WO1993012422A1 - Method and apparatus for quantitation of relevant blood parameters - Google Patents

Method and apparatus for quantitation of relevant blood parameters Download PDF

Info

Publication number
WO1993012422A1
WO1993012422A1 PCT/DK1992/000382 DK9200382W WO9312422A1 WO 1993012422 A1 WO1993012422 A1 WO 1993012422A1 DK 9200382 W DK9200382 W DK 9200382W WO 9312422 A1 WO9312422 A1 WO 9312422A1
Authority
WO
WIPO (PCT)
Prior art keywords
sample
extreme value
parameters
time
curve
Prior art date
Application number
PCT/DK1992/000382
Other languages
French (fr)
Inventor
Ole Hauch
Jens Bjerre Knudsen
Thomas Munk Plum
Original Assignee
Novo Nordisk A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to EP93902090A priority Critical patent/EP0643829B1/en
Priority to US08/244,966 priority patent/US5567869A/en
Priority to JP5510535A priority patent/JPH07502118A/en
Priority to DE69228882T priority patent/DE69228882D1/en
Publication of WO1993012422A1 publication Critical patent/WO1993012422A1/en

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/59—Transmissivity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
    • G01N15/04—Investigating sedimentation of particle suspensions
    • G01N15/05—Investigating sedimentation of particle suspensions in blood
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
    • G01N15/04—Investigating sedimentation of particle suspensions
    • G01N15/05—Investigating sedimentation of particle suspensions in blood
    • G01N2015/055—Investigating sedimentation of particle suspensions in blood for hematocrite determination
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01—Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03—Cuvette constructions
    • G01N2021/0346—Capillary cells; Microcells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N2021/1789—Time resolved
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S128/00—Surgery
    • Y10S128/22—Blood coagulation

