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    • 专利摘要:
    DEVICE FOR MEASURING COAGULATION RESPONSE IN A BLOOD SAMPLE AND METHOD OF MEASURING COAGULATION RESPONSE IN A BLOOD SAMPLE A device, system and method are revealed in which small volume blood samples are subjected to shear forces and shear stresses between two planar surfaces to which linear motion trajectories are transmitted. The formation of clots or coagulation of the samples is measured according to the dynamic mechanical coupling that occurs between the two parallel planar surfaces. The detection of the coagulation response can be achieved through optical probing or by measuring the physical effects of the connection of the blood sample to the planar surfaces, which restricts their movement.
    公开号:BR112012014421B1
    申请号:R112012014421-9
    申请日:2010-12-17
    公开日:2021-02-02
    发明作者:Robert Glenn Dennis；Thomas H. Fischer；Joseph A. Dacorta
    申请人:Entegrion, Inc；
    IPC主号:
    专利说明:

    CROSS REFERENCE TO RELATED REQUESTS
    This request relates to and claims priority to U.S. Serial No. Interim Order 61 / 287,780 filed on December 18, 2009, the disclosure of which is expressly incorporated into this document in its entirety. FIELD OF THE INVENTION
    The invention relates to a device and method that allows rapid evaluation of the coagulation response. More particularly, the invention relates to such a device and method that provide comprehensive and complex information on the coagulation response, including platelet function and fibrin polymerization, to allow the selection of appropriate treatment protocols, in particular for trauma-induced coagulopathies, but also for the diagnosis of inherited or acquired coagulation abnormalities, such as von Willebrand's disease or hemophilia. BACKGROUND OF THE INVENTION
    The process by which the body prevents blood loss is called clotting. Coagulation involves the formation of a blood clot (thrombus) that prevents further blood loss from damaged tissues, blood vessels, or organs. This is a complicated process with a cellular system made up of cells, called platelets, that circulate in the blood and serve to form a platelet plug over the damaged vessels, and a second system based on the actions of multiple proteins (called coagulation factors) that act together to produce a fibrin clot. These two systems work together to form a clot, and disturbances in either system can produce disorders that cause too much or too little clotting.
    Platelets serve three primary functions: (1) adherence to the injured blood vessel (a phenomenon called platelet adhesion), (2) attachment to other platelets to increase the forming buffer (a phenomenon called platelet aggregation), and (3) supply of support for the processes of the coagulation cascade (molecules on the platelet surface accelerate considerably several key reactions).
    When a blood vessel ruptures, substances that are not normally in direct contact with the blood flow are exposed. These substances (mainly collagen and fixed multimeric von Willibrand factor) allow platelets to adhere to the broken surface. Once a platelet adheres to the surface, it releases chemicals that attract additional platelets to the damaged area, called platelet aggregation. These two processes are the first responses to stop bleeding. The protein-based system (the coagulation cascade) serves to stabilize the buffer that has been formed and to seal the wound further.
    The platelet support role for the coagulation cascade is provided, in part, by one of the components on the outer side of a platelet, called phospholipids, which are necessary for many of the reactions in the coagulation cascade. The goal of the cascade is to form fibrin, which will form a mesh inside the platelet aggregate to stabilize the clot. All factors have an inactive form and an active form. Once activated, the factor will serve to activate the next factor in the sequence until fibrin is formed. The coagulation cascade takes place at the site of a rupture in a blood vessel that has the platelet aggregate. The fibrin forms a mesh that, together with the platelets, covers the break in the vessel wall. The fibrin mesh is then further stabilized by additional factors that upwardly cross-link the clot (similar to the formation of an intricate network of reinforced fibrin filaments).
    In the case of trauma-induced bleeding, it is important to understand the clotting response of a specific individual very quickly in order to apply appropriate therapy to treat the bleeding and ensure that the trauma is treated appropriately. Defective platelet functions, both primary (adhesive, von Willebrand factor interaction) and secondary (organization and polymerization of the fibrin polymer, integrin function) are recognized as a particularly important contributor to prolonged non-compressible bleeding. The development of homeostatic disorders in trauma patients, and the associated progression of hemorrhagic and other shock states, may be due to different factors and, therefore, require different therapies.
