WO2022022280A1 - 检测血液凝固特性的装置和其应用 - Google Patents

检测血液凝固特性的装置和其应用 Download PDF

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Publication number
WO2022022280A1
WO2022022280A1 PCT/CN2021/106174 CN2021106174W WO2022022280A1 WO 2022022280 A1 WO2022022280 A1 WO 2022022280A1 CN 2021106174 W CN2021106174 W CN 2021106174W WO 2022022280 A1 WO2022022280 A1 WO 2022022280A1
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Prior art keywords
blood
sample
coagulation
pretreatment
blood sample
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PCT/CN2021/106174
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English (en)
French (fr)
Inventor
高云飞
黄杜
刘丰
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深圳微点生物技术股份有限公司
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Priority to EP21849182.7A priority Critical patent/EP4184170A1/en
Priority to US18/018,437 priority patent/US20230341424A1/en
Publication of WO2022022280A1 publication Critical patent/WO2022022280A1/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
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/4905—Determining clotting time of blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/157—Devices characterised by integrated means for measuring characteristics of blood
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/745—Assays involving non-enzymic blood coagulation factors
    • G01N2333/7454—Tissue factor (tissue thromboplastin, Factor III)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/745—Assays involving non-enzymic blood coagulation factors
    • G01N2333/75—Fibrin; Fibrinogen
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/948—Hydrolases (3) acting on peptide bonds (3.4)
    • G01N2333/974—Thrombin
    • 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 present invention relates to medical devices and methods for testing blood coagulation properties.
  • blood samples may be anticoagulated with artificially added anticoagulants.
  • a blood sample eg, earlobe or fingertip peripheral blood, venous blood
  • Anticoagulation treatment is performed on blood, for example, anticoagulation (blood) agents such as sodium citrate are artificially added. Therefore, blood samples may be anticoagulated with artificially added anticoagulants.
  • Blood coagulation screening tests are required in clinical testing and routine screening, including prothrombin time (PT, Prothrombin Time), activated partial thromboplastin time (APTT, Activated Partial Thromboplastin Time), activated coagulation time (ACT, Detection of Activated Clotting Time), fibrinogen content (FIB, fibrinogen content) and thrombin time (TT, Thrombin Time).
  • PT prothrombin time
  • APTT activated partial thromboplastin time
  • ACT activated coagulation time
  • ACT Detection of Activated Clotting Time
  • fibrinogen content FIB, fibrinogen content
  • TT Thrombin Time
  • the existing test systems and instruments for prothrombin time/activated partial thromboplastin time/fibrinogen/thrombin time have certain shortcomings. Because the commonly used test samples in the hospital laboratory are anticoagulant, such as sodium citrate anticoagulation, the anticoagulant contained in the sample prevents the occurrence of the coagulation process of the sample, so that the anticoagulation cannot be directly tested on the existing instrument.
  • anticoagulant such as sodium citrate anticoagulation
  • the present invention provides a device for detecting blood coagulation characteristics of a blood sample, comprising:
  • a blood sample receiving and preprocessing unit which includes a blood preprocessing part, a sample addition hole and a delivery channel connected with the reaction unit;
  • the reaction unit in which the blood undergoes the coagulation process is the reaction unit in which the blood undergoes the coagulation process.
  • the blood enters the sample adding hole after passing through the blood preprocessing part of the blood sample receiving and preprocessing unit, and then is transported to the reaction unit through the delivery channel connected with the reaction unit, where the blood undergoes a coagulation process.
  • the device for detecting blood coagulation characteristics of the blood sample further comprises:
  • a blood coagulation characteristic analysis and calculation unit which can obtain a measurement result related to the blood coagulation characteristic according to the signal displayed by the blood in the reaction unit during the coagulation process;
  • the blood sample receiving and preprocessing unit and the reaction unit of the above-mentioned device for detecting blood coagulation properties of a blood sample exist in a form independent of other parts of the device, such as an insertable instrument (for example, a device comprising the blood sample)
  • a test box eg in the form of a chip of the coagulation characteristic analysis calculation unit and/or the instrument of the result presentation unit.
  • the blood sample receiving and preprocessing unit and the reaction unit of the above-mentioned apparatus for detecting blood coagulation characteristics of a blood sample and other parts of the apparatus is in the form of an all-in-one machine.
  • the blood pretreatment element in the blood sample receiving and pretreatment unit is used to remove or counteract the anticoagulant effect of the (especially artificially added) anticoagulant present in the blood sample.
  • pretreatment of blood samples refers to removing or counteracting the anticoagulant effect of anticoagulants present in blood samples (especially artificially added), and does not affect the inherent coagulation properties of the blood to be tested.
  • the reaction unit includes a module for applying a voltage difference across the blood sample and recording the electrical signal.
  • the reaction unit includes a power source, a plurality of electrodes in contact with blood contained in the reaction unit, and an A/D converter.
  • the blood coagulation characteristic analysis and calculation unit can detect the electrical signal passing through the blood sample during the measurement duration, and use this as the basis for calculating the prothrombin time (PT) of the sample, the international normalized ratio ( INR), activated partial thromboplastin time (APTT), fibrinogen (FIB) and thrombin time (TT).
  • the blood coagulation characteristic analysis and calculation unit includes a processor, which may be any one of a control logic circuit, a central processing unit, a microprocessor or other suitable types of processors.
  • the blood pretreatment element can remove or counteract the anticoagulant effect of sodium citrate. Thereby, the blood pretreatment member can restore the blood coagulation properties of the sodium citrate-containing blood sample.
  • the blood pretreatment element is prepared by using a filter material.
  • the filter material has a sheet-like porous body with many fine continuous pores communicating from one surface to the other surface.
  • the blood pretreatment member is a filter material member through which blood can pass.
  • the pore size of the filter material allows free passage of particulate matter such as cells and follicles in the blood.
  • the filter material does not produce or substantially does not produce cells, proteins or nucleic acids, various small molecules or ions in the blood. physical adsorption.
  • the material is biologically inert and does not react or inhibit substances such as cells, proteins or nucleic acids in the blood.
  • the filter material typically contains a solid deanticoagulant.
  • the material of the blood pretreatment member is a polymer material, such as polyethersulfone (PES), polyacrylonitrile (PAN), polyvinylidene fluoride (PVDF), polystyrene (PS) ) or polyvinyl chloride (PVC), or fiberglass.
  • the material of the blood pretreatment member is a hydrophilic material.
  • the blood pretreatment member contains a soluble calcium salt, such as calcium chloride.
  • Soluble calcium salts useful in the present invention include calcium chloride, calcium gluconate, calcium dihydrogen phosphate, calcium nitrate, calcium bicarbonate, calcium hydrogen sulfate, and the like.
  • the soluble calcium salt is present in the blood pretreatment element in solid form. The soluble calcium salt in the blood pretreatment part dissolves in the blood when the blood passes through, providing free calcium ions, which can be used to supplement the anticoagulation process due to the formation of a soluble complex that is difficult to dissociate with the citrate of sodium citrate. And reduce or even lack of calcium ions, thereby removing or counteracting the anticoagulant effect of sodium citrate.
  • the blood pretreatment member is prepared by contacting a polymeric material with a solution of a soluble calcium salt.
  • the blood pretreatment element is a filter block disposed above the sample addition hole or in the sample addition hole.
  • the filter block generally has the same cross-section as the sample addition hole, whereby it can be positioned above the sample addition hole or within the sample addition hole.
  • the filter block is configured such that the time and space for the blood sample to pass through the filter block allow the anticoagulant to be removed from the blood sample to sufficiently contact and react with the de-anticoagulant contained within the filter block.
  • the blood pretreatment member is a filter membrane covering the sample addition hole.
  • One end of the filter membrane covers the sample injection hole, and the other end of the filter membrane is provided with an injection port. After the blood is added from the injection port, it moves laterally to the injection hole through the filter membrane.
  • the filter membrane is set so that the time and space for the blood sample to move laterally to the sample addition hole after entering the filter membrane from the injection port allows the anticoagulant to be removed in the blood sample to fully contact and react with the de-anticoagulant contained in the filter membrane.
  • the apparatus further includes a processor. It may be any of a control logic circuit, a central processing unit, a microprocessor or other suitable type of processor.
  • the apparatus further includes a computer-readable medium.
  • Information or calculation methods related to the blood coagulation properties may be stored in the computer readable medium.
  • the device further comprises a display that presents information related to the blood coagulation properties.
  • the present invention also provides a method of detecting the blood coagulation properties of a blood sample using the apparatus described above.