Definitions

  • a blood sample for quantitation of various blood parameters is a routine by many medical investigations. Commonly, a sample of some ml is taken and sent to a laboratory where the relevant parameters such as coagulation time, haematocrit, sedimentation rate, haemoglobin percentage, etc are quantified.
  • the blood sample when taken must be added an anticoagulant to prevent the blood from coagulating on its way to the laboratory.
  • the effect of the anticoagulant is neutralized to make the sample equate a sample of fresh blood.
  • the apparatus should be handy and portable to an extent making it possible to allocate the apparatus to the patient so that the blood sample may be passed into the apparatus, which may then be placed at the bedside until the result is ready. Further, the method should make it possible to perform the measurement on a blood sample which may be provided by simply pricking a finger or an earlobe to obtain a sample not larger than 25 ⁇ l, i.e. a sample which could be provided without help from a professional to puncture a vein.
  • a method of measuring the coagulation time for a blood sample comprises the steps of entering the sample into a capillary element and measuring the coagulation time as the time elapsing from the moment when the blood sample enters the photometer measuring the translucence, which moment is indicated by a sudden fall of the translucence, until the moment when the translucence reaches a maximum after this sudden fall.
  • a method for quantitation of relevant blood parameters comprises the following steps: provision of a sample of plasma, serum or whole blood, entering the sample into a cuvette with an internal dimension less than 1 mm, illuminating the sample by a light source, measuring and recording the changes of light properties caused by the sample as a function of time, calculating parameters of the recorded light signal/time curve, - interpreting the parameters such as slopes and time spaces between extremes and/or other well-defined points of the obtained light signal/time curve.
  • a light signal/time curve may have a course with a first sharp extreme value corresponding to the moment when the sample is introduced in the measuring part of the cuvette. If for example the light signal is the translucence of the sample, this extreme value is a minimum. From this minimum the translucence will rise to a maximum being the second extreme value from which it descends again to a relatively flat minimum representing a third extreme value, whereupon it rises again to a fourth extreme value, a high maximum from which it finally descends almost linearly.
  • the recording of the curve may be made by frequent storing, e.g. once a second, of connected values for measured light signal and time elapsed from a starting moment, mainly defined by the first sudden change in the light signal corresponding to the entering of the sample. These recordings make it possible to define the extreme values and to calculate slopes in different positions on the curve. However, when only the time elapsed between two incidents is needed, the recording of the intermediate light signal values may be omitted.
  • the time elapsing from the starting moment until a well-defined point in relation to the second extreme value is taken as an expression of the coagulation time.
  • the slope of the curve when passing from the first extreme value to the second extreme value may be taken as an expression of the sedimentation rate.
  • the difference between the first extreme value and the following second extreme value is taken as an expression of the haematocrit value.
  • the slope of the curve when passing from a well-defined point in relation to the second extreme value to a well-defined point in relation to the third extreme value is taken as an expression of the fibrinogen concentration and the platelet-related coagulation activity. As the slope of the curve varies, this value may be more precisely defined as e.g. the slope of its inflection, or the slope may be calculated as the difference between the second extreme value and a third extreme value or between well-defined points in relation to the extreme values divided by the time difference between these two extremes or points.
  • the time it takes for the light signal curve to pass the third extreme value is calculated as the time interval from the moment when the light signal value passes a set value differing by a predetermined amount from this third extreme value when approaching this value, until the moment when the light signal value passes again this set value after having passed the third extreme value, and this calculated time is taken as an expression of the activity of the fibrinolytic system.
  • the slope of the light signal curve when passing from a well-defined point in relation to its third extreme value to a well-defined point in relation to its fourth extreme value is taken as an expression of the rate of fibrin degeneration.
  • the difference between the value in a well-defined point in relation to the third extreme value and a well defined point in relation to the fourth extreme value may be taken as an expression of the amount of fibrin in the sample and consequently of the original fibrinogen concentration.
  • An apparatus for performing the method according to the inventio comprises a cuvette with an internal dimension less than 1 mm for receiving a bloo 5 sample, a light source for illuminating the sample, means for measuring the ligh signal from the sample in the cuvette, means for recording the measured light signal values, means for calculating the parameters of the recorded light signal versus time curve, and means for displaying the results of this calculation.
  • the calculation means may further convert the calculated curve values to clinical chemistry quantities.
  • the cuvette may be a capillary tube, and more cuvettes working in parallel may be provided each having its own measuring channel. This makes it possible to make a control on the measurement by taking it as an indication that the measurement should be rejected if the measuring results from the two parallel channels deviate by more than a preset value. Further, the use of more parallel cuvettes makes it possible to directly compare two samples, e.g one of the cuvettes may be coated by an active substance whereby a comparison of the samples in the two cuvettes gives an indication of the effect of the active substance.
  • the cuvettes may be disposable so that after use they may be removed from the apparatus and replaced by new ones.
  • the cuvettes may be mounted in an independent support piece which is designed to be accommodated in the apparatus and after use be removed from the apparatus and disposed of.
  • the cuvettes mounted in the independent support piece may be capillary tubes which are so placed in the support piece that their inlet ends lie closely up against each other. This makes it possible to fill the two capillary tubes simultaneously from the same drop of blood.
  • the means for measuring the light signal from the samples may comprise a light source and a light sensor placed in a specific geometric relation to each other.
  • the geometry is chosen with regard to which light signal should be measured. If translucence should be measured, connected light sources and sensors are placed opposite each other, whereas a measurement of scattered or reflected light is preferably measured by a sensor placed so that it would receive no light directly from the light source. It should be noticed that in the last mentioned case the light signal value is low when no sample is in the cuvette to reflect the light and will suddenly rise when the sample enters the cuvette.
