WO2020133188A1 - 一种凝血分析仪及其纤维蛋白原浓度检测方法 - Google Patents

一种凝血分析仪及其纤维蛋白原浓度检测方法 Download PDF

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Publication number
WO2020133188A1
WO2020133188A1 PCT/CN2018/124787 CN2018124787W WO2020133188A1 WO 2020133188 A1 WO2020133188 A1 WO 2020133188A1 CN 2018124787 W CN2018124787 W CN 2018124787W WO 2020133188 A1 WO2020133188 A1 WO 2020133188A1
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Prior art keywords
sample
movement
magnetic bead
motion
magnetic
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PCT/CN2018/124787
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English (en)
French (fr)
Inventor
李聪
武振兴
郭文恒
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北京普利生仪器有限公司
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Application filed by 北京普利生仪器有限公司 filed Critical 北京普利生仪器有限公司
Priority to PCT/CN2018/124787 priority Critical patent/WO2020133188A1/zh
Priority to PCT/CN2019/084127 priority patent/WO2020133842A1/zh
Priority to CN201980073589.9A priority patent/CN113015906B/zh
Publication of WO2020133188A1 publication Critical patent/WO2020133188A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors

Definitions

  • the invention relates to a medical device, in particular to a coagulation analyzer based on the magnetic bead method and a method for detecting the concentration of fibrinogen.
  • the coagulation analyzer is used to analyze the blood coagulation and anticoagulation, fibrinolysis and antifibrinolysis function of the patient's blood.
  • the detection items include plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), thrombin time (TT) and related clotting factors and other derivative items.
  • Fibrinogen or blood coagulation factor I
  • FIB Fibrinogen
  • FIB can be sequentially converted into fibrin monomer and soluble fibrin polymer under the action of thrombin, and under the action of activated coagulation factor XIII, they cross-link with each other to form an insoluble cross-linked fibrin clot, which leads to blood coagulation.
  • Clauss method is based on the principle of fibrinogen and thrombin to form fibrin.
  • the fibrinogen concentration is used as the X axis and the thrombin coagulation time is used as the Y axis to create a calibration curve.
  • thrombin coagulation time is used as the Y axis to create a calibration curve.
  • the PT derivative algorithm is not suitable for abnormal PT detection values and FIB abnormalities. It can only be used as a screening method, and it needs to be re-measured by the Clauss method after it exceeds its applicable range.
  • the Clauss method needs to be used to separately detect the fibrinogen concentration, which increases the sample amount, the use cost of the FIB reagent, and the test process.
  • the invention provides a blood coagulation analyzer and a method for detecting the concentration of fibrinogen, which can be developed based on the magnetic bead method to detect the concentration of fibrinogen.
  • an embodiment provides a method for detecting the concentration of fibrinogen in a sample, including:
  • the sample After the detection of prothrombin time, the sample forms a coagulated state, and the magnetic beads are re-driven to oscillate in the coagulated sample;
  • the fibrinogen concentration in the sample is determined by detecting the second movement of the magnetic bead in the oscillating movement.
  • an embodiment provides a method for detecting the concentration of fibrinogen in a sample, including:
  • the calibration curve is based on the parameter and the fibrinogen concentration as two Curve formed by three dimensions.
  • an embodiment provides a blood coagulation analyzer, including:
  • Sample preparation device used to mix the sample and the reagent for detecting prothrombin time in the reaction vessel placed with magnetic beads to form a sample;
  • a detection device the detection device includes a driving component and a detection component, the driving component is used to drive the magnetic bead to perform an oscillating motion in a sample, and the detection component is used to detect the magnetic bead during the oscillating motion The movement of
  • a processor the processor is configured to output a first control signal to the driving part when detecting the prothrombin time, to control the driving part to drive the magnetic bead to perform an oscillating motion in the sample, and according to the detection
  • the first motion detected during the detection of the prothrombin time by the component obtains the prothrombin time
  • the processor is further used to output a second control signal to the driving component after the detection of the prothrombin time is completed to control
  • the driving part re-drives the magnetic bead to perform an oscillating motion in the sample in a solidified state, and obtains the fibrin in the sample according to the second motion detected by the detecting part after re-driving the magnetic bead to oscillate The original concentration.
  • an embodiment provides a blood coagulation analyzer, including:
  • Sample preparation device for mixing the sample and the PT reagent used to trigger the solidification of the sample in a reaction vessel placed with magnetic beads to form a solidified sample;
  • a detection device the detection device includes a driving part and a detection part, the driving part is used to drive the magnetic beads to oscillate in a sample forming a solidified state, and the detection part is used to detect the magnetic beads in the Describe the second movement in the oscillatory movement;
  • a processor the processor is configured to output a second control signal to the driving part to control the driving part to drive the magnetic bead to perform an oscillating motion in the sample forming the solidified state, and according to the first Two movement conditions to obtain parameters that reflect the flow characteristics of the sample, obtain the fibrinogen concentration in the sample according to the parameter, or obtain a calibration curve based on the parameter and the known fibrinogen concentration in the sample,
  • the calibration curve is a curve formed by the parameter and fibrinogen concentration in two dimensions.
  • an embodiment provides a computer-readable storage medium including a program that can be executed by a processor to implement the method of any one of the preceding claims.
  • the magnetic beads are re-driven to move in the test sample after solidification, and the fibrinogen concentration in the sample is determined by detecting the movement of the magnetic beads to achieve PT algorithm for the detection of fibrinogen concentration. Since the PT project and the fibrinogen concentration can be detected using the same reaction system, compared with the Clauss method of the fibrinogen concentration, FIB special reagents are saved.
  • FIG. 1 is a schematic structural diagram of a blood coagulation analyzer in an embodiment
  • FIG. 2 is a schematic structural diagram of a detection device in an embodiment
  • FIG. 3 is a schematic diagram of a driving waveform of a driving coil in an embodiment
  • FIG. 4 is a schematic diagram of magnetic beads moving in a reaction system in an embodiment
  • FIG. 5 is a flowchart of detecting the concentration of fibrinogen in an embodiment
  • 6a is a schematic diagram of an electric signal output by a receiving coil in an embodiment
  • 6b is a waveform diagram of an electrical signal after demodulation in an embodiment
  • FIG. 7 is a schematic diagram of driving waveforms in which the driving coil re-drives the movement of the magnetic beads in an embodiment
  • FIG. 8 is a force analysis diagram of magnetic beads moving in a reaction system under driving force in an embodiment
  • Fig. 11 is a calibration curve formed with two dimensions of viscosity coefficient and fibrinogen concentration
  • Figure 12 is the calibration curve formed by the work and fibrinogen concentration in two dimensions
  • Figure 13 is a calibration curve formed with acceleration and fibrinogen concentration as two dimensions
  • FIG. 14 is a flowchart of a calibration curve for detecting the concentration of fibrinogen in an embodiment.
  • connection and “connection” in this application, unless otherwise specified, include direct and indirect connection (connection).
  • the inventor realized that when fibrinogen in the reaction system was converted into an insoluble cross-linked fibrin polymer, the fluid resistance of the reaction system would rise rapidly, and the flow characteristics of the reaction system and the reaction system
  • the content of the cross-linked fibrin polymer showed a negative correlation, that is, the higher the content of the cross-linked fibrin polymer, the worse the flow characteristics of the reaction system.
  • the lower the content of the cross-linked fibrin polymer the lower the reaction system The better the flow characteristics.
  • the content of cross-linked fibrin polymer in the reaction system is positively correlated with the content of fibrinogen.
  • the inventive concept of the present invention is to obtain the formation of cross-linked fibrin polymer by measuring the flow characteristics of the reaction system, and then determine the content of fibrinogen in the sample.
  • the magnetic bead method is used for prothrombin time detection. After the prothrombin time detection is completed, insoluble cross-linked fibrin polymer has been formed in the reaction system at this time, and the reaction system is in a coagulated state The magnetic beads have stopped moving. In this case, the magnetic beads are re-driven to oscillate. The movement of the magnetic beads will be affected by the fluid resistance of the reaction system. Detecting the movement of the magnetic beads will reflect the flow characteristics of the reaction system.
  • FIG. 1 a schematic structural diagram of a coagulation analyzer for detecting fibrinogen concentration based on the concept of the present invention is shown in FIG. 1, including a sample placement area 11, a sample collection mechanism 12, a reagent placement area 13, a reagent collection mechanism 14, and a reaction vessel
  • the placement area 10 the object transfer mechanism 15, the detection device 16, and the processor 17.
  • the sample placement area 11 is used to provide a place for the test sample 11a to be placed.
  • the test sample may be platelet-poor plasma, quality control products or calibrators.
  • the sample placement area 11 is a rectangular area where multiple samples 11a can be placed.
  • the sample placement area 11 may also be a bar-shaped area, a circular area, or a sample feeding mechanism, or it may be only a location where the sample is placed.
  • the reagent placement area 13 is used to provide a place where the test reagent 13a is placed.
  • the reagent placement area 13 is a rectangular area in which multiple test reagents 13a can be placed. In an actual instrument, the reagent placement area 13 may also be a bar or circular area.
  • the reagent includes at least one of a diluent, a mixed reagent, and a trigger reagent.
  • the reaction container placement area 10 is used to provide a place for placing the test reaction container 10a.
  • the reaction vessel placement area 10 is a rectangular area, and a plurality of reaction vessels 10a can be placed.
  • the reaction vessel placement area 10 may also be a bar area, a round area, or a hopper.
  • the sample collection mechanism 12 and the reagent collection mechanism 14 constitute a sample preparation device for mixing a sample and a reagent for detecting prothrombin time into a reaction system in a reaction vessel placed with magnetic beads to form a sample for subsequent detection .
  • the sample collection mechanism 12 is used to collect the tested sample from the sample placement area 11 and add the measured sample to the reaction container 10a placed on the reaction container placement area 10
  • the reagent collection mechanism 14 is used to collect the reagent from the reagent placement area 13 And add the reagent to the reaction container 10a placed on the reaction container placement area 10.
  • the test sample and the reagent are mixed in the reaction container 10a.
  • the sample collection mechanism 12 and the reagent collection mechanism 14 may also be moving parts with a sampler, and the test sample or reagent collected in the sample placement area 11 or the reagent placement area 13 is added to Placed in the reaction vessel 10a on the reaction vessel placement area 10.
  • the detection device 16 is used for detecting the coagulation item based on the magnetic bead method on the sample (analyte) mixed with the test sample and the reagent under the control of the processor, and outputs an electric signal reflecting the coagulation condition to the processor 17.
  • the detection device includes a drive component and a detection component.
  • the drive component is used to drive the magnetic bead to oscillate in the sample, and the detection component is used to detect the motion of the magnetic bead in the oscillating motion.
  • the structure of the detection device 16 is shown in FIG. 2, the drive component is the drive coil 210, the detection component is the measurement coil 220, and the structure of the reaction vessel used in the magnetic bead method is shown in FIG. 2, for easy visibility
  • the reaction container 200 is subjected to a sectional view in FIG. 2.
  • a magnetic bead 201 is placed in the accommodating chamber of the reaction container 200, and the bottom of the reaction container is provided for the magnetic bead 201 to move under the drive of a magnetic field.
  • the reaction container 200 has a length direction extending along the motion track of the magnetic beads and a width direction perpendicular to the length direction.
  • the magnetic bead is made of a material that can be quickly magnetized. When the magnetic bead is in a magnetic field, it can be quickly magnetized by the magnetic field. When the magnetic field disappears, the magnetic bead quickly disappears or the residual magnetism is small.