  • the device includes:
  • a blood sample receiving and preprocessing unit which includes a blood preprocessing part, a sample addition hole and a delivery channel connected with the reaction unit;
  • the reaction unit in which the blood undergoes the coagulation process is the reaction unit in which the blood undergoes the coagulation process.
  • the device used in the method further includes:
  • a blood coagulation characteristic analysis and calculation unit which can obtain a measurement result related to the blood coagulation characteristic according to the signal displayed by the blood in the reaction unit during the coagulation process;
  • the blood pretreatment member in the blood sample receiving and pretreatment unit is used to remove or counteract the anticoagulant effect of artificially added anticoagulants present in the blood sample.
  • the blood sample is pretreated before being passed to the reaction unit to cause the blood to undergo a coagulation process.
  • pretreatment of the blood sample refers to removing or counteracting the anticoagulant effect of the artificially added anticoagulant in the blood sample, and does not affect the inherent coagulation properties of the blood to be tested.
  • the blood pretreatment member can remove or counteract the anticoagulant effect of sodium citrate, that is, the blood pretreatment member can restore the blood coagulation properties of a blood sample containing sodium citrate.
  • the blood pretreatment element is prepared by using a filter material.
  • the filter material typically contains a solid deanticoagulant.
  • the blood pretreatment element is a filter block disposed above the sample addition hole or in the sample addition hole.
  • the filter block generally has the same cross-section as the sample addition hole, whereby it can be positioned above the sample addition hole or within the sample addition hole.
  • the filter block is configured such that the time and space for the blood sample to pass through the filter block allow the anticoagulant to be removed from the blood sample to sufficiently contact and react with the de-anticoagulant.
  • the blood pretreatment member is a filter membrane covering the sample addition hole.
  • One end of the filter membrane covers the sample injection hole, and the other end of the filter membrane is provided with an injection port. After the blood is added from the injection port, it moves laterally through the filter membrane to the injection hole.
  • the filter membrane is configured such that the time and space for the blood sample to move laterally from the injection port through the filter membrane to the injection hole allows the anticoagulant to be removed in the blood sample to sufficiently contact and react with the de-anticoagulant.
  • the method is used to detect at least one of the following blood coagulation properties:
  • TT Thrombin time
  • APTT Activated partial thromboplastin time
  • Fig. 1 is a schematic structural diagram of an exemplary apparatus 301 for detecting blood coagulation properties of the present invention.
  • FIG. 2 is a schematic structural diagram of an exemplary test cartridge 202 of the device of the present invention.
  • FIG. 2A is an embodiment of the test cartridge provided by the present invention, wherein the blood pretreatment element is a filter column disposed above or in the sample addition hole.
  • Fig. 2B is another embodiment of the test box provided by the present invention, wherein the blood pretreatment member is a filter membrane disposed above the sample addition hole.
  • FIG. 3 is a schematic diagram showing the structure of the test box used in the device in the comparative test.
  • 3A and FIG. 3B are test boxes corresponding to the designs of FIG. 2A and FIG. 2B respectively.
  • Figure 3C is a test cartridge used in a prior art device without a blood pretreatment unit.
  • the present invention provides a device for detecting blood coagulation properties of a blood sample.
  • FIG. 1 is a schematic structural diagram of an exemplary apparatus for detecting blood coagulation properties of the present invention.
  • the apparatus 301 for detecting blood coagulation characteristics includes a blood sample receiving and preprocessing unit 201 , a reaction unit 204 , a blood coagulation characteristic analysis and calculation unit 316 and a result presentation unit 320 .
  • the blood sample receiving and preprocessing unit 201 includes a blood preprocessing part 203 , a sample injection hole and a delivery channel connected with the reaction unit.
  • the blood sample receiving and preprocessing unit is used to preprocess the original blood sample, and then transmit the processed blood sample to the reaction unit 204 .
  • the blood sample receiving and preprocessing unit of the device provided by the present invention includes a blood preprocessing part, a sample adding port and a delivery channel connected with the reaction unit.
  • blood samples for testing blood coagulation properties may be anticoagulated with artificially added anticoagulants.
  • the pretreatment of blood samples refers to removing or counteracting the anticoagulant effect of artificially added anticoagulants, and does not affect the inherent coagulation properties of the blood to be tested.
  • the device provided by the present invention is used to detect the coagulation properties of blood of a subject.
  • Coagulation of blood refers to the process by which blood forms a blood clot, which generally consists of three stages: during the first stage, blood vessel wall damage or trauma triggers the attachment and activation of platelets; during the second stage, activated platelets provide Facets of aggregation and activation of coagulation factors and complexes; in the third stage, coagulation factors interact to generate thrombin, which converts fibrinogen to fibrin.
  • Fibrin chains bind aggregated platelets in order to help reinforce platelet-fibrin hemostats.
  • the second and third stages of blood coagulation may be referred to as the coagulation cascade for the interaction between each of the coagulation factors. Since thrombin is formed during these stages, these are the main stages of coagulation. Thrombin is a coagulation effector enzyme with biologically important functions such as activation of platelets, conversion of fibrinogen to the fibrin network, and feedback amplification of coagulation.
  • the coagulation cascade reaction can be summarized into three pathways: intrinsic pathway, extrinsic pathway and common pathway. Intrinsic pathways can be triggered by surface contacts, while extrinsic pathways can be triggered by tissue/cell defects. Both of these can lead to the formation of thrombin. In the common pathway, thrombin converts fibrinogen to fibrin, which can then form a cross-linked fibrin network.
  • the coagulation properties of blood include, but are not limited to, Prothrombin Time (PT, Prothrombin Time), Activated Partial Thromboplastin Time (APTT, Activated Partial Thromboplastin Time), Activated Clotting Time (ACT, Activated Clotting Time), fibrinogen content (FIB, fibrinogen content) and thrombin time (TT, Thrombin Time).
  • PT Prothrombin Time
  • APTT Activated Partial Thromboplastin Time
  • ACT Activated Partial Thromboplastin Time
  • ACT Activated Clotting Time
  • fibrinogen content FIB, fibrinogen content
  • TT Thrombin Time
  • the reaction unit 204 is used to make the blood to be tested perform biochemical or physiological reactions in order to obtain information related to the blood coagulation characteristics.
  • blood coagulation can be determined by a method as disclosed in Chinese Patent CN103543191B, in which a voltage difference is applied to the blood sample and by measuring the time-dependent current response during blood coagulation due to coagulation reactions in the blood sample Blood coagulation properties such as zymogen time (PT), activated partial thromboplastin time (APTT), activated clotting time (ACT), fibrinogen content (FIB) and thrombin time (TT).
  • PT zymogen time
  • APTT activated partial thromboplastin time
  • ACT activated clotting time
  • FIB fibrinogen content
  • TT thrombin time
  • all or part of the components of the blood sample receiving and preprocessing unit and the reaction unit of the device for detecting blood coagulation characteristics of the present invention are set as the fixed structure of the device 301 .
  • all or part of the components of the blood sample receiving and preprocessing unit and the reaction unit of the device for detecting blood coagulation characteristics of the present invention are provided as part of a test box that is detachably connected to the main body of the device 301 .
  • the test box is a disposable test box.
  • parts of the blood sample receiving and preprocessing unit and the reaction unit form a test cartridge 202 that is insertable into a test cartridge receiving slot 304 of the body of the device 301 .
  • FIG. 2 is a schematic structural diagram of an exemplary test box 202 of the device of the present invention.
  • the test cartridge 202 is inserted into the device for detecting blood coagulation properties in a horizontal orientation; that is, FIG. 2 is a top plan view of the test cartridge.
  • FIG. 2A is an embodiment of the test box provided by the present invention, wherein the blood pretreatment element is a filter block 2031 disposed above or in the sample addition hole.
  • FIG. 2B is another embodiment of the test cartridge provided by the present invention, wherein the blood pretreatment element is a filter membrane 2032 disposed above the sample addition hole.
  • the blood sample receiving and preprocessing unit 201 includes a blood preprocessing element 203 .
  • the pretreatment of the blood sample refers to removing or counteracting the anticoagulant effect of the artificially added anticoagulant in the blood sample, and does not affect the inherent coagulation properties of the blood to be tested. Generally, this can be accomplished by contacting the blood sample with a de-anticoagulant reacted with an artificially added anticoagulant to be removed.
  • the blood sample to be processed is a blood sample containing sodium citrate
  • the blood pretreatment part 203 is used to remove or counteract the anticoagulation effect of sodium citrate.
  • the blood pretreatment element is prepared by using a filter material.
