analysis system 10
FIG. 2 is a schematic conceptual diagram schematically showing the concept of the blood state analysis system 10 according to the present technology. The blood state analysis system 10 according to the present technology is broadly provided with at least an electrical characteristic measuring device 101 and a blood state analyzing device 1. Moreover, the server 102, the display unit 103, the user interface 104, and the like may be provided as necessary. Hereinafter, each part will be described in detail.

(1) Electrical characteristic measuring device 101
The electrical characteristic measuring device 101 includes a measuring unit 16 that measures the electrical characteristic of a blood sample. The details of the measuring unit 16 are the same as those of the measuring unit 16 in the blood condition analyzer 1 described above.

(2) Blood condition analyzer 1
The blood state analysis device 1 is a device that analyzes the state of the blood sample in a state in which the drug is added, and includes at least a correction unit 11. Further, the correlation detection unit 12, the blood coagulation evaluation unit 13, the plasma drug concentration calculation unit 14, the red blood cell quantitative evaluation unit 15, and the like can be provided as necessary. It should be noted that the respective units provided in the blood condition analyzer 1 are the same as the details of the blood condition analyzer 1 described above.

(3) Server 102
The server 102 includes a storage unit 17 that stores the measurement result of the electrical characteristic measuring apparatus 101 and/or the analysis result of the blood state analyzing apparatus 1. The details of the storage unit 17 are the same as those of the storage unit 17 in the blood condition analyzer 1 described above.

(4) Display unit 103
In the display unit 103, the correction result corrected by the correction unit 11, the correlation obtained by the correlation detection unit 12, each evaluation result evaluated by the blood coagulation evaluation unit 13 and/or the erythrocyte quantitative evaluation unit 15, the plasma drug concentration calculation The plasma drug concentration calculated by the unit 14, the measurement result measured by the measuring unit 16, and the like are displayed. Although it is possible to provide a plurality of display units 103 for each data and result to be displayed, it is also possible to display all data and results on one display unit 103.

(5) User interface 104
The user interface 104 is a part for the user to operate. The user can access each unit of the blood condition analysis system 10 according to the present technology through the user interface 104.

In the blood state analysis system 10 according to the present technology described above, the electrical characteristic measuring device 101, the blood state analyzing device 1, the server 102, the display unit 103, and the user interface 104 may be connected to each other via a network.

3. Blood State Analysis Method FIG. 3 is a flowchart of the blood state analysis method according to the present technology. The blood state analysis method according to the present technology is a method of analyzing the state of the blood sample in a state in which the drug is added, and at least the correction step I is performed. If necessary, the correlation detection step II, the blood coagulation evaluation step III, the plasma drug concentration calculation step IV, the red blood cell quantitative evaluation step V, the measurement step VI, the storage step VII and the like can be performed. Hereinafter, each step will be described in detail.

(1) Correction process I
In the correction step I, based on the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result, the blood coagulation evaluation result of the blood sample is converted into the concentration of the drug present in plasma of the blood sample. Correct accordingly. The details of the correction method performed in the correction step I are the same as the correction method executed by the correction unit 11 of the blood condition analyzer 1 described above.

(2) Correlation detection step II
In the correlation detection step II, the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result is obtained. In the blood state analysis method according to the present technology, this correlation detection step II is not essential, and as described above, a predetermined correlation may be used. The details of the detection method performed in the correlation detection step II are the same as the detection method executed by the correlation detection unit 12 of the blood condition analyzer 1 described above.

(3) Blood coagulation evaluation step III
In the blood coagulation evaluation step III, the degree of blood coagulation is evaluated based on the electrical characteristics of the blood sample to obtain the blood coagulation evaluation result. This blood coagulation evaluation step III is not essential in the blood state analysis method according to the present technology, and for example, the blood coagulation evaluation result can be obtained in advance by another device or method. The details of the evaluation method performed in the blood coagulation evaluation step III are the same as the evaluation method executed by the blood coagulation evaluation unit 13 of the blood condition analyzer 1 described above.

(4) Plasma drug concentration calculation step IV
In the plasma drug concentration calculating step IV, the concentration of the drug present in the plasma in the blood sample is calculated. This plasma drug concentration calculation step IV is not essential in the blood state analysis method according to the present technology, and for example, the concentration of the drug present in plasma in the blood sample may be measured by another device or method in advance. Is also possible. The details of the calculation method performed in the plasma drug concentration calculation step IV are the same as the calculation method executed by the plasma drug concentration calculation unit 14 of the blood condition analyzer 1 described above.

