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Article: Global assays of hemostasis in the diagnostics of hypercoagulation and evaluation of thrombosis risk.

Lipets, Elena N / Ataullakhanov, Fazoil I

Thrombosis journal

2015 Volume 13, Issue 1, Page(s) 4

Abstract: Thrombosis is a deadly malfunctioning of the hemostatic system occurring in numerous conditions and states, from surgery and pregnancy to cancer, sepsis and infarction. Despite availability of antithrombotic agents and vast clinical experience justifying ...

Abstract	Thrombosis is a deadly malfunctioning of the hemostatic system occurring in numerous conditions and states, from surgery and pregnancy to cancer, sepsis and infarction. Despite availability of antithrombotic agents and vast clinical experience justifying their use, thrombosis is still responsible for a lion's share of mortality and morbidity in the modern world. One of the key reasons behind this is notorious insensitivity of traditional coagulation assays to hypercoagulation and their inability to evaluate thrombotic risks; specific molecular markers are more successful but suffer from numerous disadvantages. A possible solution is proposed by use of global, or integral, assays that aim to mimic and reflect the major physiological aspects of hemostasis process in vitro. Here we review the existing evidence regarding the ability of both established and novel global assays (thrombin generation, thrombelastography, thrombodynamics, flow perfusion chambers) to evaluate thrombotic risk in specific disorders. The biochemical nature of this risk and its detectability by analysis of blood state in principle are also discussed. We conclude that existing global assays have a potential to be an important tool of hypercoagulation diagnostics. However, their lack of standardization currently impedes their application: different assays and different modifications of each assay vary in their sensitivity and specificity for each specific pathology. In addition, it remains to be seen how their sensitivity to hypercoagulation (even when they can reliably detect groups with different risk of thrombosis) can be used for clinical decisions: the risk difference between such groups is statistically significant, but not large.
Language	English
Publishing date	2015-01-23
Publishing country	England
Document type	Journal Article
ISSN	1477-9560
ISSN	1477-9560
DOI	10.1186/s12959-015-0038-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Moderate plasma dilution using artificial plasma expanders shifts the haemostatic balance to hypercoagulation.

Sinauridze, Elena I / Gorbatenko, Alexander S / Seregina, Elena A / Lipets, Elena N / Ataullakhanov, Fazoil I

Scientific reports

2017 Volume 7, Issue 1, Page(s) 843

Abstract: Artificial plasma expanders (PEs) are widely used in modern transfusion medicine. PEs do not contain components of the coagulation system, so their infusion in large volumes causes haemodilution and affects haemostasis. However, the existing information ... ...

Abstract	Artificial plasma expanders (PEs) are widely used in modern transfusion medicine. PEs do not contain components of the coagulation system, so their infusion in large volumes causes haemodilution and affects haemostasis. However, the existing information on this effect is contradictory. We studied the effect of the very process of plasma dilution on coagulation and tested the hypothesis that moderate dilution with a PE should accelerate clotting owing to a decrease in concentration of coagulation inhibitors. The standard clotting times, a thrombin generation test, and the spatial rate of clot growth (test of thrombodynamics) were used to assess donor plasma diluted in vitro with various PEs. The pH value and Ca
MeSH term(s)	Blood Coagulation/drug effects ; Calcium/metabolism ; Humans ; Plasma Substitutes/adverse effects ; Plasma Substitutes/pharmacology ; Thrombin/antagonists & inhibitors ; Thrombin/metabolism
Chemical Substances	Plasma Substitutes ; Thrombin (EC 3.4.21.5) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2017-04-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-00927-w
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Article ; Online: Moderate plasma dilution using artificial plasma expanders shifts the haemostatic balance to hypercoagulation

Elena I. Sinauridze / Alexander S. Gorbatenko / Elena A. Seregina / Elena N. Lipets / Fazoil I. Ataullakhanov

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 12

Abstract: Abstract Artificial plasma expanders (PEs) are widely used in modern transfusion medicine. PEs do not contain components of the coagulation system, so their infusion in large volumes causes haemodilution and affects haemostasis. However, the existing ... ...

