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WO1996000395A1 - Evaluation de l'activite coagulatrice du sang - Google Patents

Evaluation de l'activite coagulatrice du sang Download PDF

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Publication number
WO1996000395A1
WO1996000395A1 PCT/US1995/008014 US9508014W WO9600395A1 WO 1996000395 A1 WO1996000395 A1 WO 1996000395A1 US 9508014 W US9508014 W US 9508014W WO 9600395 A1 WO9600395 A1 WO 9600395A1
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WO
WIPO (PCT)
Prior art keywords
sample
region
pathway
clotting
blood
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Ceased
Application number
PCT/US1995/008014
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English (en)
Inventor
Karim Boulhimez
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ChemTrak Inc
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ChemTrak Inc
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Filing date
Publication date
Application filed by ChemTrak Inc filed Critical ChemTrak Inc
Priority to AU29094/95A priority Critical patent/AU2909495A/en
Publication of WO1996000395A1 publication Critical patent/WO1996000395A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/4905—Determining clotting time of blood
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors

Definitions

  • the field of this invention is diagnostics for blood coagulation activity.
  • Blood coagulation activity means the capacity of certain blood and tissue factors to act in unison to form a polymerized, clogging substance called a fibrin clot.
  • the formation of the fibrin clot requires a significant number of different factors in a reaction cascade involving enzymes, which activate proteins which may then in turn activate other proteins further down the chain.
  • thro bin cleaves fibrinogen to form fibrin, which can then be cross-linked and involve other proteins and platelets to form the clot.
  • clotting activity is determined for monitoring patients receiving anticoagulant therapy, such as coumarin, fluindione, and warfarin. For these patients it is important to periodically determine the necessary dosage which will prevent blood clot formation (thrombosis) , while at the same time avoid breakthrough bleeding.
  • the current methodology is called prothro bin time (PT) .
  • TF and FVIIa promotes blood clotting by proteolyzing coagulation Factors IX and X, as well as VII.
  • thrombin cleaves fibrinogen and coagulation Factor Xllla stabilizes the fibrin clot by covalent cross-linking. A number of the reactions are calcium dependent.
  • APTT activated partial thromboplastin time
  • the device comprises a sample region for applying blood plasma, a bibulous first region, comprising stabilized thromboplastin and calcium at a non-acidic pH, followed by a bibulous second region comprising stabilized fibrinogen at a non-acidic pH.
  • a sample region for applying blood plasma
  • a bibulous first region comprising stabilized thromboplastin and calcium at a non-acidic pH
  • a bibulous second region comprising stabilized fibrinogen at a non-acidic pH.
  • FIG. 1 is a plan view of a device according to the subject invention
  • FIG. 2 is a plan view of the support and strip portion of the subject device
  • FIGs. 3, 4 and 5 are cross sectional views of the device according to FIG. 1 at the compartments with three different types of compartments;
  • FIG. 6 is a plan view of an alternative embodiment of a device according to this invention.
  • FIG. 7 is a plan view of the support of the device of FIG. 6;
  • FIG. 8 is an alternative embodiment of the device providing for buffer release.
  • coagulation time of a blood sample.
  • determinations include, but are not limited to, prothrombin time (P.T.), activated partial thromboplastin time (A. P. T. T.), thrombin clotting time (T. C. T.), assays for particular factors involved with clotting, and the like.
  • the devices employ bibulous or porous elements, e.g. strips, rods, fibers, etc. , providing fluid transport through the elements by capillary action. Since strips are the most convenient for the devices, strips will be used as exemplary of other bibulous supports.
  • the device In the direction of fluid flow, the device has a sample region, a bibulous region for initiating or activating endogenous agents involved with the coagulation process, followed by a region comprising fibrinogen for clot formation.