    Currently, thromboelastography (TEG) is the accepted clinical standard for testing the efficiency of whole blood clotting. For the purposes of this disclosure, it should be noted that by "whole blood" is meant a mixture of whole blood with one or more substances, a fraction of whole blood that contains one or more of the constituents of whole blood, a fraction of blood total mixed with one or more non-blood substances, or a purified blood constituent, such as blood serum or platelets, a reconstituted blood preparation, a modified blood sample, or a blood substitute.
    A TEG system was first developed in Germany in 1948 and has been gradually improved since then. However, its operating principle remains the same.
    Traditional TEG requires a relatively large blood sample, that is, about 0.36 ml in a small glass. A pin is inserted into the blood and is rotated in a sinusoidal oscillation through a small angle at a low frequency. The device measures the displacement coupling through rotation over time. The device does not measure platelet adhesion, only fibrin polymerization, and does not allow mechanical activation of the coagulation response through shear forces. Thus, the information obtained from a TEG analysis falls far short of our current understanding of the coagulation response, and requires excessive amounts of time that could result in the application of inappropriate treatment for the trauma, which leads to adverse results for a patient, possibly even death.
    Another device commonly known as the PFA-100 attempts to mimic a blood vessel by forcing blood flow through a narrow channel that leads to a filter that has an opening in it. The device measures the time it takes for the opening to plug and is essentially indicative of the platelet function response that results in coagulation. The opening closing time indirectly provides an indication of coagulation due to the platelet response. The use of such devices as the TEG and PFA-100 requires intensive laboratory training and maintenance, and they are not easily used in the field.
    Accordingly, it is desirable to provide a portable coagulation monitoring device for the diagnosis of trauma-related coagulopathies in the field, which produces rapid results, including comprehensive information on the complex mechanisms involved in coagulation, from a small blood sample. . More specifically, it is important to provide such a device that can be used by rescuers under conditions found in the field, that provides real-time information, that allows immediate treatment of a hemorrhagic event, compared to prior art systems and devices that could result in delays of 4 5 minutes or more during what is considered an important initial period of time for critical care to be applied and using non-anticoagulated blood samples that do not have to be treated with activators. and initiators as substitutes for the true decoagulation process. SUMMARY OF THE INVENTION
    In one aspect, the invention relates to a device for measuring the clotting response in a sample of native non-anticoagulated blood. The device includes two members or plates, each of which has 15 surfaces facing each other, and spaced enough to allow a relatively small blood sample to contact both surfaces at the same time without an air gap between them.
    The plates are mobile relative to each other in a parallel, linear direction, and the spacing is such that blood components can initiate coagulation or adhesion • to each of the surfaces. A drive mechanism is connected to either or both members to move one or the other in a linear fashion with respect to each other when a blood sample is in contact with their surfaces. An optical detection sensor system is provided to detect interaction of light with a blood sample located between the two limbs, the interaction of which is 30 light and its detection provides an indication of the coagulation response of the blood sample. More specifically, with the appropriate positioning of detectors and light sources, over time and according to the variation in the movement of the limbs to generate a specific shear rate, information can be obtained on both the platelet response and the response of fibrin and other blood component responses during clotting.
    More specifically, the device allows the measurement of the coagulation response based on the knowledge that the biophysical response of the blood depends, in part, on the relative shear rate between the blood and the surfaces with which it is in contact. More specifically, the higher the shear rate, the greater the platelet response, so that the platelets then adhere to the surfaces of the plates and thus cause fibrin polymerization and couple the displacement of the two plates when only one is triggered by the engines. More specifically, it is recognized that, in hemorrhagic events, platelets need to react quickly so that the use of a high shear rate for a short period of time can allow an accurate assessment of the platelet response to these conditions. Thereafter, lower shear rates can be employed in terms of relative movements of the plates or limbs with respect to each other, to obtain an accurate assessment of the fibrin response or, at an intermediate shear rate, both platelet and fibrin response .
    "Shearing" is defined in this document as the accelerating force felt by a particle in the flow of mobile fluid (blood) at the interface with the stationary solid (face of the glass plates). The shear "rate" is the differential of the velocities felt in different aspects of the particle's transverse area and is dependent on the particle's distance from the stationary surface.
    In a preferred aspect, the first member and the second members are plates that constitute a blood sample collection cartridge that is removable from the device. In the event that one or more plaques are moved relative to each other, the device is programmed to move the plaques at different speeds relative to each other to detect different mechanisms involved in a blood sample coagulation response, as previously discussed in relation to shear.