(5) Red blood cell quantitative evaluation step V
In the red blood cell quantitative evaluation step V, the hematocrit value and/or the hemoglobin amount is evaluated based on the electrical characteristics of the blood sample. This red blood cell quantitative evaluation step V is not essential in the blood state analysis method according to the present technology, and for example, it is also possible to measure the hematocrit value and/or the hemoglobin amount in the blood sample by another device or method in advance. is there. The details of the evaluation method performed in the red blood cell quantitative evaluation step V are the same as the evaluation method executed by the red blood cell quantitative evaluation unit 15 of the blood condition analyzer 1 described above.

(6) Measurement process VI
In measurement step VI, the electrical characteristics of the blood sample are measured. In the blood state analysis method according to the present technology, this measurement step VI is not essential, and it is possible to use data measured using another electric characteristic measurement method or the like. The details of the measuring method performed in the measuring step VI are the same as the measuring method executed by the measuring unit 16 of the blood condition analyzer 1 described above.

(7) Storage process VII
In the storage step VII, the correction result corrected in the correction step I, the correlation obtained in the correlation detection step II, each evaluation result evaluated in the blood coagulation evaluation step III and/or the red blood cell quantitative evaluation step V, and plasma drug concentration calculation The drug concentration in plasma calculated in step IV, the measurement result measured in measurement step VI, and the like are stored. In the blood state analysis method according to the present technology, the storage step VII is not essential, and it is possible to perform analysis each time without storing each result.

4. Blood state analysis program The blood state analysis program according to the present technology is a program used for analyzing the state of the blood sample in a state in which the drug is added, and the concentration of the drug in plasma and the blood coagulation evaluation result Based on the correlation, the blood coagulation evaluation result of the blood sample, a blood state analysis program for realizing a computer with a correction function for correcting in accordance with the concentration of the drug present in plasma in the blood sample. is there. If necessary, the computer can be made to realize a correlation detection function, a blood coagulation evaluation function, a plasma drug concentration calculation function, a red blood cell quantitative evaluation function, a measurement function, a memory function, and the like.

In other words, the blood state analysis program according to the present technology is a program for causing a computer to realize the blood state analysis method according to the present technology described above. Therefore, the details of each function are the same as each step of the blood state analysis method described above, and thus the description thereof is omitted here.

Hereinafter, the present invention will be described in more detail based on examples. The embodiments described below are examples of typical embodiments of the present invention, and the scope of the present invention should not be construed narrowly.

In Example 1, the correlation between the blood coagulation parameter obtained from the electrical characteristics of the blood sample and the hematocrit value was examined. In this example, the dielectric constant was used as an example of the electrical characteristics of the blood sample.

[experimental method]
(1) Preparation of hematocrit value of blood sample Using a vacuum blood collection tube containing citric acid (a blood collection volume of 1.8 mL, 6 tubes), venous blood of a healthy person was collected. The first one is discarded without use, and the remaining five are sedimented at the bottom of the blood collection tube by centrifugation under mild conditions (300 g x 10 minutes), and a part of the supernatant from one blood collection tube is discarded. It was taken and added to the other blood collection tube. Next, red blood cells were uniformly dispersed by re-stirring in each blood collection tube. In this way, blood samples with different hematocrit values were prepared.

(2) Measurement of electrical characteristics Each blood sample prepared above was kept warm at 37°C in advance, and a small amount of calcium chloride aqueous solution was added immediately before the start of the measurement to start the blood coagulation reaction. The dielectric constant of each blood sample was measured at a temperature of 37° C. and a frequency range of 10 MHz.

[result]
FIG. 4 shows the correlation between the blood coagulation time (CFT100) obtained by the dielectric constant measurement and the hematocrit value. As shown in FIG. 4, the blood coagulation time was found to increase with increasing hematocrit value.

Further, FIG. 5 shows the correlation between other parameters obtained by the dielectric constant measurement and the hematocrit value. In FIG. 5, A is the correlation between the coagulation start time and the hematocrit value, B is the correlation between the time at which the minimum permittivity increase intensity is shown and the hematocrit value, and C is the permittivity increase intensity during blood coagulation and the hematocrit value. Correlation, D is the correlation between coagulation rate and hematocrit value, respectively.