  • the shape of the magnetic bead may be spherical or other shapes, such as a polyhedron, which are only exemplified here and not specifically limited.
  • the detection device 16 may include an even array of drive coils 210, for example, there may be two sets of drive coils 210, and the two sets of drive coils 210 are located opposite each other at a certain distance, and are located on both sides of the reaction vessel 200 along the length of the reaction vessel 200, respectively.
  • the two driving coils 210 are applied with PWM (Pulse Width Modulation) waves with the same period but different timings, as shown in FIG. 3, thereby generating an intermittent magnetic field alternately (during the period t1 and t2, the driving coil M1 A magnetic field is generated in the illustrated period M1; during t3 and t4, the driving coil M2 generates a magnetic field in the illustrated period M2; and so on), the magnetic beads are repeatedly magnetized by the magnetic field so that the magnetic beads 201 in the reaction vessel 200 Oscillation movement is performed along the track formed by the reaction vessel.
  • the movement position and direction of the magnetic bead 201 in the period t1-t4 of a PWM wave period are shown in FIG. 4.
  • the detection device 16 may include an even-numbered array of measurement coils 220, for example, may include two sets of measurement coils 220, and the two sets of measurement coils 220 are located opposite each other at a certain distance, and are located on both sides of the reaction vessel 200 along the width direction of the reaction vessel 200, respectively. .
  • the two sets of measuring coils 220 are divided into a transmitting coil and a receiving coil.
  • the two ends of the transmitting coil are connected to a signal transmitting circuit (not shown in the figure), which is used to input a sine wave alternating current and used to generate a continuous magnetic field.
  • the two ends of the receiving coil are connected A signal receiving circuit (not shown in the figure) to detect the motion electric signal generated by the oscillating motion of the magnetic bead 201.
  • the movement electrical signal refers to an electrical signal that can reflect the movement state of the magnetic bead 201.
  • the transmitting coil generates a magnetic field, and the magnetic beads cut the magnetic field lines to change the path of the magnetic field lines, resulting in changes in the density of the magnetic field lines in some areas, thereby changing the magnetic flux received by the receiving coil.
  • the receiving coil generates the original induced electromotive force according to the received magnetic flux and generates corresponding Induced current, the induced current through circuit conversion and signal conditioning, can obtain the voltage signal containing the motion information of the magnetic bead 201, that is, the motion electric signal of the magnetic bead 201. Since the motion of the magnetic bead 201 changes the characteristics of the original induced current, the motion information of the magnetic bead 201 can be extracted from the changed induced current.
  • the measuring coil 220 When the magnetic bead 201 moves in the reaction vessel 200, the measuring coil 220 generates a corresponding induced current, which reflects the movement of the magnetic bead 201 and can be used as the motion electrical signal of the magnetic bead 201.
  • the induced current generated by the measuring coil 220 may be converted to obtain a voltage signal, and the voltage signal may be used as the motion electrical signal of the magnetic bead 201.
  • the measurement coil 220 transmits the motion electrical signal of the magnetic bead 201 obtained by the detection to the processor 17.
  • the measurement coil 220 may be connected to the processor through a signal conversion circuit (not shown) and a signal conditioning circuit (not shown).
  • the signal conversion circuit can perform analog-to-digital conversion on the motion electrical signal of the magnetic bead 201 acquired by the measuring coil 220 for at least a period of time
  • the signal conditioning circuit can be capable of converting the magnetic bead 201 acquired by the measurement coil 220 for at least a period of time.
  • the motion electric signal is preprocessed such as rectification, filtering and normalization.
  • the processor 17 is used to output a control signal to the driving part, so as to control the driving part to drive the magnetic beads to oscillate in the sample. It is used to process the motion electrical signal received from the detection component to obtain the measured parameters of the sample being tested, such as prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), thrombin Time (TT) etc.
  • the processor 17 is used to first control the detection device to detect the prothrombin time, obtain the prothrombin time according to the first movement detected by the detection component during the detection of the prothrombin time, and complete the prothrombin time.
  • the driving component is controlled to re-drive the magnetic bead to perform an oscillating motion in the sample in a solidified state, and the fibrinogen concentration in the sample is obtained according to the second motion detected by the detection component after re-driving the magnetic bead oscillation,
  • This solution is called the PT algorithm in the following examples to detect fibrinogen concentration.
  • it is not necessary to detect the prothrombin time first, but it is necessary to use a PT reagent or a reagent similar to the PT reagent component to trigger the sample to form a coagulation state.
  • the processor is used to control the driving component to drive the magnetic beads to form
  • the oscillated movement is performed on the solidified sample, and the fibrinogen concentration in the sample is obtained according to the second movement of the magnetic beads.
  • the fibrinogen concentration can be obtained, but also the calibration curve of the fibrinogen concentration (such as updating the calibration curve when using a calibrator), or the calibration of the fibrinogen concentration Calibrate the curve (for example, update the calibration curve when using a calibrator).
  • FIG. 5 Based on the above-mentioned coagulation analyzer, the flow of detecting the fibrinogen concentration based on the PT derivative algorithm based on the magnetic bead method is shown in FIG. 5 and includes the following steps 501-505:
  • Step 501 making a sample.
  • the sample collection mechanism collects the tested sample and adds the measured sample (eg, plasma) to the reaction container, and the reagent collection mechanism collects the reagent and adds the reagent to the reaction container.
  • the reagent includes, for example, a diluent and a trigger reagent. Since the PT detection is performed first in this embodiment, the trigger reagent uses a reagent for detecting prothrombin time, that is, a PT reagent.
  • the main components of the PT reagent include tissue factor, phospholipid, and calcium ion.
  • Step 502 PT detection is performed.
  • the detection process includes:
  • the processor control signal generating circuit outputs the first control signal to the driving part, as shown in the PWM signal in FIG. 3, the driving part generates an intermittent alternating magnetic field under the excitation of the first control signal, and drives the magnetic bead to oscillate in the sample movement.
  • the detection component detects the first movement of the magnetic bead in the oscillating movement.
  • the sample and the reagent are mixed and reacted, according to the waterfall-like theory, the sample is converted into prothrombin into thrombin under the trigger of the PT reagent.
  • FIB finally forms an insoluble cross-linked fibrin clot under the action of thrombin, which leads to the test Like solidification.
  • the magnetic bead moves under the driving force
  • the receiving coil receives the magnetic flux that changes periodically with the periodic position of the magnetic bead, and generates a periodically changing electrical signal according to the periodically changing magnetic flux. For example, a periodically changing induced electromotive force or a periodically changing induced current.
  • the electrical signal output by the receiving coil reflecting the first movement of the magnetic beads is shown in FIG. 6a
  • the demodulated electrical signal waveform is shown in FIG. 6b
  • the valley 601 indicates that the magnetic beads moved to the reaction vessel
  • the magnetic flux received by the receiving coil at this time is the smallest
  • the induced electromotive force generated is the smallest
  • the induced current is also the smallest.
  • the peak 602 indicates that the magnetic beads moved to the bottom of the reaction vessel.
  • the magnetic flux received by the receiving coil is the largest, the induced electromotive force generated is the largest, and the induced current is also the largest.
  • the electrical signal output by the receiving coil is processed and transmitted to the processor.
  • the processor processes the electrical signal to obtain the prothrombin time (PT) of the tested sample.
  • PT prothrombin time
  • the magnetic beads are driven again.
  • the processor outputs a second control signal to the drive component, resets the drive voltage and/or drive mode of the drive component, and causes the drive component to drive the magnetic beads Re-oscillate in the solidified sample.
  • the driving method may be, for example, a driving voltage, a driving period, a duty ratio of the driving voltage, and so on.
  • the driving force of the driving component to the magnetic bead is larger than the driving force during the PT detection process, and the driving force can be increased by increasing the driving voltage, the duty cycle of the PWM wave, etc., as shown in FIG. 7
  • the duty cycle of the PWM wave is larger than the duty cycle in the PT detection process.
  • the magnitude of the driving force for driving the magnetic bead movement may be changed (eg, increased) according to the increase in the number of oscillation cycles.
  • Step 504 Detect the second movement of the magnetic bead in the oscillating movement to obtain a parameter that reflects the flow characteristics of the sample.
  • the parameter used to reflect the flow characteristics of the sample is the viscosity coefficient.
  • the parameter used to reflect the flow characteristics of the sample may also be the fluid resistance coefficient.
  • the force analysis diagram of the magnetic bead is shown in Figure 8.
  • the magnetic bead 201 oscillates in the sample under the action of the driving coil, assuming that the direction of movement of the magnetic bead is shown in Figure 8, then At this time, while the magnetic beads by gravity G, F buoyancy floating on the reaction system, beads, magnetic beads bearing capacity of the reaction vessel N, to the reaction system f beads rolling friction slip, the driving force of the solenoid magnetic beads F magnetic fluid resistance and resistance F of the reaction system.
  • the following focuses on the work of the three forces F magnetic , f slip , and F resistance .
  • m is the mass of the magnetic bead
  • vstart and vend are the speed of the magnetic bead in the reaction vessel at the beginning and end of the half cycle
  • Fmagent is the driving force for the magnetic bead (that is, F magnet in Figure 8)
  • Smagent is beads displacement when the driving force
  • s is the path of movement of beads within a half period in the reaction vessel
  • G F and the buoyancy of the float used in the formula G represents the gravity and the buoyancy force
  • H is the magnetic The displacement of the beads under the combined force of gravity and buoyancy
  • L is the displacement of the magnetic beads under the action of the supporting force N.
  • the rolling friction force (f slip ) of the reaction system against the magnetic beads has always existed in the reaction system, and is far less than the fluid resistance (F resistance ) of the reaction system, so it is ignored.
  • the magnetic beads are similar to a single pendulum movement in the reaction vessel, that is, the magnetic beads undergo the process from the bottom of the vessel to the vessel wall to the vessel
  • the movement of the bottom or container wall-container bottom-container wall is equal in the initial position and the end position (the magnetic beads are located at both ends of the reaction cup, which is equivalent to the two ends of the single pendulum, and the linear velocity is zero), and G, F float, N three forces since no displacement in a direction where a force (i.e., H and L in the formula are zero), and therefore work is zero.
  • r is the radius of the magnetic bead
  • the driving force F magent of the magnetic bead is the standard quantity
  • the displacement S magent running under the driving force of the magnetic bead is the measurable quantity
  • F magent S magent is the work done by the driving force to drive the movement of the magnetic bead .
  • S ball is the travel distance of the magnetic bead.
  • the motion trajectory of the magnetic bead can be obtained by receiving the electrical signal output from the coil, and the displacement or path of the magnetic bead can be obtained by analyzing the motion trajectory of the magnetic bead. Only the velocity v of the magnetic beads in the formula and the viscosity coefficient ⁇ of the reaction system are unknown.
  • the velocity v of the magnetic bead can be derived by derivation of time by S ball , from which the viscosity coefficient can be calculated:
  • the viscosity coefficient is related to the moving speed of the magnetic beads in the sample, and the viscosity coefficient corresponding to the moving speed can be obtained according to the moving speed of the magnetic beads.
  • the moving speed of the magnetic beads is unpredictable. Therefore, in this embodiment, the following method is used to obtain the viscosity coefficient corresponding to the set moving speed.
  • the set moving speed may be set to 120 mm/s.
  • the calculation process of the viscosity coefficient corresponding to the set motion speed is shown in FIG. 9 and includes the following steps 901-909:
  • step 901 the driving component uses the driving force of the current motion cycle of the magnetic beads to drive the magnetic beads to move.