    The optical detection system is adapted to detect binding of the blood sample to the surfaces to couple the displacement of the plates relative to each other as an indication of platelet response during coagulation. In addition, the system can also investigate the fibrin response.
    Other features and details of the device are described in the detailed discussion that follows, the Appendices to this document, and in the appended claims in which the invention is described in a non-limiting manner.
    In an alternative aspect, a method of measuring the coagulation response in a blood sample is provided. A drop of blood for the sample is placed between and in contact with front surfaces of plates disposed in the opposite way. At least one or both plates are moved in a linear fashion with respect to each other, at a predetermined speed. The coagulation response of the droplet is optically detected.
    To detect two different types of coagulation response, the plates can be moved relative to each other at a first speed and an optically detected response, and thereafter moved at a second speed that is slower than the first speed and a second response optically detected, typically fibrin polymerization. In addition, in the case where only one plate is moved, it should be noted that the viscoelastic response of the blood sample on the surfaces of both plates can cause the movement of the first plate to induce the movement of the second plate ("coupled displacement" ), which can be measured as indicative of blood viscoelastic response, which ultimately leads to conclusions that can be inferred in relation to the coagulation response. In addition, by moving the plates at different speeds over time, it is possible to measure changes in the viscoelastic state of the blood sample while a clot is formed, which is also indicative of the coagulation response.
    Optical detection can be done by transmitting light into the sample drop, and by detecting at least one of the transmission, reflection and refraction of light through the sample drop in respective light detectors. Analog signals can be generated from the representative detection of blood clotting properties in the sample drop. The plates are preferably made of glass, more specifically clear glass, to allow light transmission of 90% or more of the intensity of the incident light.
    These and other advantages and features that characterize the invention are presented in the claims attached to this document and that form an additional part of it. However, for a better understanding of the invention, and of the advantages and objectives achieved through its use, reference should be made to the Drawings, and to the attached descriptive content, including Annexes I, II, III, and IV that are specifically incorporated in its entirety in this document for reference, in which exemplary embodiments of the invention are described. BRIEF DESCRIPTION OF THE DRAWINGS
    Figure 1 is a schematic diagram illustrating various components that make up the device and system according to the invention.
    Figure 2 is a schematic diagram of a sample cassette on which a sample drop can be loaded, and which can be used in an exemplary embodiment of the portable coagulation monitor according to the invention, for example, as shown in Figure 1 .
    Figure 3 is a schematic diagram that illustrates the relative movement of two plates in contact with blood to cause shear and initiate a coagulation response.
    Figure 4 is a perspective view of an embodiment of the device of the invention.
    Figure 5 is an exploded view of an embodiment of the device of the invention. DETAILED DESCRIPTION OF THE INVENTION
    Figure 1 schematically illustrates an exemplary portable coagulation monitor or analysis device 11 for diagnosing trauma or other related coagulopathies in which it is important to analyze the coagulation response to optimize treatment, for example, in critical field situations where the first hour is critical in terms of avoiding long-term debilitating events or even death.
    The device is housed in an impact resistant housing 13 that has all components housed therein in a conventional manner.
    At least one and preferably a pair of linear voice coil actuator motors 15 and 17 are provided to drive the movement of sample plates in a removable blood sample cassette which is illustrated in greater detail in Figure 2. Although the motors 15 and 17 and removable blood sample cassette 19 have been briefly described, the remaining components are discussed generally with reference to the drawings in a counterclockwise manner starting with the data card port 21 in the upper left corner of the device.
    Data card port 21 is useful for receiving an FD card or any memory module, which includes data in the module to calibrate device 11, and / or to remove data from device 11 for entry into another system where data can be be analyzed. A USB 23 port allows direct interface with a computer, for example, under the control of a doctor for more complex analysis.
    The microcontroller 25 operates with EEPROM 26 and manipulates data from the USB port and from the data card port 21 and can provide control for a user interface (not shown) such as LCD monitor that initially provides data and analysis purchased on the same for a user using the device. Linear voice coil actuator motors 15 and 17, and the removable blood sample cassette 19 have been briefly described and will be discussed in greater detail below.