  • the apparatus may comprise a microcomputer performing the recording of the light signal values by storing at preset time intervals the measured light signal values, performing the calculations of the curve parameters on the basis of the stored values, and translating the curve parameters into blood parameters.
  • the calculated parameters may be stored in the microcomputer and may be displayed on the display on request.
  • Figure 1 shows a perspective illustration of an embodiment of an apparatus with a support element with capillary elements inserted
  • Figure 2 schematicly shows a cross-sectional view along the line ll-ll in Figure 1
  • Figure 3 shows the support element with the capillary elements during the filling of the capillary elements
  • Figure 4 shows a translucence versus time curve for a blood sample.
  • the apparatus shown in Figure 1 corresponds in its construction to the apparatus according to WO 89/06803 meant for determining the coagulation time for a blood sample.
  • the apparatus itself is indicated as a whole by the reference number 1. It comprises a housing 3 with a display 4 on the one side. At one end of the housing 3 there is provided an opening 5 in which a support element carrying capillary elements may be inserted.
  • Figure 2 illustrates how one or more light sources 7, 9, preferably in the form of light diodes, are mounted in the housing 3 in relation to the opening 5.
  • Light meters, preferably in the form of photodiodes 8, 10, are mounted opposite the light sources 7,9 on the other side of the opening 5.
  • the apparatus is also provided with a not shown built-in microprocessor controlling the measuring sequence and calculating the blood 5 parameters on the basis of the translucence measured and stored at preset time intervals.
  • the apparatus only differs from the photometer apparatus according to the WO-application by the performances of the built-in computer which should be equipped with the necessary storage capacity and should be programmed to perform the necessary calculations and controlling. Further, the apparatus should be provided with means to call forward on request the stored and calculated data on the display, which display may further be designed to display not only digits but also curves.
  • FIG 3 shows the support element 2 with two capillary tubes 16 and
  • the support element 2 comprises a support piece 6 which is preferably made from an opaque plastic.
  • the one end of the support piece 6 is tapered to form a wedge 13 to ease the insertion in the opening 5 of the apparatus.
  • the opposite end of the support piece 6 is provided with a pair of extensions 1 forming a finger grip for the handling of the support element.
  • the support element is provided with a groove 12 which together with a similar groove on the back side forms a guide for guiding the support element when inserted in the opening 5 of the apparatus.
  • the support piece 6 is provided with a pair of windows 18 and 19, one behind each of the capillary tubes. These windows are placed so that they are in line with the light beam from the light source to the light sensor when the support element is inserted in the apparatus.
  • capillary elements are described as being capillary tubes, other forms of capillary elements such as transparent sheets with a small distance between them may be used, just as the capillary elements may be individual and designed to be inserted into the apparatus directly without a supporting element. Also a single capillary element may be used, although two are preferred.
  • the capillary elements may also be arranged so that blood sampling from venous tubes or a-v shunts is facilitated.
  • Figure 4 shows a translucence versus time curve recorded during the coagulation sequence for a blood sample.
  • the time elapsed is indicated as seconds along the X-axis, and the translucence is indicated as the output voltage in mV from 5 the photo sensor.
  • the blood sample When by the capillary effect the blood sample is sucked into the capillary element inserted in the measuring apparatus, it will cover the light beam through the window 18 or 19 when it reaches the part of the capillary element lying abreast of this window. Thereby the light sensed by the corresponding sensor will ⁇ o be damped suddenly, and a sudden fall will be seen on the translucence curve, illustrated at 41. From this minimum the translucence will slowly rise to a maximum 42, as by their gravity the blood cells are precipitated, and the translucent plasma collects above the precipitated substance. In this way the height of the maximum translucence following the first minimum is an indication of the haematocrit, i.e. the s maximum 42 is related to the volume of blood cells in relation to the volume of the whole blood.
  • the blood starts to coagulate and the translucence falls as the fibrin threads cause dispersion of light.
  • the time from the first minimum 41 to the first maximum 42 defines in the known way the coagulation o time.
  • the translucence falls until all fibrinogen is transformed into fibrin. From the minimum 43 hereby defined the translucence will rise again when the fibrinolytic system is activated.
  • the slope of the falling curve may be taken as an indication of the fibrinogen concentration in the substrate.
  • the 5 height of the first maximum 42 over the second minimum 43 may be taken as an indication of the fibrinogen value, and unlike the above mentioned slope this indication is not influenced by a possible coating of the capillary element to stimulate the formation of fibrin.
  • the second minimum 43 is a rather flat one, and a measuring of the time passing from the moment when the translucence passes a value a preset distance 46 over the minimum 43 until the moment when it reaches the same value during the rising after the minimum may be taken as an indication of how quickly the fibrinolytic system may be activated, i.e. the velocity of transforming plasminogen into plasmin. 5
  • the points on the translucence curve lying the preset distance 46 over the minimum 43 during the fall and the rise of the curve, respectively, are designated 44 and 45, respectively.
  • the slope of the curve for the rising translucence after the second minimum 43 is seen to be proportional with the plasmin concentration, and the height of a second maximum 47 over the second minimum 43 is related to the quantity of fibrin and consequently to the original fibrin concentration.
  • the determination of the slope of the curve may be made by differentiating. As the slope varies in time, it is necessary to decide what part of the curve should be used when determining this parameter. For the course from the first maximum to the second minimum and from the second minimum to the second maximum the slope of the curve may be determined as the slope of its inflection. The point of inflection may be found by differentiating the function twice.
  • the translucence of the sample is measured, it is within the scope of the invention to measure the light scattered or in any other way modulated by the presence of the sample.
  • the sensors When measuring scattered light it is appropriate not to place the sensors opposite the light source but rather angularly displaced in relation to such a 180° position. Thereby it is avoided that the sensor receives light directly from the light source, and especially where a capillary tube is used advantage may be taken of the fact that the cylindric tube acts as a lens which may focus the light on the sensor.
  • time spaces need not be defined as the time elapsing from one extreme value to the next one, but may be defined as the time space between points which are well defined in relation to these values.