  • a transport region is provided for providing buffer to the sample region for transport of the sample from the sample region to the coagulation time determination region.
  • filtration means may be provided for removing red blood cells and/or platelets from the blood sample to provide plasma to the sample region.
  • the initiation or activation region will comprise stabilized lyophilized thromboplastin, which will be non- limiting in amount, conveniently with calcium, to provide for initiation and activation of the coagulation cascade.
  • the amount of thromboplastin in the activation region is not critical, so long as it is above a minimum non- limiting amount.
  • the thromboplastin when the thromboplastin is diffusively bound to the porous strip, the thromboplastin will accumulate at the migration front, so as to have the thromboplastin concentrated at the migration front.
  • the bibulous support may be impregnated with a solution of thromboplastin, generally at a concentration in the range of 10 to 100 mg/ml, more usually in the range of 25 to 75 mg/ml, preferably about 50 mg/ml, desirably containing calcium at a concentration in the range of about 1 to 35 mM, preferably in the range of about 5 to 25 mM, at a pH of about 7 to 9, preferably about 7 to 8.5, more preferably about 7.3 to 8.5.
  • a solution of thromboplastin generally at a concentration in the range of 10 to 100 mg/ml, more usually in the range of 25 to 75 mg/ml, preferably about 50 mg/ml, desirably containing calcium at a concentration in the range of about 1 to 35 mM, preferably in the range of about 5 to 25 mM, at a pH of about 7 to 9, preferably about 7 to 8.5, more preferably about 7.3 to 8.5.
  • various'agents may be employed, which may serve in the solubilization of the thromboplastin, aiding transport of proteins, and the like.
  • Particularly saccharides find use, such as glucose, fructose, trehalose, and the like.
  • the amount of saccharide in the impregnating solution will be in from about 1 to 20 weight percent, more usually in the range of about 5 to 15 weight percent, preferably about 10 weight percent.
  • Various buffers may be employed to maintain the pH, where the buffer should have minimal calcium binding capability. Desirably, nitrogen based buffers may be employed, such as TRIS, HEPES, and the like where the concentration of buffer will generally be in the range of about 1-200 mM, preferably about 20-60 mM.
  • stabilizing agents may be employed in minor amount, usually less than about 0.1%, such as sodium azide, antibiotics, etc., antioxidants, such as -tocopherol at from about 0.1 to 0.5%, and the like.
  • the support is impregnated with the solution by any convenient means, most conveniently, soaking in the solution, generally at a reduced temperature, so as to minimize any degradation of the thromboplastin.
  • One end of the strip may be introduced into the reagent solution and the migration front monitored to define the length of the zone. Usually, where soaking is involved, in order to insure saturation of the support, the soaking will be maintained for at least 6 hours, more usually at least about 12 hours, and usually not more than about 24 hours.
  • the strip may then be dried at a temperature which does not result in significant degradation of thromboplastin activity, generally a temperature in the range of about 0 to 35°C, preferably at a temperature in the range of about 20 to 30°C. Depending on the temperature, pressure, and the like, the time for drying may vary from about 5 min. to about 12 h.
  • activators other than thromboplastin may find use.
  • the activator may be kaolin, silica, diato aceous earth, ellagic acid, silica or glass particles, associated or impregnated with a phospholipid, such as cephalin, lecithin, soybean phospholipid extract, or the like.
  • a phospholipid such as cephalin, lecithin, soybean phospholipid extract, or the like.
  • TCT one would use thrombin.
  • Factors of particular interest include Factor VIIIc, Factor VII, etc.
  • hemophilia A one monitors FVIII activity with an APTT activator.
  • the amounts used for impregnation are not critical, so long as they are not rate limiting, and can be readily optimized.
  • the bibulous strip may be chemically activated so as to covalently bond an activator, e.g. thromboplastin.