    A wireless link 27 is also provided, such as for transmitting data in the RF or IR spectrum, which provides an additional means for communicating data and programming to and from the device. Optical displacement sensors 29 and 31 detect where linear voice coil actuator motors 15 and 17 are located and control their movement limits. The digital synthesizer module 33 serves to control the operation of motors 15 and 17 through motor drivers 35 by generating the waveforms necessary to drive the voice coil actuator motors 15 and 17.
    The ADC 37 module is an analog / digital converter that obtains data from the optical and physical measurements carried out on a sample in the removable blood cassette 19, converts the data to digital format and supplies it to the microcontroller 39 that manages the data obtained to supply useful results for a user of the device.
    A 3-axis accelerometer 41 is a conventional device that considers vibrations and external effects on device 11, and serves to cancel the effects of these vibrations on any data collected as a result of analyzing a sample.
    The removable blood sample cassette 19 is shown in Figure 2 schematically and includes an upper sample plate 101 and a lower sample plate 103 between which a drop of sample blood can be deposited. Joints 105 are provided for the voice coil actuator motors in the device, which are connected to an upper linear compatible mechanism 107 and a lower linear compatible mechanism 109 that serve to drive the movement of the upper and lower plates, respectively. Optical sensors 111 are provided in position relative to the sample plates to detect light projected from, for example, a laser or other light source (not shown), through and inside a sample between the plates. The light can then be detected as light transmitted through the sample, reflected, refracted or otherwise modified in the path through the sample, and detected by optical sensors 111 to obtain information about the blood sample's coagulation properties.
    An electrical power link 113 serves to connect to an electrical power supply such as, for example, batteries or another form of electrical power. A data link 115 can also be provided to allow data collected from the sample and stored on an EEPROM 117 to be downloaded from the device. In this context, it will be observed by those of ordinary skill in the art that when cassette 19 is received in device 11, data link 115 and EEPROM 117 can be connected to various electronic components inside device 11 to have data loaded and downloaded to / from it.
    As can also be seen by those of ordinary skill in the art, Figure 3 further illustrates the operation of the device according to the invention and with parallel plates, typically having a small span of about 50 to about 250μm between the parallel plates. They slide through each other with controlled speed to create a shear stress between the plates which is represented by T = μV / D, where T is equivalent to shear stress, μ = viscosity, V = VI + V2, where V is equal to the relative linear velocity of the plates, and D = span between the plates.
    Figure 4 further illustrates, in overall view, a device 11 according to the invention showing several components thereof. As you can see from Figure 4, the device has a pocket size, preferably with overall dimensions similar to an iPhone, of about 12 cm by about 6 cm by about 2 cm. Device 11 is reinforced with an internal accelerometer that compensates for impacts and vibration. As designed, it is versatile and can measure platelet and fibrin coagulation over a wide dynamic range of shear. In addition, device 11 can operate with electrical power from a USB hub as a peripheral device with components that are readily manufactured and assembled. Typically, the biophysical resolution is less than about 2μ of displacement, and device 11 allows for a wide range of shear stresses and complete optical access. As further illustrated in the exploded view of Figure 5, device 11 is preferably made of a housing machined by monolithic CNC, of materials such as Acetal, 6A1 - 4V Ti, 2024 Al. A bottom sample window 203 cooperates with a top sample window 205 and they are moved by displacement sensor arms 207. A compatible monolithic four-bar mechanism 209 made typically of aluminum is associated with the displacement sensor arms 207. Motor assemblies 211, typically a VCA motor coil assembly, serve to move the various components and are associated with a set of magnet 213, typically made of rare earth. Optical sensor arrangements 215 serve to interrogate and measure the coagulation response. Sensor arrays 215 are typically differential infrared displacement sensor arrays.
    Preferably, in the device, the first and second surfaces of plates 101 and 103 have been coated, at least, with textures, substances or other materials to induce, delay, or otherwise modify the coagulation process in order to select for or against specific aspects and sample coagulation for diagnostic or other purposes. Modification of surfaces may include those that enhance activation or reactivity of blood or platelet protein binding. Similarly, such modification can reduce blood or platelet protein binding reactivity, or activation, as will become more clearly evident from the following detailed discussion of such treatments or coatings.
    The device is able to analyze blood rheology and the coagulation of fresh whole blood or some fraction thereof without the need to add external reagents, such as tissue factor, kaolin, initiator, citrate and others. Such substances and others can be electively added for detailed analytical reasons, but in the most desired modality of the device, they are not necessary.