  • step 902 the movement trajectory of the magnetic bead is collected by the detection component.
  • an electrical signal waveform diagram reflecting the second movement of the magnetic bead can be obtained.
  • the electrical signal waveform diagram is similar to FIG. 6b, but the signal amplitude becomes larger as the driving force increases.
  • the trajectory of the magnetic beads can be obtained from the current waveform.
  • step 903 the processor calculates the average movement speed of the magnetic bead in the current movement period according to the movement trajectory of the magnetic bead. According to the movement trajectory of the magnetic bead, the movement amplitude and displacement of each movement period of the magnetic bead can be obtained, and the velocity can be obtained by differentiating the displacement with respect to time.
  • the method of subdivision can be used to achieve the derivation.
  • step 904 the viscosity coefficient corresponding to the average movement speed of the current movement cycle is calculated using formula (3).
  • step 905 it is determined whether the number of completed motion cycles of the magnetic bead exceeds the set cycle number, for example, the set cycle number is greater than 3, if not, step 906 is executed, and if the set cycle number has been exceeded, step 907 is executed .
  • Step 906 Control the driving component to change the driving force for driving the movement of the magnetic bead, for example, increase or decrease the driving force, thereby changing the movement speed of the magnetic bead.
  • Different periods correspond to different driving forces, so that different periods correspond to different average motion speeds.
  • the size of the driving force for driving the movement of the magnetic bead can be changed (eg, increased) according to the increase of the number of oscillating cycles, so it is usually in accordance with the number of cycles Increase the driving force.
  • the magnitude of the driving force can be changed by changing the driving voltage or the duty cycle of the PWM wave. After changing the magnitude of the driving force, turn to step 901 to detect the next cycle.
  • Step 907 stop detecting the movement of the magnetic beads.
  • the purpose of stopping the detection can be achieved by stopping the driving of the magnetic beads, or it can stop the data collection of the movement of the magnetic beads regardless of whether the magnetic beads continue to move.
  • Step 908 Perform curve fitting on the motion speed and the viscosity coefficient obtained from the above exercise cycle, and obtain the viscosity coefficient curve through curve fitting.
  • the viscosity coefficient curve is a two-dimensional curve, one dimension is the viscosity coefficient, and the other The dimension is speed.
  • the motion speed and the viscosity coefficient of at least three cycles are curve-fitted to obtain a viscosity coefficient curve. Different periods correspond to different driving forces, so that different periods correspond to different average motion speeds.
  • step 909 the viscosity coefficient corresponding to the set motion speed is obtained through the viscosity coefficient curve.
  • the movement speed of the magnetic bead in the oscillating motion can also be constantly detected.
  • the instantaneous movement speed of the magnetic bead or the average movement speed in the current cycle reaches the set movement speed, according to the current time (dt) Or the parameters in the current cycle can be obtained from formula (3) to get the viscosity coefficient corresponding to the set motion speed.
  • the size of the driving force for driving the movement of the magnetic bead can be changed (eg, increased) according to the increase of the number of oscillating cycles, so it is usually in accordance with the number of cycles Increase the driving force.
  • the second movement of the magnetic bead in the oscillating motion is detected to obtain a parameter reflecting the flow characteristics of the sample.
  • the magnetic bead may be detected in the The second motion during the motion that satisfies the preset condition in the oscillating motion to obtain a parameter that reflects the flow characteristics of the sample.
  • the preset condition may be that the motion amplitude of the magnetic bead in the oscillating motion is within a preset amplitude range.
  • the motion range of the magnetic beads is judged, and the speed and viscosity coefficient are calculated when the requirements are met.
  • the calculation process is shown in FIG. 10 and includes the following steps 1001 to 1012:
  • step 1001 the driving component uses the driving force of the current motion cycle of the magnetic bead to drive the magnetic bead to move.
  • Step 1002 Collect the movement trajectory of the magnetic bead through the detection component.
  • step 1003 the processor calculates the movement amplitude of the magnetic bead according to the movement trajectory of the magnetic bead.
  • step 1004 it is determined whether the movement amplitude of the magnetic bead is less than the lower limit of the preset amplitude range. If yes, step 1009 is performed. If the movement amplitude of the magnetic bead is greater than the lower limit of the preset amplitude range, step 1005 is performed.
  • step 1005 it is determined whether the movement amplitude of the magnetic bead is greater than the upper limit of the preset amplitude range. If it is exceeded, the movement of the magnetic bead may change the nature of the reaction system. Only the current data can be used to perform the calculation, so the steering Go to step 1012; if the motion amplitude of the magnetic bead is less than the upper limit of the preset amplitude range, go to step 1006.
  • Step 1006 Calculate the average movement speed of the magnetic bead in the current movement period according to the movement trajectory of the magnetic bead.
  • step 1007 the viscosity coefficient corresponding to the average motion speed of the current motion cycle is calculated using formula (3).
  • step 1008 it is determined whether the number of motion cycles completed by the magnetic bead exceeds the set number of cycles, if not, step 1009 is executed, and if the set number of cycles has been exceeded, step 1010 is executed.
  • step 1009 the driving component is controlled to increase the driving force for driving the movement of the magnetic bead, so that the motion range of the magnetic bead increases and the speed increases. After increasing the driving force, turn to step 1001 to perform the next cycle of detection.
  • step 1010 the detection of the movement of the magnetic beads is stopped.
  • the detection of the magnetic beads can be stopped by stopping the driving of the magnetic beads.
  • Step 1011 Curve-fit the motion speed and the viscosity coefficient obtained by the above-mentioned motion cycle to obtain a viscosity coefficient curve.
  • Step 1012 Obtain the viscosity coefficient corresponding to the set motion speed through the viscosity coefficient curve.
  • step 505 is executed.
  • the fibrinogen concentration in the sample is determined according to the parameters.
  • the parameter reflecting the flow characteristics of the sample is the viscosity coefficient. Therefore, a preset calibration curve can be queried according to the viscosity coefficient to obtain the fibrinogen concentration corresponding to the parameter.
  • the calibration curve is a curve set in advance with the viscosity coefficient and fibrinogen concentration as two dimensions, as shown in Figure 11, where the viscosity coefficient is the magnetic beads moving in the reaction system at a set movement speed The corresponding viscosity coefficient at the time, the set motion speed can be set to 120mm/s.
  • the calibration curve is determined in advance through a large amount of experimental data.
  • step 502 can also be cancelled without performing PT detection.
  • step 503 is executed to drive the magnetic beads to move in the solidified sample.
  • the work F magent S magent that the driving force drives the movement of the magnetic beads is related to the viscosity coefficient and can also reflect the flow characteristics of the sample. Therefore, in other embodiments, the work F magent performed by the driving force S magent can also be used as a parameter reflecting the flow characteristics of the sample.
  • the driving force F magent of the magnetic bead is a standard quantity.
  • the displacement S magent running under the driving force of the magnetic bead can be determined by the movement trajectory of the magnetic bead, so the work done by the driving force within the preset motion period of the magnetic bead can be obtained.
  • the calibration curve is a curve with work and fibrinogen concentration as two dimensions. After learning the work done by the driving force, the fibrinogen concentration can be obtained by querying the calibration curve, as shown in FIG. 12.
  • the preset motion cycle may be, for example, all motion cycles or part of motion cycles during the motion period in which the magnetic beads meet the preset conditions during the oscillating motion, or may be the preset Nth motion cycle, or the average motion speed reaches Set the movement cycle of the movement speed.
  • the second movement of the magnetic bead in the oscillating motion is detected to obtain a parameter reflecting the flow characteristics of the sample, in some embodiments, the magnetic The second movement condition of the bead during the movement that satisfies the preset condition in the oscillating movement to obtain a parameter that reflects the flow characteristics of the sample.
  • the preset condition may be that the motion amplitude of the magnetic bead in the oscillating motion is within a preset amplitude range.
  • the work done by the driving force of the magnetic bead movement can be calculated by calculating the driving force in all motion cycles (for example, 5 motion cycles) in which the motion amplitude of the magnetic bead in the oscillation motion is within the preset amplitude range, and then The fibrinogen concentration is obtained by the work done by the driving force and the calibration curve (as shown in FIG. 12).
  • the viscosity coefficient is calculated by formula (3).
  • the viscosity coefficient can also be calculated by the formula derived in the following manner. According to the momentum formula:
  • Fmagent is the driving force for the magnetic beads (that is, F magnet in Figure 8)
  • S ball is the path of the magnetic bead movement
  • f is the fluid resistance of the reaction system (that is, F resistance in Figure 8)
  • G represents the gravity and buoyancy
  • ⁇ is the angle between Fmagent and the direction of the bead movement
  • ⁇ is the angle between G and the direction of the bead movement.
  • velocity is the first derivative of the bead displacement with respect to time
  • acceleration is the second derivative of the bead displacement with respect to time.
  • velocity and acceleration are related to the viscosity coefficient and can also reflect the flow characteristics of the sample. Therefore, in other embodiments, velocity and acceleration can also be used as parameters that reflect the flow characteristics of the sample .
  • the fibrinogen concentration in the sample can be determined according to work done by the driving force of the magnetic bead movement, or the fibrinogen concentration in the sample can be determined according to the speed of the magnetic bead and/or the acceleration of the magnetic bead, or can The fibrinogen concentration in the sample is determined according to the work done by the driving force of the magnetic bead movement, and the speed of the magnetic bead and/or the acceleration of the magnetic bead.
  • the calibration curve will also be changed accordingly to the curve determined by velocity or acceleration-fibrinogen concentration, as shown in Figure 13.
  • the parameter reflecting the flow characteristics of the sample may also be a function obtained by calculation among the work done by the driving force that drives the movement of the magnetic bead, the speed of the magnetic bead, and the acceleration of the magnetic bead.
  • the work done by the above driving force, the movement speed and acceleration of the magnetic bead can be obtained according to the movement of one period of the magnetic bead, for example, it can be the average or maximum value of the preset movement period, for example, it can be based on multiple movement periods of the magnetic bead
  • the motion situation obtained can be, for example, the average or median value of the magnetic beads over multiple cycles.
  • the preset motion cycle may be, for example, all motion cycles or part of motion cycles during the motion period in which the magnetic beads meet the preset conditions during the oscillating motion, or may be the preset Nth motion cycle, or the average motion speed reaches Set the movement cycle of the movement speed.
  • the second movement of the magnetic bead in the oscillating motion is detected to obtain a parameter reflecting the flow characteristics of the sample, in some embodiments, the magnetic The second movement condition of the bead during the movement that satisfies the preset condition in the oscillating movement to obtain a parameter that reflects the flow characteristics of the sample.
  • the preset condition may be that the motion amplitude of the magnetic bead in the oscillating motion is within the preset amplitude range, so in one embodiment, the motion amplitude of the magnetic bead in the oscillating motion may be within the preset amplitude range
  • the maximum acceleration in all exercise cycles for example, 5 exercise cycles
  • the fibrinogen concentration is obtained through the maximum acceleration and the calibration curve (as shown in FIG. 13).
  • the PT derivative algorithm can be used to detect FIB based on the optical method, the optical method is easily interfered by the color of the sample itself, so that the correct result may not be obtained or the result may not be output.
  • the magnetic bead method may be used to test the sample for coagulation.
  • the above embodiment is based on the magnetic bead method PT derivative algorithm to detect fibrinogen concentration (FIB). Normally, the FIB test is rarely detected separately by the doctor in the coagulation test project.
  • FIB testing can be performed directly, and there is no need for a separate test for the FIB project, so FIB special reagents can be saved. And the PT test and FIB test can use the same tube of blood sample, so the amount of sample can be saved.