  • an activator e.g. thromboplastin.
  • Various reactive groups may be present on the support, depending upon the nature of the support.
  • the support may be activated with cyanogen bromide, chloroacetyl chloride, Ellman's reagent, p- maleimidobenzoyl chloride, where the thromboplastin may be modified with cysteine, or the like.
  • non- covalent complexes may be formed, where non-inactivating anti-thromboplastin antibodies, or streptavidin molecules, where the thromboplastin is modified with biotin, etc. , are covalently bonded to the support.
  • the particular manner in which the activator becomes bound to the support, either covalently or through a non-covalent complex, is not critical to this invention, so long as sufficient and non-limiting thromboplastin activity is reproducibly maintained on
  • the next region comprises fibrinogen, where the amount of fibrinogen will be in substantial excess, so as not to be rate limiting and affect the sensitivity of the assay.
  • the bibulous support will be impregnated with the fibrinogen solution by any convenient means, e.g., soaking, as described above.
  • two different strips may be used or the migration front of the reagent solution may be monitored.
  • the solution will generally have from about 5 to 15 g/L, more usually from about 7.5 to 10 g/L.
  • the pH will generally be in the range of about 7.5 to 9.5, preferably from about 8 to 9, more preferably from about 8.4 to 8.8, particularly 8.6.
  • a small amount of a surfactant is employed, for example, polyethyleneoxy detergents, e.g., Triton X-100.
  • the surfactant is used in small amount, generally not exceeding 0.2 weight %, usually not exceeding 0.15% and generally in excess of about 0.05%.
  • Other non-ionic surfactants may be employed, such as octylglucoside, and the like. The particular surfactant will be selected so as not to interfere with the coagulation process, where polyethylene glycol is found to precipitate fibrinogen.
  • a solubilizing agent is also added to the mixture, particularly a saccharide, such as described above.
  • the amount of saccharide will generally be in the range of about 5 to 25 weight percent, more usually in the range of about 10 to 20 weight percent, preferably 15 weight percent. Any saccharide which is used will be selected not to precipitate the fibrinogen and be capable of inhibiting crystallization of the fibrinogen.
  • Various supports may be used, which may be the same or different for the different regions.
  • Convenient materials include cellulosic materials, such as paper, e.g., Whatman CHR1, nitrocellulose, etc.; plastic materials, such as polyethylenes, polypropylenes, etc., or other convenient material, which does not interfere with the coagulation process, provides for reasonable transport of the reactive agents, allows for long term storage, and the like.
  • the pore size controls the rate of flow of the fluid along the strip. By employing strips having a graduated pore size, the rate of flow through the strip may be varied in the different regions. Desirably, the mean pore diameter will be in the range of about 0.45 to 150 ⁇ m, more usually in the range of about 15 to 150 ⁇ m, preferably in the range of about 15 to 100 ⁇ m.
  • the clot initiation or activation strip will be from about 1 to 3 cm, more usually about 1.5 to 2.5 cm, preferably about 2 cm in length.
  • the length of the activation strip will be related to the amount of thromboplastin present on the strip, the rate of flow through the strip, and the rate of activation of FVII. The optimum length can be determined experimentally, by varying the length with samples having known clotting factor times.
  • the thickness of the strips will generally be in the range of about 0.2 to 1.5 mm, more usually from about 0.5 to 1 mm.
  • the width of the strips will generally be in the range of about 0.5 to 4 mm, more usually about 0.75 to 2 mm, preferably from about 1 to 2 mm.
  • the length of the coagulation region will be related to the strip porosity, width and thickness and can be any convenient length, so long as it provides for the necessary dynamic range for determining the clotting time.
  • the coagulation region will be at least about 0.25 times the length of the activation region, more usually 0.5 times the length of the activation region and not more than about 7 times the length of the activation region.