    According to the assembly, device 11 is configured to measure in real time, or with minimal delay, the dynamic balance between the pro and antithrombotic hemostatic situation by sequential samples from the same person or animal. In a more preferred aspect, motors 15 and 17 are linear voice coil actuating motors, but they can be any other type of device capable of driving linear movement.
    In one embodiment, the detection of coagulation is done optically by measuring the mechanical interaction between the first and second surfaces of plates 101 and 103 resulting from changes in the viscosity of the sample fluid and binding to the surfaces of the plate. In a preferred aspect, the relative movements between the two plates 101 and 103 are controlled to generate arbitrarily selected waveforms to induce desired fluid shear rates at selected amplitudes, frequency, duration, and sequence, so that the device is enabled. to emulate fluid shear as desired over a very wide range, from DC (zero shear) to shear rates that would cause fluid cavitation and subsequent destruction of the sample's cellular components, and continually include all points in the shear rate spectrum between these two points.
    More specifically, the shear rate is controlled in a sequence of values to generate specific protocols or plate movement paradigms for specific diagnosis or analytical objectives, such as rapid initiation of primary coagulation or non-destructive viscoelastic evaluation of early coagulation, in the intermediate phase , or late stage, emulation of clinically accepted or otherwise recognized shear rate protocols for comparison with other commercial or experimental devices, or validation test against known standards. Although light can be used for optical detection, it is clear that the complete electromagnetic spectrum of waves can be used to generate analog signals representative of the coagulation properties of the sample drop for both primary and secondary coagulation mechanisms.
    It should be noted that when the term "blood sample" is used in this document, it is intended to mean whole blood, a mixture of whole blood with one or more substances, a fraction of whole blood that contains one or more of the whole blood constituents, a fraction of whole blood mixed with one or more non-blood substances, or a purified blood constituent, such as serum or blood platelets, a reconstituted blood preparation, a modified blood sample, or a blood substitute.
    In a specific modality, interchangeable sample cassettes 19 can be used, each serving a different analytical, maintenance or calibration function. A cassette 19 can be for validation and calibration of device 11. Alternatively, such a disposable and replaceable cassette 19 can serve to calibrate device 11, receive the blood sample, store the blood sample, allow different sample chamber geometries for different test protocols, keep the sample in viable conditions during a test, serve for safe removal of the sample for storage such as freezing, freeze-drying, etc., or for sample disposal without exposure to the blood sample. In one embodiment, cassette 19 allows the collection of the blood sample by means of simple capillary action, eliminating the need for the use of counter devices and sample extraction.
    As will be noted by those of ordinary skill in the art, cassettes 19 can be manufactured for different tests and applications with different sample plate spacing, different surface chemical and optical properties, and similar variations for validation and analysis testing.
    Cassette 19 may contain optical interrogation electronics that allows the detection of the status, type, pH, oxygenation, metabolites and toxins of the blood, or other measures detectable by optical means. The device 11 is such that through its electronics it can be interconnected with other laboratory systems such as microscopes, etc. Plates 101 and 103 are preferably optically clear to allow optical signals to pass through the blood sample allowing direct optical viewing of a portion or the entire blood sample between planar surfaces. This allows transmission, reflection, internal reflection, selective absorption, polarization or optical rotation, frustrated internal reflection (partial or total), and conduction of laser beams or other light surfaces.
    As already noted, cassette 19 may contain a non-volatile permanent memory storage device such as EEPROM 117, to contain initial data that identifies the cassette, batch, date of manufacture, and construction details, as well as to allow for storage of key data such as user-defined sample identification information, test initiation time, test duration, and specified test output results and data, to be permanently stored with each sample until it is destroyed.
    Cassettes 19 may contain additional fluids or other materials such as additives, preservatives, sealing or barrier agents, and other similar agents that can be added to or deposited on top of the blood sample before, during, or after the test. In a modality not specifically shown in the drawings, instead of linear displacement, rotary displacement can be used to induce shear in addition to or as a substitute for the linear displacement discussed earlier.