Abstract

A method for quantitation of blood parameters comprises the steps provision of a sample of plasma, serum or blood, entering the sample into a cuvette with an internal dimension less than 1 mm, illuminating the sample by a light source, measuring and recording the changes of light properties caused by the sample as a function of time, calculating parameters of the recorded light signal/time curve such as slopes, extreme values, and the time distance between such extreme values, and interpreting the parameters as blood parameters. For the measurements an apparatus is used comprising a cuvette (16, 17) with an internal dimension less than 1 mm, a light source (7, 9), means (8, 10) for measuring currently a light signal from the sample, means for recording the measured light signal values, and means for calculating parameters of the thereby defined light signal versus time graph.

Description

Method And Apparatus For Quantitation Of Relevant Blood Parameters.
The provision of a blood sample for quantitation of various blood parameters is a routine by many medical investigations. Commonly, a sample of some ml is taken and sent to a laboratory where the relevant parameters such as coagulation time, haematocrit, sedimentation rate, haemoglobin percentage, etc are quantified.
To obtain a sample of some ml it is necessary to pass a cannula into a vein to make the necessary amount of blood flow into a vessel. The vessel must then be carefully labelled and sent to the laboratory wherefrom the determined data will issue later.
By this procedure the blood sample when taken must be added an anticoagulant to prevent the blood from coagulating on its way to the laboratory. In the laboratory the effect of the anticoagulant is neutralized to make the sample equate a sample of fresh blood.
It is wanted to provide a method and an apparatus making it possible to decide the relevant parameters on the basis of fresh blood, the measuring beginning practically at the very moment the blood sample leaves the patient's body and being ended about 30 minutes later. The apparatus should be handy and portable to an extent making it possible to allocate the apparatus to the patient so that the blood sample may be passed into the apparatus, which may then be placed at the bedside until the result is ready. Further, the method should make it possible to perform the measurement on a blood sample which may be provided by simply pricking a finger or an earlobe to obtain a sample not larger than 25 μl, i.e. a sample which could be provided without help from a professional to puncture a vein.
A method of measuring the coagulation time for a blood sample is known, which method comprises the steps of entering the sample into a capillary element and measuring the coagulation time as the time elapsing from the moment when the blood sample enters the photometer measuring the translucence, which moment is indicated by a sudden fall of the translucence, until the moment when the translucence reaches a maximum after this sudden fall.
However, it has appeared that the development of the properties of light passing through or being scattered or reflected by a blood sample beyond the time of the occurrence of the first translucence maximum reveals interesting information 5 of other relevant blood parameters.
According to the invention, a method for quantitation of relevant blood parameters comprises the following steps: provision of a sample of plasma, serum or whole blood, entering the sample into a cuvette with an internal dimension less than 1 mm, illuminating the sample by a light source, measuring and recording the changes of light properties caused by the sample as a function of time, calculating parameters of the recorded light signal/time curve, - interpreting the parameters such as slopes and time spaces between extremes and/or other well-defined points of the obtained light signal/time curve.
A light signal/time curve may have a course with a first sharp extreme value corresponding to the moment when the sample is introduced in the measuring part of the cuvette. If for example the light signal is the translucence of the sample, this extreme value is a minimum. From this minimum the translucence will rise to a maximum being the second extreme value from which it descends again to a relatively flat minimum representing a third extreme value, whereupon it rises again to a fourth extreme value, a high maximum from which it finally descends almost linearly.
The recording of the curve may be made by frequent storing, e.g. once a second, of connected values for measured light signal and time elapsed from a starting moment, mainly defined by the first sudden change in the light signal corresponding to the entering of the sample. These recordings make it possible to define the extreme values and to calculate slopes in different positions on the curve. However, when only the time elapsed between two incidents is needed, the recording of the intermediate light signal values may be omitted.
The time elapsing from the starting moment until a well-defined point in relation to the second extreme value is taken as an expression of the coagulation time.
The slope of the curve when passing from the first extreme value to the second extreme value may be taken as an expression of the sedimentation rate.
The difference between the first extreme value and the following second extreme value is taken as an expression of the haematocrit value. The slope of the curve when passing from a well-defined point in relation to the second extreme value to a well-defined point in relation to the third extreme value is taken as an expression of the fibrinogen concentration and the platelet-related coagulation activity. As the slope of the curve varies, this value may be more precisely defined as e.g. the slope of its inflection, or the slope may be calculated as the difference between the second extreme value and a third extreme value or between well-defined points in relation to the extreme values divided by the time difference between these two extremes or points.
The time it takes for the light signal curve to pass the third extreme value is calculated as the time interval from the moment when the light signal value passes a set value differing by a predetermined amount from this third extreme value when approaching this value, until the moment when the light signal value passes again this set value after having passed the third extreme value, and this calculated time is taken as an expression of the activity of the fibrinolytic system.
The slope of the light signal curve when passing from a well-defined point in relation to its third extreme value to a well-defined point in relation to its fourth extreme value is taken as an expression of the rate of fibrin degeneration. The difference between the value in a well-defined point in relation to the third extreme value and a well defined point in relation to the fourth extreme value may be taken as an expression of the amount of fibrin in the sample and consequently of the original fibrinogen concentration.
If a reagent is added to the blood sample before the measurement is performed, this measurement will show how the blood parameters are influenced b the reagent.
An apparatus for performing the method according to the inventio comprises a cuvette with an internal dimension less than 1 mm for receiving a bloo 5 sample, a light source for illuminating the sample, means for measuring the ligh signal from the sample in the cuvette, means for recording the measured light signal values, means for calculating the parameters of the recorded light signal versus time curve, and means for displaying the results of this calculation.
Appropriately, the calculation means may further convert the calculated curve values to clinical chemistry quantities.
The cuvette may be a capillary tube, and more cuvettes working in parallel may be provided each having its own measuring channel. This makes it possible to make a control on the measurement by taking it as an indication that the measurement should be rejected if the measuring results from the two parallel channels deviate by more than a preset value. Further, the use of more parallel cuvettes makes it possible to directly compare two samples, e.g one of the cuvettes may be coated by an active substance whereby a comparison of the samples in the two cuvettes gives an indication of the effect of the active substance.
The cuvettes may be disposable so that after use they may be removed from the apparatus and replaced by new ones. Also, the cuvettes may be mounted in an independent support piece which is designed to be accommodated in the apparatus and after use be removed from the apparatus and disposed of. The cuvettes mounted in the independent support piece may be capillary tubes which are so placed in the support piece that their inlet ends lie closely up against each other. This makes it possible to fill the two capillary tubes simultaneously from the same drop of blood.
