WO2024091477A1 - Dosages de lyse du caillot des euglobulines à mini-échelle et leurs procédés d'utilisation - Google Patents

Dosages de lyse du caillot des euglobulines à mini-échelle et leurs procédés d'utilisation Download PDF

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Publication number
WO2024091477A1
WO2024091477A1 PCT/US2023/035764 US2023035764W WO2024091477A1 WO 2024091477 A1 WO2024091477 A1 WO 2024091477A1 US 2023035764 W US2023035764 W US 2023035764W WO 2024091477 A1 WO2024091477 A1 WO 2024091477A1
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plasma sample
clot lysis
euglobulin
plasma
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PCT/US2023/035764
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English (en)
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Vera Ignjatovic
Neil Goldenberg
Steven BRUZEK
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The Johns Hopkins University
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Publication of WO2024091477A1 publication Critical patent/WO2024091477A1/fr

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    • 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

  • Fibrinolysis is the process of dissolving blood clots and is a component of the coagulation system that protects the vasculature from excessive thrombus formation. Alterations in the fibrinolytic system may contribute to abnormal thrombosis or bleeding.
  • a euglobulin clot lysis test was first described in 1948 and is a plasma fibrinolytic test designed to assess how fast clots break down in blood. This test is fully manual and highly subjective, with visual observation of clot formation and lysis used to determine clot formation and lysis times.
  • mini-scale ECLA involving significantly less plasma consumption, greater automation, and higher throughout capabilities.
  • mini-scale automated euglobulin clot lysis assay comprising obtaining a plasma sample from a subject, wherein the plasma sample is in an amount of less than about 75 L; obtaining a euglobulin fraction pellet from the plasma sample; resuspending the euglobulin fraction pellet in a buffer to create a suspension; adding a calcium/tissue factor protein buffer to the suspension; using a spectrophotometer to determine a median optical density (OD) value and a maximum OD of the suspension; and calculating a euglobulin clot lysis time.
  • mini- ECLA mini-scale automated euglobulin clot lysis assay
  • the plasma sample is in an amount of less than about 70 pL, such as less than about 65 pL, less than about 60 pL, less than about 55 pL, less than about 50 pL, less than about 45 pL, less than about 40 pL, less than about 35 pL, less than about 30 pL, less than about 25 pL, or about 25 pL, and in certain embodiments, the plasma sample comprises a platelet-poor plasma sample.
  • the euglobulin clot lysis time is measured at time intervals from a period of 0 to 10 hours, such as 1 minute to 10 hours or 10 hours, and in certain embodiments, the time intervals range from every 1 minute to every 5 minutes, such as every 3 minutes.
  • the spectrophotometer is a thermoregulated spectrophotometer, and in certain embodiments, the thermoregulated spectrophotometer is thermoregulated at 37 °C. In certain embodiments, an absorbance of the spectrophotometer for determining the median and maximum ODs is at 405 nm.
  • the subject is selected from the group consisting of a human, a dog, a cat, a horse, a cow, a sheep, a goat, and a nonhuman mammal, and in certain embodiments, the subject has or is suspected of having an abnormal blood condition, such as an abnormal blood condition selected from the group consisting of hemophilia, bleeding disorders, and thrombotic disorders.
  • the abnormal blood condition is a hyper-fibrinolytic condition, and in certain embodiments, the abnormal blood condition is a hypo-fibrinolytic condition.
  • the abnormal blood condition may be a secondary result of a primary condition, such as infection or prior infection of the subject with a virus, e.g., Covid virus.
  • the methods disclosed herein further comprise comparing the euglobulin clot lysis time to a second euglobulin clot lysis time obtained from at least one control sample, and in certain aspects, the methods disclosed herein further comprise obtaining a plasma sample from the subject before, during, and/or after treating the subject with at least one therapeutic agent.
  • the present disclosure provides a kit for analyzing the euglobulin clot lysis time of a plasma sample in an amount of less than about 75 pL comprising a microplate, such as a 96-well microplate; an acetic acid buffer; a sodium borate buffer; tissue factor protein; and a calcium buffer, and optionally instructions for use.