    As interpreted, device 11 is capable of distributing mechanical shear to the blood sample over a wide dynamic range of mechanical oscillations, which includes 0.0001 Hz to 1,000 Hz, by employing a previously disclosed digital synthesizer 33, typically a dual channel, with the ability to generate regular periodic waveforms such as sine waves, triangular waves, square wave cycles, variable frequency, and amplitude, in addition to the ability to generate arbitrary waveforms with rapid changes in all parameters, such as sweep speed, amplitude, etc., or which can also keep mechanical displacements of one or both planar surfaces steady (DC). Motors 15 and 17 can be driven by actuators 35 in a way in which one or both of the drive mechanisms are coupled with motors 15 and 17, and can be used simultaneously to effect linear displacement, or in which either one can be employed individually or in conjunction with the other mechanism that serves as a precision sensor for mechanical displacement. In such a system, mechanical features are incorporated such as 4 bars of compatible multi-bar monolithic mechanisms, to eliminate mechanical hysteresis by using wavy or sliding bearing surfaces in addition to those associated with the blood sample itself.
    Data reduction and analysis software can be incorporated into the electronics of the device to allow the resulting measured blood clotting parameters to be stored for later retrieval, transferred to a computer or other device for display, storage or analysis, displayed graphically , displayed in numerical format with physical units, or displayed in iconic or symbolic format to indicate a diagnosis, clinical indication, or parametric change of specific clinical significance. The software will allow the resulting data to be represented in a way that allows the user to compare the results directly with similar or analogous results that would be expected from other devices with similar functions, or to display the data in such a way that it makes comparison with values or standard extensions accepted for accepted coagulation parameters. In this context, it is noted that a user interface (not shown) is implemented with the device such as an LCD user interface.
    Device 11 employs plate movement protocols 101 and 103 coupled with data analysis and reduction software to enable direct assessment, for example, of platelet function, coagulation cascade function, red blood cell (RBC) rheology, aggregation of RBC, the effects of pro or anticoagulation agents, fibrinolysis, and other blood clotting characteristics. Device 11, with appropriate user requirements and user interfaces, can be classified as "simple" (classification according to CLIA "abandoned") to allow home use and by unqualified users. The disposable cassette is configured to collect and store the blood sample through simple unqualified collection of the fluid sample without requiring the use of any measuring pipette, syringe, or other measuring device to collect the blood sample. Cassette 19 allows safe handling, storage, retrieval, and disposal of the collected blood sample and can be manufactured to allow adjustment of the surface area and spacing between the plates to allow the use of very small volumes of blood, typically in the order of less than about 1 ml.
    Device 11 and cassette 19 allow optical microscopic inspection of most or all of the sample volume before, during, or after coagulometric analysis, using both inverted and standard microscopic arrangements. Device 11 can be used to diagnose and quantify diseases and blood clotting disorders that include, but are not limited to, congenital, induced and acquired conditions such as trauma-induced coagulopathies (ICT), von Willebrand disease (vWD), consumption coagulation factor, platelet consumption, thrombasthenia, metabolic platelet exhaustion, hemodilution, overactivation of protein C, S, and fibrinolytic pathways, altered RBC rheology, and improperly administered coagulation modulation therapy, and other blood clotting diseases and conditions.
    In addition, device 11 can quickly assess coagulopathies in the field in less than 15 minutes, and preferably less than 4 minutes, at the site of an injury or trauma, during transport, or at any other time during the course of the procedure. rescue, first response, treatment, surgical intervention, or recovery. Use of feedback and feeding technology serves to stabilize the blood sample to withstand the shock effects of impact, vibration, and external mechanical noise. You can test the time course of changes in both primary and secondary coagulation during the initial phase of the medical response to trauma and blood loss. Similarly, primary and secondary coagulation tests and changes to these mechanisms can be performed during the course of surgery.
    Device 11 can be used for rapid in-vitro screening of bioactive compounds designed to affect primary or secondary coagulation mechanisms. The device can also be used to guide the clinical treatment of diseases of the primary or secondary coagulation mechanisms.
    Similarly, device 11 and cassette 19 can be modified for use in measuring the rheological properties of other body substances of clinical and research interest, such as pulmonary mucus, for the study and clinical guidance of the treatment of cystic fibrosis, for example. For example, such applications require a specially designed (disposable) cassette and specialized firmware and test protocols, or for use in the study of new and innovative fluids with variable rheology.
    Device 11 employs optoelectronic and wireless means to allow more than one device to be employed simultaneously, or with multiple samples, each with different test initiation times and different test durations or different sample test chamber protocols, for provide a rich series of coagulation data to a central computer or data collection and display device. This allows many samples to be monitored simultaneously to track dynamic changes in an individual's blood clotting state during surgery or recovery, or during transport or treatment in the field.
