Coagulation testing devices, systems and methods of use

Abstract

To provide a coagulation test device for measuring clotting time and clot characteristics of a whole blood sample under different hemostatic conditions.SOLUTION: A device is configured to: activate a vacuum source to move a whole blood sample from a container into a plurality of channels in a cartridge and subsequently into a plurality of reagent chambers where the blood mixes with a reagent, and then through a plurality of serpentine channels to a plurality of test chambers; activate an actuator to shake the cartridge; receive signals from a plurality of sensors each associated with one of the test chambers, where the signals are based on the presence of a spherical member within a magnetic field generated by a magnet positioned adjacently to each of the test chambers; determine whether coagulopathy is present in the whole blood for each test chamber; and output to a display an indicator of whether coagulopathy is present in the whole blood for each test chamber.SELECTED DRAWING: Figure 1

Description

[Background technology]

[0001]

[0001] Most existing coagulation tests, both point-of-care (POC) and laboratory-based, diagnose bleeding disorders but provide insufficient information regarding the underlying cause of the bleeding. Current management of bleeding patients often involves the use of "massive transfusion protocols" (MTPs). This protocol approach uses a one-size-fits-all approach to manage all patients without considering the underlying cause of the coagulation disorder in each individual patient. Laboratory testing of factor levels or viscoelastic testing requires time and skilled technical staff to perform. Summary of the Invention

[0002]

[0002] The coagulation testing device described herein requires little or no laboratory skill to operate and provides personalized, evidence-based results that can aid in making treatment decisions within 15 minutes of inserting the sample tube and obtaining the results. Cases of treatment selection and dosing leading to thromboembolic events have also been reported. The device allows for in vitro testing of potential therapeutic agents, which can help determine the underlying cause of coagulation disorders and protect against the administration of drugs that may cause thromboembolic events.

[0003] The coagulation testing device described herein is an in vitro diagnostic point-of-care device for measuring clotting time and clot characteristics of whole blood samples under different hemostatic conditions. The results of the test are used as an aid in the management of patients with coagulation disorders of unknown etiology to help physicians determine appropriate clinical interventions to stop bleeding. Furthermore, the device addresses and solves an important problem in perioperative medicine by examining the effect of specific hemostatic therapeutic agents on whole blood clotting time in bleeding patients.

[0004] In current clinical practice, abnormal test results are typically addressed by educated guesswork based on experience in the course of treatment leading to administration. The coagulation testing device described herein provides physicians with personalized, clinical guidance regarding the etiology of a patient's specific coagulation disorder. The device simultaneously compares the effects of several hemostatic agents on whole blood clotting time and derives an underlying etiology based on the observed response between the hemostatic agents.

[0005] In one embodiment, a device for processing a cartridge containing a whole blood sample is disclosed herein. The device includes a recess for receiving the cartridge, a vacuum source coupled to the cartridge, an actuator coupled to the cartridge to vibrate the cartridge, and a controller. The controller is configured to: activate the vacuum source to move the whole blood sample from a container through multiple flow paths within the cartridge, then through multiple reagent chambers where the blood mixes with reagents, and then through multiple serpentine flow paths to multiple test chambers; receive signals from multiple sensors, each associated with one of the test chambers, based on the presence of a spherical member within a magnetic field generated by a magnet positioned adjacent to each of the test chambers; determine whether a clotting disorder is present in the whole blood in each test chamber; and output an indication to a display indicating whether a clotting disorder is present in the whole blood in each test chamber.

[0006] In another embodiment, a system is disclosed herein that includes a cartridge containing a whole blood sample, the cartridge including a plurality of test chambers and a metal sphere within each test chamber, and a device configured to receive the cartridge. The device includes a plurality of sensors, each sensor positioned adjacent to one of the test chambers, and a controller configured to activate a vacuum source and move the cartridge to move a portion of the whole blood sample into each of the test chambers, receive signals from each of the sensors while the cartridge is moving, determine whether the metal spheres are moving within the test chambers, determine whether the whole blood sample in each test chamber exhibits a coagulation disorder, and output an indication to a display indicating whether a coagulation disorder is present in the whole blood in each test chamber.

[0007] In a further embodiment, disclosed herein is a method for determining clotting characteristics of a whole blood sample, the method including: introducing the whole blood sample into a cartridge having multiple test flow paths, each test flow path including a reagent chamber, a test chamber, and metal spheres within each test chamber, mixing the whole blood sample with reagent in each of the reagent chambers, vibrating the cartridge, detecting movement of the metal spheres within each of the test chambers with two sensors positioned adjacent each of the test chambers, determining, by a controller, one or more clot characteristics of the whole blood sample based on the detection of movement of the metal spheres, and generating an indicia of the clot characteristics for display to a user.

[0008] Other aspects of the invention will become apparent by consideration of the detailed description and accompanying drawings. [Brief explanation of the drawings]

[0009] [Figure 1]

[0009] FIG. 1 is a perspective view showing a coagulation testing device according to one embodiment. [Figure 2]

[0010] FIG. 2 is a block diagram showing the coagulation testing device shown in FIG. 1. [Figure 3]

[0011] 2 is a perspective view of the coagulation test device shown in FIG. 1 with the test cartridge and protective cover removed. [Figure 4]

[0012] 2 is a perspective top view showing a test cartridge with a sample tube inserted therein, used with the coagulation test device shown in FIG. 1. FIG. [Figure 5A]

[0013] 5 is a perspective view showing a fluid path of the test cartridge shown in FIG. 4. [Figure 5B]

[0014] 5 is a rear perspective view of the test cartridge shown in FIG. 4, showing the hydrophobic membrane. [Figure 6]

[0015] FIG. 1 is a perspective view of a coagulation testing device with a test cartridge in place prior to testing. [Figure 7]

[0016] 5 is an enlarged cross-sectional view showing a test chamber and a spherical member in the test cartridge shown in FIG. 4. [Figure 8]

[0017] 1 is a graphical representation of the relationship between the velocity of movement of a spherical member within a test chamber and the resulting shear rate applied to a blood sample within the test chamber. [Figure 9]

[0018] FIG. 10 is a diagram showing the difference in magnetic field diagrams. [Figure 10]

[0019] FIG. 10 graphically illustrates sensor detection of a spherical member within a testing chamber. [Figure 11]

[0020] 2 is a flowchart showing a method of operation of the coagulation testing device shown in FIG. 1. [Figure 12]

[0021] FIG. 1 shows a decision tree for determining the cause of a coagulopathy based on the response to a hemostatic reagent. [Figure 13]

[0022] FIG. 12 graphically illustrates the sensor signal at the onset of clot formation. [Figure 14]

[0023] 10A-10C are graphical illustrations of detecting movement of a spherical member within a test chamber when a weak blood clot is present within the test chamber. DETAILED DESCRIPTION OF THE INVENTION

[0010]

[0024] Before describing embodiments of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0011]

[0025] The following description and accompanying drawings describe and illustrate one or more embodiments. These embodiments are not limited to the specific details described herein and may be modified in various ways. Other embodiments not described herein may exist. Furthermore, functionality described herein as being performed by a single component may also be performed by multiple components in a distributed manner. Similarly, functionality performed by multiple components may be integrated and performed by a single component. Similarly, a component described as performing a particular function may also perform additional functions not described herein. For example, a device or structure "configured" in a particular way is configured in at least that way, but may also be configured in a manner not described. Furthermore, some embodiments described herein may include one or more electronic processors configured to perform the described functions by executing instructions stored on a non-transitory computer-readable medium. Similarly, the embodiments described herein may be implemented as a non-transitory computer-readable medium storing instructions executable by one or more electronic processors to perform the described functions. As used in this application, "non-transitory computer-readable medium" includes any computer-readable medium, but does not consist of a transitory, propagating signal. Thus, a non-transitory computer-readable medium may include, for example, a hard disk, a CD-ROM, an optical storage device, a magnetic storage device, a ROM (read-only memory), a RAM (random access memory), a SIM card, a register memory, a processor cache, or any combination thereof.