  • a microplate such as a 96-well microplate
  • an acetic acid buffer such as a 96-well microplate
  • tissue factor protein tissue factor protein
  • calcium buffer a calcium buffer
  • the present disclosure provides a method for identifying or diagnosing a subject with an abnormal blood condition, the method comprising obtaining a plasma sample from the subject, wherein the plasma sample is in an amount of less than about 75 pL; obtaining a euglobulin fraction pellet from the plasma sample; resuspending the euglobulin fraction pellet in a buffer to create a suspension; adding a calcium/tissue factor protein buffer to the suspension; using a spectrophotometer to determine a median optical density (OD) value and a maximum OD of the suspension; calculating a euglobulin clot lysis time for the plasma sample; comparing the euglobulin clot lysis time for the plasma sample to a control euglobulin clot lysis time from a normal plasma sample; and identifying or diagnosing the subject with an abnormal blood condition if the euglobulin clot lysis time for the plasma sample is significantly different from the control euglobulin clo
  • the plasma sample from the subject is in an amount of less than about 70 pL, such as less than about 65 pL, less than about 60 pL, less than about 55 pL, less than about 50 pL, less than about 45 pL, less than about 40 pL, less than about 35 pL, less than about 30 pL, less than about 25 pL, or about 25 pL, and in certain embodiments, the normal plasma sample is in an amount of less than about 70 pL, such as less than about 65 pL, less than about 60 pL, less than about 55 pL, less than about 50 pL, less than about 45 pL, less than about 40 pL, less than about 35 pL, less than about 30 pL, less than about 25 pL, or about 25 pL.
  • the abnormal blood condition is a hyper-fibrinolytic condition or a hypo-fibrinolytic condition.
  • FIG. 1A is a graph showing the average OD measurements over time for the mini-ECLA protocol as described in Example 1 with FACT control, A2AP -deficient, PAI-1 deficient, and plasminogen deficient plasmas, wherein the average 50% clot lysis time ⁇ 3 standard deviations is marked for each plasma.
  • FIG. IB is a graph showing the average OD measurements over time for the standard ECLA protocol as described in Example 1 with FACT control, A2AP-deficient, PA1- 1 deficient, and plasminogen deficient plasmas, wherein the average 50% clot lysis time ⁇ 3 standard deviations is marked for each plasma.
  • FIG. 2A is a graph showing the average OD measurements over time for the mini-ECLA runs with FACT in the presence of varying concentrations of Tissue Factor addition, showing the ability to generate physiologic clot formation in the mini-ECLA.
  • FIG. 2B is a graph showing the average OD measurements over time for the mini-ECLA runs with plasminogen-deficient plasma in the presence of varying concentrations of Tissue Factor addition, showing the ability to generate physiologic clot formation in the mini-ECLA.
  • FIG. 3A is a graph showing the average OD measurements over time for concentration ranges of PAI- 1 deficient plasma, wherein the average 50% clot lysis time ⁇ 3 standard deviations is marked for each plasma concentration. The plot is normalized to clot formation at 0 minutes for visual comparison of clot lysis times.
  • FIG. 3B is a graph showing the average OD measurements over time for concentration ranges of A2AP deficient plasma, wherein the average 50% clot lysis time ⁇ 3 standard deviations is marked for each plasma concentration. The plot is normalized to clot formation at 0 minutes for visual comparison of clot lysis times.
  • FIG. 3C is a graph showing the average OD measurements over time for concentration ranges of plasminogen-deficient plasma, wherein the average 50% clot lysis time ⁇ 3 standard deviations is marked for each plasma concentration. The plot is normalized to clot formation at 0 minutes for visual comparison of clot lysis times.
  • FIG. 3D is a graph showing the average OD measurements over time for concentration ranges of excess tPA plasma, wherein the average 50% clot lysis time ⁇ 3 standard deviations is marked for each plasma concentration. The plot is normalized to clot formation at 0 minutes for visual comparison of clot lysis times.
  • FIG. 4A is a graph showing the average OD measurements over time for regular (non-mini) ECLA runs with FACT and samples 100% deficient in plasminogen, PAL 1, and A2AP. Error bars represent ⁇ 1 S.D. of the mean adjusted Clot Lysis Time at the median OD value when applicable.
  • FIG. 4B is a graph showing the average OD measurements over time for mini- ECLA runs with FACT and sample 100% deficient in plasminogen, PAI-1, and A2AP. Error bars represent ⁇ 1 S.D. of the mean adjusted Clot Lysis Time at the median OD value when applicable.
