RU2548780C1 - Method for assessing functional state of haemostasis system - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haemocoagulogy, and can be used for detecting a group of individuals suffering a risk of haemocoagulation complications. Substance of the method: measuring initial blood coagulation trace amplitude, determining initial and final blood coagulation parameters and comparing them to corresponding normal blood coagulation parameters; if observing oppositely directed deviations, the disturbed functional state of the haemostasis system is diagnosed. A time constant is determined according to a calibration curve; the calibration procedure a priori covers two measured U₁, U₂ and known U₀₁, U₀₂ values of lower t₁ and upper t₂=kt₁ limits of the adaptive range; the calibration curve U_0i is a blood limit strength function compensating an uncertainty T* of the random time constant T₀ and relating the reference U_ri and measured U_i characteristics by normalising the measured values by the known ones

the calibration curve U_0i shows the actual values of the time constant T₀ and blood limit strengthU₀

which are used to draw the calibration curve of the blood limit strength, reference performance U_ri

and to determine initial T_i and final T_f blood coagulation parameters

wherein U_i, U_f are the normalised initial and final blood coagulation thresholds.

EFFECT: invention enables reducing a procedure error by tens orders, increasing a coagulation time accuracy by 4 orders, and reducing the efficiency three times as much that eventually provides higher metrological effectiveness of computer analysers applicable for the purpose of automating the process of detecting the individuals having a risk of haemocoagulation complications.

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Description

The present invention relates to medicine, namely to hemocoagulogy, and can be used to identify individuals at risk of developing hemocoagulation complications.

A known instrumental method for assessing the functional state of the hemostasis system is thromboelastography (TEG), which consists in graphical (photo-optical or mechanical) recording of the viscosity characteristics of blood and plasma during their coagulation, followed by determination of thromboelastogram parameters characterizing the process under study [USSR Author's Certificate No. 1520450, M class G01N 33/86, publ. 11/07/89, BI N41].

The disadvantages of this method are the low sensitivity and reproducibility, the inability to detect subtle shifts in the blood coagulation system and to conduct an analytical assessment of the revealed violations.

A known method for determining the functional state of the hemostatic system by registering an electrocoagulogram of blood [see Prince Koblov L.F. Methods and devices for the study of hemostasis. - M .: Medicine, 1975, p.75-79], which consists in recording changes in the electrical resistance of a blood sample, poured into a cell with two electrodes. The cell oscillates, so that the blood alternately closes and opens the electrodes. The recording of the research result has the form of a series of periodic pulses with a repetition rate of 0.1 Hz (6 pulses per minute), the envelope of which characterizes the blood coagulation process. The amplitude of the pulses corresponds to the resistance of the blood located at the moment between the electrodes of the measuring cell. When evaluating the electrocoagulogram, the following indicators are taken into account: T1 - coagulation start time: T2 - coagulation end time; T is the duration of coagulation; Am is the magnitude of the maximum amplitude; Ao is the value of the minimum amplitude. By changing these parameters, one gets an idea of various disorders of the blood coagulation system.

The disadvantages of this method are inertia, relatively low accuracy and sensitivity of measurements due to the occurrence of intense side physical and chemical processes associated with the movement of the electrodes and the test medium relative to each other.

A known method for determining the functional state of the hemostatic system [see RF patent No. 2109297, G01N 33/86, 1998], which consists in measuring the amplitudes of the recording of the blood coagulation process at its beginning, then, after one, two and three minutes from its beginning, the blood coagulation rates for the second and third are determined minutes, calculate their inverse values and compare all four with the same indicators of blood coagulation normal. In the presence of multidirectional deviations, a functional condition of the hemostasis system is diagnosed.

The disadvantages of the method are low accuracy and the duration of its implementation.

The prototype adopted a method for determining the functional state of the hemostatic system [see RF patent No. 2430380, G01N 33/86, 2011], which consists in measuring the amplitude of the recording of the blood coagulation process at its beginning, determining the indicators of the beginning and end of the coagulation process of the electrocoagulogram of blood and comparing them with the same parameters of the blood coagulation process in normal and in case of multidirectional deviations, the functional state of the hemostasis system is diagnosed, the current amplitude of blood resistance is recorded at the first moment of time, and the second blood resistance is measured at a multiple point in time from the initial time values for two time points and resistances are limiting blood resistance and time constant by which the blood is calculated resistance at the beginning and end of the coagulation process and the found parameters define the start and end indicators clotting process.

The disadvantages of the prototype are the relatively low accuracy and sensitivity of the measurement and the duration of the measurement.

The technical task of the method is to increase metrological efficiency, namely the accuracy of measurements, and reduce the time of research.

The technical task is achieved as follows.