  • the filter material has a sheet-like porous body with many fine continuous pores communicating from one surface to the other surface. Examples of such a porous body include films or blocks made of polymer materials (for example, PES, PAN, PVDF, PS, and PVC), or glass fibers.
  • the pore size of the filter material allows free passage of particulate matter such as cells and follicles in the blood. By controlling the pore size of the filter material and the liquid passing distance and time, when the blood passes through the filter material, the filter material does not produce or substantially does not produce cells, proteins or nucleic acids, various small molecules or ions in the blood. physical adsorption.
  • the material is biologically inert and does not react or inhibit substances such as cells, proteins or nucleic acids in the blood.
  • the filter material generally contains solid deanticoagulant.
  • the blood pretreatment element comprises a solid soluble calcium salt.
  • Soluble calcium salts useful in the present invention include calcium chloride, calcium gluconate, calcium dihydrogen phosphate, calcium nitrate, calcium bicarbonate, calcium hydrogen sulfate, and the like.
  • the blood pretreatment member contains calcium chloride. Soluble calcium salts can release free calcium ions in the blood, which form insoluble soluble complexes with the citrate group of sodium citrate, reducing the sodium citrate in anticoagulation, thereby removing or offsetting Anticoagulant effect of sodium citrate.
  • Soluble calcium salts can bind to the filter material forming the blood pretreatment element by adsorption. For example, by soaking the filter material in a solution containing the soluble calcium salt, drying the filter material containing the soluble calcium salt can be obtained, and then the filter material can be processed into a desired shape.
  • the blood pretreatment member is a filter block disposed above the sample addition hole or in the sample addition hole, and has the same cross-section as the sample addition hole.
  • the test box 202 includes a sample injection hole 212 and a delivery channel 210 connected with the reaction unit.
  • the test box 202 is inserted into the device for detecting blood coagulation characteristics in a horizontal direction, that is, the filter column is perpendicular to the horizontal plane in operation.
  • a filter block 2031 is arranged above the sample introduction hole 212, and the top of the filter block is the injection port.
  • the blood enters the filter block 2031, passes through the filter column under the action of gravity and capillary action, and enters the injection hole 212, and flows to the reaction zone through the microfluidic delivery channel 210.
  • the filter block generally has the same or similar cross-section as the sample addition hole, and can be arranged above the sample addition hole or in the sample addition hole.
  • the filter block is configured such that the time and space for the blood sample to pass through the filter block allow the anticoagulant to be removed from the blood sample to sufficiently contact and react with the de-anticoagulant.
  • the blood pretreatment member is a filter membrane disposed above the sample introduction hole.
  • the test box 202 includes a sample addition hole 212 and a transport channel 210 connected to the reaction unit.
  • a filter membrane 2032 is arranged above the sample addition hole 212, and one end of the filter membrane covers the sample addition hole 212.
  • An injection port 205 is provided at the other end of the filter membrane. After the blood is added from the injection port, it moves laterally to the injection hole 212 through the filter membrane.
  • the filter membrane is configured such that the time and space for the blood sample to move laterally from the injection port through the filter membrane to the injection hole allows the anticoagulant to be removed in the blood sample to sufficiently contact and react with the de-anticoagulant.
  • the test cartridge 202 also includes a reaction zone 204 encompassed by a dashed line 206 having one or more reagents 208 or other substances selected for one or more types of tests.
  • different tests eg, PT, APTT, ACT, FIB or TT
  • reagent 208 may be pre-applied (eg, printed, placed, etc.) and immobilized at reaction zone 204 .
  • the test cartridge 202 may also include a plurality of electrodes 214 to form an electrochemical cell.
  • the first electrode 216 may be connected to the first portion 218 of the reaction zone 204 and the second electrode 220 may be connected to the second portion 222 of the reaction zone 204 .
  • the third electrode 224 is also connected to the reaction zone 204 .
  • the electrochemical cell at reaction zone 204 consists of three electrodes, eg, a working electrode, a counter electrode, and a reference electrode.
  • the counter electrode and reference electrode may be combined to provide a two electrode configuration.
  • the blood sample 104 is located between a plurality of electrodes, such as the first electrode 216 and the second electrode 220, when the blood from the injection port enters the reaction zone 204. Additionally, in examples where reagents or other substances are used during testing of the blood sample, the blood sample 104 may interact with the reagents 208 or other substances in the reaction zone 204 . Furthermore, although only a single electrochemical cell is shown in this example, in other examples, multiple electrochemical cells may be included to provide multiple reaction zones 204 . For example, different reaction zones 204 may include different types of reagents 208 or substances suitable for different types of assays. These reaction zones can be connected to a single sample receiver 212 by channels.
  • the blood sample reacts with the reagent 208, which can trigger a series of biochemical reactions leading to coagulation.
  • the blood sample 104 is in contact with a plurality of electrodes 214 .
  • the electrodes 214 and the blood sample 104 located in the reaction zone 204 become galvanic parts of the complete circuit for testing the blood sample 104 .
  • the device may apply a voltage difference across electrodes 214 to detect electrical signals at the output terminals of the circuit for a certain period of time (ie, the measurement duration) in order to obtain a representation of a function of time (ie, a measurement function of time) multiple measurements.
  • the device 301 for detecting blood coagulation characteristics provided by the present invention also has a casing 303 (not shown in the figure).
  • the housing isolates the interior of the instrument from the atmosphere to prevent sample contamination and damage to parts.
  • the housing panel is usually made of metal material.
  • the housing may have an openable and closable sample window for sample introduction and removal.
  • the housing may have an external device interface for connecting with external devices, a display screen for displaying an operation interface, various control switches, keys or buttons, and the like.
  • the apparatus 301 also includes a test cartridge receiving slot 304 and a heater 306 .
  • the heater 306 can ensure that the blood sample 104 is maintained at a consistent temperature at the test time to ensure that the test is consistent across multiple samples.
  • the apparatus 301 may also include a plurality of electrical connections 308 for connecting the electrodes of the test cartridge 202 to the circuit 310 of the device 302 .
  • electrodes 214 may be connected to power source 312 and analog/digital converter 314 .
  • the power supply 312 may provide a voltage difference across the blood sample 104 in the reaction zone 214 of the test cartridge 202 during testing of the blood sample 104 .
  • A/D converter 314 may measure the resulting electrical signal, eg, at an output terminal. In some cases, the output terminals may correspond to one or more of the electrodes 214 .
  • Apparatus 301 may also include one or more processors 316, one or more computer-readable media 318, a display 320, a power adapter port 322, and one or more communication interfaces 324, such as external data ports or other suitable communication interfaces.
  • the processor 316 may be any of a control logic circuit, a central processing unit, a microprocessor, or other suitable type of processor. In some examples, each processor 316 may itself include one or more processors or processing cores.
  • computer readable medium 318 may be an example of a tangible non-transitory computer storage medium and may include any type of technology for storage of information, such as computer readable instructions, data structures, program modules or other Data, implemented volatile and non-volatile memory and/or removable and non-removable media.
  • Such computer readable medium 318 may include, but is not limited to, RAM, ROM, EEPROM, flash memory, or other computer readable medium technology, computer storage technology or may be used to store information and may be used by processor 316 directly or through another computing device any other medium that is accessed.
  • computer readable media 318 may include computer storage media capable of storing and maintaining instructions, modules or components executable by processor 316 .
  • Computer readable medium 318 may be used to store any number of functional components executable by processor 316 .
  • these functional components include instructions, code, or programs that are executable by processor 316 and, when executed, implement operational logic for performing the actions attributed to device 302 .
  • the functional components of the device 302 maintained in the computer readable medium 318 may include a test module 326 executable by the processor 316 to perform tests on the blood sample, such as applying a voltage difference across the blood sample and obtaining measurements of electrical signals.
  • the functional components may also include an analysis module 330, which may be executed by the processor 316 to perform some of the functions described herein, such as determining the time measurement function 114, one or more corresponding cumulative characteristics 116, and/or blood coagulation characteristics 118 .
  • the analysis module 330 may also determine blood coagulation characteristics based at least in part on the accumulated characteristics 116 and/or the measurements 112 or the measurement function 114 over time.
  • the computer readable medium 318 may store data such as the measurement results 112, the measurement function 114 of time, the cumulative characteristic 116, the blood coagulation characteristic 118, or information related thereto.
  • the computer readable medium 318 may also optionally include other functional components and data, such as a user interface module, a communication module, medical history, past blood clotting test results or other modules, applications, programs, drives, data, etc.