  • FIG. 4C is a graph showing the average OD measurements over time for mini- ECLA runs for either 0 pM or 1 pM of relipidated tissue factor together with either 0 ng/mL or 0.7 ng/mL of tissue plasminogen activator.
  • FIG. 4D is a graph showing a representative curve of a mini-ECLA run showing the main data outputs, including maximum OD (clot formation), median OD (50% clot lysis), area under the curve (AUC), and aCLT.
  • a horizontal bar at 1.0 represents normal CLTR in FACT plasma.
  • a horizontal bar at 1.0 represents normal CLTR OD Adjusted in FACT plasma.
  • FIG. 7A are box and whisker plots showing CLTR values for convalescent, critically ill, and Covid patient plasma as determined using a mini-ECLA.
  • FIG. 7B are box and whisker plots showing fibrinolytic indices (FI2%) for convalescent, critically ill, and Covid patient plasma as determined using a CloFAL turbidimetric assay.
  • FIG. 7C is a plot showing the fibrinolytic indices FI2% plotted against the corresponding CLTR values for convalescent, critically ill, and Covid patient plasma, showing the correlation coefficient (r) and p value of the correlation coefficient.
  • FIG. 8A are box and whisker plots showing CLTR OD Adjusted values for convalescent, critically ill, and Covid patient plasma as determined using a mini-ECLA.
  • FIG. 8B are box and whisker plots showing fibrinolytic indices (FI2%) for convalescent, critically ill, and Covid patient plasma as determined using a CloFAL turbidimetric assay.
  • FIG. 8C is a plot showing the fibrinolytic indices FI2% plotted against the corresponding CLTR OD Adjusted values for convalescent, critically ill, and Covid patient plasma, showing the correlation coefficient (r) and p value of the correlation coefficient.
  • FIG. 9A are box and whisker plots showing the change in OD ratio, or delta OD ratio (DODR) values for convalescent, critically ill, and Covid patient plasma as determined using a mini-ECLA.
  • DOE delta OD ratio
  • FIG. 9B are box and whisker plots showing coagulation indices (CI%) for convalescent, critically ill, and Covid patient plasma as determined using a CloFAL turbidimetric assay.
  • FIG. 9C is a plot showing the coagulation indices CI% plotted against the corresponding DODR values for convalescent, critically ill, and Covid patient plasma, showing the correlation coefficient (r) and p value of the correlation coefficient.
  • FIG. 10A are box and whisker plots showing the area under the curve ratio (AUCR) for convalescent, critically ill, and Covid patient plasma as determined using a mini- ECLA.
  • AUCR area under the curve ratio
  • FIG. 10B are box and whisker plots showing AUC% for convalescent, critically ill, and Covid patient plasma as determined using a CloFAL turbidimetric assay/
  • FIG. 10C is a plot showing the AUC% plotted against the corresponding AUCR values for convalescent, critically ill, and Covid patient plasma, showing the correlation coefficient (r) and p value of the correlation coefficient.
  • ECLA automated euglobulin clot lysis assay
  • the absorbance readings are performed at about 405 nm about every 3 minutes for up to about 10 hours in a thermoregulated spectrophotometer at about 37 °C.
  • Total patient plasma that may be used for the assay disclosed herein is less than about 70 L, such as about 50 pL.
  • a mini-ECLA clot lysis time may be calculated as the time the absorbance reaches the median OD value between the minimum and maximum OD readings (50% clot lysis), minus the time at maximum OD reading (full clot formation). The methods disclosed herein retain the use of pooled normal plasma standards and both hyperfibrolytic and hypofibrolytic controls.
  • a 96-well microplate to which 300 pL of cold, 0.02% acetic acid is added to 25 pL of platelet-poor plasma in duplicate for each specimen. After a 10 minute incubation on wet ice, the plate is spun at 2000 x g at 25 °C for 5 minutes. The supernatant is removed by plate inversion, and 100 pL of Milli-Q water is added to each well. The plate is spun at 2000 x g at 25 °C for 5 minutes, and the supernatant is again removed by plate inversion.
  • the euglobulin fraction pellet is resuspended in 100 pL of prewarmed (37 °C) sodium borate buffer, mixed by shaking, and incubated at 37 °C for 3 minutes. To one of the duplicates, 100 pL of pre-warmed (37 °C) calcium buffer is added. The remaining well is used as a negative control.
  • the plate reader protocol comprises absorbance readings at 405 nm every 3 minutes for 10 hours, with an initial orbital shaking step and incubation at 37 °C for the duration of the run.
  • Mini-ECLA clot lysis time is calculated as the time the absorbance reaches the median OD value between the minimum and maximum OD readings (50% clot lysis), minus the time at maximum OD reading (full clot formation).