The means for measuring the light signal from the samples may comprise a light source and a light sensor placed in a specific geometric relation to each other. The geometry is chosen with regard to which light signal should be measured. If translucence should be measured, connected light sources and sensors are placed opposite each other, whereas a measurement of scattered or reflected light is preferably measured by a sensor placed so that it would receive no light directly from the light source. It should be noticed that in the last mentioned case the light signal value is low when no sample is in the cuvette to reflect the light and will suddenly rise when the sample enters the cuvette. According to the invention, the apparatus may comprise a microcomputer performing the recording of the light signal values by storing at preset time intervals the measured light signal values, performing the calculations of the curve parameters on the basis of the stored values, and translating the curve parameters into blood parameters. The calculated parameters may be stored in the microcomputer and may be displayed on the display on request.
In the following the invention is described with reference to the drawing, in which
Figure 1 shows a perspective illustration of an embodiment of an apparatus with a support element with capillary elements inserted, Figure 2 schematicly shows a cross-sectional view along the line ll-ll in Figure 1 , Figure 3 shows the support element with the capillary elements during the filling of the capillary elements,
Figure 4 shows a translucence versus time curve for a blood sample. The apparatus shown in Figure 1 corresponds in its construction to the apparatus according to WO 89/06803 meant for determining the coagulation time for a blood sample. The apparatus itself is indicated as a whole by the reference number 1. It comprises a housing 3 with a display 4 on the one side. At one end of the housing 3 there is provided an opening 5 in which a support element carrying capillary elements may be inserted.
Figure 2 illustrates how one or more light sources 7, 9, preferably in the form of light diodes, are mounted in the housing 3 in relation to the opening 5. Light meters, preferably in the form of photodiodes 8, 10, are mounted opposite the light sources 7,9 on the other side of the opening 5.
The apparatus is also provided with a not shown built-in microprocessor controlling the measuring sequence and calculating the blood 5 parameters on the basis of the translucence measured and stored at preset time intervals. The apparatus only differs from the photometer apparatus according to the WO-application by the performances of the built-in computer which should be equipped with the necessary storage capacity and should be programmed to perform the necessary calculations and controlling. Further, the apparatus should be provided with means to call forward on request the stored and calculated data on the display, which display may further be designed to display not only digits but also curves.
Figure 3 shows the support element 2 with two capillary tubes 16 and
17 during the filling of the tubes from a blood drop 21 provided by pricking a finger 20. The support element 2 comprises a support piece 6 which is preferably made from an opaque plastic. The one end of the support piece 6 is tapered to form a wedge 13 to ease the insertion in the opening 5 of the apparatus. The opposite end of the support piece 6 is provided with a pair of extensions 1 forming a finger grip for the handling of the support element. Moreover, the support element is provided with a groove 12 which together with a similar groove on the back side forms a guide for guiding the support element when inserted in the opening 5 of the apparatus. Finally, the support piece 6 is provided with a pair of windows 18 and 19, one behind each of the capillary tubes. These windows are placed so that they are in line with the light beam from the light source to the light sensor when the support element is inserted in the apparatus.
Although in the embodiment just described the capillary elements are described as being capillary tubes, other forms of capillary elements such as transparent sheets with a small distance between them may be used, just as the capillary elements may be individual and designed to be inserted into the apparatus directly without a supporting element. Also a single capillary element may be used, although two are preferred. The capillary elements may also be arranged so that blood sampling from venous tubes or a-v shunts is facilitated.
Figure 4 shows a translucence versus time curve recorded during the coagulation sequence for a blood sample. The time elapsed is indicated as seconds along the X-axis, and the translucence is indicated as the output voltage in mV from 5 the photo sensor.
When by the capillary effect the blood sample is sucked into the capillary element inserted in the measuring apparatus, it will cover the light beam through the window 18 or 19 when it reaches the part of the capillary element lying abreast of this window. Thereby the light sensed by the corresponding sensor will ιo be damped suddenly, and a sudden fall will be seen on the translucence curve, illustrated at 41. From this minimum the translucence will slowly rise to a maximum 42, as by their gravity the blood cells are precipitated, and the translucent plasma collects above the precipitated substance. In this way the height of the maximum translucence following the first minimum is an indication of the haematocrit, i.e. the s maximum 42 is related to the volume of blood cells in relation to the volume of the whole blood.
At the time for the first maximum the blood starts to coagulate and the translucence falls as the fibrin threads cause dispersion of light. The time from the first minimum 41 to the first maximum 42 defines in the known way the coagulation o time.
From its first maximum the translucence falls until all fibrinogen is transformed into fibrin. From the minimum 43 hereby defined the translucence will rise again when the fibrinolytic system is activated. The slope of the falling curve may be taken as an indication of the fibrinogen concentration in the substrate. Also the 5 height of the first maximum 42 over the second minimum 43 may be taken as an indication of the fibrinogen value, and unlike the above mentioned slope this indication is not influenced by a possible coating of the capillary element to stimulate the formation of fibrin.
After the passage of the second minimum 43 the fibrin is by the action o of plasmin decomposed to fibrin split products, and the sample becomes more translucent. The second minimum is a rather flat one, and a measuring of the time passing from the moment when the translucence passes a value a preset distance 46 over the minimum 43 until the moment when it reaches the same value during the rising after the minimum may be taken as an indication of how quickly the fibrinolytic system may be activated, i.e. the velocity of transforming plasminogen into plasmin. 5 The points on the translucence curve lying the preset distance 46 over the minimum 43 during the fall and the rise of the curve, respectively, are designated 44 and 45, respectively. As it is not possible to know at forehand the translucence value for the minimum, it is here necessary to look back into the recorded values when the appearance of the -minimum is detected. The slope of the curve for the rising translucence after the second minimum 43 is seen to be proportional with the plasmin concentration, and the height of a second maximum 47 over the second minimum 43 is related to the quantity of fibrin and consequently to the original fibrin concentration.
Having passed its second maximum value, the translucence falls almost linearly.
By recording the translucence at preset time intervals, data are stored making it possible to determine relevant parameters of the translucence/time-curve. In the computer such parameters may be translated into corresponding blood parameters. Another possibility is to make the computer display the curve directly, as many professionals would prefer to make their evaluation from a knowledge of the course of the curve. For others it may be sufficient to know that the different parameters should be maintained within certain intervals.
The determination of the slope of the curve may be made by differentiating. As the slope varies in time, it is necessary to decide what part of the curve should be used when determining this parameter. For the course from the first maximum to the second minimum and from the second minimum to the second maximum the slope of the curve may be determined as the slope of its inflection. The point of inflection may be found by differentiating the function twice.
Although in the example described the translucence of the sample is measured, it is within the scope of the invention to measure the light scattered or in any other way modulated by the presence of the sample. When measuring scattered light it is appropriate not to place the sensors opposite the light source but rather angularly displaced in relation to such a 180° position. Thereby it is avoided that the sensor receives light directly from the light source, and especially where a capillary tube is used advantage may be taken of the fact that the cylindric tube acts as a lens which may focus the light on the sensor.
It shall be noticed that the time spaces need not be defined as the time elapsing from one extreme value to the next one, but may be defined as the time space between points which are well defined in relation to these values.