  • Measurements 112 obtained by device 301 for blood sample 104 may be stored in computer readable medium 318 and analyzed, eg, by execution of analysis module 330 by processor 316 .
  • the analysis module 330 may determine the magnitude of the cumulative characteristic 116 of the measurement function 114 .
  • the cumulative characteristic 116 may be derived or selected empirically prior to obtaining the measurements 112 or, in some cases, prior to manufacturing the device 302 .
  • a criterion for selecting a suitable cumulative characteristic 116 is generally to obtain a good correlation with the blood coagulation characteristic 118 so that the cumulative characteristic 116 can be used to determine the blood coagulation characteristic 118 .
  • the processing of the measurement function 114 , the accumulated characteristic 116 , and/or the blood coagulation characteristic 118 for determining the time may be performed by execution of the analysis module 330 on the device 301 by the processor 316 . In other examples, some or all of the processing may be performed by external computing device 328 .
  • device 302 may provide measurement results 112 to computing device 328, and computing device 328 may execute analysis module 330 on the processor of computing device 328 to determine measurement function 114 of time, apply cumulative characteristic 116 and/or determine blood Freezing properties 118 .
  • verification module 326 or other suitable application or communication module on device 302 may communicate with computing device 328 over connection 332 to provide measurement results 112 to computing device 328 .
  • computing device 328 may expose a programming interface or API (application programming interface) that device 302 may use to provide measurement results 112 .
  • device 302 may provide blood clotting properties 118 or information related to blood clotting properties to computing device 328 .
  • Communication interface 324 may support wired and/or wireless connections 332 to various networks, such as cellular networks, radio communications, Wi-Fi networks, short-range or near-field networks (eg, ), infrared signals, LAN, WAN, Internet, direct cable connection, etc.
  • the communication interface 324 may include a USB (Universal Serial Bus) port, an IEEE 802.3 port, or other wired connection.
  • communication interface 324 may allow apparatus 301 to access a wireless communication network or device.
  • the apparatus 301 also includes a display 320, which may be passive, emissive, or any other form of display.
  • display 320 may comprise any suitable type, such as a liquid crystal display, plasma display, light emitting diode display, organic light emitting diode display, and the like. Additionally, in some examples, display 320 may have a touch sensor associated therewith to enable touch input from a user. Furthermore, in other examples, apparatus 301 may not include a display.
  • Test items prothrombin time (PT), activated partial thromboplastin time (APTT), activated clotting time (ACT), fibrinogen content (FIB) and thrombin time (TT)
  • the manual of the electrochemical detector which can perform prothrombin time (PT)/activated partial thromboplastin time (APTT)/fibrinogen (FIB)/coagulation on human fresh non-anticoagulated venous whole blood or capillary whole blood In vitro quantitative assay of enzymatic time (TT).
  • the structure of the apparatus includes the device 301 described in Embodiment 1 (as shown in Figures 1 and 2) and all parts of the test box 202 in it except the blood sample preprocessing part 203, that is, including the blood sample receiving and preprocessing unit 201, the reaction unit 204, the blood coagulation characteristic analysis and calculation unit 316 and the result presentation unit 320, etc., but the blood sample preprocessing unit 203 is not provided.
  • the Q-1 type electrochemical detector adopts a single-use PT, APTT, FIB and TT quadruple detection card, and its top plan view is shown in FIG. Structures other than the membrane 2032 include the sample application hole 212, the delivery channel 210, the reaction zone 204, the electrode 214, and the like.
  • the quadruple detection card In use, insert the quadruple detection card into the Q-1 type In the detection card slot of the electrochemical detector (equivalent to the test box receiving slot 304 in FIG. 1 ), after the blood sample is added to the sample addition hole 212 , the blood sample enters the reaction zone 204 through the delivery channel 210 .
  • a constant voltage is output to the electrode 214.
  • the electrochemical detector monitors the process of blood coagulation and generates changes in the current signal.
  • the blood coagulation characteristic analysis calculator set in the instrument generates the coagulation curve of current and time changes according to the set program.
  • the curve changes and generates corresponding characteristics (height, area, etc.), and the coagulation characteristics of this curve are analyzed and the coagulation of the sample is calculated.
  • Proenzyme Time PT
  • International Normalized Ratio IMR
  • APTT Activated Partial Thromboplastin Time
  • FIB Fibrinogen
  • TT Thrombin Time
  • the The electrochemical detector Q-1 is improved by adding an additional blood pretreatment unit to obtain the device of the present invention.
  • Pretreatment unit for anticoagulation is added to obtain the device of the present invention.
  • FIG. 3B and FIG. 3C respectively show the schematic structural diagrams of the detection cards with two different designs of the device of the present invention.
  • a filter column 2031 is arranged above the sample addition hole 212 of the detection card.
  • the detection card is inserted horizontally Electrochemical detector, that is, the filter column is perpendicular to the horizontal plane during operation.
  • the anticoagulant containing sodium citrate is added dropwise to the top of the filter column, the blood enters the filter column, passes through the filter column under the capillary action and enters the sample injection hole, and flows to the reaction zone through the microfluidic transport channel.
  • a filter membrane 2032 is provided above the sample addition hole 212 of the detection card, one end of the filter membrane covers the sample addition hole, and the other end of the membrane is the sample introduction port 205 .
  • the anticoagulant containing sodium citrate is added dropwise to the injection port, and the blood is absorbed by the filter membrane and then moves laterally to the injection hole through the filter membrane, and flows to the reaction zone through the microfluidic delivery channel.
  • Calcium chloride (purity >96%, Sinopharm Chemical Reagent Co., Ltd., China) was dissolved in deionized water to prepare a 0.05 mol/L aqueous solution.
  • the above membrane materials were soaked in calcium chloride solution for 10 minutes respectively, and the soaked membrane materials were dried at 45°C for 8 hours for later use.
  • the blood samples were collected from the recruited volunteers, and the peripheral blood was collected by pricking the finger, and the blood samples of the same volunteer were respectively prepared as control samples and test samples (sodium citrate anticoagulation).
  • Control sample peripheral blood primary blood
  • Test samples (10) were tested with the apparatus and setup shown in Figure 3A. The results were all displayed as "No Coag", i.e. no blood sample coagulation was detected.