  • These reagents can take the form of various colorants, latex particles, microvesicles, such as liposomes, carbon particles, colloidal suspensions, e.g. polystyrene particles, latex particles, etc., or silica.
  • Colorants, such as bilirubin, which colorants have protein affinity find particular use as well.
  • the particles will generally be of a diameter in the range of about O.l ⁇ to 50 ⁇ .
  • a filter can be used which removes red blood cells and/or platelets, so as to deliver plasma sample to the sample region.
  • filters have been reported in the literature, such as U.S. Patent Nos. 5,423,989, 4,816,224, and 4,477,575.
  • the glass fibers should be coated to prevent coagulation.
  • isotonic saline as diluent may be used or a buffer which will generally have a pH as indicated above for the activation solution, having an analogous concentration of buffer, and such other reagents as may be appropriate, such as calcium ion, generally with a concentration in the range of about the range indicated for the activation solution, nonionic detergents, in from about 0.1 to 1.5%, border enhancers as indicated above, and the like.
  • the buffer may also have an agent which complexes calcium prior to clotting, such as citrate at a concentration of about 0.5 to 5%.
  • the biological sample is placed in the sample region.
  • the blood sample may have been subject to prior treatment to remove the red blood cells and platelets, such as centrifugation, filtration, or the like.
  • the sample which is applied to the sample region will be a volume from about 5 to 100 ⁇ l, where the amount of sample will depend upon whether the sample has been diluted and/or diluent is also employed in the assay or the sample provides the only liquid for transport, the absorption volume of the bibulous strips, and the like.
  • the sample will generally be in the range of about 5 to 100 ⁇ l, while where the sample is the primary source of fluid, the sample will generally be in the range of about 5 to 50 ⁇ l, so that the sample will vary from about 5 to 100 ⁇ l.
  • the sample comprising the thrombin upon entering the coagulation region will cause the fibrinogen to clot.
  • plasma extracts may include PPSB preparation, prothrombin (FII) , Stuart Factor, Antihemophiliac Factor B, Factor VII, etc.
  • the reagents may be present in the sample region or activation region.
  • a solid housing or platform 4 includes sample well 1.
  • the bottom of sample well 1 has two orofices 2a and 2b in proximity to bibulous migration support strips 3a and 3b.
  • the ends of the strips 3a and 3b are under the orofices 2a and 2b, respectively, which provides that the sample flows from the sample well into the strips 3a and 3b.
  • a slide 5, having transparent window 5a, is attached to platform 4. The window is supplied with reference mark 6 and graduations 7 to evaluate the distance traveled by the fluid on the strips 3a and 3b.
  • Zone 8 of strip 3a is impregnated with the coagulation activating agents, thromboplastin and calcium, as well as any other appropriate reagents to solubilize the thromboplastin, intiate the coagulation cascade of the components in the sample and stabilize the storage unstable reagents.
  • Zone 9 has fibrinogen, so that prothrombin activated in zone 8 will react with the fibrinogen causing a clot in relation to the clotting activity of the sample.
  • the zone 10 of strip 3b is impregnated with the necessary factors for causing clotting of the fibrinogen in zone 11, e.g.
  • zone 10 one may introduce normal blood or plasma in substantial excess to the factors in the blood sample, as well as solubilizing and stabilizing agents. Depending upon the amount of blood introduced in zone 10, the clotting activity or inhibitor in the sample may be overwhelmed so as to have little, if any, effect on the clotting time in the control. Alternatively, one may look to the combination of clotting times from the normal blood and sample blood, so that the distance to clotting observed from the control should be shorter than or equal to the distance to clotting observed with the sample.
  • an inert composition which provides for an equalization of the viscosity of the control and the sample to provide for a more accurate comparison.
  • the inert composition will be present in the sample pathway.