Abstract	Abstract Artificial plasma expanders (PEs) are widely used in modern transfusion medicine. PEs do not contain components of the coagulation system, so their infusion in large volumes causes haemodilution and affects haemostasis. However, the existing information on this effect is contradictory. We studied the effect of the very process of plasma dilution on coagulation and tested the hypothesis that moderate dilution with a PE should accelerate clotting owing to a decrease in concentration of coagulation inhibitors. The standard clotting times, a thrombin generation test, and the spatial rate of clot growth (test of thrombodynamics) were used to assess donor plasma diluted in vitro with various PEs. The pH value and Ca+2 concentration were maintained strictly constant in all samples. The effect of thrombin inhibitors on dilution-induced hypercoagulation was also examined. It was shown that coagulation was enhanced in plasma diluted up to 2.0–2.5-fold with any PE. This enhancement was due to the dilution of coagulation inhibitors in plasma. Their addition to plasma or PE could partially prevent the hypercoagulation shift.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2017-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The modification of the thrombin generation test for the clinical assessment of dabigatran etexilate efficiency.

Gribkova, Irina V / Lipets, Elena N / Rekhtina, Irina G / Bernakevich, Alex I / Ayusheev, Dorzho B / Ovsepyan, Ruzanna A / Ataullakhanov, Fazoil I / Sinauridze, Elena I

Scientific reports

2016 Volume 6, Page(s) 29242

Abstract: A new oral anticoagulant, dabigatran etexilate (DE, a prodrug of direct thrombin inhibitor (DTI) dabigatran), has been used clinically to prevent thrombosis. The assessment of dabigatran efficiency is necessary in some clinical cases, such as renal ... ...

Abstract	A new oral anticoagulant, dabigatran etexilate (DE, a prodrug of direct thrombin inhibitor (DTI) dabigatran), has been used clinically to prevent thrombosis. The assessment of dabigatran efficiency is necessary in some clinical cases, such as renal insufficiency, risk of bleeding, and drug interactions. However, a specific thrombin generation test (TGT) that is one of the most informative and sensitive to anticoagulant therapy (calibrated automated thrombinography (САТ)) shows a paradoxical increase of test parameters, such as endogenous thrombin potential (ETP) and peak thrombin, in patients receiving DE. The paradoxical behaviour of ETP and peak thrombin in these patients in the presence of DTIs is mostly caused by a decrease in the activity of thrombin in the α2-macroglobulin-thrombin complex that is used as a calibrator in CAT. For a correct estimation of the TGT parameters in patient's plasma containing DTIs we proposed to use our previously described alternative calibration method that is based on the measurement of the fluorescence signal of a well-known concentration of the reaction product (7-amino-4-methylcoumarin). In this study, the validity of such approach was demonstrated in an ex vivo study in patients with knee replacement and two special patients with multiple myeloma, who received DE for thrombosis prophylaxis.
Language	English
Publishing date	2016-07-05
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep29242
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Article ; Online: New factor Xa inhibitors based on 1,2,3,4-tetrahydroquinoline developed by molecular modelling.

Ilin, Ivan / Lipets, Elena / Sulimov, Alexey / Kutov, Danil / Shikhaliev, Khidmet / Potapov, Andrey / Krysin, Michael / Zubkov, Fedor / Sapronova, Lyudmila / Ataullakhanov, Fazoyl / Sulimov, Vladimir

Journal of molecular graphics & modelling

2019 Volume 89, Page(s) 215–224

Abstract: Factor Xa is a serine protease representing a crucial element in the coagulation process and an attractive target for anticoagulant therapy. At the present time there are several chemical classes of factor Xa inhibitors with proven activity. Furthermore, ...