  • the calibration curve can also be calibrated to update the calibration curve.
  • the process of detecting the calibration curve of the fibrinogen concentration is shown in FIG. 14 and includes the following steps 1401 to 1405:
  • Step 1401 making a sample.
  • the sample collection mechanism collects the tested sample and adds the measured sample (such as standard plasma or calibrator) to the reaction container, and the reagent collection mechanism collects the reagent and adds the reagent to the reaction container.
  • the reagent includes, for example, diluent and trigger reagent , Trigger reagent uses PT reagent. After the sample and reagent are mixed and incubated with stirring, a sample for testing is made. When the detection process is to obtain a calibration curve, the fibrinogen concentration of the sample is known at this time.
  • Step 1402 waiting for the sample to solidify.
  • the sample converts prothrombin into thrombin, and FIB finally forms an insoluble cross-linked fibrin clot under the action of thrombin, resulting in the coagulation of the sample.
  • Step 1403 driving the magnetic beads to move.
  • a predetermined driving voltage and/or driving method is used to make the magnetic beads oscillate in the solidified sample.
  • step 1404 the second movement of the magnetic bead in the oscillating movement is detected to obtain a parameter reflecting the flow characteristics of the sample.
  • the parameter reflecting the flow characteristics of the sample is the viscosity coefficient
  • the viscosity coefficient obtained in this step is similar to step 504 and will not be repeated here.
  • Step 1405 a calibration curve is obtained according to the obtained parameters reflecting the flow characteristics of the sample and the known concentration of fibrinogen in the sample.
  • step 1101 the fibrinogen concentration of the sample is unknown, and the parameters reflecting the flow characteristics of the sample can be obtained through steps 1101-1104.
  • the calibration curve can determine the concentration of fibrinogen in the sample.
  • This application also provides a coagulation analyzer according to an embodiment, which is used to measure and analyze the coagulation/anticoagulation, fibrinolysis/antifibrinolysis function of the specimen.
  • the coagulation time method used in this embodiment is a method that uses the specimen coagulation process as transmitted light
  • the measurement items of the clotting time method include PT (prothrombin time), APTT (activated partial thrombin time), TT (thrombin time), and FIB (fibrinogen amount).
  • any tangible, non-transitory computer-readable storage medium can be used, including magnetic storage devices (hard disks, floppy disks, etc.), optical storage devices (CD-ROM, DVD, Blu-ray disks, etc.), flash memory, and/or the like .
  • These computer program instructions can be loaded onto a general purpose computer, special purpose computer, or other programmable data processing equipment to form a machine, so that these instructions executed on a computer or other programmable data processing device can generate a device that implements a specified function.
  • Computer program instructions can also be stored in a computer-readable memory, which can instruct the computer or other programmable data processing device to operate in a specific manner, so that the instructions stored in the computer-readable memory can form a piece Manufactured products, including implementation devices that implement specified functions.
  • Computer program instructions can also be loaded onto a computer or other programmable data processing device, so that a series of operating steps are performed on the computer or other programmable device to produce a computer-implemented process that allows the computer or other programmable device to execute Instructions can provide steps for implementing specified functions.

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Abstract

一种凝血分析仪及其纤维蛋白原浓度检测方法，在PT检测完成后，重新驱动磁珠在凝固后的被测试样中运动，通过检测磁珠的运动情况确定样本中纤维蛋白原浓度，从而实现了基于磁珠法的检测纤维蛋白原浓度的PT衍算法。

Description

一种凝血分析仪及其纤维蛋白原浓度检测方法 技术领域
本发明涉及一种医疗设备，具体涉及一种基于磁珠法的凝血分析仪及其纤维蛋白原浓度检测方法。
背景技术
凝血分析仪用于对患者的血液进行凝血和抗凝、纤溶和抗纤溶功能进行分析，检测项目包括血浆凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)、凝血酶时间(TT)以及相关凝血因子等衍生项目的检测。
纤维蛋白原(FIB)，即凝血因子Ⅰ，其是凝血过程中的重要组份，具有重要的临床价值。FIB在凝血酶的作用下可依次转变为纤维蛋白单体和可溶性的纤维蛋白聚合体，在活化凝血因子ⅩⅢ的作用下相互交联形成不溶性的交联纤维蛋白凝块，从而导致血液凝固。
在全自动凝血分析仪上测定纤维蛋白原浓度的方法主要有两种：Clauss法和凝血酶原时间(PT)衍算法。Clauss法是依据纤维蛋白原与凝血酶作用最终形成纤维蛋白的原理，以纤维蛋白原的浓度作为X轴、以凝血酶凝固时间作为Y轴制作定标曲线，通过测定样本的凝血酶凝固时间、查询定标曲线来确定样本中的纤维蛋白原含量。该方法具有线性范围宽、准确性好、精密度好、灵敏度高等优点，是测定FIB浓度单项检查的首选方法。但该方法需要加入特定量的FIB试剂(即包含凝血酶的试剂)进行单独检测。
关于PT衍算法，当前只有基于光学法凝固法的PT衍算法，其依据纤维蛋白原转化为纤维蛋白会导致反应体系浊度变化的原理，以纤维蛋白原的浓度作为X轴、以反应体系的吸光度作为Y轴制作定标曲线或计算公式，通过在测定样本的凝血酶原时间的同时记录反应体系的浊度变化，查询定标曲线或通过计算以确定样本中纤维蛋白原的含量。该方法在正常值及高值部分能够取得与Clauss法一样较高的相关性和准确度，并且是在测试PT的同时开展测试，与Clauss法相比可以节约FIB试剂、提高多项混合时的测试速度。但是，PT衍算法不适用于PT检测值异常、 FIB异常等情形，只能作为筛选方法，超出其适用范围后需要重新使用Clauss法测定。