[0012]

[0026] Furthermore, the phraseology and terminology used herein are for descriptive purposes and should not be considered limiting. For example, the use of "including," "containing," "comprising," "having," and variations thereof herein is intended to encompass the preceding items and their equivalents and additional items. The terms "connected" and "coupled" are used broadly and encompass both direct and indirect connections and couplings. Furthermore, "connected" and "coupled" are not limited to physical or mechanical connections or couplings, but may include electrical connections or couplings, whether direct or indirect. Furthermore, electronic communications and notifications may occur using wired connections, wireless connections, or combinations thereof, and may be transmitted over various types of networks, communication channels, and connections directly or through one or more intermediary devices. Furthermore, relational terms such as first and second, above and below, etc., may be used herein solely to distinguish one entity or operation from another, without necessarily requiring or implying any actual relationship or order between such entities or operations. The articles "a" and "an" are used herein to refer to one or to more than one (at least one) of the grammatical object of the article. For example, "an element" means at least one element and may include a plurality of elements. Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0013]

[0027] Embodiments are described herein with reference to flowchart diagrams and / or block diagrams and / or drawings. The flowcharts, block diagrams, and other diagrams in this disclosure illustrate the architecture, functionality, and operation of possible implementations of systems, methods, computer program products (non-transitory computer-readable media that store executable instructions for an electronic processor, such as a microprocessor, to perform a set of functions), and the like, according to various embodiments of the present invention. In this regard, each block in a flowchart or block diagram herein or the accompanying drawings may represent a module, segment, or portion of instructions, including one or more executable instructions for implementing the specified logical function(s). In some alternative implementations, the functions depicted in the blocks or diagrams may occur in a different order than that depicted in the figures. For example, two blocks shown in succession may actually be executed substantially in parallel, depending on the functionality involved, or the blocks may be executed in the reverse order, as the case may be. It will also be understood that each block in the block diagrams and / or flowchart diagrams and / or drawings, and / or combinations of blocks in the block diagrams and / or flowchart diagrams and / or drawings, may be implemented by a dedicated hardware-based system that performs the specified functions or operations, or may embody a combination of dedicated hardware and computer instructions.

[0014]

[0028] Various terms are used herein that are well understood by those skilled in the art, and the intended meanings of these terms do not deviate from their generally accepted meanings.

[0015]

[0029] The terms anticoagulant or anticoagulant are sometimes used interchangeably and refer to compositions added to or present in a biological sample that prevent natural or artificial clotting and prolong clotting time. Examples of anticoagulants include, but are not limited to, sodium citrate, hirudin, and chelating agents represented by ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), 1,2-diaminocyclohexanetetraacetic acid (DCTA), ethylenebis(oxyethylenenitrilo)tetraacetic acid (EGTA), or complexing agents such as heparin and heparin species such as heparin sulfate and low molecular weight heparin, coumarins and indanediones, factor Xa inhibitors, and thrombin inhibitors.

[0016]

[0030] As used herein, the term coagulation disorder refers to any bleeding disorder that affects the way a patient's blood clots. As used herein, the term hypercoagulability refers to a state of abnormal elevation toward clot formation. As used herein, the term hypocoagulability refers to a state of abnormal depression away from clot formation.

[0017]

[0031] As used herein, examples of excitation sources can be magnetic fields, electromagnetic fields, light, or ultrasonic energy. As used herein, an excitation sensor is a means capable of detecting the presence, absence, or change in an excitation source when affected or disturbed by a test element in a sample.

[0018]

[0032] The terms clot lysis and fibrinolysis may be used interchangeably and herein refer to the breakdown of fibrin, usually by the enzymatic action of plasmin. The terms clot integrity and clot strength may be used interchangeably and herein refer to the strength of the clot formed as a result of fibrin and reticulated platelets. As used herein, the term early thrombolysis refers to the early dissolution of the clot after formation, indicating a defect in hemostasis.

[0019]

[0033] 1 and 2 illustrate a coagulation testing device 10 according to some embodiments. The coagulation testing device 10, according to some embodiments, provides the ability to assess the clotting time and determine clot characteristics of whole blood simultaneously under multiple hemostatic conditions. As shown in FIG. 1, the coagulation testing device 10 includes a housing 14, a recessed compartment 18 configured to receive a cartridge 30, and a display 26. As shown, the recessed compartment 18 and the display 26 are positioned adjacent to one another within the housing 14, although other configurations and orientations between the recessed compartment 18 and the display 26 are possible.

[0020]

[0034] 2 , the coagulation testing device 10 also includes a vacuum source 12 supported by a housing 14 and a heater 16 supported by the housing 14. The coagulation testing device 10 further includes a controller 20 including an electronic processor 24 and a computer-readable, non-transitory memory 28. The memory 28 stores instructions that are executed by the electronic processor 24 to implement the functions of the controller 20 as described herein. The controller 20 is also coupled to a display 26 and configured to output graphical information and data. For example, in some implementations, the device 10 is configured to output specific data regarding the hemostatic reagent being tested and the whole blood clotting time of each flow path to the display 26 during the course of the test. Hemostatic agents may include fibrinogen, factor VIII, factor IX, cryoprecipitate, human plasma, factor VIII and von Willebrand factor, three-factor prothrombin complex concentrate (PCC), four-factor prothrombin complex concentrate (PCC), protamine sulfate, platelets, heparinase, factor VII, factor VIIa, and factor XIII, although other suitable hemostatic agents may also be employed. Upon completion of the test, the display 26 may also display diagnostic and other test characteristics derived from analysis of the test flow path data. The controller 20 is also coupled to the vacuum source 12 and heater 16 to control their activation and deactivation.

[0021]

[0035] Referring to FIG. 3 , recessed compartment 18 is configured to accept cartridges 30, allowing for up to 18 channels for clotting time tests in a single cartridge 30. In one configuration, cartridge 30 is approximately the size of a microtiter plate (e.g., 9.7 mm x 11.8 mm) and performs 18 individual clotting tests. Additional or fewer channels may be used within the cartridge 30 envelope. For example, for illustrative purposes, FIGS. 4 through 5B show 18 channels in cartridge 30, but cartridge 30 may include more or fewer channels. In one embodiment, device 10 accepts a sample tube containing 4.5 ml of whole blood. With 18 clotting test channels, this embodiment creates 18 aliquots of approximately 150 microliters for testing. The structure and dimensions of cartridge 30 may be modified to reduce the sample volume to 2.7 ml by reducing the size of the reagent chambers and subsequent test chambers.

[0022]

[0036] With continued reference to FIG. 3 , the recessed compartment 18 is mechanically coupled to a gear drive 38 for vibrating the cartridge 30 and the specimen therein. The gear drive 38 is in communication with the controller 20 via an actuator 32 (e.g., a motor, pump, etc.). In one embodiment, the actuator provides a vibration / oscillation rate between 90 and 180 degrees per second, with an oscillation angle between 10 and 75 degrees. The cycle period is between 1 and 5 seconds. In other embodiments, the actuator may provide a suitable oscillation rate and oscillation angle that may be below or above the parameters set forth herein. Similarly, the cycle period may be appropriately adjusted within the operating range of the device 10.