  • substances which can be used are water soluble substances, including proteins, such as albumin, sugars, such as dextran and saccharides, and the like.
  • one may divide the well by wall lc into two compartments la and lb, so that different media (e.g. control and sample) or different reagents may be added to the different compartments.
  • a filter 16 may be placed over the openings 2a and 2b, which is covered by an absorbent membrane 14.
  • the filter 16 serves to remove red blood cells and/or platelets which might interfere with the assay and feeds plasma to the strips 3a and 3b.
  • Figures 6 and 7 depict an alternative embodiment, comprising a platform 170 having well 100.
  • the well has a single opening 120 in proximity to the strip 110.
  • a slide 172 having a clear window 173 is attached to the support 170 with a graduation scale 174 to evaluate the distance covered by the sample.
  • Zone 130 extends a significant distance away from the sample well 100 and activation zone 160 and is impregnated with fibrinogen.
  • Zone 140 extends away from the sample well 100 in the opposite direction of zone 130 and is also impregnated with fibrinogen.
  • Activation zone 160 of the strip may be impregnated with thromboplastin and calcium and an inert composition which dissolves with the sample, adjusting the viscosity such that in coming out of zone 160 the fluid is substantially identical in viscosity to the fluid coming out of zone 150.
  • the inert composition components have been previously described.
  • Zone 150 has a a source of clotting factors to act as the control, such as PPSB and a clotting activation agent (thromboplastin and calcium) , which may be separately placed in zone 150 or other technique used to prevent reaction, while zone 140 is impregnated with the clot formation reagents (fibrinogen and optionally FXIIIa) .
  • a source of clotting factors to act as the control such as PPSB and a clotting activation agent (thromboplastin and calcium) , which may be separately placed in zone 150 or other technique used to prevent reaction, while zone 140 is impregnated with the clot formation reagents (fibrinogen and optionally FXIIIa) .
  • Zones 180 and 190 indicate the presence of clots, so that the distances can be compared for the control and sample, using slide 172 to measure.
  • the length of zone 140 will be shorter than the length of zone 130, since the sample is expected to have a slower coagulating time than the control.
  • the devices may be prepared out of any convenient material which is stable, inert, and may be readily handled.
  • the device may be prepared from glass fiber, plastic, treated cardboard or paper, or the like, so long as the material provides for the necessary physical parameters.
  • the particular shape and the dimensions of the material are not critical to this invention, so long as they come within the indicated parameters to provide an observable result.
  • Fig. 8 a device is depicted which is shown in greater detail in U.S. Patent No. 5,132,086, which disclosure is incorporated herein by reference. Particularly Figs. 2, 3a, 3b and 4 and their decription are incorporated as part of this disclosure.
  • the parts of the device comprise a base plate 40, a slide 42 and a cover plate (not shown) .
  • the base plate consists of a cutout to accept the slide 42, a slot 46 with locating pins 48 into which the assay strip 50 and transport strip 52 are precisely positioned, maintaining about a 2mm gap 54 between them, and a well 56 designed to capture the released transport solution, e.g. wicking buffer.
  • the slide 42 consists of a vented receptor site 58 into which the sample receiving pad 59 is inserted, an arm 60 with shearing action designed to facilitate the release of the transport solution from a pouch which is housed in a well of the cover plate, and a snap 61 to lock the slide in place, once pulled.
  • the strip 50 has two regions, a clotting activation region 62 and a clotting region 64.
  • the clotting activation region 62 is impregnated with thromboplastin and calcium ion, while the clotting region 64 is impregnated with fibrinogen. Initially the slide is at the position indicated in Fig. 8, where the sample receiving pad 59 is out of register with strips 50 and 52.
  • the slide 42 is pulled to the right to bring the sample receiving pad 59 in register with strips 50 and 52.