在采用磁珠法进行凝血项目检测时，需要采用Clauss法单独检测纤维蛋白原浓度，增加了样本用量、FIB试剂的使用成本和测试流程。
发明内容
本发明提供一种凝血分析仪及其纤维蛋白原浓度检测方法，可基于磁珠法开展PT衍算法以检测纤维蛋白原浓度。
根据第一方面，一种实施例中提供一种检测样本中纤维蛋白原浓度的方法，包括：
将样本和用于检测凝血酶原时间的试剂在放置有磁珠的反应容器中混合并形成试样；
驱动所述磁珠做振荡运动，通过检测所述磁珠的第一运动情况以对所述样本进行凝血酶原时间检测；
进行凝血酶原时间检测后，所述试样形成凝固状态，重新驱动所述磁珠在凝固状态的试样中做振荡运动；
通过检测所述磁珠在所述振荡运动中的第二运动情况确定样本中纤维蛋白原浓度。
根据第二方面，一种实施例中提供一种检测样本中纤维蛋白原浓度的方法，包括：
将样本和用于触发样本凝固的PT试剂在放置有磁珠的反应容器中混合，并形成凝固状态的试样；
驱动所述磁珠在凝固状态的试样中做振荡运动；
检测所述磁珠在所述振荡运动中的第二运动情况以获得用于反映所述试样流动特性的参数；
根据所述参数确定样本中的纤维蛋白原浓度，或根据所述参数和已知的样本中纤维蛋白原浓度得到定标曲线，所述定标曲线是以所述参数和纤维蛋白原浓度为两个维度形成的曲线。
根据第三方面，一种实施例中提供一种凝血分析仪，包括：
试样制作装置，用于将样本和用于检测凝血酶原时间的试剂在放置有磁珠的反应容器中混合并形成试样；
检测装置，所述检测装置包括驱动部件和检测部件，所述驱动部件用于驱动所述磁珠在试样中做振荡运动，所述检测部件用于检测所述磁珠在所述振荡运动中的运动情况；
处理器，所述处理器用于在检测凝血酶原时间时向所述驱动部件输出第一控制信号，以控制所述驱动部件驱动所述磁珠在试样中做振荡运动，并根据所述检测部件在检测凝血酶原时间的期间检测的第一运动情况得到凝血酶原时间；所述处理器还用于在完成凝血酶原时间检测后，向所述驱动部件输出第二控制信号，以控制所述驱动部件重新驱动所述磁珠在形成凝固状态的试样中做振荡运动，并根据所述检测部件在重新驱动所述磁珠振荡后检测的第二运动情况得到所述样本中纤维蛋白原浓度。
根据第四方面，一种实施例中提供一种凝血分析仪，包括：
试样制作装置，用于将样本和用于触发样本凝固的PT试剂在放置有磁珠的反应容器中混合，并形成凝固状态的试样；
检测装置，所述检测装置包括驱动部件和检测部件，所述驱动部件用于驱动所述磁珠在形成凝固状态的试样中做振荡运动，所述检测部件用于检测所述磁珠在所述振荡运动中的第二运动情况；
处理器，所述处理器用于向所述驱动部件输出第二控制信号，以控制所述驱动部件驱动所述磁珠在形成凝固状态的试样中做振荡运动，并根据所述磁珠的第二运动情况获得用于反映所述试样流动特性的参数，根据所述参数得到所述样本中纤维蛋白原浓度，或根据所述参数和已知的样本中纤维蛋白原浓度得到定标曲线，所述定标曲线是以所述参数和纤维蛋白原浓度为两个维度形成的曲线。
根据第五方面，一种实施例中提供一种计算机可读存储介质，包括程序，所述程序能够被处理器执行以实现上述权利要求中任一项所述的方法。
依据上述实施例，基于磁珠法，在PT检测完成后，重新驱动磁珠在凝固后的被测试样中运动，通过检测磁珠的运动情况确定样本中纤维蛋白原浓度，实现了基于磁珠法的检测纤维蛋白原浓度的PT衍算法。由于PT项目和纤维蛋白原浓度可使用同一反应体系进行检测，相对于纤维蛋白原浓度的Clauss法，节约了FIB专用试剂。
附图说明
图1为一种实施例中凝血分析仪的结构示意图；
图2为一种实施例中检测装置的结构示意图；
图3为一种实施例中驱动线圈的驱动波形示意图；
图4为一种实施例中磁珠在反应体系中运动的示意图；
图5为一种实施例中检测纤维蛋白原浓度的流程图；
图6a为一种实施例中接收线圈输出的电信号示意图；
图6b为一种实施例中解调后的电信号波形图；
图7为一种实施例中驱动线圈重新驱动磁珠运动的驱动波形示意图；
图8为一种实施例中磁珠在驱动力驱动下在反应体系中运动时的受力分析图；
图9为一种实施例中计算粘滞系数的流程图；
图10为另一种实施例中计算粘滞系数的流程图；
图11为以粘滞系数和纤维蛋白原浓度为两个维度形成的定标曲线；
图12为功和纤维蛋白原浓度为两个维度形成的定标曲线；
图13为以加速度和纤维蛋白原浓度为两个维度形成的定标曲线；
图14为一种实施例中检测纤维蛋白原浓度的标定曲线的流程图。
具体实施方式
下面通过具体实施方式结合附图对本发明作进一步详细说明。其中不同实施方式中类似元件采用了相关联的类似的元件标号。在以下的实施方式中，很多细节描述是为了使得本申请能被更好的理解。然而，本领域技术人员可以毫不费力的认识到，其中部分特征在不同情况下是可以省略的，或者可以由其他元件、材料、方法所替代。在某些情况下，本申请相关的一些操作并没有在说明书中显示或者描述，这是为了避免本申请的核心部分被过多的描述所淹没，而对于本领域技术人员而言，详细描述这些相关操作并不是必要的，他们根据说明书中的描述以及本领域的一般技术知识即可完整了解相关操作。
另外，说明书中所描述的特点、操作或者特征可以以任意适当的方式结合形成各种实施方式。同时，方法描述中的各步骤或者动作也可以按照本领域技术人员所能显而易见的方式进行顺序调换或调整。因此， 说明书和附图中的各种顺序只是为了清楚描述某一个实施例，并不意味着是必须的顺序，除非另有说明其中某个顺序是必须遵循的。
本文中为部件所编序号本身，例如“第一”、“第二”等，仅用于区分所描述的对象，不具有任何顺序或技术含义。而本申请所说“连接”、“联接”，如无特别说明，均包括直接和间接连接(联接)。
在研发过程中，发明人意识到当反应体系中的纤维蛋白原转换为不溶性的交联的纤维蛋白聚合体后，会导致反应体系的流体阻力快速上升，而反应体系的流动特性和反应体系中的交联的纤维蛋白聚合体的含量呈现负相关，即交联的纤维蛋白聚合体含量越高，反应体系的流动特性越差，反之，交联的纤维蛋白聚合体含量越低，反应体系的流动特性越好。而反应体系中的交联的纤维蛋白聚合体的含量和纤维蛋白原的含量正相关。
因此，本发明的发明构思是通过测定反应体系的流动特性来获取交联的纤维蛋白多聚体的生成情况，进而确定样本中的纤维蛋白原的含量。
在本发明实施例中，采用磁珠法进行凝血酶原时间检测，在完成凝血酶原时间检测后，此时反应体系中已形成不溶性的交联的纤维蛋白多聚体，反应体系处于凝固状态，磁珠已停止运动，在这种情况下，重新驱动磁珠做振荡运动，磁珠的运动情况将受到反应体系流体阻力的影响，检测磁珠的运动情况将反映反应体系的流动特性。
请参考图1，基于本发明构思检测纤维蛋白原浓度的凝血分析仪的结构示意图如图1所示，包括样本放置区11、样本采集机构12、试剂放置区13、试剂采集机构14、反应容器放置区10、被测物转运机构15、检测装置16和处理器17。
样本放置区11用于提供被测样本11a放置的场所，被测样本可以是乏血小板血浆、质控品或校准品。图示中，样本放置区11是一个矩形区域，可放置多个被测样本11a。实际仪器中，样本放置区11也可以是一个条形区域、圆形区域或样本进给机构，也可以仅是一个放置样本的位置。
试剂放置区13用于提供放置测试用试剂13a的场所。图示中，试剂放置区13是一个矩形区域，可放置多个测试用试剂13a。实际仪器中，试剂放置区13也可以是一个条形或圆形区域。试剂包括稀释液、混合试 剂和触发试剂中的至少一种。
反应容器放置区10用于提供放置测试用反应容器10a的场所。图示中，反应容器放置区10是一个矩形区域，可放置多个反应容器10a。实际仪器中，反应容器放置区10也可以是一个条形区域、圆形区域或料斗。
样本采集机构12和试剂采集机构14构成试样制作装置，用于将样本和用于检测凝血酶原时间的试剂在放置有磁珠的反应容器中混合成反应体系，形成供后续检测的试样。
样本采集机构12用于从样本放置区11采集被测样本，并将被测样本添加到放置在反应容器放置区10上的反应容器10a中，试剂采集机构14用于从试剂放置区13采集试剂，并将试剂添加到放置在反应容器放置区10上的反应容器10a中。被测样本和试剂在反应容器10a中混合。在有的实施例中，样本采集机构12和试剂采集机构14也可以是带有采样器的运动部件，通过移动将在样本放置区11或试剂放置区13采集到的被测样本或试剂添加到放置在反应容器放置区10上的反应容器10a中。
检测装置16用于在处理器的控制下对由被测样本和试剂混合后的试样(被测物)基于磁珠法进行凝血项目检测，并输出反映凝固情况的电信号至处理器17。检测装置包括驱动部件和检测部件，驱动部件用于驱动所述磁珠在试样中做振荡运动，检测部件用于检测所述磁珠在所述振荡运动中的运动情况。
一种实施例中，检测装置16的结构如图2所示，驱动部件是驱动线圈210，检测部件是测量线圈220，磁珠法采用的反应容器的结构如图2所示，为方便看清结构，图2中对反应容器200进行了剖视处理。反应容器200的容纳腔内放置有磁珠201，反应容器的底部供磁珠201在磁场的驱动下运动。为方便描述，反应容器200具有沿磁珠运动轨道延伸的长度方向和与长度方向垂直的宽度方向。在本申请实施例中，磁珠采用能够被快速磁化的材料制成，当磁珠处于磁场中时，它能够被磁场快速磁化，当磁场消失后，磁珠磁性快速消失或剩磁小。该磁珠的形状可以采用球形，也可以采用其他形状，例如多面体，此处仅举例说明，不做具体限定。可选地，检测装置16可以包括偶数组驱动线圈210，例如驱动线圈210可以有两组，两组驱动线圈210间隔一定距离相对设置，分别沿反应容器200的长度方向位于反应容器200的两侧。两个驱动线 圈210被施加以周期相同但时序不同的PWM(Pulse Width Modulation，脉冲宽度调制)波，如图3所示，从而交替产生间歇式磁场(在t1和t2这段期间，驱动线圈M1在图示的时段M1中产生磁场；在t3和t4这段期间，驱动线圈M2在图示的时段M2中产生磁场；如此类推)，通过磁场反复磁化磁珠使得反应容器200内的磁珠201沿反应容器形成的轨道进行振荡运动。磁珠201在一个PWM波周期的t1-t4时间段的运动位置和运动方向如图4所示。
可选地，检测装置16可以包括偶数组测量线圈220，例如可以包括两组测量线圈220，两组测量线圈220间隔一定距离相对设置，分别沿反应容器200的宽度方向位于反应容器200的两侧。两组测量线圈220分为发射线圈和接收线圈，发射线圈的两端连接信号发射电路(图中未示出)，用于输入正弦波交流电，用于产生连续的磁场，接收线圈的两端连接信号接收电路(图中未示出)，以检测磁珠201的振荡运动而产生的运动电信号。所述的运动电信号，是指能够反映磁珠201运动状态的电信号。发射线圈产生磁场，磁珠切割磁力线运动，改变磁力线的路径，导致磁力线在一些区域的密度发生变化，从而改变接收线圈接收到的磁通量，接收线圈根据接收到的磁通量产生原感应电动势，并产生相应的感应电流，该感应电流经过电路转换和信号调理，能够得到包含磁珠201运动信息的电压信号，即磁珠201的运动电信号。由于磁珠201的运动，改变了原感应电流的特征，因而可从改变后的感应电流中可以提取出磁珠201的运动信息。
当磁珠201在反应容器200内运动时，该测量线圈220产生相应的感应电流，该感应电流反映了该磁珠201运动情况，可以作为该磁珠201的运动电信号。当然，也可以对测量线圈220产生的感应电流进行转换后获得电压信号，并将该电压信号作为该磁珠201的运动电信号。
测量线圈220将其检测获得的磁珠201的运动电信号传送至处理器17。可选地，该测量线圈220可以通过信号转换电路(未示出)和信号调理电路(未示出)连接至处理器。例如，信号转换电路能够对测量线圈220获取的磁珠201在至少一段持续时间内的运动电信号进行模数转换，信号调理电路能够对测量线圈220获取的磁珠201在至少一段持续时间内的运动电信号进行整流、滤波及归一化等预处理。