  • tissue factor may generate physiologic conditions of clot formation and reduce previous issues of reduced clot formation in mini-volume processing.
  • changes in proportions/ratios of plasma to buffers disclosed herein may generate a robust signal in miniscale version without sacrificing sensitivity to protein-deficient states.
  • the euglobulin fraction pellet was resuspended in 100 pL of pre-warmed (37 °C) sodium borate buffer, mixed by shaking, and incubated at 37 °C for 3 minutes. To one of the duplicates, 100 pL of pre-warmed (37 °C) calcium buffer was added. The remaining well was used as a negative control. Absorbance readings were conducted at 405 nm every 3 minutes for 10 hours, with an initial orbital shaking step and incubation at 37 °C for the duration of the run. Mini-ECLA clot lysis time was calculated as the time the absorbance reaches the median OD value between the minimum and maximum OD readings (50% clot lysis), minus the time at maximum OD reading (full clot formation).
  • Table 1 illustrates the methods disclosed herein as compared to a standard ECLA method.
  • the mini-ECLA methods disclosed herein are capable of generating physiologic clot formation in the presence of Tissue Factor.
  • FIGS. 3 A-3D illustrate that the mini-ECLA methods disclosed herein may be diagnostic for all deficient plasma states relative to data from existing standard ECLA methods.
  • FIG. 4A shows a clot lysis tracing of an original ECLA method with FACT and 100% deficient plasma samples.
  • FIG. 4B shows a clot lysis tracing of a volume reduction mini-ECLA with FACT and 100% deficient plasma samples.
  • error bars show +/- SD of the mean adjusted Clot Lysis Time at the median OD value.
  • FIG. 4B the results are concordant to the results of the original ECLA method.
  • FIG. 4C shows a clot lysis tracing of the modified mini-ECLA final configuration development through the addition of relipidated tissue factor (TF) and tissue plasminogen activator (tPA), and
  • FIG. 4D shows a representative clot lysis tracing of the modified mini-ECLA disclosed herein, showing exemplary main data outputs.
  • FIG. 5 A shows a fibrinogen concentration curve for various percent fibrinogen samples of plasma, from 100% (FACT) to 30% fibrinogen, using a modified mini-ECLA process as disclosed herein.
  • FIG. 5A shows a fibrinogen concentration curve for various percent fibrinogen samples of plasma, from 100% (FACT) to 30% fibrinogen, using a modified mini-ECLA process as disclosed herein.
  • FIG. 5C shoes the area under the curve (AUC) for each of the 6 fibrinogen levels with a 95% confidence interval shown
  • FIG. 5D shows the clot lysis time ratio (CLTR) for each of the 6 fibrinogen levels with a 95% confidence interval shown
  • FIG. 5E shows the clot lysis time ratio OD adjusted (CLTR OD Adjusted) for each of the 6 fibrinogen levels with a 95% confidence interval shown.
  • FIG. 6D shows the average CLTR OD Adjusted for each of the deficient plasma types shown in FIG. 6C.
  • FIG. 7 A shows the CLTR from a modified mini-ECLA process as disclosed herein for each of the three patient populations
  • FIG. 7B shows the CloFAL FI2% (fibrinolytic index) for each of the three patient population
  • FIG. 7C shows a plot of the CLTR plotted against the corresponding CloFAL FI2%, with the correlation coefficient (r) and p value of correlation coefficient shown as plot inset.
  • FIG. 8A shows the CLTR OD Adjusted for each of the patient populations
  • FIG. 8B shows the CloFAL FI2%
  • FIG. 8C shows a plot of the CLTR OD Adjusted plotted against the corresponding CloFAL FI2%, with the correlation coefficient (r) and p value of correlation coefficient shown as plot inset
  • FIG. 9A shows the delta OD ratio (DODR) for each of the patient populations
  • FIG. 9B shows the CloFAL CI% (coagulation index)
  • FIG. 9C shows a plot of the DODR plotted against the corresponding CloFAL CI%, with the correlation coefficient (r) and p value of correlation coefficient shown as plot inset.
  • FIG. 9A shows the delta OD ratio (DODR) for each of the patient populations
  • FIG. 9B shows the CloFAL CI% (coagulation index)
  • FIG. 9C shows a plot of the DODR plotted against the corresponding CloFAL CI%, with the correlation coefficient (r) and p value of correlation coefficient
  • FIG. 10A shows the area under the curve ratio (AUCR) for each of the patient populations, while FIG. 10B shows the CloFAL AUC%, and FIG. 10C shows a plot of the AUCR plotted against the corresponding CloFAL AUC%, with the correlation coefficient (r) and p value of correlation coefficient shown as plot inset.
  • AUCR area under the curve ratio