Claims

1. A method for quantitation of blood parameters, characterized in, that it comprises the following steps: provision of a sample of plasma, serum or whole blood, 5 - entering the sample into a cuvette with an internal dimension less than
1 mm, illuminating the sample by a light source, measuring and recording the changes of light properties caused by the sample as a function of time, ιo - calculating parameters of the recorded light signal/time curve, interpreting the parameters as blood parameters.
2. A method according to claim 1 , characterized in, that the recording is made by frequently storing connected values for measured light signal and time elapsed from a starting moment.
s 3. A method according to claim 1 or 2, characterized in, that the time for a first extreme value caused by the introduction of the sample into the cuvette is interpreted as the starting moment for the measurement.
4. A method according to any of the preceding claims, characterized in, that the time elapsing from a starting moment to a well defined point in relation o to the second occurring extreme value is taken as an expression of the coagulation time.
5. A method according to any of the preceding claims, characterized in, that the slope of the curve when passing from the first extreme value to the second extreme value is taken as an expression of the sedimentation rate.
6. A method according to any of the preceding claims, characterized in, that the heigth of the curve when passing from the first extreme value to the second extreme value is taken as an expression of the haemotocrit.
7. A method according to any of the preceding claims, characterized in, that the difference between a second extreme value and a third extreme value is taken as an expression of the fibrinogen concentration.
8. A method according to any of the preceding claims, characterized in, that the slope of the curve when passing from a second extreme value is taken as an expression of the fibrinogen concentration and platelet related coagulation activity.
9. A method according to any of the preceding claims, characterized in, that the time it takes for the light signal curve to pass a third extreme value is calculated as the time interval from the moment when the light signal value passes a set value differing by a predetermined amount from this third extreme value when approaching this value, until the moment when the light signal value again passes this set value after having passed the third extreme value, and this calculated time is taken as an expression of the activity of the fibrinolytic system.
10. A method according to any of the preceding claims, characterized in, that the slope of the light signal curve when passing from a well-defined point in relation to its third extreme value to a well-defined point in relation to its fourth extreme value is taken as an expression of the rate of fibrin degeneration.
11. A method according to any of the preceding claims, characterized in, that the difference between the value in a well-defined point in relation to the third extreme value and a well defined point in relation to the fourth extreme value on the light signal/time curve is taken as an expression of the amount of fibrin in the sample and consequently of the original fibrinogen concentration.
12. An apparatus for quantitation of blood parameters by performing the method according to claims 1-11, characterized in, that it comprises a cuvette with an internal dimension less than 1 mm for receiving a blood sample, a light source for illuminating the sample, means for measuring the fight signal from the
5 sample in the cuvette, means for recording the measured light signal values, means for calculating the parameters of the recorded light signal versus time curve, and means for displaying the results of this calculation.
13. An apparatus according to claim 12, characterized in, that the calculation means further converts the calculated curve parameters to blood parameters.
14. An apparatus according to claim 13, characterized in, that the cuvette is a capillary element.
15. An apparatus according to claim 14,characterized in, that the cuvette is a capillary tube.
16. An apparatus according to claim 15, characterized in, that more parallel acting capillary tubes are provided.
17. An apparatus according to any of claims 12 - 16, characterized in, that the cuvette is mounted in a disposable part of the apparatus.
18. An apparatus according to any of claims 12 - 17, characterized in, that the means for measuring the light signal comprises a light source and a light sensor facing each other on opposite sides of the cuvette element.
19. An apparatus according to any of claims 12 - 18, characterized in, that it comprises a microcomputer performing the current recording by storing at preset time intervals the measured translucence values, performing the calculations of the curve parameters on the basis of the stored values, and translating the curv parameters into blood parameters.
PCT/DK1992/000382 1991-12-19 1992-12-18 Method and apparatus for quantitation of relevant blood parameters WO1993012422A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP93902090A EP0643829B1 (en) 1991-12-19 1992-12-18 Method and apparatus for quantitation of relevant blood parameters
US08/244,966 US5567869A (en) 1991-12-19 1992-12-18 Method and apparatus for quantitation of relevant blood parameters
JP5510535A JPH07502118A (en) 1991-12-19 1992-12-18 Quantification methods and devices for related blood parameters
DE69228882T DE69228882D1 (en) 1991-12-19 1992-12-18 METHOD AND DEVICE FOR QUANTIFYING RELEVANT BLOOD PARAMETERS

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK912031A DK203191D0 (en) 1991-12-19 1991-12-19 METHOD AND APPARATUS FOR DETERMINING RELEVANT BLOOD PARAMETERS
DK2031/91 1991-12-19

Publications (1)

Publication Number Publication Date
WO1993012422A1 true WO1993012422A1 (en) 1993-06-24

Family

ID=8109588

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1992/000382 WO1993012422A1 (en) 1991-12-19 1992-12-18 Method and apparatus for quantitation of relevant blood parameters

Country Status (8)

Country Link
US (1) US5567869A (en)
EP (1) EP0643829B1 (en)
JP (1) JPH07502118A (en)
AT (1) ATE178716T1 (en)
AU (1) AU3344793A (en)
DE (1) DE69228882D1 (en)
DK (1) DK203191D0 (en)
WO (1) WO1993012422A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102326069A (en) * 2009-02-18 2012-01-18 霍夫曼-拉罗奇有限公司 Test method and test device for investigating a body fluid