[0023]

[0037] The recessed compartment 18 also includes one or more vacuum ports 42 that interface with the cartridge 30, one or more heater regions 46 for the incubation and testing regions, a plurality of magnets 50, and a plurality of sensors 54 that communicate with the controller 20.

[0024]

[0038] One embodiment of cartridge 30 is shown in Figure 4. Cartridge 30 includes housing 58, waste collection area 62, and one or more vacuum ports 66 configured to interface with one or more vacuum ports 42 on recessed compartment 18. Cartridge 30 also includes reagent vacuum area 70, sample tube interface 74, sample tube housing 78 configured to receive sample tube 82 (shown in sample tube housing 78 in Figure 4), and test channel vacuum area 84.

[0025]

[0039] The cartridge 30 is designed for injection molding and secondary assembly operations. The cartridge 30 is sealed with a membrane that is blood-compatible and does not affect clotting. The cartridge 30 contains multiple chambers that are spaced apart from one another. A blood sample is introduced into the cartridge 30 by a vacuum source 12. A hydrophobic filter 34 (FIG. 5B) is used to stop the flow of blood once it is fully aspirated. The vacuum port 66 is at atmospheric pressure when the cartridge 30 is outside the device 10. When pressure is applied to the sample, Therefore, the sample remains in the sample tube 82 until the sample tube 82 is loaded onto the device 10 and the sample sequence begins.

[0026]

[0040] Cartridge 30 includes a common supply flow path X (shown in FIG. 5A) that connects the sample inlet to chambers containing individual hemostasis reagents. Each reagent chamber is connected to one of vacuum ports 66 through a series of hydrophobic filters 34 for each flow path. As sample is drawn into cartridge 30, each flow path fills sequentially at a flow rate set by the predetermined reduced pressure of vacuum source 12. When an individual flow path is completely filled, the hydrophobic filter 34 shown in FIG. 5B for that flow path is blocked, stopping the flow path from filling beyond its capacity. The remaining flow paths also fill until each of the filters is blocked. Controller 20 can monitor the duration of the applied reduced pressure as well as the pressure drop across the filters to determine when all of the flow paths are filled.

[0027]

[0041] The fluidic system of cartridge 30, according to some embodiments, is further described and illustrated in Figures 5A and 5B. Cartridge 30 includes a waste region 86, a sample supply channel 90 in communication with waste region 86, and one or more hemostasis reagent chambers 94 in communication with sample supply channel 90 via respective channels 98. Cartridge 30 also includes one or more serpentine mixing channels 102 at the outlet of each hemostasis reagent chamber 94. The serpentine mixing channels 102 are in fluid communication with one or more anticoagulant reversal chambers 106 (for cases where an anticoagulant is used to anticoagulate the whole blood sample), which are in turn in communication with one or more coagulation test chambers 110. As described above and illustrated herein, cartridge 30 is shown as including 18 individual test flow paths 112, each including a reagent chamber 94, a serpentine fluid path 102, and a test chamber 110, although in other configurations cartridge 30 may include more or less than 18 test flow paths 112.

[0028]

[0042] 6 illustrates a system for determining the clotting characteristics of a whole blood sample 100, including device 10 and cartridge 30. Specifically, cartridge 30 is shown in place within recessed compartment 18 of device 10. Vacuum port 42 within recessed compartment 18 communicates with vacuum port 66 on cartridge 30.

[0029]

[0043] Clot formation in whole blood or plasma can be measured in many different ways. Electrical conduction requires contact with the whole blood. Capacitive measurements do not require contact and can measure through a barrier membrane, but these techniques require some type of electrical connection to the test device to send and receive signals. The coagulation test device 10 described herein uses a non-contact measurement method in which a sphere 114 made of magnetic material is located inside each of the 18 test chambers 110 and is used to determine the viscosity of the whole blood in each test chamber 110. Figure 7 shows an enlarged cross-sectional view of the test chambers 110 and the spherical members 114 located therein. When the test chambers 110 are vibrated, the spherical members 114 rotate within the whole blood in each test chamber 110. A sensor 54 is positioned proximate to the test chambers 110 to measure the presence of the spherical members 114 in the test chambers 110 as they are vibrated by the device 10. In one configuration, the test chambers 110 have a width of 3.0 mm and a length of 18 mm to accommodate a specimen aliquot volume of approximately 150 microliters. In other configurations, the test chambers 110 may have a width of 1.5 mm and a length of 10 mm to reduce the specimen aliquot volume to approximately 70 microliters. In one exemplary configuration, the spacing between the test chambers 110 is 4.5 mm, thereby allowing 18 clotting time test channels to be incorporated within the envelope of the cartridge 30. Other suitable dimensions are possible within the scope of the devices described herein.

[0030]

[0044] The speed of movement within the test chamber 110 is detected by the spherical member 114. This is done by measuring the change in magnetic flux as the magnetic field passes near a sensor 54 positioned along the path of the test chamber 110. The sensor 54 does not require contact with the test chamber 110 and can be spaced up to 0.8 mm from the test chamber surface. The sensor 54 detects a signal from each test chamber 110 generated within the housing 58 of the cartridge 30. This non-contact measurement method allows for complete separation between the cartridge 30 and the device 10, thereby eliminating the need for the device 10 to come into contact with the whole blood sample. This configuration also eliminates the need for device cleaning or maintenance steps between samples. It also eliminates the possibility of the device failing due to blood clots in the device's fluid pathways.

[0031]

[0045] Each test chamber 110 is associated with two sensors 54, spaced a distance (e.g., 9.5 mm) apart and linearly positioned along the path of travel of the spherical member 114 within the test chamber. Referring to FIG. 9 , each sensor 54 comprises a magnetic member 118 (e.g., comprised of one or more rare earth metals) of sufficient magnetic field strength to extend into the test chamber region and to a Hall Effect sensor 122 positioned between the magnetic member 118 and the test chamber 110. The Hall Effect sensor 122 generates a voltage signal proportional to the magnetic field between 8 and 10 millivolts per gauss. At the start of an oscillation cycle, the controller 20 records a baseline static reading of the magnetic field for each sensor 54. This baseline measurement is used to set the amount of magnetic field disturbance as the spherical member 114 passes over the sensor 54. As the spherical member 114 passes over the sensor 54, it creates a disturbance in the static magnetic field that is detected by the sensor 54. This magnetic flux disturbance is detected by the Hall effect sensors 122 and converted to a voltage. The voltage signal from each sensor 54 is then sent to the controller 20. A signal threshold is set to remove signal artifacts. The voltage signals from the sensors 54 are converted to digital signals by a series of analog-to-digital converters. Because there are two sensors 54 positioned per test chamber 110, the time between the peaks of the disturbances from the two sensors 54 is directly related to the transit time of the spherical member 114 within the test chamber 110. In this manner, the viscosity of the fluid within the test chamber 110 can be tracked as the device 10 vibrates the test chamber 110 and passes the spherical member 114 past the sensors 54 over a period of time. Figure 9 shows magnetic field maps illustrating the interaction with the test chamber 110 and the spherical member 114. As shown in Figure 9, the map on the left shows how the spherical member generates more field lines than the map on the right, where no spherical member is present.