Abstract	Factor Xa is a serine protease representing a crucial element in the coagulation process and an attractive target for anticoagulant therapy. At the present time there are several chemical classes of factor Xa inhibitors with proven activity. Furthermore, three factor Xa inhibitors have been approved for the medical use to date. However, therapy with these medications is accompanied by substantial adverse effects. In this background, the structure-based computational approach combining molecular docking and semiempirical quantum chemical calculations was applied for a search for new effective factor Xa inhibitors. We have undertaken a few virtual screening procedures to select potential candidates for synthesis and subsequent testing. The first screen of the focused library resulted in identifying 20 compounds among which 7 compounds showed the noticeable inhibition of factor Xa at maximal concentrations, allowed by solubility. The subsequent additional screens identified 20 additional candidates. Of these, 5 substances were shown to be capable of inhibiting factor Xa at 5 μM. The best two found 1,2,3,4-tetrahydroquinoline derivatives identified by means of modelling have demonstrated IC50 values in the micromolar range. One of them turned out to be selective factor Xa inhibitor over trypsin, factors IIa, IXa and XIa.
MeSH term(s)	Anticoagulants/chemistry ; Anticoagulants/pharmacology ; Drug Design ; Factor Xa Inhibitors/chemistry ; Factor Xa Inhibitors/pharmacology ; Humans ; Hydrogen Bonding ; Ligands ; Models, Molecular ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Molecular Structure ; Protein Binding ; Quinolines/chemistry ; Quinolines/pharmacology
Chemical Substances	Anticoagulants ; Factor Xa Inhibitors ; Ligands ; Quinolines ; 1,2,3,4-tetrahydroquinoline (CCR50N1Z9G)
Language	English
Publishing date	2019-03-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1396450-1
ISSN	1873-4243 ; 1093-3263
ISSN (online)	1873-4243
ISSN	1093-3263
DOI	10.1016/j.jmgm.2019.03.017
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Article ; Online: Circulating contact-pathway-activating microparticles together with factors IXa and XIa induce spontaneous clotting in plasma of hematology and cardiologic patients.

Lipets, Elena / Vlasova, Olga / Urnova, Evdokiya / Margolin, Oleg / Soloveva, Anna / Ostapushchenko, Olga / Andersen, John / Ataullakhanov, Fazoil / Panteleev, Mikhail

PloS one

2014 Volume 9, Issue 1, Page(s) e87692

Abstract: Background and objective: Using an in vitro experimental model of immobilized tissue factor-initiated clot growth in platelet-free plasma (thrombodynamics), we observed formation of activator-independent isolated spontaneous clots (SC) throughout the ... ...

Abstract	Background and objective: Using an in vitro experimental model of immobilized tissue factor-initiated clot growth in platelet-free plasma (thrombodynamics), we observed formation of activator-independent isolated spontaneous clots (SC) throughout the plasma volume in patients with cardiac infarction, acute leukemia, hemolytic anemia, and some other disorders. The aim of this work was to characterize this phenomenon and to identify the mechanisms of SC formation. Methods and results: Tissue factor inhibitor (VIIai) prevented SC in only 2 out of 23 patient plasma samples. Specific inhibitors of factors IXa and XIa were efficient in all 8 cases that we tested. Also, only factors IXa and XIa added to normal donors' plasma induced SC formations from isolated centers, in a pattern similar to that in patients' plasma. In contrast, factors VIIa, Va, tissue factor induced uniform plasma clotting. SC disappeared after high-speed centrifugation. However, phospholipid supplementation of centrifuged plasma returned them at least partially in 5 out of 22 patients' plasmas, indicating some other role of microparticles than providing phospholipid surface. Circulating procoagulant microparticles isolated from plasma directly activated factor XII in buffer and in diluted plasma. Flow cytometry revealed an increase in procoagulant microparticles in patients' plasmas with SC. Conclusion: Our data suggest that combination of circulating active factors (specifically, factors IXa and XIa) with circulating procoagulant and contact-pathway-activating microparticles is the predominant mechanism causing spontaneous clotting in patient plasma.
MeSH term(s)	Acute Disease ; Anemia, Hemolytic/blood ; Anemia, Hemolytic/pathology ; Blood Coagulation ; Cell-Derived Microparticles/metabolism ; Cell-Derived Microparticles/pathology ; Factor IXa/metabolism ; Factor XIa/metabolism ; Female ; Humans ; Leukemia/blood ; Leukemia/pathology ; Male ; Myocardial Infarction/blood ; Myocardial Infarction/pathology
Chemical Substances	Factor IXa (EC 3.4.21.22) ; Factor XIa (EC 3.4.21.27)
Language	English
Publishing date	2014-01-31
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0087692
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Task-oriented modular decomposition of biological networks: trigger mechanism in blood coagulation.

Panteleev, Mikhail A / Balandina, Anna N / Lipets, Elena N / Ovanesov, Mikhail V / Ataullakhanov, Fazoil I

Biophysical journal

2010 Volume 98, Issue 9, Page(s) 1751–1761

Abstract: Analysis of complex time-dependent biological networks is an important challenge in the current postgenomic era. We propose a middle-out approach for decomposition and analysis of complex time-dependent biological networks based on: 1), creation of a ... ...