In the method for determining the functional state of the hemostasis system, which consists in measuring the amplitude of the recording of the blood coagulation process at its beginning, the indicators of the beginning and end of the coagulation process of the electrocoagulogram of blood are determined and compared with the same indicators of the blood coagulation process in normal and diagnosed with multidirectional deviations the functional state of the hemostatic system, in contrast to the prototype, determine the time constant by the calibration characteristic, calibres y conduct a priori for two measured and known values of the upper and lower boundaries of the adaptive range, the calibration characteristic is the function of the limiting blood voltage, compensating for the uncertainty of the time constant, chosen arbitrarily, and linking the reference and measured characteristics by normalizing the measured values with known ones, find the actual values of the time constant and the limiting blood stress, according to which the calibration character is consistently built The veristika of the limiting blood stress, the reference characteristic and determine the indicators of the beginning and end of the blood coagulation process.

The essence of the proposed method is illustrated in figures 1-4.

1. The time constant T _{0 is} determined from the calibration function U _0i (t).

(фиг.1, кривая 2) значений верхней и нижней границ адаптивного диапазона процесса гемостаза. У пациентов с известным значением амплитуды напряжения крови U_э1, U_э2 для интервалов времени измерения t₁ и t₂ регистрируют измеренные значения амплитуды напряжения крови U₁ и U₂.2. Calibration is carried out a priori for two known reference U _ei (Fig. 1 curve 1) and measured U _i , $$i=\overline{\mathrm{1,2}}$$

(figure 1, curve 2) of the values of the upper and lower boundaries of the adaptive range of the hemostasis process. In patients with a known value of the amplitude of the blood voltage U _e1 , U _e2 for the measurement time intervals t ₁ and t ₂ register the measured values of the amplitude of the blood voltage U ₁ and U ₂ .

3. The calibration characteristic is the characteristic U _0i (Fig. 1, curve 3) of the limiting blood voltage, compensating for the uncertainty of the time constant T *, chosen arbitrarily, and linking the reference U _ei and the measured U _i dependencies due to the normalization of the measured values known (Fig. 1 curve 3)

$$U_{0i}=\frac{{\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0\cdot U_i}{U_{\mathrm{uh}i}}\cdot exp\left(\frac{t_i}{T*}-\frac{t_{\mathrm{uh}i}}{T_0}\right).(\mathrm{one})$$

From the calibration characteristic U _0i restore the characteristic U _i identical to the reference

, $$U_i=U_{0i}\cdot exp\left(\frac{-t_i}{T*}\right)$$

,

which is as close as possible to the reference curve U _ei :

. $$U_{\mathrm{uh}i}={\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0\cdot exp\left(\frac{-t_{\mathrm{uh}i}}{T_0}\right)$$

.

The reference characteristic U _ei = U and the characteristic identical to it, U _{i are} obtained from the exponential dynamic characteristic with the desired informative parameters T ₀ , U ₀ :

$$U={\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0\cdot exp\left(\frac{-t}{T_0}\right),(2)$$

where T ₀ is the time constant of the hemostasis process and U ₀ is the ultimate blood pressure. The physical meaning of informative parameters follows from the limit relations:

, т.е. U₀ - предельное напряжение крови для t=0, $$l\underset{t\to 0}{im}U={\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0\cdot \exp \left(\frac{0}{T_0}\right)={\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0$$

, i.e. U ₀ is the limiting blood pressure for t = 0,

, т.е. T₀ - постоянная времени. $$\underset{t\to 0}{\lim U}={\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0\cdot \exp \left(\frac{-T_0}{T_0}\right)={\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0\exp =2.73{\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0$$

, i.e. T ₀ - time constant.

In practice, one of the informative parameters of the studied characteristics is usually unknown. In this case, one parameter is set arbitrarily T *, and the second takes the form of a function U _0i , which compensates for the ignorance of the first informative parameter. Using this function, the measured curve is calibrated.

We arbitrarily set the parameter T * = const instead of the unknown real value of the time constant T ₀ . To compensate for the arbitrariness of the constant T *, the limiting blood pressure U ₀ becomes a characteristic U _0i , compensating for the ignorance of the time constant T ₀ .

The calibration function for the known parameters T ₀ , U ₀ is the exponential dynamic characteristic (2).

We express the calibration characteristic U _0i from the system of equations with known parameters T ₀ , U _{0 of the} characteristic U _ei , which is the reference (obtained by approximating the experimental data), and the characteristic U _i , which is measured, with an arbitrary constant T * and characteristic U _0i :

$$\{\begin{array}{l}{U}_{\mathrm{uh}i}={\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0\cdot exp\left(\frac{-t_{\mathrm{uh}i}}{T_0}\right)\\ U_i=U_{0i}\cdot exp\left(\frac{-t_i}{T*}\right)\end{array}.(3)$$

We divide one equation of the system into another in order to express the calibration characteristic:

. $$\frac{U_{\mathrm{uh}i}}{U_i}=\frac{U_0}{U_{0i}}\cdot \exp \left(\frac{t_i}{T*}-\frac{t_{\mathrm{uh}i}}{T_0}\right)$$

.