[0032]

[0046] The test chambers 110, sensors 54, and controller 20 determine the transit time of the spherical member 114 within each test chamber at a predetermined, programmable vibration rate. The viscosity of the fluid within each test chamber 110 is proportional to the transit time within that chamber. Therefore, the progression of clotting can be viewed as the relationship between the increase in fluid viscosity and time. The clotting cascade is truly a cascade of events and is therefore nonlinear. By tracking the transit time of the device 10, it is possible to detect and monitor the quiescent blood state as it approaches clotting. Shortly after this initial onset of clotting, the fluid rapidly approaches high viscosity by forming a clot, as shown in Figure 13. The angle of the trajectory from the fluid state to clot formation is also measured and used as a basis for diagnosing a clear cause or deficiency of crystalline platelet function.

[0033]

[0047] In addition to clotting time, device 10 can determine the integrity or strength of a forming clot. Each test chamber 110 in device 10 has two independent sensors 54 (as described above), which allow for calculation of transit time. If the spherical member 114 is unable to cross both sensors 54 within the test chamber, transit time cannot be calculated. This is indicative of a clot that is preventing the spherical member 114 from fully moving within the test chamber 110. However, because the force of gravity acting on the spherical member 114 within the test chamber is less than 1 G, the spherical member 114 may be held back by a weak clot, which will cause the spherical member 114 to continue moving only a limited distance along the entire length of the chamber. Device 10 can calculate both The signals from the sensors 54 can be monitored to detect that one of the two sensors 54 continues to emit a signal. This signal indicates a weak clot that is preventing the spherical member 114 from moving the full length of the test chamber 110, but still allowing the spherical member 114 to move. As shown in FIG. 14, only one of the two sensors continues to indicate movement of the spherical member 114.

[0034]

[0048] 14 shows the spherical member 114 crossing only one of the sensors 54 with each cartridge oscillation or duty cycle, indicating a weak clot. The frequency with which the spherical member 114 is detected by one of the two sensors 54 indicates the integrity of the clot, with a higher frequency of signal generation indicating a weak clot. A decrease in the number of single sensor signals indicates an increase in clot strength. A lack of movement of the spherical member 114 indicates a strong clot after clot formation, resulting in a frequency of zero or a frequency below a threshold set by the device 10. The device 10 sets a cutoff value for clot integrity.

[0035]

[0049] In one embodiment, the duty cycle of the spherical member 114 is proportional to the integrity of the clot, with a duty cycle above 40% indicating a significantly weaker clot, a duty cycle between 25% and 40% indicating a slightly weaker clot, a duty cycle between 10% and 25% indicating a slightly stronger clot, and a duty cycle between 0% and 10% indicating a stronger clot.

[0036]

[0050] The relative size of the spherical members 114 within the test chamber and the diameter of the test chamber favor clotting in a manner similar to physiological clotting mechanisms. Shear stress within the human vasculature is known to promote clotting. Many clotting test systems require the addition of high surface area procoagulants, such as celite or kaolin, to shorten normal clotting times to levels that meet the need for rapid clotting times. The methods and apparatus described herein allow for the creation of a 500 s clotting time within each test channel. -1 and 4,000 seconds -1The system eliminates the need for procoagulants by generating physiological shear rates and shear stresses between 100 and 1,000 dynes per second. Figure 8 shows the relationship between the speed of movement of the spherical member 114 within the test chamber 110 and the resulting shear rate, based on the diameter of the test chamber 110 and the relative size of the spherical member 114 within the test chamber. The shear rate can be adjusted by changing the oscillation angle, the diameter of the test chamber, and the relative diameter of the spherical member. However, if a more rapid time to test results is desired, the system can also be used with the addition of procoagulants such as kaolin, citrate, tissue factor, phospholipids, or other suitable activators.

[0037]

[0051] Referring to FIG. 11 , sample processing begins (at 200) with powering on the device 10. The device 10 undergoes a quality control test (at 204). The device 10 performs quality checks to ensure all electromechanical subsystems are in good working order. Subsystems such as the vacuum system, temperature measurement element, and magnetic sensor are all tested before the user can begin a sample test. Additionally, the device is provided with a reusable QC cartridge, which the device vibrates in a manner similar to a sample test to ensure all electromechanical systems are operating properly. The reusable cartridge test results are recorded in the controller or memory. The QC cartridge is removed, and the device is ready to accept the next patient sample. The device 10 then identifies (at 208) the sample tube (filled with whole blood from the patient, the sample tube containing a unique barcode). The device 10 allows for the entry of all information necessary to run the test without operator input. The device 10 may include a barcode scanner 40 in communication with the controller 20. The operator places the barcode of the sample tube in front of the scanner 40. The scanner 40 records the barcode and specimen information in memory 28 or other storage device (e.g., a database local or remote to device 10). The device 10 has an override feature that can allow manual entry of patient information via the display 26 (e.g., a touchscreen). The patient specimen must also be associated with a test cartridge 30. The operator places the barcode on the cartridge in front of the scanner 40. The scanner 40 records the cartridge 30 information in memory 28 or other storage device (e.g., a database local or remote to device 10). If the specimen tube does not have a barcode, the operator can be prompted to enter the information via an on-screen keyboard on the display 26.

[0038]

[0052] A sample and cartridge 30 are loaded into the device 10 (at 212), and the operator identifies the sample and cartridge 30 via the user interface on the display 26 (at 216). A cover 130 on the device is lowered onto the recessed compartment 18. The cover 130 includes a vacuum connection that interfaces with the vacuum port 66 on the cartridge 30, necessary to move fluid through the cartridge 30 during sample processing and before initiating a clotting time test. The vacuum port 66 on the cartridge 30 is connected to the vacuum port 42 of the device 10 by the act of closing the cover 130. The cover 130 also applies pressure to the cartridge 30 to maintain a uniform distance between the cartridge 30 and the sensor 54 within the device 10. The operator initiates a test sequence via the user interface on the display 26.

[0039]

[0053] To allow for time between sample collection and sample testing, samples presented to device 10 are typically anticoagulated, as is common practice in most blood testing procedures. Device 10 can also test non-anticoagulated samples using cartridges that do not contain an anticoagulant reversal agent (e.g., calcium), but there are time constraints for loading the non-anticoagulated sample into cartridge 30 and placing it in device 10.

[0040]

[0054] Cartridge 30 is configured to accept a sample vacuum draw tube (e.g., a vacuum container with a flexible cap) as a sample injection device within sample tube housing 78. This eliminates the need to pipette the sample into cartridge 30, a process common in laboratory instruments but not required by device 10. An operator inserts the sample draw tube directly into cartridge 30 (within sample tube housing 78) and places cartridge 30 in recessed compartment 18 of device 10. Cartridge 30 prevents blood sample migration into the cartridge by controlling the outlet path to prevent opening before placement in device 10. The sample within the tube is accessed by one or more needles (e.g., two needles) that pierce the flexible cap. An operator inserts the sample tube into a sample tube receptacle on the cartridge. With gentle insertion force, the needle assembly pierces the sample tube cap. When a vacuum is applied, one needle functions to aspirate the sample, while the other needle functions as an outlet, allowing blood to flow out of the draw tube.

[0041]

[0055] The device 10 processes the sample using (at 220) a known set of pre-programmed parameters. The first step is to pierce the flexible cap to draw blood from the sample tube, filling the sample supply channel 90 and the connected reagent-containing chamber 94. Blood moves from the sample tube into the cartridge 30 at point X (shown in FIG. 5A), filling the sample supply channel 90 and beginning to fill the reagent-containing chamber 94. The controller 20 activates the vacuum source 12 in the housing 14 to apply a vacuum to the blood sample in the cartridge. A pressure regulator along with the vacuum pump is read by the device 10 so that the pressure is controlled to a predetermined value. Typical vacuum levels for sample aspiration are between 50 millibars (mb) and 100 mb. In this sequence, the initial sample is divided into 18 equally separated aliquots of blood sample.