  • sample number INR APTT FIB TT 1 3.6% -1.5% -3.0% 2.7% 2 3.6% 3.8% -1.6% -1.2% 3 3.1% -1.9% -5.0% -0.7% 4 -9.1% -4.7% -1.2% 2.7% 5 -6.0% 6.0% 1.8% -2.9% 6 4.7% -2.2% -3.2% -6.8% 7 2.2% -2.8% -3.7% -1.5% 8 -4.3% -3.0% 6.2% 6.0% 9 2.5% 2.3% -7.3% -0.4% 10 -2.7% 1.2% 2.7% -2.7%

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Abstract

一种确定血液凝固特性的装置301，包括：血样接收和预处理单元201，其包括血液预处理件203、加样孔212和与反应单元204相连接的输送通道210，血液预处理件203用于去除或抵消在血样中存在的人为加入的抗凝剂的抗凝血作用；反应单元204，血液在其中产生凝血过程；血液凝固特性分析计算单元316，其可在测量持续时间内检测经过血样的电信号，以获得表示时间的测量函数的多个测量结果；以及，结果呈现单元320。还提供了采用以上装置检测血样的血液凝固特性的方法。

Description

检测血液凝固特性的装置和其应用
本申请要求2020年7月31日提交的、申请号为202010759776.7、发明名称为“检测血液凝固特性的装置和其应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及用于检验血液凝固特性的医学设备和方法。
背景技术
在医学检测和研究领域，在对血液进行检测的过程中，在从受试者获得血液样本(例如耳垂或指尖末梢血、静脉血)之后，为了避免血样在储存或转移期间发生凝固，通常对血液进行抗凝处理，例如人为加入枸橼酸钠等抗凝(血)剂。因此，血样可能经过抗凝处理，其具有人为加入的抗凝剂。
在临床检测和常规筛查中需要进行血液凝固筛查检验，包括对凝血酶原时间(PT，Prothrombin Time)、活化部分凝血活酶时间(APTT，Activated Partial Thromboplastin Time)、活化凝血时间(ACT，Activated Clotting Time)、纤维蛋白原含量(FIB，fibrinogen content)和凝血酶时间(TT，Thrombin Time)的检测。现在本领域已提供各种检测仪器，由临床实验室、健康从业者等检验特定条件下的血液凝固特性的类型。
然而，现在已有的检测凝血酶原时间/活化部分凝血活酶时间/纤维蛋白原/凝血酶时间的测试系统和仪器存在一定的缺陷。由于医院检验科常用的测试样本为抗凝血，例如枸橼酸钠抗凝血，样本中含有抗凝剂阻止样本凝血过程的发生，导致抗凝血无法在现有仪器上直接测试。
本领域还需要能够直接使用抗凝全血，例如枸橼酸钠抗凝全血进行快速测试凝血酶原时间、活化部分凝血活酶时间、纤维蛋白原、凝血酶时间四种凝血指标的仪器和方法。
发明内容
本发明提供了一种检测血样的血液凝固特性的装置，其包括：
血样接收和预处理单元，其包括血液预处理件、加样孔和与反应单元相连接的输送通道；
和
反应单元，血液在其中产生凝血过程。
其中，血液在通过所述血样接收和预处理单元的血液预处理件后进入加样孔，然后经过与反应单元相连接的输送通道被输送到所述反应单元，血液在其中产生凝血过程。
在本发明的其中一个方面，所述检测血样的血液凝固特性的装置还包括：
血液凝固特性分析计算单元，其可根据反应单元中血液在凝血过程显示的信号获得与血液凝固特性相关的测量结果；
和/或
结果呈现单元。
在本发明的其中一个方面，上述检测血样的血液凝固特性的装置的血样接收和预处理单元以及反应单元以独立于装置的其它部分的形式存在，例如为可插入仪器(例如为包括所述血液凝固特性分析计算单元和/或所述结果呈现单元的仪器)的检验盒(如芯片形式)。
在本发明的其中一个方面，上述检测血样的血液凝固特性的装置的血样接收和预处理单元以及反应单元与所述装置的其它部分(例如所述血液凝固特性分析计算单元和/或所述结果呈现单元的仪器)为一体机的形式。
在本发明的其中一个方面，所述血样接收和预处理单元中的血液预处理件用于去除或抵消在血样中存在的(特别是人为加入的)抗凝剂的抗凝血作用。在本发明中，对血样的预处理是指去除或抵消在血样中存在的(特别是人为加入的)抗凝剂的抗凝血作用，并且不影响待测血液本身固有的凝固特性。
在本发明的其中一个方面，所述反应单元包括在血样上施加电压差和记录电信号的模块。例如，所述反应单元包括电源、多个与容纳在反 应单元中的血液接触的电极和A/D转换器。
在本发明的其中一个方面，所述血液凝固特性分析计算单元可在测量持续时间内检测经过所述血样的电信号，以此为根据计算样本的凝血酶原时间(PT)、国际标准化比值(INR)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)和凝血酶时间(TT)。在本发明的其中一个方面，所述血液凝固特性分析计算单元包含处理器，其可以是控制逻辑电路、中央处理单元、微处理器或其他合适类型的处理器中的任一个。
在本发明的其中一个方面，所述血液预处理件可去除或抵消枸橼酸钠的抗凝作用。由此，所述血液预处理件可恢复含有枸橼酸钠的血液样品的血液凝固特性。
在本发明的其中一种实施方式中，所述血液预处理件为采用过滤材料制备而得。过滤材料具有从一个面连通至另一个面的很多微细的连续孔的片状多孔质体。在本发明中，所述血液预处理件为可供血液通过的过滤材料件。在本发明的其中一种实施方式中，所述过滤材料的孔径可使得血液中的细胞、滤泡等颗粒物质自由通过。通过控制所述过滤材料的孔径和液体通过距离和时间，可使得血液通过所述过滤材料时，过滤材料对血液中的细胞、蛋白或核酸、各种小分子或离子不产生或基本上不产生物理吸附。优选的，所述材料为生物惰性的，不对血液中的细胞、蛋白或核酸等物质发生反应或产生抑制。在本发明的实施方式中，所述过滤材料通常含有固体的去抗凝物。
在本发明的其中一个方面，所述血液预处理件的材料为聚合物材料，例如为聚醚砜(PES)、聚丙烯腈(PAN)、聚偏氟乙烯(PVDF)、聚苯乙烯(PS)或聚氯乙烯(PVC)，或为玻璃纤维。在本发明的其中又一个方面，所述血液预处理件的材料为亲水性材料。
在本发明的其中一个方面，所述血液预处理件含有可溶性钙盐，例如氯化钙。可用于本发明的可溶性钙盐包括氯化钙，葡萄糖酸钙，磷酸二氢钙，硝酸钙，碳酸氢钙，硫酸氢钙等。在本发明的其中一个方面，所述可溶性钙盐以固体形式存在在所述血液预处理件内。血液预处理件中的可溶性钙盐在血液经过时溶于血液，提供游离的钙离子，其可用于补充抗凝血中因与枸橼酸钠的枸橼酸根形成难解离的可溶性络合物而减少甚至缺失的钙离子，由此去除或抵消枸橼酸钠的抗凝作用。
在本发明的其中一个方面，所述血液预处理件通过将聚合物材料接触可溶性钙盐的溶液而制备。
在本发明的其中一个方面，所述血液预处理件为设置在加样孔上方或加样孔内的过滤块。所述过滤块通常具有与加样孔相同的横截面，由此，其可设置在加样孔上方，或是设置在加样孔内。所述过滤块设置为使得血样通过所述过滤块的时间和空间允许血样中待去除的抗凝剂可以充分与过滤块内含有的去抗凝物接触和反应。
在本发明的其中另一个方面，所述血液预处理件为覆盖在加样孔上方的过滤膜。过滤膜的一端覆盖加样孔，在过滤膜的另一端设置进样口。血液从所述进样口加入后，经过滤膜横向移动到加样孔。所述过滤膜设置为使得血样从进样口进入过滤膜后横向移动到加样孔的时间和空间允许血样中待去除的抗凝剂可以充分与过滤膜内含有的去抗凝物接触和反应。
在本发明的其中一个方面，所述装置还包括处理器。其可以是控制逻辑电路、中央处理单元、微处理器或其他合适类型的处理器中的任一个。
在本发明的其中一个方面，所述装置还包括计算机可读介质。与所述血液凝固特性相关的信息或计算方法可存储在所述计算机可读介质中。
在本发明的其中一个方面，所述装置还包括显示器，其呈现与所述血液凝固特性相关的信息。
本发明还提供了一种检测血样的血液凝固特性的方法，其采用前面描述的装置。在本发明中，所述装置包括：
血样接收和预处理单元，其包括血液预处理件、加样孔和与反应单元相连接的输送通道；
反应单元，血液在其中产生凝血过程。
在本发明的又一个方面，所述方法采用的装置还包括：
血液凝固特性分析计算单元，其可根据反应单元中血液在凝血过程显示的信号获得与血液凝固特性相关的测量结果；
结果呈现单元。
在本发明的其中一个方面，所述血样接收和预处理单元中的血液预 处理件用于去除或抵消在血样中存在的人为加入的抗凝剂的抗凝血作用。在本发明提供的方法中，在将血样传递到反应单元使得血液产生凝血过程之前对血样进行预处理。在本发明中，对血样进行预处理是指去除或抵消在血样中存在的人为加入的抗凝剂的抗凝血作用，并且不影响待测血液本身固有的凝固特性。