As shown in FIG. 5, the coagulation start time (see A), the time at which the minimum permittivity increasing intensity (see B), and the permittivity increasing intensity during blood coagulation (see C) were almost the same as the hematocrit value increased. It was found that the solidification rate increased (see D) and generally decreased with increasing hematocrit value.

In Example 2, the correlation between the blood coagulation ability parameter obtained from the electrical characteristics of the blood sample and the plasma concentration of the added drug was examined. In this example, the dielectric constant was used as an example of the electrical characteristics of the blood sample.

[experimental method]
(1) Measurement of electrical characteristics Using a vacuum blood collection tube containing citric acid (a blood collection amount of 1.8 mL, 6 tubes), venous blood of 2 healthy subjects was collected. Discard the first one without using it, heat the remaining five at 37°C in advance, and change the concentration of 12 μL of calcium chloride aqueous solution per 180 μL of blood in the range of 100 mM to 400 mM immediately before the start of measurement. In addition, the blood coagulation reaction was started. The dielectric constant of each blood sample was measured at a temperature of 37° C. and a frequency range of 10 MHz.

[result]
The correlation between the blood coagulation time (CFT100) obtained by the dielectric constant measurement and the hematocrit value is shown in FIG. As shown in FIG. 6, the blood coagulation time was found to increase with an increase in calcium concentration.

Further, FIG. 7 shows the correlation between other parameters obtained by the dielectric constant measurement and the calcium concentration. In FIG. 7, A shows the correlation between the coagulation start time and the calcium concentration, and B shows the correlation between the CFT 50 hours (the midpoint between the time showing the minimum dielectric constant increasing strength and the dielectric coagulation time) and the calcium concentration. ..

As shown in FIG. 7, both parameters were found to increase with increasing calcium concentration.

Example 2 is the result of changing the concentration of calcium chloride to be added to a blood sample having a constant hematocrit value. That is, it was found that the parameter indicating blood coagulation ability changes depending on the calcium concentration in plasma.

The results of Examples 1 and 2 mean that the reliability of the blood coagulation time as a test result decreases when the calcium concentration in blood (plasma) is unknown. For example, if a blood coagulation time longer than the normal value is obtained as a test result, it is not possible to immediately determine whether the bleeding tendency is due to a decrease in blood coagulation ability, or simply because the calcium concentration in plasma is high. I knew I couldn't. This is because even if the same amount of calcium solution having the same concentration is added, if the hematocrit value in the blood sample is different, the effective calcium concentration existing in plasma will also be changed.

From the above results, the blood coagulation evaluation result changes depending on the concentration of the drug present in plasma, so by correcting the blood coagulation evaluation result in accordance with the concentration of the drug existing in plasma, It turns out that highly accurate evaluation can be performed.

It was also found that the concentration of the drug present in plasma in the blood sample can be calculated based on the hematocrit value and/or the amount of hemoglobin in the blood sample.