[0042]

[0056] The controller 20 selects the specific valve in the vacuum port 66, thereby controlling the direction of the vacuum. The blood sample continues to move through the various flow paths within the cartridge 30. The reagent chambers 94 contain individual doses of various hemostatic agents. These hemostatic agents are dried and remain in the reagent chambers 94 as part of the manufacturing process. The drying method can be lyophilization or air drying, depending on the properties of the reagent. The cartridge is designed such that the vacuum source 12 draws the blood sample from the bottom of the reagent chambers 94 into the reagent chambers 94 and to the top of the chambers. The dried reagent is rehydrated by the incoming blood sample volume (at 224). Each reagent chamber 94 contains a hydrophobic filter that prevents the reagent chamber from overfilling. The device 10 applies vacuum for a predetermined period of time or monitors the pressure drop across the hydrophobic filters until all hydrophobic filters are blocked.

[0043]

[0057] Each analyte-reagent complex must be isolated from its nearest neighbor to avoid cross-contamination. After filling an individual reagent chamber 94, the device 10 empties the analyte supply channel 90 connecting the reagent chambers 94 by closing the valve used to direct the analyte into the reagent chamber 94 and opening the valve that directs the contents of the analyte supply channel 90 to the waste region 62 within the cartridge 30. The absorbent material collects waste from the supply channel 90. Each analyte aliquot is then separated from its neighboring reagent chamber 94 by a wide gap created by the empty supply channel 90.

[0044]

[0058] Coagulation is a temperature-dependent phenomenon. The controller 20 supplies thermal energy to the cartridge 30 (via the heater region 36 of the recessed section 18) to activate the heater 16 to bring the specimen aliquot in the reagent chamber 94, which has a typical test temperature of 37°C, to a programmable temperature value between 25°C and 40°C. This range allows for testing of specimens under normal, hypothermic, and hyperthermic conditions. The specimen aliquot is incubated with the hemostatic agent for a programmable period, typically between 1 and 10 minutes. In other embodiments, the specimen aliquot is incubated with the hemostatic agent for between 3 and 5 minutes. This allows the temperature of the specimen aliquot to equilibrate to the proper temperature and allows the hemostatic agent to completely dissolve and diffuse into the specimen aliquot.

[0045]

[0059] At this point, the blood sample and reagent are anticoagulated to prevent the blood sample from beginning to clot until all sample aliquots are ready for testing. Before starting the clotting time test for each test flow path, the anticoagulant must be reversed. A serpentine flow path 102 connects the reagent chamber 94 to the test chamber 110. The narrow diameter of the serpentine increases the fluid velocity as it moves from the reagent area to the test area. A precise amount of dried or lyophilized calcium lies along the flow path of each flow path. The moving fluid rehydrates the calcium, which mixes with the sample aliquot as it moves. The cartridge 30 contains a discrete amount of calcium in each flow path just before the sample enters the test area. The calcium mixes with the aliquot as it advances to the test area. The anticoagulant in each aliquot is then reversed, initiating the clotting cascade.

[0046]

[0060] The controller 20 sends a signal (at 228) to redirect the vacuum source 12 via a valve, directing the flow of the specimen aliquot from the reagent chamber 94 to the test chamber 110. Typical vacuum levels are between 50 mb and 100 mb. To facilitate filling of the flow path and minimize the possibility of trapping air bubbles within the test chamber 110, the cartridge 30 and test chamber 110 are positioned at an angle between 10 and 40 degrees relative to the horizontal position of the cartridge when placed in the device. Each test chamber 110 has a hydrophobic filter aligned with the vacuum source 12 to prevent overfilling of the test chamber and drawing blood into the device vacuum system.

[0047]

[0061] With all (or a portion) of the test chambers 110 filled and the anticoagulation state of the specimen aliquot reversed, the controller 20 activates (at 232) the actuator 32 to begin oscillation of the cartridge 30 about its central axis about the test channel 110 and initiate a coagulation test. This action causes the spherical members 114 within the cartridge 30 to uniformly rotate from one end of the test channel to the other. Each oscillation cycle causes the spherical members 114 within each test channel to pass over the sensors 54 associated with each channel 110, generating signals proportional to the viscosity of the blood specimen within each test channel 110. The sensors 54 transmit the generated signals to the controller 20.

[0048]

[0062] As described above, device 10 uses a non-contact method to detect the movement and transit time of spherical member 114 within the cartridge flow channel. The current method uses the magnetic properties of a 400 series stainless steel ball, although other non-contact detection methods such as ultrasonic, electromagnetic, or optical may also be used.

[0049]

[0063] Each sensor 54 includes a pair of neodymium-iron-boron rare-earth magnets 118 and two Hall-effect sensors 122, one for each flow path 110. Each magnet 118 is spaced approximately 9.5 mm apart along the linear path of each test flow path and generates a localized magnetic field that passes through the Hall-effect sensor 122 and into that specific region of the cartridge 30. As a magnetic stainless steel ball passes through the magnetic field, the Hall-effect sensor 122 detects a change in magnetic flux above the static baseline signal caused by the presence of the magnetic ball, generating a voltage. The device measures the baseline (static) magnetic signal at the start of each cycle. The voltage from each sensor 54 (if any) is sent to the controller 20 for further processing.

[0050]

[0064] Other excitation sources and sensor technologies can be employed to measure clotting activity in each flow path, but may be subject to inter-flow path crosstalk. Ultrasonic sensors can also be used in each flow path. In this case, the spherical members 114 in each flow path do not need to be magnetic, but they must be of a density much greater than whole blood so that the ultrasonic reflection is large enough to receive a signal. Electromagnetic sensors, similar to miniature metal detectors, can also be used. In this case, the spherical members need to be conductive but not magnetic. Optical detection of spherical members can also be used. In this case, a reflective sensor element providing an excitation light source and an adjacent photodetector would detect the reflection of the spherical member as it passes over the optical sensor. The advantage of using magnetic detection is that it is self-isolating, since the magnetic fields between the flow paths are all of the same polarity and do not interfere with adjacent flow paths at a close separation distance of 4 mm.

[0051]

[0065] During the first few minutes of the test, a baseline or normal viscosity of the sample aliquot is established. As fibrin begins to form in each of the test channels, a viscosity increase of between 10% and 20% is observed and recorded by the controller 20. Shortly after this increase, the clotting cascade progresses rapidly, reaching a point where the viscosity of the sample in a given channel exceeds the ability of the spherical member to pass through the sample. The sensor 54 along that particular channel 110 detects the elimination of generated voltage. The controller 20 interprets this as clot formation and records the time of clot. The test proceeds until all channels clot or the preprogrammed maximum test time is reached (e.g., the test is complete at 236).

[0052]

[0066] As previously mentioned, clot integrity or strength is also considered when considering clotting time and determining complete clots. Only clotting times associated with firm clots are considered in determining the cause of coagulation disorders. Physical observation of a weak clot reveals small fibers formed around the spherical member that prevent the sphere from traveling the entire length of the test flow path, but allows the spherical member to travel a short distance and across one of two sensors in the test flow path. In contrast, a highly complete clot is considered when determining the cause of coagulation disorders. An intact clot completely captures the spherical member, allowing little or no movement after clot formation.