Abstract	Analysis of complex time-dependent biological networks is an important challenge in the current postgenomic era. We propose a middle-out approach for decomposition and analysis of complex time-dependent biological networks based on: 1), creation of a detailed mechanism-driven mathematical model of the network; 2), network response decomposition into several physiologically relevant subtasks; and 3), subsequent decomposition of the model, with the help of task-oriented necessity and sensitivity analysis into several modules that each control a single specific subtask, which is followed by further simplification employing temporal hierarchy reduction. The technique is tested and illustrated by studying blood coagulation. Five subtasks (threshold, triggering, control by blood flow velocity, spatial propagation, and localization), together with responsible modules, can be identified for the coagulation network. We show that the task of coagulation triggering is completely regulated by a two-step pathway containing a single positive feedback of factor V activation by thrombin. These theoretical predictions are experimentally confirmed by studies of fibrin generation in normal, factor V-, and factor VIII-deficient plasmas. The function of the factor V-dependent feedback is to minimize temporal and parametrical intervals of fibrin clot instability. We speculate that this pathway serves to lessen possibility of fibrin clot disruption by flow and subsequent thromboembolism.
MeSH term(s)	Animals ; Blood Coagulation ; Cysteine Endopeptidases/metabolism ; Factor V/metabolism ; Factor VIII/metabolism ; Factor X/metabolism ; Feedback, Physiological ; Fibrin/biosynthesis ; Humans ; Models, Biological ; Neoplasm Proteins/metabolism ; Prothrombin/metabolism ; Rabbits ; Time Factors
Chemical Substances	Neoplasm Proteins ; Factor V (9001-24-5) ; Prothrombin (9001-26-7) ; Factor VIII (9001-27-8) ; Factor X (9001-29-0) ; Fibrin (9001-31-4) ; Cysteine Endopeptidases (EC 3.4.22.-) ; cancer procoagulant (EC 3.4.22.26)
Language	English
Publishing date	2010-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2010.01.027
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Zs.A 235: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Circulating contact-pathway-activating microparticles together with factors IXa and XIa induce spontaneous clotting in plasma of hematology and cardiologic patients.

Elena Lipets / Olga Vlasova / Evdokiya Urnova / Oleg Margolin / Anna Soloveva / Olga Ostapushchenko / John Andersen / Fazoil Ataullakhanov / Mikhail Panteleev

PLoS ONE, Vol 9, Iss 1, p e

2014 Volume 87692

Abstract: BACKGROUND AND OBJECTIVE: Using an in vitro experimental model of immobilized tissue factor-initiated clot growth in platelet-free plasma (thrombodynamics), we observed formation of activator-independent isolated spontaneous clots (SC) throughout the ... ...

Abstract	BACKGROUND AND OBJECTIVE: Using an in vitro experimental model of immobilized tissue factor-initiated clot growth in platelet-free plasma (thrombodynamics), we observed formation of activator-independent isolated spontaneous clots (SC) throughout the plasma volume in patients with cardiac infarction, acute leukemia, hemolytic anemia, and some other disorders. The aim of this work was to characterize this phenomenon and to identify the mechanisms of SC formation. METHODS AND RESULTS: Tissue factor inhibitor (VIIai) prevented SC in only 2 out of 23 patient plasma samples. Specific inhibitors of factors IXa and XIa were efficient in all 8 cases that we tested. Also, only factors IXa and XIa added to normal donors' plasma induced SC formations from isolated centers, in a pattern similar to that in patients' plasma. In contrast, factors VIIa, Va, tissue factor induced uniform plasma clotting. SC disappeared after high-speed centrifugation. However, phospholipid supplementation of centrifuged plasma returned them at least partially in 5 out of 22 patients' plasmas, indicating some other role of microparticles than providing phospholipid surface. Circulating procoagulant microparticles isolated from plasma directly activated factor XII in buffer and in diluted plasma. Flow cytometry revealed an increase in procoagulant microparticles in patients' plasmas with SC. CONCLUSION: Our data suggest that combination of circulating active factors (specifically, factors IXa and XIa) with circulating procoagulant and contact-pathway-activating microparticles is the predominant mechanism causing spontaneous clotting in patient plasma.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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