在本发明的其中一个方面，所述血液预处理件可去除或抵消枸橼酸钠的抗凝作用，即所述血液预处理件可恢复含有枸橼酸钠的血液样品的血液凝固特性。
在本发明的其中一种实施方式中，所述血液预处理件为采用过滤材料制备而得。在本发明的实施方式中，所述过滤材料通常含有固体的去抗凝物。
在本发明的其中一个方面，所述血液预处理件为设置在加样孔上方或加样孔内的过滤块。所述过滤块通常具有与加样孔相同的横截面，由此，其可设置在加样孔上方，或是设置在加样孔内。所述过滤块设置为使得血样通过所述过滤块的时间和空间允许血样中待去除的抗凝剂可以充分与去抗凝物接触和反应。
在本发明的其中另一个方面，所述血液预处理件为覆盖在加样孔上方的过滤膜。过滤膜的一端覆盖加样孔，在过滤膜的另一端设置进样口。血液从进样口加入后，经过滤膜横向移动到加样孔。所述过滤膜设置为使得血样从进样口通过所述过滤膜横向移动到加样孔的时间和空间允许血样中待去除的抗凝剂可以充分与去抗凝物接触和反应。
在本发明的其中又一个方面，所述方法用于检测下列血液凝固特性中的至少一项：
纤维蛋白原含量(FIB)；
凝血酶时间(TT)；
凝血酶原时间(PT)；
活化部分凝血活酶时间(APTT)。
附图说明
具体实施方式参照附图来阐述。
图1是本发明的示例性的检测血液凝固特性的装置301的结构示意 图。
图2是示例性的本发明的装置的检验盒202的结构示意图。图2A为本发明提供的检验盒的一种实施方式，其中所述血液预处理件为设置在加样孔上方或加样孔内的过滤柱。图2B为本发明提供的检验盒的另一种实施方式，其中所述血液预处理件为设置在加样孔上方的过滤膜。
图3示意比较试验中的装置采用的检验盒的结构示意图。其中图3A和图3B分别是对应图2A和图2B的设计的检验盒。图3C为现有技术装置采用的检验盒，不具有血液预处理单元。
具体实施方式
出于讨论的目的，一些示例实施方式在用于检验血液凝固属性的检验设备和系统的环境中被描述。然而，对于按照本公开的领域的技术人员来说显而易见，这里的实施方式不限于所提供的特定示例，而是可以扩展至其他类型的设备、装置和系统以及其他类型的检验。
本发明提供了一种用于检测血样的血液凝固特性的装置。
图1为本发明的示例性的检测血液凝固特性的装置的结构示意图。
如图1所示，检测血液凝固特性的装置301包括血样接收和预处理单元201，反应单元204，血液凝固特性分析计算单元316和结果呈现单元320。
在图1所示的示例性检测血液凝固特性的装置中，血样接收和预处理单元201包括血液预处理件203，加样孔和与反应单元相连接的输送通道。血样接收和预处理单元用于对原始血样进行预处理，然后将处理后的血样传输到反应单元204。本发明提供的装置的血样接收和预处理单元包括血液预处理件、加样口和与反应单元相连接的输送通道。
在医学检测和研究领域，在对血液进行检测的过程中，在从受试者获得血液样本(例如耳垂或指尖末梢血、静脉血)之后，为了避免血样在储存或转移期间发生凝固，通常对血液进行抗凝处理，例如人为加入枸橼酸钠等抗凝(血)剂。因此，用于检测血液凝固特性的血样可能经过抗凝处理，其具有人为加入的抗凝剂。在本发明中，对血样的预处理是指去除或抵消人为加入的抗凝剂的抗凝血作用，并且不影响待测血液本身固有的凝固特性。
本发明提供的装置用于检测受试者的血液的凝固特性。血液的凝固是指血液形成血凝块的过程，其通常包括三个阶段：在第一阶段期间，血管壁损伤或创伤触发血小板的附着和活化；在第二阶段中，活化的血小板提供用于凝固因子和复合物的聚集和活化的面；在第三阶段中，凝固因子互相作用以产生凝血酶，这将纤维蛋白原(fibrinogen)转换为纤维蛋白(fibrin)。纤维蛋白链绑定聚合的血小板，以便有助于加固血小板-纤维蛋白止血栓。血液凝固的第二和第三阶段可以被称为用于凝固因子中的每一个之间的相互作用的凝血瀑布反应(coagulation cascade)。由于在这些阶段中形成凝血酶，这些是凝血的主要阶段。凝血酶是凝血效应酶，具有生物学上重要的功能，例如，血小板的活化、纤维蛋白原至纤维蛋白网络的转换以及凝固的反馈放大。凝血瀑布反应可以被概括为三个途径：内源性路径、外源性路径和共同路径。内源性路径可以由表面接触触发，而外源性路径可以由组织/细胞缺陷触发。这两个均可以导致凝血酶的形成。在共同路径中，凝血酶将纤维蛋白原转换为纤维蛋白，然后，纤维蛋白可以形成交联的纤维蛋白网状物。
血液的凝固特性包括而不限于凝血酶原时间(PT，Prothrombin Time)、活化部分凝血活酶时间(APTT，Activated Partial Thromboplastin Time)、活化凝血时间(ACT，Activated Clotting Time)、纤维蛋白原含量(FIB，fibrinogen content)和凝血酶时间(TT，Thrombin Time)。
在图1所示的示例性检测血液凝固特性的装置中，反应单元204用于为获得与血液凝固特性相关的信息而使得待测的血液进行生化或生理反应。例如，通过如中国专利CN103543191B中公开的方法，其中对血液样品给予电压差，并通过测量对血液凝固期间的与时间相关的由于血样中的凝固反应而引起的电流响应，可用于确定血液的凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、活化凝血时间(ACT)、纤维蛋白原含量(FIB)和凝血酶时间(TT)等血液凝固特性。所述方法的其中一个原理是基于：凝固期间，存在针对电导率而逐步增强的内摩擦力，从而导致累计导电能量损耗。
在本发明的一种实施方式中，本发明的检测血液凝固特性的装置的所述血样接收和预处理单元和反应单元的全部或部分器件设置为装置301的固定结构。
在本发明的又一种实施方式中，本发明的检测血液凝固特性的装置的血样接收和预处理单元和反应单元的全部或部分器件设置为可装卸地与装置301的主体连接的检验盒的形式。优选的，所述检验盒为一次性使用的检验盒。由此，接收和容纳血样的器件可实现一次性使用，降低样品污染和检测结果失真的风险。
在图1所示的示例性检测血液凝固特性的装置中，血样接收和预处理单元和反应单元的部分结构形成检验盒202，其可插入到装置301的主体的检验盒接收槽304。
图2为示例性的本发明的装置的检验盒202的结构示意图。在工作中，检验盒202以水平方向插入检测血液凝固特性的装置；即图2为检验盒的俯视平面图。图2A为本发明提供的检验盒的一种实施方式，其中所述血液预处理件为设置在加样孔上方或加样孔内的过滤块2031。图2B为本发明提供的检验盒的另一种实施方式，其中所述血液预处理件为设置在加样孔上方的过滤膜2032。
如图1和图2所示，血样接收和预处理单元201包括血液预处理件203。在本发明中，对血样的预处理是指去除或抵消在血样中存在的人为加入的抗凝剂的抗凝血作用，并且不影响待测血液本身固有的凝固特性。一般而言，可以通过将血样与待去除的人为加入的抗凝剂反应的去抗凝物接触而实现。在本发明的其中一个示例性实施方式中，待处理的血样为含有枸橼酸钠的血样，所述血液预处理件203用于去除或抵消枸橼酸钠的抗凝作用。
在本发明的其中一种实施方式中，血液预处理件为采用过滤材料制备而得。过滤材料具有从一个面连通至另一个面的很多微细的连续孔的片状多孔质体。作为这种多孔质体，例如可以列举聚合物材料(例如为PES、PAN、PVDF、PS、PVC)制的膜或块等，或为玻璃纤维。在本发明的其中一种实施方式中，所述过滤材料的孔径可使得血液中的细胞、滤泡等颗粒物质自由通过。通过控制所述过滤材料的孔径和液体通过距离和时间，可使得血液通过所述过滤材料时，过滤材料对血液中的细胞、蛋白或核酸、各种小分子或离子不产生或基本上不产生物理吸附。优选的，所述材料为生物惰性的，不对血液中的细胞、蛋白或核酸等物质发生反应或产生抑制。在本发明的实施方式中，所述过滤材料通常含有固 体的去抗凝物。
在本发明的其中一种实施方式中，所述血液预处理件包含固体的可溶性钙盐。可用于本发明的可溶性钙盐包括氯化钙，葡萄糖酸钙，磷酸二氢钙，硝酸钙，碳酸氢钙，硫酸氢钙等。在本发明的其中一种实施方式中，所述血液预处理件含有氯化钙。可溶性钙盐在血液中可释放游离的钙离子，其与枸橼酸钠的枸橼酸根形成难解离的可溶性络合物，使抗凝血中的枸橼酸钠减少，由此去除或抵消枸橼酸钠的抗凝作用。
可溶性钙盐可通过吸附作用结合在形成血液预处理件的过滤材料上。例如，通过将过滤材料浸泡在含有所述可溶性钙盐的溶液中，经干燥可获得包含可溶性钙盐的过滤材料，然后可将过滤材料加工成需要的形状。
在本发明的一种实施方式中，所述血液预处理件为设置在加样孔上方或加样孔内的过滤块，具有与加样孔相同的横截面。