[0053]

[0067] After clot formation, the clot integrity can be assessed by the sensor signal. Clot formation is determined when the sensors 54 no longer detect two sensor peaks for each device vibration cycle. In a clot of high integrity / strength, neither sensor 54 generates a signal after clot formation. In a clot of low integrity, a weak clot, one of the sensors 54 continues to generate a signal, indicating that the clot has displaced the spherical member 114 a limited distance. Clot integrity is quantified by examining the average signal in the flow path from the time the clot first forms to the end of a programmable test period between 300 and 1,800 seconds, when at least one sensor reports no signal. The lower the number, the higher the clot integrity. A high-integrity clot produces a value between zero and 100. A medium-integrity clot produces a value between 101 and 400. A low-integrity clot produces a clot strength value above 401, even as high as 2,000.

[0054]

[0068] The device 10 compares clotting time and clot integrity to two untreated or reference flow paths within the cartridge 30 against a flow path containing a therapy. Other clotting tests determine clotting time in seconds and compare it to a preset clotting time range. The device 10 examines clotting time relative to a reference sample flow path, in the form of a clotting time ratio, as a way to determine response to various hemostatic agents. A value of 1.0 indicates no difference between the hemostatic agent and the reference sample flow path. A value less than 1.0 indicates a shortening of clotting time compared to the reference flow path, while a value greater than 1.0 indicates an increase in clotting time. The coefficient of variation (CV) for clotting time can be as high as 12%, and therefore the threshold for a "response" to a reagent is based on a shortening greater than this CV. A shortening of clotting time normalized to the reference flow path of more than 20% due to a high-integrity clot (below 100) is considered a reasonable response to a reagent in a particular flow path. If the clotting time of a test chamber is below the lower limit of a preset normal range (typically between 120 and 270 seconds), the result for that chamber is indicated as possibly hypercoagulable. If the clotting time is above the upper limit of the established normal range, the test chamber is designated as hypocoagulable.

[0055]

[0069] The etiology of the coagulation disorder is determined by the aforementioned clotting time ratio and clot strength of each test chamber 110 compared to a reference sample aliquot contained within the cartridge 30. The combination of information on hemostatic agents that shorten clotting time and those that do not shorten clotting time isolates a specific etiology or group of factors that may be deficient and causing the coagulation disorder. For example, referring to the decision tree in FIG. 12, if the cartridge 30 and sample respond with a shortened clotting time in the cryoprecipitate flow path (indicated by a ratio <0.8) but not in the factor VIII flow path (indicated by a ratio >0.8), the deficiency may be von Willebrand factor or fibrinogen, since cryoprecipitate contains all three coagulation factors. Similarly, if the sample responds to the fibrinogen flow path and the cryoprecipitate flow path but not to the factor VIII or VIII / vWF complex flow paths, the determination may be fibrinogen deficiency.

[0056]

[0070] These responses to various hemostatic agents form a pattern or signature indicative of a particular condition that is reported at the end of the test sequence. The display 26 can provide a visual display of the clotting time and ratio to an untreated reference flow path for each flow path. The display 26 can also provide a deficiency or diagnosis of the results, subject to interpretation by a physician, regarding the possible cause of the coagulation disorder based on the clotting time, clotting ratio, and clot strength across all test flow paths. The analysis performed by the controller is multivariate in nature, examining all flow path data in determining the etiology of the coagulation disorder. The device 10 can also include a printer to print the information and data output on the display 26. A threshold ratio to the reference flow path sets the response to therapy. A unique relationship between flow paths of up to 12% is possible. Because there is variability, thresholds are set to take this into account. A response to the hemostatic reagent is defined as a ratio greater than a predetermined threshold (e.g., a 20% or greater change compared to the reference flow path).

[0057]

[0071] The device 10 can also be used to examine how a clot breaks down after clot formation has been established. Typically, there is a process called fibrinolysis, in which the clot naturally dissolves. In the device 10 described herein, the cartridge 30 can continue to vibrate for approximately 30 to 60 minutes, while monitoring for the spherical member 114 to resume movement. While this should not occur in a normal specimen, some patients, such as trauma patients, may become hyperfibrinolytic, in which the clot dissolves too quickly and bleeding begins again.

[0058]

[0072] An initial vibration cycle of between 1 and 2 seconds allows sufficient time for the spherical member 114 to travel from one end of the cartridge 30 to the other. As clot formation begins, the viscosity of the specimen aliquot increases, increasing the travel time. The device can apply an adaptive approach to vibration cycle parameters.

[0059]

[0073] For completeness, various aspects of the invention are described in the following numbered paragraphs.

[0074] Item 1. A cartridge containing a whole blood sample, the cartridge including a plurality of test chambers and a metal sphere within each test chamber; a device configured to receive the cartridge, The device is a plurality of sensors, each sensor positioned adjacent one of the test chambers; a controller; The controller activating a vacuum source to move a portion of the whole blood specimen into each of the test chambers; Move the cartridge receiving a signal from each of the sensors while the cartridge is moving; determining whether the metal sphere is moving within the inspection chamber; determining whether the whole blood specimen in each test chamber exhibits a coagulopathy; The system is configured to output an indication on a display indicating whether or not a coagulopathy is present in the whole blood in each test chamber.

[0060]

[0075] Item 2. The system of item 1, wherein each sensor includes a magnet and a Hall Effect sensor.

[0076] Item 3. The system of item 2, wherein the magnet generates a magnetic field in the vicinity of an inspection chamber associated with the magnet, the metal sphere within the inspection chamber generates a disturbance in the magnetic field, and the sensor detects the disturbance and sends a signal to the controller to determine whether the sphere is moving within the inspection chamber.

[0061]

[0077] Item 4. The system of item 1, further comprising a plurality of vacuum ports in the cartridge selectively coupled to a vacuum source, and further comprising a plurality of hydrophobic filters along each of the vacuum ports.

[0062]

[0078] Item 5. The system of item 4, wherein the cartridge includes multiple reagent chambers, one reagent chamber associated with one of the test chambers, and the hydrophobic filter is configured to stop the flow of blood when each of the reagent chambers is filled.

[0063]

[0079] Item 6. The system of item 5, wherein the device further includes a heating element configured to apply thermal energy to the cartridge and the whole blood sample.

[0080] Item 7. The heating element heats the whole blood sample to a temperature between 34°C and 37°C. Item 6. The system according to item 6.

[0064]

[0081] Item 8. The system of item 6, wherein the heating element heats the whole blood sample to a temperature between 30 degrees Celsius and 33 degrees Celsius.

[0082] Item 9. The system of item 7, wherein the whole blood specimen is mixed with the reagent in each of the reagent chambers and incubated for between 1 minute and 10 minutes.

[0065]

[0083] Item 10. The system of item 9, wherein the reagent in each of the reagent chambers is separated from adjacent reagent chambers.

[0084] Item 11. The system of item 1, wherein the controller is further configured to determine the length of time until clot formation in each of the test chambers.

[0066]

[0085] Item 12. The system of item 11, wherein the length of time is based on how long a sensor associated with one of the test chambers detects movement of the metal sphere.

[0086] Item 13. The system of item 1, wherein each test chamber includes two of the sensors.

[0067]

[0087] Item 14. The system of item 13, wherein the controller is further configured to determine clot formation.

[0088] Item 15. The system of item 14, wherein clot formation is determined when the controller detects the absence of two peaks in each oscillation cycle, indicating that the metal sphere has stopped moving within the test chamber.

[0068]

[0089] Item 16. The system of item 14, wherein the controller is further configured to determine clot integrity.

[0090] Item 17. The system of item 16, wherein a high integrity clot is determined when neither of the two sensors generates a signal after clot formation.

[0069]

[0091] Item 18. The system of item 16, wherein a low integrity clot is determined when one of the two sensors continues to generate a signal indicating that the clot is allowing the metal sphere to travel a limited distance.