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1280143B1 (en) * 1995-03-15 1998-01-05 S I R E Sas Di De Monte Duic G PROCEDURE FOR THE DETERMINATION OF BLOOD SEDIMENTATION AND RELATED DEVICE
CA2235772C (en) * 1995-10-23 2002-12-31 Cytometrics, Inc. Method and apparatus for reflected imaging analysis
JPH09308624A (en) * 1996-05-23 1997-12-02 Minolta Co Ltd Attachment for concentration measuring instrument and concentration measuring system
HU222809B1 (en) * 1997-10-03 2003-10-28 77 Elektronika Műszeripari Kft. Method and apparatus for detecting chemical component from sample mostly for detecting glucose content of blood from blood sample
IT1311616B1 (en) * 1999-11-08 2002-03-14 Sire Analytical Syst Srl PROCEDURE FOR THE DETERMINATION OF THE BLOOD SEDIMENTATION SPEED AND OTHER RELATED PARAMETERS, AND RELATED
US6563585B1 (en) 1999-11-24 2003-05-13 University Of Maryland Biotechnology Institute Ratiometric fluorometer
US7029628B2 (en) * 2000-12-28 2006-04-18 Stat-Chem Inc. Portable co-oximeter
FR2829286B1 (en) * 2001-09-03 2008-04-04 Ge Med Sys Global Tech Co Llc DEVICE AND METHOD FOR TRANSMITTING X-RAYS
US7061593B2 (en) * 2001-11-08 2006-06-13 Optiscan Biomedical Corp. Device and method for in vitro determination of analyte concentrations within body fluids
US6958809B2 (en) 2001-11-08 2005-10-25 Optiscan Biomedical Corporation Reagent-less whole-blood glucose meter
US6989891B2 (en) 2001-11-08 2006-01-24 Optiscan Biomedical Corporation Device and method for in vitro determination of analyte concentrations within body fluids
US7050157B2 (en) * 2001-11-08 2006-05-23 Optiscan Biomedical Corp. Reagent-less whole-blood glucose meter
US6662386B1 (en) * 2002-11-19 2003-12-16 Rickie Allen Bowerman Shower back scrubbing device
US20040132167A1 (en) * 2003-01-06 2004-07-08 Peter Rule Cartridge lance
US20040132168A1 (en) * 2003-01-06 2004-07-08 Peter Rule Sample element for reagentless whole blood glucose meter
US6983177B2 (en) * 2003-01-06 2006-01-03 Optiscan Biomedical Corporation Layered spectroscopic sample element with microporous membrane
US20040131088A1 (en) * 2003-01-08 2004-07-08 Adtran, Inc. Shared T1/E1 signaling bit processor
US20050037384A1 (en) * 2003-04-15 2005-02-17 Braig James R. Analyte detection system
WO2005111580A1 (en) * 2004-05-07 2005-11-24 Optiscan Biomedical Corporation Sample element with fringing-reduction capabilities
US7907985B2 (en) 2005-02-14 2011-03-15 Optiscan Biomedical Corporation Fluid handling cassette with a fluid control interface and sample separator
US9561001B2 (en) 2005-10-06 2017-02-07 Optiscan Biomedical Corporation Fluid handling cassette system for body fluid analyzer
US9554742B2 (en) 2009-07-20 2017-01-31 Optiscan Biomedical Corporation Fluid analysis system
EP2456355B1 (en) 2009-07-20 2016-09-14 Optiscan Biomedical Corporation Adjustable connector and dead space reduction
EP2580589B1 (en) 2010-06-09 2016-08-31 Optiscan Biomedical Corporation Measuring analytes in a fluid sample drawn from a patient
WO2013006716A1 (en) 2011-07-06 2013-01-10 Optiscan Biomedical Corporation Sample cell for fluid analysis system
US9279800B2 (en) 2012-01-13 2016-03-08 Alcor Scientific, Inc. Apparatus, method, system for the determination of the aggregation rate of red blood cells
US9625465B2 (en) 2012-05-15 2017-04-18 Defined Diagnostics, Llc Clinical diagnostic systems
US9081001B2 (en) 2012-05-15 2015-07-14 Wellstat Diagnostics, Llc Diagnostic systems and instruments
US9213043B2 (en) 2012-05-15 2015-12-15 Wellstat Diagnostics, Llc Clinical diagnostic system including instrument and cartridge
US9909977B2 (en) * 2013-10-16 2018-03-06 Institut National De La Sante Et De La Recherche Medical Simultaneous monitoring of fibrinogen and haematocrit in whole blood
JP6799245B2 (en) * 2016-02-25 2020-12-16 国立研究開発法人産業技術総合研究所 How to measure changes in the amount of fibrin in blood

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4848900A (en) * 1987-06-22 1989-07-18 Kuo Cheng Deng Computerized automatic monitoring and recording system of erythrocyte sedimentation process
WO1989006803A1 (en) * 1988-01-14 1989-07-27 Nordisk Gentofte A/S Apparatus for determination of the coagulation time of a blood sample