Note that the present technology may also be configured as below.
(1)
The state of the blood sample in the state where one or more agents selected from the group consisting of an anticoagulant treatment release agent, a coagulation activator, an anticoagulant, a platelet activator and an antiplatelet agent are added to the blood sample. A device for analyzing
Based on the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result, the blood coagulation evaluation result of the blood sample is corrected corresponding to the concentration of the drug present in the plasma of the blood sample. A blood state analysis device including a correction unit.
(2)
The blood condition analyzer according to (1), wherein the correlation is predetermined.
(3)
The blood condition analyzer according to (1), further comprising a correlation detection unit that obtains a correlation between the concentration of the drug in plasma and the blood coagulation evaluation result.
(4)
The blood condition analyzer according to any one of (1) to (3), further including a blood coagulation evaluation unit that evaluates the degree of blood coagulation based on the electrical characteristics of the blood sample and obtains the blood coagulation evaluation result. ..
(5)
Any one of (1) to (4), further comprising a plasma drug concentration calculating unit that calculates the concentration of the drug present in plasma in the blood sample based on the hematocrit value and/or the hemoglobin amount of the blood sample. The blood condition analyzer according to.
(6)
The blood condition analyzer according to any one of (1) to (5), further comprising a red blood cell quantitative evaluation unit that obtains a hematocrit value and/or a hemoglobin amount of the blood sample based on the electrical characteristics of the blood sample.
(7)
A blood condition analyzer according to claim 6, wherein the concentration of the drug present in the plasma of the blood sample is calculated based on the hematocrit value and/or the hemoglobin amount obtained by the red blood cell quantitative evaluation unit. ..
(8)
The blood condition analyzer according to any one of (1) to (7), including a measurement unit that measures the electrical characteristics of the blood sample.
(9)
Based on the electrical characteristics of the blood sample, to evaluate the degree of blood coagulation, a blood coagulation evaluation unit to obtain the blood coagulation evaluation result,
An erythrocyte quantitative evaluation unit that obtains a hematocrit value and/or a hemoglobin amount of the blood sample based on the electrical characteristics of the blood sample;
(8) The blood state analyzer according to (8).
(10)
The blood coagulation evaluation unit evaluates the degree of blood coagulation based on the electrical characteristics of the blood sample at the first frequency,
The blood condition analysis according to (9), wherein the red blood cell quantitative evaluation unit obtains a hematocrit value and/or a hemoglobin amount based on an electrical characteristic of the blood sample at a second frequency different from the first frequency. apparatus.
(11)
An electrical characteristic measuring device comprising a measuring unit for measuring the electrical characteristic of a blood sample,
When the blood sample is added with one or more agents selected from the group consisting of anticoagulant release agents, coagulation activators, anticoagulants, platelet activators and antiplatelet agents, An apparatus for analyzing a state, wherein, based on the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result, the blood coagulation evaluation result of the blood sample is present in the plasma of the blood sample. A blood condition analyzing apparatus having a correction unit that corrects according to the concentration of the drug;
A blood condition analysis system having:
(12)
The blood condition analysis system according to (11), further comprising a server that stores a measurement result of the electrical characteristic measuring device and/or an analysis result of the blood condition analyzing device.
(13)
The blood condition analyzing system according to (12), wherein the server is connected to the electrical characteristic measuring device and/or the blood condition analyzing device via a network.
(14)
The state of the blood sample in the state where one or more agents selected from the group consisting of an anticoagulant treatment release agent, a coagulation activator, an anticoagulant, a platelet activator and an antiplatelet agent are added to the blood sample. Is a method of analyzing
Based on the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result, the blood coagulation evaluation result of the blood sample is corrected corresponding to the concentration of the drug present in the plasma of the blood sample. A blood state analysis method for performing a correction step.
(15)
The state of the blood sample in the state in which one or more agents selected from the group consisting of anticoagulant release agent, coagulation activator, anticoagulant, platelet activator and antiplatelet agent are added to the blood sample There is a program used for analysis,
Based on the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result, the blood coagulation evaluation result of the blood sample is corrected corresponding to the concentration of the drug present in the plasma of the blood sample. A blood condition analysis program that allows the computer to implement the correction function.

DESCRIPTION OF SYMBOLS 1 Blood state analysis device 11 Correction part 12 Correlation detection part 13 Blood coagulation evaluation part 14 Plasma drug concentration calculation part 15 Red blood cell quantitative evaluation part 16 Measuring part 17 Storage part 10 Blood condition analysis system 101 Electrical characteristic measurement device 102 Server 103 Display unit 104 User interface I Correction process I
II Correlation detection step III Blood coagulation evaluation step IV Plasma drug concentration calculation step V Red blood cell quantitative evaluation step VI Measurement step VII Storage step

Claims (17)