如图2A所示，所述检验盒202包括加样孔212和与反应单元相连接的输送通道210。在工作中，检验盒202以水平方向插入检测血液凝固特性的装置，即过滤柱在工作中与水平面垂直。在加样孔212的上方设置过滤块2031，过滤块的顶部为进样口。当原始血样滴加到进样口，血液即进入过滤块2031，在重力作用和毛细作用下通过过滤柱而进入到加样孔212内，通过微流控形式的输送通道210流至反应区。所述过滤块通常具有与加样孔相同或相似的横截面，可设置在加样孔上方，或是设置在加样孔内。所述过滤块设置为使得血样通过所述过滤块的时间和空间允许血样中待去除的抗凝剂可以充分与去抗凝物接触和反应。
在本发明的其中一种实施方式中，所述血液预处理件为设置在加样孔上方的过滤膜。
如图2B所示，所述检验盒202包括加样孔212和与反应单元相连接的输送通道210，在加样孔212的上方设置过滤膜2032，过滤膜的一端覆盖加样孔212，在过滤膜的另一端设置进样口205。血液从进样口加入后，经过滤膜横向移动到加样孔212。所述过滤膜设置为使得血样从进样口通过所述过滤膜横向移动到加样孔的时间和空间允许血样中待去除的抗凝剂可以充分与去抗凝物接触和反应。
如图1和图2所示，检验盒202还包括虚线206包含的反应区204， 其具有包括一个或多个试剂208或者针对一种或多种类型的检验而选择的其他物质。通常，不同检验(例如，PT、APTT、ACT、FIB或TT)具有其自身的试剂208或者适用于检测特定特性的其他物质。作为一个示例，可以在反应区204处预先应用(例如，印制、放置等)和固定试剂208。
检验盒202还可以包括多个电极214，以形成电化学电池。例如，第一电极216可以连接至反应区204的第一部分218，第二电极220可以连接至反应区204的第二部分222。第三电极224也连接至反应区204。在该示例中，反应区204处的电化学电池由三个电极，例如工作电极、反电极和参考电极，构成。在其他示例中，可以将反电极和参考电极进行组合以提供两电极配置。
相应地，可以看出，当来自加样口的血液进入反应区204时，血样104位于多个电极，例如第一电极216和第二电极220，之间。此外，在血样的检验期间使用试剂或其他物质的示例中，血样104可以在反应区204中与试剂208或其他物质相互作用。此外，尽管在该示例中只示出了单个电化学电池，但是在其他示例中，可以包括多个电化学电池，以提供多个反应区204。例如，不同反应区204可以包括不同类型的试剂208或者适用于不同类型的检验的物质。这些反应区可以通过通道连接至单个样本接收器212。
在反应区204内，血样与试剂208发生反应，这可以触发一系列导致凝固的生化反应。在反应区204中，血样104与多个电极214相接触。当检验盒202被插入到装置301中时，位于反应区204中的电极214和血样104变为用于检验血样104的完整电路的电化部分。例如，装置可以在电极214上施加电压差，以在一定时间段(即，测量持续时间)内检测电路的输出端子处的电信号，以便获得表示时间的函数(即，时间的测量函数)的多个测量。
本发明提供的检测血液凝固特性的装置301还具有外壳303(图上未示出)。外壳可将仪器内部与大气间隔开，以免样品污染和零件损坏。外壳面板通常为金属材料制成。外壳可具有可打开和关闭的样品窗，用于放入和取出样品。另外外壳可具有与外部设备连接的外部设备接口，显示操作界面的显示屏，各种操控开关、按键或按钮等。
如图1所示，装置301还包括检验盒接收槽304和加热器306。加热器306可以确保在检验时间将血样104维持在一致的温度，以确保检验在多个样本上的一致。
装置301还可以包括用于将检验盒202的电极与设备302的电路310相连接的多个电连接308。例如，电极214可以连接至电源312和模拟/数字转换器314。电源312可以在检验血样104期间在检验盒202的反应区214中提供血样104上的电压差。A/D转换器314可以测量结果电信号，例如在输出端子处。在一些情况下，输出端子可以与电极214中的一个或多个相对应。
装置301还可以包括一个或多个处理器316、一个或多个计算机可读介质318、显示器320、电源适配器端口322以及一个或多个通信接口324，例如外部数据端口或其他合适的通信接口。处理器316可以是控制逻辑电路、中央处理单元、微处理器或其他合适类型的处理器中的任一个。在一些示例中，每个处理器316自身可以包括一个或多个处理器或处理核心。
根据设备302的配置，计算机可读介质318可以是有形非瞬态计算机存储介质的示例，并可以包括以用于存储信息的任何类型的技术，例如计算机可读指令、数据结构、程序模块或其他数据，实现的易失性和非易失性存储器和/或可移除和不可移除介质。这种计算机可读介质318可以包括但不限于RAM、ROM、EEPROM、闪存、或者其他计算机可读介质技术、计算机存储技术或可以用于存储信息且可以由处理器316直接或通过另一计算设备接入的任何其他介质。相应地，计算机可读介质318可以包括能够存储和维持处理器316可执行的指令、模块或组件的计算机存储介质。
计算机可读介质318可以用于存储处理器316可执行的任何数目的功能组件。在一些实施方式中，这些功能组件包括处理器316可执行且在被执行时实现用于执行归于设备302的动作的运算逻辑的指令、代码或程序。在计算机可读介质318中维持的设备302的功能组件可以包括检验模块326，其可由处理器316执行以执行对血样的检验，例如在血样上施加电压差以及获得对电信号的测量结果。功能组件还可以包括分析模块330，其可以由处理器316执行，用以执行这里描述的一些功能， 例如确定时间的测量函数114、一个或多个对应的累计特性116和/或血液凝固特性118。例如，分析模块330还可以至少部分地基于累计特性116和/或测量结果112或时间的测量函数114来确定血液凝固特性。此外，计算机可读介质318可以存储诸如测量结果112、时间的测量函数114、累计特性116、血液凝固特性118或与此相关的信息等数据。此外，根据设备302的类型，计算机可读介质318还可以可选地包括其他功能组件和数据，例如用户接口模块、通信模块、医疗历史、过去的血液凝固检验结果或其他模块、应用、程序、驱动器、数据等。
由装置301针对血样104获得的测量结果112可以存储在计算机可读介质318中，并被分析，例如通过由处理器316执行分析模块330而被分析。分析模块330可以确定测量函数114的累计特性116的量值。在获得测量结果112之前，或者在一些情况下，在制造设备302之前，可以凭经验导出或选择累计特性116。例如，选择合适累计特性116的标准通常是：获得与血液凝固特性118的良好相关性，以使累计特性116能够用于确定血液凝固特性118。
在一些示例中，用于确定时间的测量函数114、累计特性116和/或血液凝固特性118的处理可以通过由处理器316在装置301上执行分析模块330来执行。在其他示例中，一些或所有处理可以由外部计算设备328执行。例如，设备302可以将测量结果112提供给计算设备328，并且计算设备328可以在计算设备328的处理器上执行分析模块330，以确定时间的测量函数114，应用累计特性116和/或确定血液凝固特性118。在这种情形下，检验模块326或者设备302上的其他合适的应用或通信模块可以通过连接332来与计算设备328进行通信，以将测量结果112提供给计算设备328。在其他示例中，计算设备328可以暴露设备302可以使用来提供测量结果112的编程接口或API(应用编程接口)。在其他示例中，不提供测量结果112，而是设备302可以将血液凝固特性118或者与血液凝固特性相关的信息提供给计算设备328。
通信接口324可以支持有线和/或无线连接332通往各个网络，例如蜂窝网络、无线电通信、Wi-Fi网络、短距离或近场网络(例如
Figure PCTCN2021106174-appb-000001
)、红外信号、局域网、广域网、互联网、直接线缆连接等等。作为一个示例，通信接口324可以包括USB(通用串行总线)端口、IEEE 802.3端口或其他有线连接。在其他示例中，通信接口324可以允许装置301接入无线通信网络或设备。
如图1所示，装置301还包括显示器320，显示器320可以是无源、发射型或者任何其他形式的显示器。在一些示例中，显示器320可以包括任何合适类型，例如液晶显示器、等离子体显示器、发光二极管显示器、有机发光二极管显示器等等。此外，在一些示例中，显示器320可以具有与其相关联的触摸传感器，以实现来自用户的触摸输入。此外，在其他示例中，装置301可以不包括显示器。
实施例2血液的凝固特性的检测和比较：
检测项目：凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、活化凝血时间(ACT)、纤维蛋白原含量(FIB)和凝血酶时间(TT)
1.仪器：