  • a ridge in the cover plate squeezes the sample pad to control the volume of the sample in the sample pad.
  • Movement of the slide opens the buffer containing pouch in well 56, which initiates the assay.
  • the buffer is transported to sample receiving pad 59 transporting the sample into activation region 62.
  • the factors associated with clotting in the sample particularly prothrombin to thrombin, are activated. Movement of the buffer carries the activated factors into clotting region 64, where depending upon the components of the sample controlling clotting, a clot will form some distance into the clotting region. This distance may then be related to prothrombin time.
  • a second control strip may also be provided, where the sample receiving pad may or may not be involved. The nature of control strips has already been discussed.
  • Example 1 Polyethylene (Interflo®: Mean Pore Diameter 40 ⁇ m) of a size of 150 mm x 150 mm was dipped in a thromboplastin-calcium solution (thromboplastin, 50 mg/ml; calcium 20 mM) at one end and the solution allowed to rise until the migration front reached 75% of the height of the polyethylene piece. The piece was then dried at 30°C in vacuo . The piece was then cut into strips of 150 mm x 1.5 mm. These provide the sample strips.
  • thromboplastin-calcium solution thromboplastin, 50 mg/ml; calcium 20 mM
  • a control strip in the unimpregnated portion of the strip, 5 ⁇ l of a preparation of normal human plasma in a 5% sucrose solution containing sodium deoxycholate (0.01 - 0.04%) and sodium azide (0.4 g/L) was added. A plastic support coated with adhesive is employed. One then fixes the sample strip and control strip by means of the adhesive to the support, so that the two strips are parallel. A sample well is then affixed to the ends of the two strips at the un-impregnated end of the sample strip, but in fluid transfer relationship with both strips.
  • Water tightness is achieved at the level of the openings in the base by heat welding at 130°C.
  • Example 2 Following the protocol of Example 1, the reagents are deposited on the strips and lyophilized by dipping the plastic in liquid nitrogen and dehydrating in vacuo .
  • Example 3 Following the procedure of Example 1, an aliquot of total blood is deposited into the sample well, whereby it migrates along the two strips. The migration front is readily visible in fewer than 5 minutes due to natural coloration of the blood in contrast to the support base. The red blood cells provide for coloration of the fibrin clot.
  • Example 4 Following the procedure of Example 1, a specific quantity of citrated plasma is mixed with a specific quantity of carbon particles (10v/2v) colloidal solution. A known quantity of the mixture is placed in the sample well, and the sample allowed to migrate along the two strips, where the border is readily detectable due to the carbon particles imprisoned in the fibrin clot. The test can be read in fewer than 5 minutes after addition of the sample.
  • Example 5 Strips were prepared as follows. Thromboplastin (lyophilized) is regeneratd with 3ml of Tris* HC1 buffer (100 mM, CaCl 2 20 mM, glucose 10%, pH 8.4). The strip (porous plastic of pore diameter 25 to 35 ⁇ , 0.6 mm thickness),a length of 2 cm, is impregnated with the solution. A second strip of the same material as the first strip is impregnated with a fibrinogen reagent solution comprising human fibrinogen (8.8 g,lL), glucose (15 wt. %) , in Tris* HC1 buffer (100 mM, pH 8.6, Triton X-100, 0.09%).
  • Tris* HC1 buffer 100 mM, pH 8.6, Triton X-100, 0.09%.
  • a temperature response study was performed at 37°C, 23°C and 15°C. At both 37°C and 23°C, the distance was shown to correlate with prothrombin time of the samples over a range of prothrombin times of 100% to 20%. It is evident from the above results, that the subject invention provides for a simple, convenient and rapid method for the determination of clotting time. Disposable devices are provided which may be used without technical competence, simply by adding blood to a device. The device then performs all of the necessary actions and when the assay is completed, the distance may be readily determined and correlated with prothrombin time. Since the migration distance is fixed, one need not observe the assay, but can read the result at a later time. In this way, within a short time, the migration distance can be determined and related to prothrombin time.