In accordance with the laws of calibration and t _ei = t _i follows the calibration characteristic U _0i , which relates the standard and measured curves:

$$U_{0i}=\frac{{\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0\cdot U_i}{U_{\mathrm{uh}i}}\cdot exp\left(\frac{t_i}{T*}-\frac{t_i}{T_0}\right).(\mathrm{four})$$

Therefore, the calibration characteristic is the function of the limiting blood voltage, compensating for the uncertainty of the time constant chosen arbitrarily (figure 1, curve 3).

:4. From the calibration characteristic U _0i , the actual values of the time constant T ₀ and the limiting blood voltage U _{0 are found} , which are informative parameters that deliver the optimum calibration characteristic. From characteristic (4) we compose a system of equations for $$i=\overline{\mathrm{1,2}}$$

:

$$\{\begin{array}{l}{\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_{0\mathrm{one}}={\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0\cdot exp\left(\frac{t_{\mathrm{one}}}{T*}-\frac{t_{\mathrm{one}}}{T_0}\right)\\ {\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_{02}={\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0\cdot exp\left(\frac{t_2}{T*}-\frac{t_2}{T_0}\right)\end{array}.(5)$$

Dividing one equation of system (5) into another and prologarithmic, determine the time constant algorithm T ₀ :

$${\mathrm{<figure-callout\; id="0"\; label="T"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">T</figure-callout>}}_0=\frac{t_2-t_{\mathrm{one}}}{\ln \left(U_{01}/U_{02}\right)+\frac{t_2-t_{\mathrm{one}}}{T*}}.(6)$$

Expressing T ₀ from the first and second equations of system (5) and equating them to each other

, $$\frac{t_{\mathrm{one}}}{t_2}=\frac{\ln \left(U_{01}/U_0\right)}{\ln \left(U_{02}/U_2\right)}=k$$

,

find an algorithm for determining the limiting voltage of blood:

$${\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_0=\sqrt[k-\mathrm{one}]{\frac{{\left({\mathrm{<figure-callout\; id="0"\; label="U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">U</figure-callout>}}_{0\mathrm{one}}\right)}^{\mathrm{<figure-callout\; id="0"\; label="k\; U"\; filenames="00000035.png,00000036.png"\; state="\{\{state\}\}">k\; </figure-callout>}}}{U_{}}}.(7)$$

5. From the actual values of the time constant T ₀ and the limiting blood voltage U ₀ , the calibration characteristic U _{0i of the} limiting blood voltage and the reference characteristic U _{ei are successively constructed} . The calibration result is the identity of the measured characteristic U _i reference U _ei , i.e. U _i ≡U _ei .

For informative parameters (6) and (7), a calibration characteristic U _0i (4) is constructed (approximated) (Fig. 1 curve 3), according to which, according to (3), a calibrated characteristic U _di (Fig. 1 curve 4) is found that is identical to the reference desired characteristic.

The informative parameters found determine the beginning and end of the blood coagulation process:

$$\{\begin{array}{l}{T}_n=T\cdot ln\left(\frac{U_0}{U_n}\right)\\ T_{\mathrm{to}}=T\cdot ln\left(\frac{U_0}{U_{\mathrm{to}}}\right)\end{array}.(8)$$

The obtained values of the beginning of T _n and the end of T _{to the} process of hemocoagulation are compared in magnitude with the same parameters of the process of hemocoagulation of healthy people. If multidirectional deviations from the norm are detected, a violation of the functional state of the hemostatic system is diagnosed.

1. We prove the metrological effectiveness of the proposed method relative to the prototype according to the methodological error ε ₁ (figure 2):

$${\epsilon }_{\mathrm{one}}=\left|\frac{U_{\mathrm{uh}i}-U_i}{U_{\mathrm{uh}i}}\right|.(9)$$

From the graph (figure 2) it can be seen that the methodological error of the prototype varies from 3 to 12%.

We estimate the methodological error ε ₂ between the reference 1 and calibrated 4 characteristics (figure 1)

$${\epsilon }_{\mathrm{one}}=\left|\frac{U_{\mathrm{uh}i}-U_{di}}{U_{\mathrm{uh}i}}\right|.(\mathrm{one}0)$$

From the graph (figure 3) it can be seen that the relative error does not exceed 2.4 * 10 ^-16 or 2.4 * 10 ^-14 % due to the use of the calibration characteristics in the adaptive range with normalized values at the borders.

2. Let us evaluate the metrological efficiency by clotting time.

Coagulation start time according to the reference characteristic (Fig. 4, curve 1) T _n1 = 170, coagulation end time T _k1 = 460 for normalized amplitudes U _n = 7.34 U _k = 4.33. The limiting parameters U ₀ = 10, T ₀ = 550 found by algorithms (7) and (8).