[0070]

[0092] Item 19. The system of item 16, wherein the clot integrity is based on the average signal in the test chamber generated by the two sensors from the time the clot is formed to the end of the test.

[0071]

[0093] Item 20. The system of item 5, wherein the cartridge includes 18 test chambers.

[0094] Item 21. The system of item 20, wherein each of the 18 test chambers is associated with one of the reagent chambers, and each of the 18 test chambers receives a whole blood-reagent complex from the associated reagent chamber.

[0072]

[0095] Item 22. The system of item 1, wherein the metal sphere in each test chamber passes over a sensor associated with each test chamber to generate a signal proportional to the viscosity of the whole blood specimen in each test chamber.

[0073]

[0096] Item 23. The system of item 1, wherein the controller is further configured to determine a diagnosis based on the coagulation disorder result.

[0097] Item 24. The system of item 23, wherein the controller is further configured to output the diagnosis on a display.

[0074]

[0098] Item 25. A device for processing a cartridge containing a whole blood sample, a recess for receiving a cartridge; a vacuum source coupled to the cartridge; an actuator coupled to the cartridge for vibrating the cartridge; a controller; The controller activating a vacuum source to move the whole blood specimen from the container through a plurality of channels in the cartridge, then into a plurality of reagent chambers where the blood mixes with reagent, then through a plurality of serpentine channels and into a plurality of test chambers; activating an actuator to vibrate the cartridge; receiving, from a plurality of sensors, each sensor associated with one of the test chambers, a signal based on the presence of the spherical member within a magnetic field generated by a magnet disposed adjacent to each of the test chambers; determining whether a coagulopathy is present in the whole blood in each test chamber; The device is configured to output an indication to a display indicating whether or not a coagulopathy is present in the whole blood in each test chamber.

[0075]

[0099] Item 26. The device of item 25, further comprising a plurality of vacuum ports in the cartridge selectively coupled to a vacuum source, and further comprising a plurality of hydrophobic filters along each of the vacuum ports, the hydrophobic filters configured to stop blood flow when each of the reagent chambers is filled.

[0076]

[0100] Item 27. A method configured to apply thermal energy to a cartridge and a whole blood sample. 26. The device of claim 25, further comprising a heating element.

[0101] Item 28. The heating element heats the whole blood sample to a temperature between 34°C and 37°C. Item 28. The device according to item 27.

[0077]

[0102] Item 29. The heating element heats the whole blood sample to a temperature between 30°C and 33°C. Item 28. The device according to item 27.

[0103] Item 30. The whole blood sample is mixed with the reagent in each of the reagent chambers and left for 1 minute. 29. The device of item 28, wherein the device is incubated for between 1 and 10 minutes.

[0078]

[0104] Item 31. The reagent in each of the reagent chambers is transferred from the adjacent reagent chamber. 31. The device of item 30, wherein the device is spaced apart.

[0105] Item 32. The controller determines the time until clot formation in each of the test chambers. Item 26. The device of item 25, further configured to determine the length of time.

[0079]

[0106] Item 33. The length of time is determined by measuring the time of a sensor associated with one of the test chambers. Item 33. The device of item 32, wherein the detection is based on how long the spherical member moves.

[0107] Item 34. The device according to Item 25, wherein each test flow path includes two of the sensors. vinegar.

[0080]

[0108] Item 35. The controller is further configured to determine clot formation. The device described in item 34.

[0109] Item 36. The device of item 35, wherein clot formation is determined when the controller detects the absence of two peaks in each oscillation cycle, indicating that the spherical member has stopped moving within the test chamber.

[0081]

[0110] Item 37. The controller is further configured to determine clot integrity. Item 36. The device according to item 35.

[0111] Item 38. High completion is achieved when neither of the two sensors generates a signal after clot formation. 38. The device according to item 37, wherein the integrity of the blood clot is determined.

[0082]

[0112] Item 39. One of the two sensors detects the blood clot moving across the spherical member for a limited distance. 38. The device of claim 37, wherein a low integrity clot is determined if the device continues to emit a signal indicating that the clot is being moved.

[0083]

[0113] Item 40. Clot integrity is the measurement of two events from the time a clot is formed to the end of the test. Item 38. The device of item 37, based on an average signal in the test chamber generated by the sensor.

[0084]

[0114] Item 41. The cartridge according to Item 25, wherein the cartridge contains 18 test chambers. Vice.

[0115] Item 42. Each of the 18 test chambers is connected to one of the reagent chambers. Item 42. The device of item 41, wherein each of the 18 test chambers receives a whole blood-reagent complex from an associated reagent chamber.

[0085]

[0116] Item 43. The spherical member in each test chamber controls the viscosity of the whole blood sample in each test chamber. 26. The device of claim 25, wherein the temperature is passed over a sensor associated with each test chamber to generate a signal proportional to the temperature.

[0086]

[0117] Item 44. The controller determines the diagnosis based on the results of the coagulation disorder. Item 26. The device of item 25 further configured.

[0118] Item 45. The controller is further configured to output diagnostics on the display. Item 26. The device according to item 25,

[0087]

[0119] Item 46. A method for determining the coagulation characteristics of a whole blood sample, comprising: introducing a whole blood sample into a cartridge having a plurality of test channels, each test channel including a reagent chamber, a test chamber, and a metal sphere within each of the test chambers; mixing the whole blood sample with the reagent in each of the reagent chambers; vibrating the cartridge; detecting movement of the metal sphere within each of the test chambers with two sensors positioned adjacent to each of the test chambers; determining, by the controller, one or more clot characteristics of the whole blood sample based on the detection of the movement of the metal spheres; and generating an indicator indicative of the clot characteristics for display to a user.

[0088]

[0120] Item 47. Reverse the anticoagulant in the whole blood sample before it enters the test chamber. Item 47. The method according to item 46, further comprising the step of:

[0121] Item 48. The cartridge contains calcium. In addition, the whole blood sample is Item 48. The method of item 47, wherein the calcium is contacted between the outlet of the test chamber and the inlet of the test chamber.

[0089]

[0122] Item 49. Determining one or more clot characteristics is performed by measuring the clot characteristics of the whole blood sample. Item 47. The method of item 46, comprising determining the formation.

[0123] Item 50. The step of determining blood clot formation involves moving a metal sphere in the test chamber. Item 49. The method of item 49, comprising the step of the controller detecting the absence of two peaks in each vibration cycle, which indicates that the vibration has stopped.

[0090]

[0124] Item 51. The method according to Item 50, wherein one of the clot properties is clot integrity.

[0125] Item 52. High completion is indicated when neither of the two sensors generates a signal after clot formation. 52. The method of claim 51, wherein the integrity of the clot is determined.

[0091]

[0126] Item 53. One of the two sensors detects a blood clot moving over a limited distance through a metal sphere. 52. The method of claim 51, wherein a low integrity clot is determined if the blood vessel continues to emit a signal indicating that the blood vessel is capable of moving.

[0092]

[0127] Item 54. Clot integrity is the measurement of two events from the time a clot is formed to the end of the test. Item 52. The method of item 51, based on an average signal in the test chamber generated by the sensor.

[0093]

[0128] Item 55. The step of vibrating the cartridge is to vibrate the cartridge in a predetermined dura Item 52. The method of item 51, comprising oscillating the metal sphere in a duty cycle, wherein the duty cycle of the metal sphere is based on detecting movement of the metal sphere.

[0094]

[0129] Item 56. The duty cycle of the metal sphere is proportional to the clot integrity. The method described below.