采用深圳微点生物技术股份有限公司生产和销售的
Figure PCTCN2021106174-appb-000002
电化学检测仪(型号Q-1，粤械注准20172401103)，并对所述仪器进行改进得到本发明提供的装置。
根据Q-1型
Figure PCTCN2021106174-appb-000003
电化学检测仪的使用手册，其可对人体新鲜无抗凝静脉全血或者毛细管全血进行凝血酶原时间(PT)/活化部分凝血活酶时间(APTT)/纤维蛋白原(FIB)/凝血酶时间(TT)的体外定量检测。该仪器的结构包括如实施例1描述(如图1和图2所示)的设备301和其中的检验盒202中除了血样预处理件203之外的各个部分，即包括血样接收和预处理单元201，反应单元204，血液凝固特性分析计算单元316和结果呈现单元320等，但不具备血样预处理件203。
Figure PCTCN2021106174-appb-000004
电化学检测仪Q-1型采用一次性使用的PT、APTT、FIB和TT四联检测卡，其俯视平面图如图3A所示，其具有图2示意的检验盒202中除过滤柱2031或过滤膜2032以外的结构，包括加样孔212，输送通道210和反应区204和电极214等。
在使用中，将该四联检测卡插入到Q-1型
Figure PCTCN2021106174-appb-000005
电化学检测仪的检测卡插槽(相当于图1中的检验盒接收槽304)，在加样孔212加入血样后，血样通过输送通道210进入反应区204。仪器工作时，恒定的电压输出到电极214上。在反应区内，血液被诱发一系列的生化反应开始凝 固。电化学检测仪监测血液凝固的过程，产生电流信号的变化，仪器内设置的血液凝固特性分析计算器根据设定的程序生成电流与时间变化的凝血曲线。伴随着凝血过程中凝血因子的激活以及纤维蛋白原转化成纤维蛋白的过程，曲线发生变化并产生相应的特征(高度，面积等)，对这一曲线的凝血特征进行分析并计算出样本的凝血酶原时间(PT)、国际标准化比值(INR)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)和凝血酶时间(TT)，并将结果报告在检测仪的屏幕上。
在本实施例中，对
Figure PCTCN2021106174-appb-000006
电化学检测仪Q-1型进行改进，加入了额外的血液预处理单元而得到本发明的装置，具体而言，是增加了具有去除含枸橼酸钠的抗凝血中枸橼酸钠的抗凝作用的预处理单元。
图3B和图3C分别显示本发明装置的采用两种不同设计的检测卡的结构示意图。
如图3B所示，在检测卡的加样孔212的上方设置过滤柱2031。在工作中，检测卡以水平方向插入
Figure PCTCN2021106174-appb-000007
电化学检测仪，即过滤柱在工作中与水平面垂直。将含枸橼酸钠的抗凝血滴加到过滤柱顶部，血液进入过滤柱，在毛细作用下通过过滤柱而进入到加样孔内，通过微流控形式的输送通道流至反应区。
如图3C所示，在检测卡的加样孔212的上方设置过滤膜2032，过滤膜的一端覆盖加样孔，在膜的另一端为进样口205。将含枸橼酸钠的抗凝血滴加到进样口位置，血液被滤膜吸收后经过滤膜横向移动到加样孔，通过微流控形式的输送通道流至反应区。
2.过滤柱/过滤膜的制备
过滤柱膜材：
Figure PCTCN2021106174-appb-000008
滤膜膜材
Figure PCTCN2021106174-appb-000009
对过滤柱/过滤膜进行加载氯化钙的处理
将氯化钙(纯度>96％,国药集团化学试剂有限公司，中国)溶解在去离子水中，配置成0.05mol/L的水溶液。将上述膜材分别浸泡在氯化钙溶液中10min，浸泡过后的膜材在45℃条件下烘干8h备用。
3.血样，采集自招募的志愿者，进行扎手指采集末梢血，将同一个志愿者的血样分别制备对照样本和测试样本(枸橼酸钠抗凝血)。
对照样本：末梢血原血
测试样本：3.2％枸橼酸钠，枸橼酸钠:原血＝1:9；
4.检测
将测试样本(10例)经如图3A所示仪器和设置进行测试。结果均显示为“No Coag”，即检测不到血样凝固。
将对照样本和测试样本分别经图3B(5例，过滤柱：样本编号1-5)或图3C(5例，过滤膜：样本6-10)所示仪器和设置进行测试。
检测结果如下：
Figure PCTCN2021106174-appb-000010
偏差分析如下：
样本编号 INR APTT FIB TT
1 3.6％ -1.5％ -3.0％ 2.7％
2 3.6％ 3.8％ -1.6％ -1.2％
3 3.1％ -1.9％ -5.0％ -0.7％
4 -9.1％ -4.7％ -1.2％ 2.7％
5 -6.0％ 6.0％ 1.8％ -2.9％
6 4.7％ -2.2％ -3.2％ -6.8％
7 2.2％ -2.8％ -3.7％ -1.5％
8 -4.3％ -3.0％ 6.2％ 6.0％
9 2.5％ 2.3％ -7.3％ -0.4％
10 -2.7％ 1.2％ 2.7％ -2.7％
结果分析：从指尖血原液和枸橼酸钠抗凝血测试结果分析，枸橼酸钠抗凝血通过本发明的仪器和设置后，凝血功能恢复，指尖血和抗凝血测试INR/APTT/FIB/TT结果偏差均在±10％内。

Claims (16)

  1. 一种检测血样的血液凝固特性的装置，包括：
    血样接收和预处理单元，其包括血液预处理件、加样孔和与反应单元相连接的输送通道；其中所述血液预处理件用于去除或抵消在血样中存在的抗凝剂的抗凝血作用；和
    反应单元，血液在其中产生凝血过程。
  2. 根据权利要求1所述的装置，其还包括：
    血液凝固特性分析计算单元，其可根据反应单元中血液在凝血过程显示的信号获得与血液凝固特性相关的测量结果，例如，其可在测量持续时间内检测经过所述血样的电信号，以此为根据计算样本的凝血酶原时间(PT)、国际标准化比值(INR)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)和凝血酶时间(TT)；和/或
    结果呈现单元。
  3. 根据权利要求1或2所述的装置，其中，所述血液预处理件为可供血液通过的过滤材料制备而得。
  4. 根据权利要求3所述的装置，其中，所述血液预处理件的材料为聚合物材料，或为玻璃纤维。
  5. 根据权利要求4所述的装置，其中，所述血液预处理件的材料为聚合物材料，其为聚醚砜(PES)、聚丙烯腈(PAN)、聚偏氟乙烯(PVDF)、聚苯乙烯(PS)、聚氯乙烯(PVC)或其组合。
  6. 根据权利要求1所述的装置，其中所述血液预处理件可去除或抵消枸橼酸钠的抗凝作用。
  7. 根据权利要求6所述的装置，其中所述血液预处理件含有可溶性钙盐。
  8. 根据权利要求7所述的装置，其中所述血液预处理件含有氯化钙。
  9. 根据权利要求1所述的装置，其中所述血液预处理件为设置在加样孔上方或加样孔内的过滤块。
  10. 根据权利要求1所述的装置，其中所述血液预处理件为覆盖在加样孔上方的过滤膜。
  11. 一种检测血样的血液凝固特性的方法，其采用权利要求1-10中任一项所述的装置，所述装置包括：
    血样接收和预处理单元，其包括血液预处理件、加样孔和与反应单元相连接的输送通道；其中所述血液预处理件用于去除或抵消在血样中存在的人为加入的抗凝剂的抗凝血作用；
    反应单元，血液在其中产生凝血过程，
    所述方法包括在将血样传递到反应单元使得血液产生凝血过程之前对血样进行预处理。
  12. 根据权利要求11所述的方法，其中所述装置还包括：
    血液凝固特性分析计算单元，其可根据反应单元中血液在凝血过程显示的信号获得与血液凝固特性相关的测量结果，例如，其可在测量持续时间内检测经过所述血样的电信号，以此为根据计算样本的凝血酶原时间(PT)、国际标准化比值(INR)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)和凝血酶时间(TT)；
    结果呈现单元。
  13. 根据权利要求11或12所述的方法，其中，所述血液预处理件可去除或抵消枸橼酸钠的抗凝作用，即所述血液预处理件可恢复含有枸橼酸钠的血液样品的血液凝固特性。
  14. 根据权利要求13所述的方法，其中所述血液预处理件为设置在加样孔上方或加样孔内的过滤块。
  15. 根据权利要求13所述的方法，其中所述血液预处理件为覆盖在加样孔上方的过滤膜。
  16. 根据权利要求11所述的方法，其用于检测下列血液凝固特性中的至少一项：
    纤维蛋白原含量(FIB)；
    凝血酶时间(TT)；
    凝血酶原时间(PT)；
    活化部分凝血活酶时间(APTT)。
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