A device for analyzing a state of the blood sample based on electrical characteristics of the blood sample in a state where a drug is added to the blood sample,
Based on the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result based on electrical characteristics at a frequency of 3 MHz to 15 MHz, the blood coagulation evaluation result of the blood sample is stored in the plasma of the blood sample. A correction unit for correcting the concentration of the existing drug,
The correction unit, based on the concentration dependence of the test value obtained by the correlation, or a correction function using a correction constant determined by the correlation, a test value at the concentration of the drug as a reference. Blood condition analyzer that corrects The blood condition analyzer according to claim 1, wherein the correlation is predetermined. The blood state analyzer according to claim 1, further comprising a correlation detection unit that obtains a correlation between the concentration of the drug in plasma and the blood coagulation evaluation result. The blood condition analyzer according to claim 1, further comprising a blood coagulation evaluation unit that evaluates the degree of blood coagulation based on the electrical characteristics of the blood sample to obtain the blood coagulation evaluation result. .. 5. The plasma drug concentration calculating unit for calculating the concentration of the drug present in the plasma in the blood sample based on the hematocrit value and/or the hemoglobin amount of the blood sample. The blood condition analyzer according to. The blood condition analyzer according to claim 1, further comprising a red blood cell quantitative evaluation unit that obtains a hematocrit value and/or a hemoglobin amount of the blood sample based on the electrical characteristics of the blood sample. 7. The plasma drug concentration calculating unit for calculating the concentration of the drug present in the plasma in the blood sample based on the hematocrit value and/or the hemoglobin amount obtained by the red blood cell quantitative evaluation unit. Blood condition analyzer. The blood state analyzing apparatus according to claim 1, further comprising a measuring unit that measures an electrical characteristic of the blood sample. Based on the electrical characteristics of the blood sample, to evaluate the degree of blood coagulation, a blood coagulation evaluation unit to obtain the blood coagulation evaluation result,
An erythrocyte quantitative evaluation unit for obtaining a hematocrit value and/or an amount of hemoglobin based on the electrical characteristics of the blood sample;
The blood condition analyzer according to claim 8, further comprising: The blood coagulation evaluation unit evaluates the degree of blood coagulation based on the electrical characteristics of the blood sample at the first frequency,
The red blood cell quantitative evaluation unit obtains a hematocrit value and/or a hemoglobin amount based on an electrical characteristic of the blood sample at a second frequency different from the first frequency,
The blood condition analyzer according to claim 9. 11. The drug according to claim 1, wherein the drug is selected from any one or more of an anticoagulation treatment releasing agent, a coagulation activator, an anticoagulant, a platelet activator, and an antiplatelet agent. The blood condition analyzer described. The correlation between the concentration of the drug in plasma and the blood coagulation evaluation result is determined from two or more different concentrations of the drug present in the plasma in the blood sample. Item 6. The blood condition analyzer according to item. An electrical characteristic measuring device comprising a measuring unit for measuring the electrical characteristic of a blood sample,
A device for analyzing the state of the blood sample based on the electrical characteristics of the blood sample in the state where a drug is added to the blood sample, the concentration of the agent in plasma and the electrical characteristics at a frequency of 3 MHz to 15 MHz. Based on the correlation with the blood coagulation evaluation result based on, the blood coagulation evaluation result of the blood sample, a correction unit for correcting in accordance with the concentration of the drug present in the plasma in the blood sample, The correction unit, based on the concentration dependence of the test value obtained by the correlation, or a correction function using a correction constant determined by the correlation, a test value at the concentration of the drug as a reference. A blood condition analyzer that corrects
A blood condition analysis system having: The blood condition analysis system according to claim 13, further comprising a server that stores the measurement result of the electrical characteristic measuring device and/or the analysis result of the blood condition analyzing device. The server, via the network, the electrical characteristic measuring device and / or blood condition analysis system of claim 14 wherein said is connected to the blood state analyzer. A method of analyzing the state of the blood sample based on the electrical characteristics of the blood sample in a state where a drug is added to the blood sample,
Based on the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result based on electrical characteristics at a frequency of 3 MHz to 15 MHz, the blood coagulation evaluation result of the blood sample is stored in the plasma of the blood sample. A correction step for correcting the concentration of the existing drug is performed, and in the correction step, the concentration dependence of the test value obtained by the correlation or the correction constant determined by the correlation is used. A blood state analysis method, which corrects a test value at a concentration of the drug as a reference based on a correction function. Used in analysis of the state of the blood sample based on the electrical characteristics of the blood sample in the state of adding a drug to the blood sample,
Based on the correlation between the concentration of the drug in plasma and the blood coagulation evaluation result based on electrical characteristics at a frequency of 3 MHz to 15 MHz, the blood coagulation evaluation result of the blood sample is stored in the plasma of the blood sample. In a blood condition analysis program for causing a computer to realize a correction function for correcting the concentration of the existing drug,
The correction function is based on the concentration dependence of the test value obtained by the correlation, or a correction function using a correction constant determined by the correlation, and the test value at the concentration of the drug as a reference. A blood condition analysis program that corrects