处理器17用于向驱动部件输出控制信号，以控制驱动部件驱动磁珠 在试样中做振荡运动。并用于从检测部件接收到的运动电信号进行处理，得到被测样本的测量参数，例如凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)、凝血酶时间(TT)等。在一种实施例中，处理器17用于先控制检测装置检测凝血酶原时间，根据检测部件在检测凝血酶原时间的期间检测的第一运动情况得到凝血酶原时间，在完成凝血酶原时间检测后，控制驱动部件重新驱动磁珠在形成凝固状态的试样中做振荡运动，并根据检测部件在重新驱动所述磁珠振荡后检测的第二运动情况得到样本中纤维蛋白原浓度，这种方案以下实施例中称为PT衍算法检测纤维蛋白原浓度。而在另一种实施例中，不需要先检测凝血酶原时间，但需要采用PT试剂或与PT试剂成分类似的试剂对样本进行触发形成凝固状态，处理器用于控制驱动部件驱动磁珠在形成凝固状态的试样中做振荡运动，并根据所述磁珠的第二运动情况得到样本中纤维蛋白原浓度。通过这两种实施例不仅可以得到纤维蛋白原浓度，也可以得到纤维蛋白原浓度的定标曲线(如使用校准品的情况下进行定标曲线的更新)，或对纤维蛋白原浓度的定标曲线进行校准(如使用校准品的情况下进行定标曲线的更新)。
基于上述凝血分析仪，基于磁珠法的PT衍算法检测纤维蛋白原浓度的流程如图5所示，包括以下步骤501-步骤505：
步骤501，制作试样。样本采集机构采集被测样本，并将被测样本(例如：血浆)添加到反应容器中，试剂采集机构采集试剂，并将试剂添加到反应容器中，试剂包括例如稀释液和触发试剂。由于本实施例先进行PT检测，因此触发试剂采用检测凝血酶原时间的试剂，即PT试剂，该PT试剂主要成分有组织因子、磷脂和钙离子。样本和试剂经搅拌混合和孵育后，制作成用于检测的试样。
步骤502，进行PT检测。其检测过程包括：
处理器控制信号发生电路向驱动部件输出第一控制信号，如图3所示的PWM信号，驱动部件在第一控制信号的激励下产生间歇式交变磁场,驱动磁珠在试样中做振荡运动。
同时，检测部件检测磁珠在振荡运动中的第一运动情况。样本和试剂混合反应后，根据瀑布样学说，样本在PT试剂的触发下，将凝血酶原转化为凝血酶，FIB在凝血酶的作用下最终形成不溶性的交联纤维蛋白凝块，从而导致试样凝固。在此变化过程中，磁珠在驱动力的作用下运 动，接收线圈接收到随磁珠的周期性位置变化而周期性变化的磁通量，根据该周期性变化的磁通量产生周期性变化的电信号，例如周期性变化的感应电动势或周期性变化的感应电流。一实施例中，接收线圈输出的反映磁珠第一运动情况的电信号如图6a所示，经解调后的电信号波形如图6b所示，其中波谷601指示是磁珠运动到反应容器壁上的情况，此时接收线圈接收到的磁通量最小，产生的感应电动势最小，感应电流也最小。波峰602指示是磁珠运动到反应容器底部的情况，此时接收线圈接收到的磁通量最大，产生的感应电动势最大，感应电流也最大。
接收线圈输出的电信号经处理后传输到处理器，处理器对该电信号进行处理，得到被测样本的凝血酶原时间(PT)。
步骤503，重新驱动磁珠运动。在进行凝血酶原时间检测后，试样已经形成凝固状态，此时，处理器向驱动部件输出第二控制信号，重新设定驱动部件的驱动电压和/或驱动方式，使驱动部件驱动磁珠重新在凝固状态的试样中做振荡运动。驱动方式例如可以是驱动电压、驱动周期、驱动电压的占空比等等。为保证磁珠的运动，驱动部件对磁珠的驱动力相对于PT检测过程中的驱动力要大，可通过增加驱动电压、PWM波的占空比等方式增加驱动力，如图7所示，一实施例中，PWM波的占空比相对于PT检测过程中的占空比要大。
在所述振荡运动中，可以根据振荡周期个数的增长而改变(例如增大)用于驱动所述磁珠运动的驱动力的大小。
步骤504，检测磁珠在振荡运动中的第二运动情况以获得用于反映试样流动特性的参数。
FIB在凝血酶的作用下最终形成不溶性的交联纤维蛋白凝块，从而导致试样凝固，FIB浓度越高，形成交联纤维蛋白凝块的密度越大，试样的流动性越差，在一种实施例中，用于反映试样流动特性的参数是粘滞系数。当然，在其他实施例中，用于反映试样流动特性的参数还可以是流体阻力系数。
在试样凝固后，磁珠的受力分析图如图8所示，当磁珠201在驱动线圈的作用下在试样中进行振荡时，假设磁珠的运动方向如图8所示，则此时磁珠同时受到自身重力G、反应体系对磁珠的浮力F 浮、反应容器对磁珠的支持力N、反应体系对磁珠的滚动摩擦力f 滑、电磁铁对磁珠的驱动力F 磁和反应体系的流体阻力F 阻。下面着重分析F 磁、f 滑、F 阻三个 力的做功情况。
针对磁珠运动周期的一半(一个完整的感生电动势振荡周期)应用动能定理，存在以下关系：
Figure PCTCN2018124787-appb-000001
其中，m是磁珠的质量，vstart和vend分别是磁珠在反应容器内运动半周期开始和结束时的速度，Fmagent是对磁珠的驱动力(即图8中的F 磁)，Smagent是磁珠在驱动力作用时的位移，s是磁珠在反应容器内运动半周期内的路程，重力G和浮力F 浮的方向相反，在公式中采用G表示重力和浮力的合力，H是磁珠在重力和浮力的合力作用下的位移，L是磁珠在支持力N作用下的位移。
反应体系对磁珠的滚动摩擦力(f 滑)一直存在于反应体系中，并且远小于反应体系的流体阻力(F 阻),因此忽略。
在磁珠往复运动过程中，对于磁珠运动的半周期而言，由于反应容器的结构，磁珠在反应容器内近似于单摆运动，即：磁珠经历了由容器底部-容器壁-容器底部或容器壁-容器底部-容器壁的运动，其在初始位置和终止位置(磁珠位于反应杯的两端，相当于单摆的两端，此时线速度为零)的速度相等，且G、F 浮、N三个力由于没有产生力所在方向上的位移(即公式中H和L都为零)，因此做功为零。
根据流体阻力公式f＝6π·η·r·v，公式(1)简化为：
Figure PCTCN2018124787-appb-000002
式中：r为磁珠的半径，磁珠驱动力F magent为标定量，磁珠驱动力下运行的位移S magent为可测定量，F magentS magent是驱动力驱动磁珠运动所做的功。S ball是磁珠运动的路程，可通过接收线圈输出的电信号得到磁珠的运动轨迹，分析磁珠的运动轨迹即可得到磁珠的位移或路程。仅有式中的磁珠运动速度v、反应体系的粘滞系数η为未知数。磁珠运动速度v可通过S ball对时间求导得到，由此可以计算出粘滞系数：
Figure PCTCN2018124787-appb-000003
由公式(3)可知，粘滞系数与磁珠在试样中的运动速度有关，根据磁珠的运动速度可得到与该运动速度对应的粘滞系数，速度越大，粘滞系数越小。因此需要设定磁珠的一个运动速度，得到磁珠在试样中按照该设定运动速度运动时的粘滞系数。
但磁珠的运动速度是不可预知的，因此，在本实施例中，采用以下方法得到设定运动速度对应的粘滞系数，例如设定运动速度可以定为120mm/s。在一个具体实例中，设定运动速度对应的粘滞系数计算过程如图9所示，包括以下步骤901-步骤909：
步骤901，驱动部件采用磁珠当前运动周期的驱动力驱动磁珠运动。
步骤902，通过检测部件采集磁珠的运动轨迹。根据检测部件的接收线圈的输出可得到反映磁珠的第二运动情况的电信号波形图，该电信号波形图类似于图6b，但信号幅度会随着驱动力的增加而变大。从电流波形图即可以得到磁珠的运动轨迹。
步骤903，处理器根据磁珠的运动轨迹计算磁珠在当前运动周期的平均运动速度。根据磁珠的运动轨迹可以得到磁珠每个运动周期的运动幅度和位移，将位移对时间求导即可得到速度。当然，对于非连续的采样点，可以采用细分的方法实现所述的求导。
步骤904，利用公式(3)计算当前运动周期的平均运动速度对应的粘滞系数。
步骤905，判断磁珠已完成的运动周期数是否超过设定周期数，例如设定周期数是大于3的数，如果没有，则执行步骤906，如果已超过设定周期数，则执行步骤907。
步骤906，控制驱动部件改变驱动磁珠运动的驱动力，例如增加或减小驱动力，从而改变磁珠的运动速度。不同的周期对应有不同的驱动力，从而不同的周期对应有不同的平均运动速度。根据上述步骤503的描述，在所述振荡运动中，可以根据振荡周期个数的增长而改变(例如增大)用于驱动所述磁珠运动的驱动力的大小，因此通常是随着周期数的增加而增大驱动力。可通过改变驱动电压或PWM波的占空比来改变驱 动力的大小。在改变驱动力大小后转向步骤901进行下一周期的检测。
步骤907，停止对磁珠运动情况的检测。可以通过停止对磁珠的驱动达到停止检测的目的，也可以不管磁珠是否继续运动，只是停止对磁珠运动情况的数据采集。
步骤908，将上述运动周期得到的运动速度和粘滞系数进行曲线拟合，通过曲线拟合得到粘滞系数曲线，粘滞系数曲线是一个二维的曲线，一个维度是粘滞系数，另一个维度是速度。在一些实施例中，将至少三个周期的运动速度和粘滞系数进行曲线拟合，得到粘滞系数曲线。不同的周期对应有不同的驱动力，从而不同的周期对应有不同的平均运动速度。
步骤909，通过粘滞系数曲线得到设定运动速度对应的粘滞系数。
当然，在其他实施例中，也可以不断检测磁珠在振荡运动中的运动速度，当磁珠的即时运动速度或当前周期内的平均运动速度达到设定运动速度时，根据当前时刻(dt)或当前周期内的参数由公式(3)得到设定运动速度对应的粘滞系数。根据上述步骤503的描述，在所述振荡运动中，可以根据振荡周期个数的增长而改变(例如增大)用于驱动所述磁珠运动的驱动力的大小，因此通常是随着周期数的增加而增大驱动力。随着运动周期数的增加，磁珠运动速度不断增加，从而磁珠的即时运动速度或当前周期内的平均运动速度达到设定运动速度。步骤504中，检测所述磁珠在所述振荡运动中的第二运动情况以获得用于反映所述试样流动特性的参数，在一些实施例中，可以是检测所述磁珠在所述振荡运动中满足预设条件的运动期间的第二运动情况以获得用于反映所述试样流动特性的参数。预设条件，可以是磁珠在所述振荡运动中的运动振幅处于预设振幅范围内。
在一个具体实例中，对磁珠的运动幅度进行判断，符合要求时再计算速度和粘滞系数，计算过程如图10所示，包括以下步骤1001-步骤1012：
步骤1001，驱动部件采用磁珠当前运动周期的驱动力驱动磁珠运动。
步骤1002，通过检测部件采集磁珠的运动轨迹。
步骤1003，处理器根据磁珠的运动轨迹计算磁珠的运动幅度。
步骤1004，判断磁珠的运动幅度是否小于预设幅度范围的下限，如果是，则执行步骤1009，如果磁珠的运动幅度大于预设幅度范围的下限，则执行步骤1005。
步骤1005，判断磁珠的运动幅度是否大于预设幅度范围的上限，如果是，如果已经超出，则磁珠的运动有可能会改变反应体系的性质，只能采纳当前的数据执行计算，因此转向执行步骤1012；如果磁珠的运动幅度小于预设幅度范围的上限，则执行步骤1006。
步骤1006，根据磁珠的运动轨迹计算磁珠在当前运动周期的平均运动速度。
步骤1007，利用公式(3)计算当前运动周期的平均运动速度对应的粘滞系数。
步骤1008，判断磁珠已完成的运动周期数是否超过设定周期数，如果没有，则执行步骤1009，如果已超过设定周期数，则执行步骤1010。
步骤1009，控制驱动部件增加驱动磁珠运动的驱动力，使磁珠的运动幅度增加，速度增大。在增大驱动力后转向步骤1001进行下一周期的检测。
步骤1010，停止对磁珠运动情况的检测，例如可以通过停止对磁珠的驱动达到停止检测的目的。
步骤1011，将上述运动周期得到的运动速度和粘滞系数进行曲线拟合，得到粘滞系数曲线。
步骤1012，通过粘滞系数曲线得到设定运动速度对应的粘滞系数。
步骤504之后，执行步骤505。