[0130] Item 57. Clot integrity is improved when the metal sphere duty cycle exceeds 40%. Item 57. The method according to Item 56, wherein the concentration is low in the case of

[0095]

[0131] Item 58. Clot integrity was evaluated using metal spheres with a duty cycle of 25% and 40%. Item 57. The method according to item 56, wherein the degree is moderate if the degree is between 0.1 and 1.2.

[0132] Item 59. Clot integrity was evaluated using metal spheres with a duty cycle of 10% and 25%. Item 57. The method according to Item 56, wherein the concentration is high when the concentration is between 0.1 and 1.2.

[0096]

[0133] Item 60. Clot integrity is measured with a metal sphere duty cycle between 0% and 10%. Item 57. The method according to Item 56, wherein the concentration is extremely high when

[0134] Item 61. The step of determining one or more clot characteristics includes determining the viscosity of the whole blood sample. Item 47. The method of item 46, comprising determining:

[0097]

[0135] Item 62. Viscosity is based on the transit time of a metal sphere between two sensors. The method described below.

[0136] Item 63. Viscosity increases as a clot forms in a whole blood sample. The method described in 2.

[0098]

[0137] Item 64. A blood clot is formed when the viscosity is between 10% and 20% of the predetermined baseline. Item 64. The method of item 63, wherein the formation begins.

[0138] The above detailed description is by way of example only and is intended to cover all aspects of the invention as defined by the appended claims and their equivalents. It should be understood that these should not be taken as limitations on the scope of the invention which is defined solely by the appended claims.

[0099]

[0139] Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Various features and advantages of the invention are set forth in the following claims.

Claims

1. 1. A device for processing a cartridge containing a whole blood sample, comprising: a recess for receiving the cartridge; a vacuum source coupled to the cartridge; an actuator coupled to the cartridge for vibrating the cartridge; Controller and the controller comprising: activating the vacuum source to move the whole blood sample from a container through a plurality of flow paths within the cartridge, then into a plurality of reagent chambers where the whole blood sample mixes with reagent, then through a plurality of serpentine flow paths, and into a plurality of test chambers, each of which includes a spherical member; activating the actuator to vibrate the cartridge such that tilting of the cartridge applies a force that moves the spherical members within each testing chamber; receiving signals from a plurality of sensors, each sensor associated with one of the test chambers, based on the presence of a spherical member within a magnetic field generated by a magnet positioned adjacent each of the test chambers; determining whether a coagulopathy is present in the whole blood sample in each test chamber based on the signal; outputting an indication to a display indicating whether a coagulopathy is present in the whole blood sample in each test chamber; It is configured as follows: two sensors of the plurality of sensors are disposed adjacent to each test chamber, and the two sensors disposed adjacent to each test chamber are spaced apart along a path along which the spherical member is moved by the force; device.

2. 10. The device of claim 1, further comprising a plurality of vacuum ports in the cartridge selectively coupled to the vacuum source, and a plurality of hydrophobic filters along each of the vacuum ports, the hydrophobic filters configured to stop blood flow when each of the reagent chambers is filled.

3. The device of claim 1 , further comprising a heating element configured to apply thermal energy to the cartridge and the whole blood sample.

4. 4. The device of claim 3, wherein the heating element heats the whole blood sample to a temperature between 34 degrees Celsius and 37 degrees Celsius.

5. 4. The device of claim 3, wherein the heating element heats the whole blood sample to a temperature between 30 degrees Celsius and 33 degrees Celsius.

6. 5. The device of claim 4, wherein the whole blood sample is mixed with reagent in each of the reagent chambers and incubated for between 1 minute and 10 minutes.

7. 7. The device of claim 6, wherein the reagent in each of the reagent chambers is spaced apart from adjacent reagent chambers.

8. The device of claim 1 , wherein the controller is further configured to determine a length of time to clot formation in each of the test chambers.

9. 9. The device of claim 8, wherein the amount of time is based on how long the sensor associated with one of the test chambers detects movement of the spherical member.

10. The device of claim 1 , wherein the controller is further configured to determine clot formation.

11. 11. The device of claim 10, wherein clot formation for a test chamber is determined when the controller detects an absence of peaks in the signals from the two sensors positioned adjacent to that test chamber during each vibration cycle of the vibration of the cartridge, indicating that the spherical member has stopped moving within that test chamber.

12. The device of claim 10 , wherein the controller is further configured to determine clot strength.

13. 13. The device of claim 12, wherein a high intensity clot is determined when neither of the two sensors produces a signal after the clot has formed.

14. 13. The device of claim 12, wherein a low intensity clot is determined when one of the two sensors continues to generate a signal indicating that the clot is allowing the spherical member to move a limited distance.

15. 10. The device of claim 1, wherein the cartridge includes 18 test chambers.

16. 16. The device of claim 15, wherein each of the 18 test chambers is associated with one of the reagent chambers, and each of the 18 test chambers receives a whole blood-reagent complex from the associated reagent chamber.

17. 10. The device of claim 1, wherein the spherical member in each test chamber passes over the sensor associated with each test chamber to generate a signal proportional to the viscosity of the whole blood specimen in each test chamber.

18. The device of claim 1 , wherein the controller is further configured to determine a diagnosis based on the coagulation disorder result.

19. 20. The device of claim 18, wherein the controller is further configured to output the diagnosis on the display.

20. 1. A method for determining the coagulation characteristics of a whole blood sample, comprising: introducing the whole blood sample into a cartridge having a plurality of test channels, each test channel including a reagent chamber, a test chamber, and a metal sphere within each test chamber; mixing the whole blood sample with a reagent in each of the reagent chambers; vibrating the cartridge such that tilting the cartridge applies a force that moves the metal spheres within each testing chamber; detecting movement of the metal sphere within each of the test chambers by two sensors positioned adjacent to each of the test chambers and spaced apart along a path along which the metal sphere is moved by the force; determining, by a controller, one or more coagulation properties of the whole blood sample based on the detection of the movement of the metal spheres; generating an indicia indicative of said coagulation characteristic for display to a user; A method comprising:

21. 21. The method of claim 20, further comprising initiating a coagulation cascade in the whole blood sample before the whole blood sample enters the testing chamber.

22. 22. The method of claim 21, wherein the cartridge contains calcium, and further wherein the whole blood sample contacts the calcium between the outlet of the reagent chamber and the inlet of the test chamber.

23. 21. The method of claim 20, wherein determining one or more coagulation properties comprises determining clot formation of the whole blood sample.

24. 24. The method of claim 23, wherein determining blood clot formation includes the step of the controller detecting the absence of peaks in the signals from the two sensors positioned adjacent to a test chamber during each vibration cycle of the vibration of the cartridge, wherein the absence of peaks in the signals from the two sensors positioned adjacent to a test chamber during each vibration cycle of the vibration of the cartridge indicates that the metal sphere has stopped moving within that test chamber.

25. 25. The method of claim 24, wherein one of the coagulation properties is clot strength.

26. 26. The method of claim 25, wherein a high intensity clot is determined if neither of the two sensors produces a signal after the clot has formed.

27. 26. The method of claim 25, wherein a low intensity clot is determined when one of the two sensors continues to generate a signal indicating that the clot is allowing the metal sphere to move a limited distance.

28. 21. The method of claim 20, wherein determining one or more coagulation properties comprises determining a viscosity of the whole blood specimen.

29. 29. The method of claim 28, wherein the viscosity is based on the transit time of the metal sphere between the two sensors.

30. 30. The method of claim 29, wherein the viscosity increases as a clot forms in the whole blood sample.

Images