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Abstract

La présente invention concerne une méthode de dosage de lysine du caillot des euglobulines automatisée pour calculer un temps de lyse du caillot des euglobulines à partir d'un échantillon de plasma dans une quantité inférieure à environ 75 μL. Un kit d'analyse du temps de lyse du caillot des euglobulines d'un échantillon de plasma en une quantité inférieure à environ 75 μL, ainsi qu'une méthode d'identification ou de diagnostic d'un sujet présentant un état sanguin anormal sont également divulgués dans la présente invention.
PCT/US2023/035764 2022-10-24 2023-10-24 Dosages de lyse du caillot des euglobulines à mini-échelle et leurs procédés d'utilisation WO2024091477A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011260A1 (fr) * 1991-11-25 1993-06-10 Baxter Diagnostics Inc. Procede de mesure de la capacite fibrinolytique du plasma humain total
US20080268483A1 (en) * 2004-09-22 2008-10-30 The Regents Of The University Of Colorado Methods for a Global Assay of Coagulation and Fibrinolysis
US20170023594A1 (en) * 2012-07-18 2017-01-26 Theranos, Inc. Low-volume coagulation assay

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011260A1 (fr) * 1991-11-25 1993-06-10 Baxter Diagnostics Inc. Procede de mesure de la capacite fibrinolytique du plasma humain total
US20080268483A1 (en) * 2004-09-22 2008-10-30 The Regents Of The University Of Colorado Methods for a Global Assay of Coagulation and Fibrinolysis
US20170023594A1 (en) * 2012-07-18 2017-01-26 Theranos, Inc. Low-volume coagulation assay

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BOUDJELTIA K ZOUAOUI; CAUCHIE PH; REMACLE CL; GUILLAUME M; BROHéE D; HUBERT JL; VANHAEVERBEEK M: "A new device for measurement of fibrin clot lysis: application to the Euglobulin Clot Lysis Time", BMC BIOTECHNOLOGY, BIOMED CENTRAL LTD, vol. 2, no. 1, 2 May 2002 (2002-05-02), pages 8, XP021005900, ISSN: 1472-6750, DOI: 10.1186/1472-6750-2-8 *

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