在步骤505中，根据参数确定样本中的纤维蛋白原浓度。请继续参考图5所示，根据得到的反映试样流动特性的参数查询预设的定标曲线，得到该参数对应的纤维蛋白原浓度。本实施例中，反映试样流动特性的参数是粘滞系数，因此可根据粘滞系数查询预设的定标曲线，得到所述参数对应的纤维蛋白原浓度。定标曲线是预先设定的、以粘滞系数和纤维蛋白原浓度为两个维度形成的曲线，如图11所示，其中的粘滞系数是磁珠以设定运动速度在反应体系中运动时对应的粘滞系数，设定运动速度可以定为120mm/s。定标曲线是预先通过大量实验数据确定的。
当不需要检测凝血酶原时间(PT)时，也可以取消步骤502，不做PT检测，待试样凝固后，执行步骤503，驱动磁珠在已凝固的试样中运动。
根据公式(3)，驱动力驱动磁珠运动所做的功F magentS magent与粘滞系数相关，也可反映试样的流动特性，因此在其他的实施例中，驱动力做 的功F magentS magent也可以作为反映试样流动特性的参数。磁珠驱动力F magent为标定量，磁珠驱动力下运行的位移S magent可通过磁珠的运动轨迹测定得到，因此可得到驱动力在磁珠的预设运动周期内做的功。定标曲线就是以功和纤维蛋白原浓度作为两个维度的曲线，在得知驱动力做的功后通过查询定标曲线，即可得到纤维蛋白原浓度，如图12所示。
预设运动周期，例如可以是磁珠在做振荡运动中满足预设条件的运动期间中的所有运动周期或其中部分运动周期，还可以是预设的第N个运动周期，或平均运动速度达到设定运动速度的运动周期。根据上述步骤504中所述，检测所述磁珠在所述振荡运动中的第二运动情况以获得用于反映所述试样流动特性的参数，在一些实施例中，可以是检测所述磁珠在所述振荡运动中满足预设条件的运动期间的第二运动情况以获得用于反映所述试样流动特性的参数。预设条件，可以是磁珠在所述振荡运动中的运动振幅处于预设振幅范围内。因此在一实施例中，可以通过计算磁珠在振荡运动中的运动振幅处于预设振幅范围内的所有运动周期(例如5个运动周期)中的驱动力驱动磁珠运动所做的功，然后通过该驱动力所做的功和定标曲线(如图12所示)得到纤维蛋白原浓度。
上述实施例中，通过公式(3)来计算粘滞系数，在另一种实施例中，粘滞系数也可以通过以下方式推导出的公式进行计算。根据动量公式可知：
Figure PCTCN2018124787-appb-000004
其中，F是磁珠受到的合力，m是磁珠的质量，v是磁珠的运动速度。在磁珠运动速度方向上应用牛顿第二定律，可得到如下等式：
Figure PCTCN2018124787-appb-000005
Fmagent是对磁珠的驱动力(即图8中的F 磁)，S ball是磁珠运动的路程，f是反应体系的流体阻力(即图8中的F 阻)，G表示重力和浮力的合力，α是Fmagent和磁珠运动方向的夹角，β是G和磁珠运动方向的夹角。
流体阻力公式f＝6π·η·r·v代入等式(4)，得到：
Figure PCTCN2018124787-appb-000006
即有：
Figure PCTCN2018124787-appb-000007
由此可以得出粘滞系数η：
Figure PCTCN2018124787-appb-000008
根据公式(5)，速度是磁珠位移对时间的一阶导数，加速度是磁珠位移对时间的二阶导数，当得到磁珠的速度和加速度后，也可以得到粘滞系数η，即磁珠的加速度与粘滞系数η相关。因此，本方法也称为加速度法。当然，对于非连续的采样点，可以采用细分的方法实现所述的求导。
根据公式(3)和(5)可知，速度和加速度与粘滞系数相关，也可反映试样的流动特性，因此在其他的实施例中，速度和加速度也可以作为反映试样流动特性的参数。例如，可以根据磁珠运动的驱动力所做的功确定样本中的纤维蛋白原浓度，或者可以根据磁珠的速度和/或所述磁珠的加速度确定样本中的纤维蛋白原浓度，或者可以根据磁珠运动的驱动力所做的功，以及所述磁珠的速度和/或所述磁珠的加速度确定样本中的纤维蛋白原浓度。当将速度或加速度作为反映试样流动特性的参数时，定标曲线也将相应地改为速度或加速度-纤维蛋白原浓度确定的曲线，如图13所示。
同理，反映试样流动特性的参数也可以是驱动磁珠运动的驱动力所做的功、磁珠的速度和磁珠的加速度中的多个通过计算得到的函数。
上述的驱动力做的功、磁珠的运动速度和加速度可以根据磁珠的一个周期的运动情况得到，例如可以是预设运动周期的平均值或最大值，例如可以根据磁珠多个运动周期的运动情况得到，例如可以是磁珠多个周期的平均值或中位值。
预设运动周期，例如可以是磁珠在做振荡运动中满足预设条件的运 动期间中的所有运动周期或其中部分运动周期，还可以是预设的第N个运动周期，或平均运动速度达到设定运动速度的运动周期。根据上述步骤504中所述，检测所述磁珠在所述振荡运动中的第二运动情况以获得用于反映所述试样流动特性的参数，在一些实施例中，可以是检测所述磁珠在所述振荡运动中满足预设条件的运动期间的第二运动情况以获得用于反映所述试样流动特性的参数。预设条件，可以是磁珠在所述振荡运动中的运动振幅处于预设振幅范围内，因此在一实施例中，可以通过计算磁珠在振荡运动中的运动振幅处于预设振幅范围内的所有运动周期(例如5个运动周期)中的最大加速度，然后通过该最大加速度和定标曲线(如图13所示)得到纤维蛋白原浓度。
基于光学法虽然可以进行PT衍算法检测FIB，但光学法容易受到样本本身颜色的干扰，从而可能不能得到正确的结果或者不能输出结果。当样本中含有对光学检测结果有影响的干扰物时，可能会采用磁珠法对样本进行凝血项目检测。上述实施例是基于磁珠法的PT衍算法检测纤维蛋白原浓度(FIB)，通常情况下，医生制定出的凝血检测项目中FIB检测很少单独检测，当PT检测和FIB检测联合检测时，在采用磁珠法检测完PT项目后，可直接进行FIB检测，不需要针对FIB项目进行单独检测，因此可节约FIB专用试剂。并且PT检测和FIB检测可采用同一管血样，因此可节约样本的用量。
在另一实施例中，基于上述凝血分析仪，如使用校准品的情况下，还可以进行定标曲线的校准从而更新定标曲线。检测得到纤维蛋白原浓度的标定曲线的流程如图14所示，包括以下步骤1401-步骤1405：
步骤1401，制作试样。样本采集机构采集被测样本，并将被测样本(例如标准血浆或校准品)添加到反应容器中，试剂采集机构采集试剂，并将试剂添加到反应容器中，试剂包括例如稀释液和触发试剂，触发试剂采用PT试剂。样本和试剂经搅拌混合和孵育后，制作成用于检测的试样。当检测过程是为了得到定标曲线时，此时样本的纤维蛋白原浓度是已知的。
步骤1402，等待试样凝固。样本在PT试剂的触发下，将凝血酶原转化为凝血酶，FIB在凝血酶的作用下最终形成不溶性的交联纤维蛋白凝块，从而导致试样凝固。
步骤1403，驱动磁珠运动。采用预定的驱动电压和/或驱动方式，使磁珠在凝固状态的试样中做振荡运动。
步骤1404，检测磁珠在振荡运动中的第二运动情况以获得用于反映试样流动特性的参数。当反映试样流动特性的参数是粘滞系数时，本步骤中得到的是粘滞系数，本步骤与步骤504相类似，在此不再赘述。
步骤1405，根据得到的反映试样流动特性的参数和已知的样本中纤维蛋白原浓度得到定标曲线。
如果检测过程是为了对未知的被测样本进行检测，则在步骤1101中，样本的纤维蛋白原浓度是未知的，通过步骤1101-1104可得到反映试样流动特性的参数，根据该参数查询定标曲线即可确定出样本中的纤维蛋白原浓度。
本申请还提供一实施方式的凝血分析仪，其用于测定并分析标本的凝固/抗凝、纤溶/抗纤溶功能本实施方式所用的凝固时间法是一种将标本凝固过程作为透射光的变化检测或磁珠在磁力驱动下于标本内运动变化检测的测定方法。凝固时间法的测定项目有PT(凝血酶原时间)、APTT(活化部分凝血酶时间)、TT(凝血酶时间)和FIB(纤维蛋白原量)等。
本文参照了各种示范实施例进行说明。然而，本领域的技术人员将认识到，在不脱离本文范围的情况下，可以对示范性实施例做出改变和修正。例如，各种操作步骤以及用于执行操作步骤的组件，可以根据特定的应用或考虑与系统的操作相关联的任何数量的成本函数以不同的方式实现(例如一个或多个步骤可以被删除、修改或结合到其他步骤中)。
另外，如本领域技术人员所理解的，本文的原理可以反映在计算机可读存储介质上的计算机程序产品中，该可读存储介质预装有计算机可读程序代码。任何有形的、非暂时性的计算机可读存储介质皆可被使用，包括磁存储设备(硬盘、软盘等)、光学存储设备(CD-ROM、DVD、Blu Ray盘等)、闪存和/或诸如此类。这些计算机程序指令可被加载到通用计算机、专用计算机或其他可编程数据处理设备上以形成机器，使得这些在计算机上或其他可编程数据处理装置上执行的指令可以生成实现指定的功能的装置。这些计算机程序指令也可以存储在计算机可读存储器中，该计算机可读存储器可以指示计算机或其他可编程数据处理设备以特定的方式运行，这样存储在计算机可读存储器中的指令就可以形成一件制 造品，包括实现指定功能的实现装置。计算机程序指令也可以加载到计算机或其他可编程数据处理设备上，从而在计算机或其他可编程设备上执行一系列操作步骤以产生一个计算机实现的进程，使得在计算机或其他可编程设备上执行的指令可以提供用于实现指定功能的步骤。
虽然在各种实施例中已经示出了本文的原理，但是许多特别适用于特定环境和操作要求的结构、布置、比例、元件、材料和部件的修改可以在不脱离本披露的原则和范围内使用。以上修改和其他改变或修正将被包含在本文的范围之内。
前述具体说明已参照各种实施例进行了描述。然而，本领域技术人员将认识到，可以在不脱离本披露的范围的情况下进行各种修正和改变。因此，对于本披露的考虑将是说明性的而非限制性的意义上的，并且所有这些修改都将被包含在其范围内。同样，有关于各种实施例的优点、其他优点和问题的解决方案已如上所述。然而，益处、优点、问题的解决方案以及任何能产生这些的要素，或使其变得更明确的解决方案都不应被解释为关键的、必需的或必要的。本文中所用的术语“包括”和其任何其他变体，皆属于非排他性包含，这样包括要素列表的过程、方法、文章或设备不仅包括这些要素，还包括未明确列出的或不属于该过程、方法、系统、文章或设备的其他要素。此外，本文中所使用的术语“耦合”和其任何其他变体都是指物理连接、电连接、磁连接、光连接、通信连接、功能连接和/或任何其他连接。
具有本领域技术的人将认识到，在不脱离本发明的基本原理的情况下，可以对上述实施例的细节进行许多改变。因此，本发明的范围应根据以下权利要求确定。

Claims (43)

  1. 一种检测样本中纤维蛋白原浓度的方法，其特征在于，包括：
    将样本和用于检测凝血酶原时间的试剂在放置有磁珠的反应容器中混合并形成试样；
    驱动所述磁珠做振荡运动，通过检测所述磁珠的第一运动情况以对所述样本进行凝血酶原时间检测；
    进行凝血酶原时间检测后，所述试样形成凝固状态，重新驱动所述磁珠在凝固状态的试样中做振荡运动；
    通过检测所述磁珠在所述振荡运动中的第二运动情况确定样本中纤维蛋白原浓度。
  2. 根据权利要求1所述的方法，其特征在于，重新驱动所述磁珠在凝固状态的试样中做振荡运动包括：重新设定驱动方式驱动所述磁珠在凝固状态的试样中做振荡运动。
  3. 根据权利要求1或2所述的方法，其特征在于，所述通过检测所述磁珠在所述振荡运动中的第二运动情况确定样本中纤维蛋白原浓度，包括：
    检测所述磁珠在所述振荡运动中的第二运动情况以获得用于反映所述试样流动特性的参数；
    根据所述参数确定所述样本中纤维蛋白原浓度。
  4. 一种检测样本中纤维蛋白原浓度的方法，其特征在于，包括：
    将样本和用于触发样本凝固的PT试剂在放置有磁珠的反应容器中混合，并形成凝固状态的试样；