Find the actual time values (Fig. 4, curve 4) according to the algorithms (8):

T_н=170,01 и T_к=459,98. $$\{\begin{array}{l}{T}_n=5\mathrm{fifty}\cdot ln\left(\frac{\mathrm{one}0}{7.34}\right),\\ T_{\mathrm{to}}=5\mathrm{fifty}\cdot ln\left(\frac{\mathrm{one}0}{4.33}\right).\end{array}$$

T _n = 170.01 and T _k = 459.98.

We calculate the error in the time of the beginning of coagulation between characteristics 4 and 1

$${\epsilon }_n=\left|\frac{T_{n\mathrm{one}}-T_{n\mathrm{four}}}{T_{n\mathrm{one}}}\right|=\left|\frac{\mathrm{one}70-\mathrm{<figure-callout\; id="7"\; label="one"\; filenames="00000035.png,00000038.png"\; state="\{\{state\}\}">one</figure-callout>}70,0\mathrm{one}}{\mathrm{one}70}\right|=0,006\%$$

and end of coagulation

. $${\epsilon }_{\mathrm{to}}=\left|\frac{T_{\mathrm{to}\mathrm{one}}-T_{n\mathrm{four}}}{T_{\mathrm{to}\mathrm{one}}}\right|=\left|\frac{\mathrm{four}60-\mathrm{four}\mathrm{59,}98}{\mathrm{four}60}\right|=0,00\mathrm{four}\%$$

.

According to characteristic 2 (figure 4, curve 2) for normalized thresholds of amplitudes U _n = 7.34, U _k = 4.33 we find the clotting time of the prototype T _n2 = 130 and T _k2 = 375.

Let us evaluate the error of the coagulation end time between the reference 1 and the measured 2 characteristics

$${\epsilon }_{\mathrm{to}}=\left|\frac{T_{\mathrm{to}\mathrm{one}}-T_{\mathrm{to}2}}{T_{\mathrm{to}\mathrm{one}}}\right|$$

$${\epsilon }_{\mathrm{to}}=\left|\frac{\mathrm{four}60-375}{\mathrm{four}60}\right|=18.48\%$$

and the error of the beginning of coagulation

$${\epsilon }_{н}=\left|\frac{170-130}{170}\right|=\mathrm{23,53}\%$$

. $${\epsilon }_n=\left|\frac{T_{n\mathrm{one}}-T_{n2}}{T_{n\mathrm{one}}}\right|$$

$${\epsilon }_n=\left|\frac{\mathrm{one}70-\mathrm{one}\mathrm{thirty}}{\mathrm{one}70}\right|=23.53\%$$

.

, из которого видно, что эффективность предлагаемого решения на четыре порядка выше прототипа, т.к. соответствуют η_к=2,17E-4 и η_н=2,55E-4.The efficiency η in clotting time accuracy is calculated as the ratio of the first to second error $$\left(\frac{{\epsilon }_{\mathrm{one}}}{{\epsilon }_2}\right)$$

, which shows that the effectiveness of the proposed solution is four orders of magnitude higher than the prototype, because correspond to η _k = 2.17E-4 and η _n = 2.55E-4.

Thus, the determination of the actual values due to normalization of the measured values known by the calibration characteristic of the limiting blood pressure, in contrast to the known solutions, reduces the methodological error by tens of orders, the accuracy of the coagulation time increases by 4 orders of magnitude, and the efficiency decreases by three times, which ultimately reduces increases the metrological efficiency of computer analyzers to automate the identification of individuals at risk of developing hemocoagulation complications.

Claims (1)

A method for determining the functional state of the hemostasis system, which consists in measuring the amplitude of the recording of the blood coagulation process at its beginning, determining the beginning and end of the coagulation process of the electrocoagulogram of blood and comparing them with the same indicators of the blood coagulation process in normal and diagnosing functional disorders with multidirectional deviations the state of the hemostatic system, characterized in that they determine the time constant by the calibration characteristic, calibration a priori for the two measured U ₁ , U ₂ and known U ₀₁ , U ₀₂ values of the lower t ₁ and upper t ₂ = kt ₁ boundaries of the adaptive range, the calibration characteristic of U _0i is the function of the blood pressure limit, compensating for the uncertainty of the time constant T ₀ selected arbitrarily T *, and linking the reference U _ei and the measured U _i characteristics due to the normalization of the measured values by known

the calibration characteristic U _0i find the actual values of the time constant T ₀ and the ultimate voltage U ₀ blood

which consistently build the calibration characteristic of the limiting blood voltage, the reference characteristic U _ei

and determine the beginning of T _n and the end of T _{to the} process of blood coagulation

where U _n , U _to - normalized voltage thresholds of the beginning and end of the blood coagulation process.

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