    As discussed earlier, certain embodiments of the invention may take the form of adding coatings to plates 101 and 105, typically glass plates, on surfaces that come in contact with the blood sample. These coatings may be of a character to promote platelet adhesion and activation, such as collagen, more specifically type IV collagen, of human or bovine origin. Likewise, the coating can be derived from the extracellular matrix (ECM) of cultured fibroblasts, or from cultured endothelium, or derived from the natural subendothelial tissue of living blood vessels of human or animal origin. Particular molecular components of the matrix, such as vitronectin or fibronectin, may form the coating or be an enriched resource of the matrix to enhance the adhesion properties. The coating may also be of a synthetic nature to promote platelet adhesion and / or activation, such as polyamides or polyglucosamines, more specifically β-N-acetyl polyglucosamine of natural or synthetic origin. Other embodiments may incorporate coatings on plates 101 and 105 to modulate platelet function, such as materials capable of releasing platelet function activators, that is, adenosine diphosphate or epinephrine, or platelet function inhibitors such as prostaglandins, that is, prostacyclin or prostaglandin El .
    Another embodiment of the invention may take the form of adding coatings to plates 101 and 105 that promote, initiate, or modulate the fibrin coagulation and polymerization process. These coatings can take the form of materials capable of releasing micronized silica, or kaolin, or tissue factor (natural or recombinant), or such other agents that are known to promote steps in the coagulation cascade. The coatings may also be of a nature to reverse anticoagulants that may be present in the blood sample, such as a material capable of releasing the heparinase enzyme to remove heparin, or mineralized calcium to reverse citrate. These coatings may be preferred for blood testing of patients who do not have enough platelet counts or work to be able to initiate clotting by the shear-induced platelet activation mechanism. For the same reason, the coatings can incorporate a source of phospholipids, of natural or synthetic origin, or contain partial or total thromboplastins to mimic agents used in standard clinical coagulation tests such as prothrombin time (PT) or thromboplastin time partial (PTT).
    In yet another embodiment of the invention, coatings that inhibit or modulate or reverse the effects of hyperfibrinolysis in the blood sample, such as materials capable of releasing epsilon aminocaproic acid (EACA), or tranexamic acid, or aprotinin, or others, may be added to the plates. antiplasmin compounds or chemicals that affect the action of the plasmin enzyme. These coatings may be preferred for testing the blood of patients in a severe state of hyperfibrinolysis that obscures the ability to extract other useful information from the components of the hemostasis / coagulation system in the sample (and thus the patient) unless the effects plasmin in the test system is ablated. Likewise, coatings may contain buffering compounds of an acidic or basic nature to adjust the pH of the blood sample to the desired optimal level from pH 7.2 to 7.4 or other specified levels, to avoid loss of information when the sample is excessively acidic or basic due to severe conditions in the patient. These buffering compounds can take the form of released amino acids or salts or other soluble zwitterionic polymeric compounds biocompatible with blood for the purpose of producing and maintaining the desired pH.
    These and other coatings to be added to plates 101 and 105 of the present invention generally do not alter the geometry of the blood sample space between plates 101 and 105, or the movement and control of plates 101 and 105 by the motorized mechanism, in addition to the capacity of the system to be adjusted to keep the required span within specifications. For this reason, the preferred methods of manufacturing these coatings on glass plates may include the use of deposition and electrostatic charge of the desired materials directly in contact with the glass members, or by depositing fine molecular hydrogels and conductive emulsions containing the desired agents. in a release format suitable for activation immediately when contacted by the blood sample.
    The specified coatings can be made up of single agents for a single purpose, or it can be a mixture of a combination of several or more of the coatings specified for multiple support purposes. One embodiment may comprise having different coatings on the two surfaces, one of a kind and the other of a different kind or at different densities or modification of the similar coating on the opposite member. In an additional embodiment, one or more coatings can be applied at different densities or concentration in different areas of one or both surfaces, or with linear, radial, or other coating density gradients on one or both surfaces. The pattern or gradient for each type of coating may differ from that of other surface coating treatments on the same or opposite surfaces. Although in an exemplary embodiment the surfaces are made of glass, they can be of any other material capable of accepting the coatings on them, and of functioning in the intended manner, as will be evident for those of ordinary skill.