    驱动所述磁珠在凝固状态的试样中做振荡运动；
    检测所述磁珠在所述振荡运动中的第二运动情况以获得用于反映所述试样流动特性的参数；
    根据所述参数确定样本中的纤维蛋白原浓度，或根据所述参数和已知的样本中纤维蛋白原浓度得到定标曲线，所述定标曲线是以所述参数和纤维蛋白原浓度为两个维度形成的曲线。
  5. 根据权利要求3或4所述的方法，其特征在于，根据所述参数确定样本中的纤维蛋白原浓度包括：根据所述参数查询预设的定标曲线，得到所述参数对应的纤维蛋白原浓度。
  6. 根据权利要求5所述的方法，其特征在于，所述参数包括以所 述磁珠在所述试样中按照设定运动速度运动时的粘滞系数，所述定标曲线是以设定运动速度对应的粘滞系数和纤维蛋白原浓度为两个维度形成的曲线。
  7. 根据权利要求6所述的方法，其特征在于，检测所述磁珠的第二运动情况以获得用于反映所述试样流动特性的参数包括：
    通过分析磁珠的运动轨迹得到所述磁珠的运动速度；
    根据所述磁珠的运动速度得到所述设定运动速度对应的粘滞系数。
  8. 根据权利要求7所述的方法，其特征在于，根据所述磁珠的运动速度得到所述设定运动速度对应的粘滞系数包括：
    采用所述磁珠当前运动周期的驱动力驱动所述磁珠运动；
    采集所述磁珠的运动轨迹；
    根据所述磁珠的运动轨迹计算所述磁珠在当前运动周期的平均运动速度；
    计算当前运动周期中对应所述平均运动速度的粘滞系数；
    改变驱动所述磁珠运动的驱动力，进行下一周期的检测；
    循环上述步骤得到至少三个周期的运动速度和粘滞系数；
    将至少三个周期的运动速度和粘滞系数进行曲线拟合，得到粘滞系数曲线；
    通过所述粘滞系数曲线得到所述设定运动速度对应的粘滞系数。
  9. 根据权利要求8所述的方法，其特征在于，所述计算当前运动周期中对应所述平均运动速度的粘滞系数包括：通过当前运动周期的驱动力驱动所述磁珠运动所做的功和所述磁珠在当前运动周期的平均运动速度得到当前运动周期对应所述平均运动速度的粘滞系数；或通过所述磁珠在当前运动周期的平均运动速度和加速度得到对应所述平均运动速度的粘滞系数。
  10. 根据权利要求3-5中任一项所述的方法，其特征在于，所述参数包括驱动所述磁珠运动的驱动力所做的功、所述磁珠的速度和所述磁珠的加速度中的至少一种。
  11. 根据权利要求10所述的方法，其特征在于，所述根据所述参数确定样本中的纤维蛋白原浓度包括：根据所述磁珠运动的驱动力所做的功确定样本中的纤维蛋白原浓度。
  12. 根据权利要求10所述的方法，其特征在于，所述根据所述参 数确定样本中的纤维蛋白原浓度包括：根据所述磁珠的速度和/或所述磁珠的加速度确定样本中的纤维蛋白原浓度。
  13. 根据权利要求11或12所述的方法，其特征在于，所述根据所述参数确定样本中的纤维蛋白原浓度包括：根据所述磁珠运动的驱动力所做的功，以及所述磁珠的速度和/或所述磁珠的加速度确定样本中的纤维蛋白原浓度。
  14. 根据权利要求10所述的方法，其特征在于，所述参数是磁珠多个运动周期的平均值。
  15. 根据权利要求3-5中任一项所述的方法，其特征在于，所述磁珠的第二运动情况包括磁珠的运动轨迹信息。
  16. 根据权利要求15所述的方法，其特征在于，所述检测所述磁珠在所述振荡运动中的第二运动情况以获得用于反映所述试样流动特性的参数，包括：检测所述磁珠在所述振荡运动中满足预设条件的运动期间的第二运动情况以获得用于反映所述试样流动特性的参数。
  17. 根据权利要求16所述的方法，其特征在于，所述预设条件包括：所述磁珠在所述振荡运动中的运动振幅处于预设振幅范围内。
  18. 根据权利要求3或4所述的方法，其特征在于，所述方法还包括：
    判断所述磁珠的摆动是否满足结束检测条件；
    当不满足结束检测条件时，改变驱动所述磁珠运动的驱动力，进行下一周期的检测；
    当满足结束检测条件时结束检测。
  19. 根据权利要求18所述的方法，其特征在于，所述结束检测条件包括：所述磁珠的运动幅度超出预设振幅范围的上限或所述磁珠在所述振荡运动中的振荡周期数大于预设周期数。
  20. 根据权利要求1-19任一所述的方法，其特征在于，所述驱动所述磁珠在凝固状态的试样中做振荡运动，包括：在所述振荡运动中，根据振荡周期个数的增长而改变用于驱动所述磁珠运动的驱动力的大小。
  21. 一种凝血分析仪，其特征在于，包括：
    试样制作装置，用于将样本和用于检测凝血酶原时间的试剂在放置有磁珠的反应容器中混合并形成试样；
    检测装置，所述检测装置包括驱动部件和检测部件，所述驱动部件用于驱动所述磁珠在试样中做振荡运动，所述检测部件用于检测所述磁珠在所述振荡运动中的运动情况；
    处理器，所述处理器用于在检测凝血酶原时间时向所述驱动部件输出第一控制信号，以控制所述驱动部件驱动所述磁珠在试样中做振荡运动，并根据所述检测部件在检测凝血酶原时间的期间检测的第一运动情况得到凝血酶原时间；所述处理器还用于在完成凝血酶原时间检测后，向所述驱动部件输出第二控制信号，以控制所述驱动部件重新驱动所述磁珠在形成凝固状态的试样中做振荡运动，并根据所述检测部件在重新驱动所述磁珠振荡后检测的第二运动情况得到所述样本中纤维蛋白原浓度。
  22. 根据权利要求21所述的凝血分析仪，其特征在于，所述驱动部件重新驱动所述磁珠在形成凝固状态的试样中做振荡运动包括：所述驱动部件按照重新设定的驱动方式驱动所述磁珠在凝固状态的试样中做振荡运动。
  23. 根据权利要求21或22所述的凝血分析仪，其特征在于，所述处理器根据所述磁珠的运动情况得到所述样本中纤维蛋白原浓度包括：检测所述磁珠的运动情况以获得用于反映所述试样流动特性的参数，根据所述参数确定所述样本中纤维蛋白原浓度。
  24. 一种凝血分析仪，其特征在于，包括：
    试样制作装置，用于将样本和用于触发样本凝固的PT试剂在放置有磁珠的反应容器中混合，并形成凝固状态的试样；
    检测装置，所述检测装置包括驱动部件和检测部件，所述驱动部件用于驱动所述磁珠在形成凝固状态的试样中做振荡运动，所述检测部件用于检测所述磁珠在所述振荡运动中的第二运动情况；
    处理器，所述处理器用于向所述驱动部件输出第二控制信号，以控制所述驱动部件驱动所述磁珠在形成凝固状态的试样中做振荡运动，并根据所述磁珠的第二运动情况获得用于反映所述试样流动特性的参数，根据所述参数得到所述样本中纤维蛋白原浓度，或根据所述参数和已知的样本中纤维蛋白原浓度得到定标曲线，所述定标曲线是以所述参数和纤维蛋白原浓度为两个维度形成的曲线。
  25. 根据权利要求23或24所述的凝血分析仪，其特征在于，所述 处理器根据所述磁珠的运动情况得到所述样本中纤维蛋白原浓度包括：根据所述参数查询预设的定标曲线，得到所述参数对应的纤维蛋白原浓度。
  26. 根据权利要求25所述的凝血分析仪，其特征在于，所述参数包括以所述磁珠在所述试样中按照设定运动速度运动时的粘滞系数，所述定标曲线是以设定运动速度对应的粘滞系数和纤维蛋白原浓度为两个维度形成的曲线。
  27. 根据权利要求26所述的凝血分析仪，其特征在于，所述处理器检测所述磁珠的第二运动情况以获得用于反映所述试样流动特性的参数包括：
    通过分析磁珠的运动轨迹得到所述磁珠的运动速度；
    根据所述磁珠的运动速度得到所述设定运动速度对应的粘滞系数。
  28. 根据权利要求27所述的凝血分析仪，其特征在于，所述处理器通过检测所述磁珠的运动速度得到所述设定运动速度对应的粘滞系数包括：
    控制驱动部件采用所述磁珠当前运动周期的驱动力驱动所述磁珠运动；
    采集所述磁珠的运动轨迹；
    根据所述磁珠的运动轨迹计算所述磁珠在当前运动周期的平均运动速度；
    计算当前运动周期中对应所述平均运动速度的粘滞系数；
    改变驱动所述磁珠运动的驱动力，进行下一周期的检测；
    循环上述步骤得到至少三个周期的运动速度和粘滞系数；
    将至少三个周期的运动速度和粘滞系数进行曲线拟合，得到粘滞系数曲线；
    通过所述粘滞系数曲线得到所述设定运动速度对应的粘滞系数。
  29. 根据权利要求28所述的凝血分析仪，其特征在于，所述处理器计算当前运动周期中对应所述平均运动速度的粘滞系数包括：通过当前运动周期的驱动力驱动所述磁珠运动所做的功和所述磁珠在当前运动周期的平均运动速度得到当前运动周期对应所述平均运动速度的粘滞系数；或通过所述磁珠在当前运动周期的平均运动速度和加速度得到对应所述平均运动速度的粘滞系数。
  30. 根据权利要求23-25中任一项所述的凝血分析仪，其特征在于，所述参数包括驱动所述磁珠运动的驱动力所做的功、所述磁珠的速度和所述磁珠的加速度中的至少一种。
  31. 根据权利要求30所述的凝血分析仪，其特征在于，所述处理器根据所述参数确定样本中的纤维蛋白原浓度包括：根据所述磁珠运动的驱动力所做的功确定样本中的纤维蛋白原浓度。
  32. 根据权利要求30所述的凝血分析仪，其特征在于，所述处理器根据所述参数确定样本中的纤维蛋白原浓度包括：根据所述磁珠的速度和/或所述磁珠的加速度确定样本中的纤维蛋白原浓度。
  33. 根据权利要求31或32所述的凝血分析仪，其特征在于，所述处理器根据所述参数确定样本中的纤维蛋白原浓度包括：根据所述磁珠运动的驱动力所做的功，以及所述磁珠的速度和/或所述磁珠的加速度确定样本中的纤维蛋白原浓度。
  34. 根据权利要求30所述的凝血分析仪，其特征在于，所述参数是磁珠多个运动周期的平均值或中位值。
  35. 根据权利要求23-25中任一项所述的凝血分析仪，其特征在于，所述磁珠的第二运动情况包括磁珠的运动轨迹信息。
  36. 根据权利要求35所述的凝血分析仪，其特征在于，所述处理器检测所述磁珠在所述振荡运动中的第二运动情况以获得用于反映所述试样流动特性的参数，包括：检测所述磁珠在所述振荡运动中满足预设条件的运动期间的第二运动情况以获得用于反映所述试样流动特性的参数。
  37. 根据权利要求36所述的凝血分析仪，其特征在于，所述预设条件包括：所述磁珠在所述振荡运动中的运动振幅处于预设振幅范围内。
  38. 根据权利要求23或24所述的凝血分析仪，其特征在于，所述处理器还用于：
    判断所述磁珠的摆动是否满足结束检测条件；
    当不满足结束检测条件时，改变驱动所述磁珠运动的驱动力，进行下一周期的检测；
    当满足结束检测条件时结束检测。
  39. 根据权利要求38所述的凝血分析仪，其特征在于，所述结束检测条件包括：磁珠的摆动幅度超出预设振幅范围的上限或磁珠在所述 振荡运动中的振荡周期数大于预设周期数。
  40. 根据权利要求21-39中任一项所述的凝血分析仪，其特征在于，驱动所述磁珠在凝固状态的试样中做振荡运动，包括：在所述振荡运动中，根据振荡周期个数的增长而改变用于驱动所述磁珠运动的驱动力的大小。
  41. 根据权利要求25所述的凝血分析仪，其特征在于还包括显示器，所述显示器用于显示所述定标曲线和用于反映所述试样流动特性的参数。
  42. 根据权利要求21-41中任一项所述的凝血分析仪，其特征在于，所述驱动部件通过产生间歇式磁场的方式驱动所述磁珠在形成凝固状态的试样中做振荡运动，所述检测部件包括发射端和接收端，所述发射端用于产生连续性磁场，所述接收端用于接收所述连续性磁场经磁珠运动切割后的磁通量，根据所述磁通量输出用于反映所述运动部件的运动情况的电信号。
  43. 一种计算机可读存储介质，其特征在于，包括程序，所述程序能够被处理器执行以实现如权利要求1-20中任一项所述的方法。
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