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Abstract

L'invention concerne des procédés et un dispositif à usage unique pour déterminer le temps de coagulation d'un échantillon de plasma de sang. Ce dispositif comprend une région (59) pour l'échantillon et une région (62) d'activation des phases successives de la coagulation des éléments du plasma. Le temps de coagulation est déterminé par la distance de migration du fluide ou la distance de formation des caillots par rapport à la région (59) de l'échantillon. La région d'activation (62) est imprégnée de thromboplastine pour activer les facteurs de coagulation et une région de coagulation (64) est imprégnée avec un excédent de fibrinogène pour améliorer la formation des caillots. On peut également prévoir d'autres réactifs, qui peuvent être mobiles ou non.
PCT/US1995/008014 1994-06-23 1995-06-23 Evaluation de l'activite coagulatrice du sang Ceased WO1996000395A1 (fr)

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Application Number Priority Date Filing Date Title
AU29094/95A AU2909495A (en) 1994-06-23 1995-06-23 Evaluation of blood coagulation activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9407733A FR2721714B1 (fr) 1994-06-23 1994-06-23 Dispositif d'évaluation de l'activité coagulante sanguine d'un échantillon biologique, jetable après usage unique, et procédé de mise en Óoeuvre.
FR94/07733 1994-06-23

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PCT/FR1995/000829 Ceased WO1996000390A1 (fr) 1994-06-23 1995-06-22 Procede et dispositif jetable d'evaluation de l'activite coagulante sanguine
PCT/US1995/008014 Ceased WO1996000395A1 (fr) 1994-06-23 1995-06-23 Evaluation de l'activite coagulatrice du sang

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5787901A (en) * 1997-01-28 1998-08-04 Akzo Nobel N.V. Method for the measurement of blood coagulation properties with absorbent materials
US7021122B1 (en) 1998-03-19 2006-04-04 Orgenics Biosensors Ltd. Device for the determination of blood clotting by capacitance or resistance
WO2009097188A1 (fr) * 2008-01-30 2009-08-06 Ortho-Clinical Diagnostics, Inc. Cartes d'essai d'immunodiagnostic ayant des indices indicateurs
WO2014091262A1 (fr) * 2012-12-14 2014-06-19 Subotics Innovációs Kft (Subotics Innovation Ltd.) Dispositif de goutte-à-goutte intraveineux jetable pour autocontrôle à domicile de valeur inr, caractérisant la coagulation sanguine
US10488424B2 (en) * 2014-03-03 2019-11-26 University Of Cincinnati Devices and methods for analyzing a blood coagulation property
CN115087870A (zh) * 2019-03-27 2022-09-20 血运有限公司 用于测量血液样品中纤维蛋白原浓度的方法和装置

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CN113740326B (zh) * 2021-09-06 2022-04-29 中国人民解放军军事科学院军事医学研究院 一种全血中纤维蛋白原浓度快速检测装置及其检测方法

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5787901A (en) * 1997-01-28 1998-08-04 Akzo Nobel N.V. Method for the measurement of blood coagulation properties with absorbent materials
US7021122B1 (en) 1998-03-19 2006-04-04 Orgenics Biosensors Ltd. Device for the determination of blood clotting by capacitance or resistance
WO2009097188A1 (fr) * 2008-01-30 2009-08-06 Ortho-Clinical Diagnostics, Inc. Cartes d'essai d'immunodiagnostic ayant des indices indicateurs
US8058073B2 (en) 2008-01-30 2011-11-15 Ortho-Clinical Diagnostics, Inc. Immunodiagnostic test cards having indicating indicia
US8211365B2 (en) 2008-01-30 2012-07-03 Ortho-Clinical Diagnostics, Inc. Immunodiagnostic test cards having indicating indicia
RU2468867C2 (ru) * 2008-01-30 2012-12-10 Орто-Клиникал Дайэгностикс, Инк. Карты иммунодиагностического тестирования с указательными индикаторами
WO2014091262A1 (fr) * 2012-12-14 2014-06-19 Subotics Innovációs Kft (Subotics Innovation Ltd.) Dispositif de goutte-à-goutte intraveineux jetable pour autocontrôle à domicile de valeur inr, caractérisant la coagulation sanguine
CN105008922A (zh) * 2012-12-14 2015-10-28 海默环球股份有限公司 用于家用自助检查血液凝固国际标准化比值(inr)的一次性体外诊断(ivd)装置
CN105008922B (zh) * 2012-12-14 2018-07-17 海默环球股份有限公司 用于家用自助检查血液凝固国际标准化比值(inr)的一次性体外诊断(ivd)装置
US10488424B2 (en) * 2014-03-03 2019-11-26 University Of Cincinnati Devices and methods for analyzing a blood coagulation property
CN115087870A (zh) * 2019-03-27 2022-09-20 血运有限公司 用于测量血液样品中纤维蛋白原浓度的方法和装置
EP3948302A4 (fr) * 2019-03-27 2023-01-04 Haemokinesis Pty. Ltd. Procédé et dispositif de mesure de la concentration de fibrinogène dans des échantillons de sang

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AU2889795A (en) 1996-01-19
FR2721714A1 (fr) 1995-12-29
WO1996000390A1 (fr) 1996-01-04
FR2721714B1 (fr) 1996-09-06

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