    Although the present invention has been illustrated by a description of various modalities and although these modalities have been described in considerable detail, it is not the applicants' intention to restrict, or in any way limit the scope of the appended claims to such detail. The invention in its broadest aspects is therefore not limited to specific details, devices and representative methods, and to the illustrative example shown and described. Accordingly, modifications to such details can be made without departing from the spirit or scope of the Applicants' general inventive concept of monitoring global hemostatic function in a portable device employing shear-induced platelet activation and the full spectrum of the response of Blood coagulation.
    权利要求:
    Claims (15)
    [0001]
    1. DEVICE FOR MEASURING COAGULATION RESPONSE IN A BLOOD SAMPLE, characterized by comprising: a first member that has a first surface, and a second member that has a second surface, and said first member is positioned to have said first surface facing said second surface of said second member, and spaced enough to allow a drop of sample blood to contact said first surface and said second surface and initiate coagulation, and said first member and second member are linearly movable in relation to each other; a drive mechanism connected to at least one of said first member and said second member to linearly move said first member and said second member relative to each other in parallel when a blood sample is in contact with said first surface and said second surface; and an optical detection sensor system for detecting, by measuring the mechanical interaction between the first and second surfaces that results from changes in the viscosity of the blood sample and binding to the plate surfaces, as an indication of the coagulation response of said sample of blood.
    [0002]
    2. DEVICE, according to claim 1, characterized in that said first member and second member constitute a blood sample collection cartridge that is removable from said device.
    [0003]
    3. DEVICE, according to claim 2, characterized in that said blood sample collection cartridge further comprises a memory device in said cartridge for storing data relating to a tested blood sample.
    [0004]
    4. DEVICE, according to claim 1, characterized in that the actuation mechanism is programmed to move the first member and the second member at different speeds in relation to each other to detect different mechanisms involved in a coagulation response of a blood sample .
    [0005]
    5. DEVICE, according to claim 1, characterized in that said optical detection sensor system is adapted to detect binding of the blood sample to the first surface and the second surface as an indication of platelet response during coagulation.
    [0006]
    6. DEVICE, according to claim 1, characterized in that said first and second surfaces (1 and 2) have at least one that is treated to induce, delay, or modify the coagulation process to select for or against specific aspects sample coagulation for other purposes.
    [0007]
    7. DEVICE, according to claim 6, characterized in that said surface treatment intensifies the binding, reactivity, or activation of the blood or platelet protein.
    [0008]
    8. DEVICE, according to claim 6, characterized in that said surface treatment reduces the binding, reactivity, or activation of the blood or platelet protein.
    [0009]
    9. DEVICE, according to claim 1, characterized by being configured to analyze blood rheology and coagulation of fresh whole blood or some fraction thereof without the addition of external reagents.
    [0010]
    10. DEVICE, according to claim 1, characterized by being configured to measure, without any functional delay, the dynamic balance between the pro and antithrombotic hemostatic situation by sequential samples from the same person or animal.
    [0011]
    11. DEVICE, according to claim 1, characterized in that it also comprises at least one microcontroller to control the operation of said drive mechanism and optical detection sensor system.
    [0012]
    12. DEVICE, according to claim 1, characterized in that it further comprises at least one displacement sensor for detecting and controlling the amount of relative movement between said first member and said second member.
    [0013]
    13. DEVICE, according to claim 1, characterized by also comprising a connection interface module for connection and communication between the device and an external system.
    [0014]
    14. DEVICE, according to claim 1, characterized in that said drive mechanism comprises a device capable of driving linear displacement.
    [0015]
    15. DEVICE, according to claim 1, characterized by also comprising an analog / digital converter connected to the optical detection sensor system to convert analog signals indicative of a blood sample's coagulation response into digital signals for storage in the same.
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    法律状态:
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-07-16| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|
    2020-11-17| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-02-02| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 10 (DEZ) ANOS CONTADOS A PARTIR DE 02/02/2021, OBSERVADAS AS CONDICOES LEGAIS. |
    2021-07-27| B16C| Correction of notification of the grant|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 17/12/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO |
    优先权:
    申请号 | 申请日 | 专利标题
    US28778009P| true| 2009-12-18|2009-12-18|
    US61/287,780|2009-12-18|
    PCT/US2010/060911|WO2011075614A2|2009-12-18|2010-12-17|Portable coagulation monitoring device and method of assessing coagulation response|
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