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3307392A (en) * 1964-05-04 1967-03-07 Research Corp Automatic prothrombin timer apparatus and method
US3458287A (en) * 1965-04-29 1969-07-29 Medical Laboratory Automation Method and means of determining endpoint times in blood clotting tests
US3814585A (en) * 1972-09-26 1974-06-04 R Bailly Method and apparatus for testing blood coagulation
DE2431342C3 (en) * 1973-07-27 1978-10-26 Behringwerke Ag, 3550 Marburg Method for measuring the plasminogen content by determining the formation of fibrin in a sample
US3923397A (en) * 1974-05-29 1975-12-02 Dolive Stephen E Hematocrit measuring method
JPS5469497A (en) * 1977-11-12 1979-06-04 Kyoto Daiichi Kagaku Kk Method and device for measuring blood solidification time
US4303336A (en) * 1978-08-28 1981-12-01 Baxter Travenol Laboratories, Inc. Method and apparatus for making a rapid measurement of the hematocrit of blood
JPS6093349A (en) * 1983-10-28 1985-05-25 Mochida Pharmaceut Co Ltd Device for measuring blood component and method of use thereof
JP2610434B2 (en) * 1987-06-05 1997-05-14 株式会社 京都第一科学 Blood coagulation ability measurement method
DE3900493A1 (en) * 1989-01-10 1990-07-12 Thomae Gmbh Dr K METHOD FOR DETERMINING OVERALL FIBRINOLYTIC ACTIVITY IN PLASMA
TW221493B (en) * 1990-07-10 1994-03-01 Cardiovascular Diagnostics Inc

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4848900A (en) * 1987-06-22 1989-07-18 Kuo Cheng Deng Computerized automatic monitoring and recording system of erythrocyte sedimentation process
WO1989006803A1 (en) * 1988-01-14 1989-07-27 Nordisk Gentofte A/S Apparatus for determination of the coagulation time of a blood sample

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN, Vol. 13, No. 138, P-852; & JP,A,63 305 255 (KYOTO DAIICHI KAGAKU K.K. et al.), 13 December 1988. *
PATENT ABSTRACTS OF JAPAN, Vol. 9, No. 239, P-391; & JP,A,60 093 349 (MOCHIDA SEIYAKU K.K. et al.), 25 May 1985. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102326069A (en) * 2009-02-18 2012-01-18 霍夫曼-拉罗奇有限公司 Test method and test device for investigating a body fluid
US9052293B2 (en) 2009-02-18 2015-06-09 Roche Diabetes Care, Inc. Test method and test device for analysing a body fluid
US10244970B2 (en) 2009-02-18 2019-04-02 Roche Diabetes Care, Inc. Test method and test device for analysing a body fluid
US10694984B2 (en) 2009-02-18 2020-06-30 Roche Diabetes Care, Inc. Test method and test drive for analysing a body fluid

Also Published As

Publication number Publication date
DK203191D0 (en) 1991-12-19
ATE178716T1 (en) 1999-04-15
EP0643829A1 (en) 1995-03-22
DE69228882D1 (en) 1999-05-12
AU3344793A (en) 1993-07-19
JPH07502118A (en) 1995-03-02
US5567869A (en) 1996-10-22
EP0643829B1 (en) 1999-04-07

Similar Documents

Publication Publication Date Title
EP0643829B1 (en) Method and apparatus for quantitation of relevant blood parameters
US8460938B2 (en) Blood viscosity analysis
CA1321901C (en) Apparatus for the measuring of a blood sample
JP4659457B2 (en) Method and apparatus for ultrasonic measurement of red blood cell index
EP1579196B1 (en) Method and device for measurements in blood
US5506145A (en) Determination of an individual's inflammation index from whole blood fibrinogen and hematocrit or hemoglobin measurements
US6064896A (en) Non-invasive measurement of blood glucose using instruments that have less precise detection capability
KR20030030939A (en) Devices for physiological fluid sampling and methods of using the same
IL119904A0 (en) An automated method for discriminating platelets from cells and apparatus for carrying out same
US3951606A (en) Apparatus for prothrombin testing
WO2004044560A1 (en) Photometric determination of coagulation time in undiluted whole blood
WO2005054847A1 (en) Hematocrit and analyte concentration determination
US4293307A (en) Method and apparatus for analyzing liquid
JPS62266438A (en) Method and device for detecting relative dynamic liquid surface activity
US6150174A (en) Method for measurement of whole blood coagulation parameters
Pagliaro et al. A non-invasive strategy for haemoglobin screening of blood donors
Prichard et al. Clinical evaluation of the ABL-77 for point-of-care analysis in the cardiovascular operating room
US4875364A (en) Method for measuring hemoglobin
CN114235906B (en) Method for detecting blood glucose concentration in real time in-vitro blood glucose degradation process
RU2051383C1 (en) Device for determining blood coagulation time
AU617418B2 (en) Apparatus for determination of the coagulation time of a blood sample
Barton et al. A comparison of reagent strips and the refractometer for measurement of urine specific gravity in hospitalized children
US20070285651A1 (en) Methods and devices for measuring sample coagulation
TR2022006586A1 (en) A NEW METHOD FOR RAPID ESTIMATION OF CEREREBRINAL FLUID (CSF) PRESSURE DURING LUMBAR PUNCTION
Hedlund et al. Clinical experience with the Diametrics IRMA (Immediate Response Mobile Analysis) blood analysis system

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR CA CS FI HU JP KP KR LK MG MN MW NO NZ PL RO RU SD UA US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 1993902090

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 08244966

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1993902090

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: CA

WWG Wipo information: grant in national office

Ref document number: 1993902090

Country of ref document: EP