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  1. Article: Sources of bias and limitations of thrombinography: inner filter effect and substrate depletion at the edge of failure algorithm.

    Jackson, Joseph W / Longstaff, Colin / Woodle, Samuel A / Chang, William C / Ovanesov, Mikhail V

    Thrombosis journal

    2023  Volume 21, Issue 1, Page(s) 104

    Abstract: Background: Fluorogenic thrombin generation (TG) is a global hemostasis assay that provides an overall representation of hemostasis potential. However, the accurate detection of thrombin activity in plasma may be affected by artifacts inherent to the ... ...

    Abstract Background: Fluorogenic thrombin generation (TG) is a global hemostasis assay that provides an overall representation of hemostasis potential. However, the accurate detection of thrombin activity in plasma may be affected by artifacts inherent to the assay-associated fluorogenic substrate. The significance of the fluorogenic artifacts or their corrections has not been studied in hemophilia treatment applications.
    Methods: We sought to investigate TG in hemophilia plasma samples under typical and worst-case fluorogenic artifact conditions and assess the performance of artifact correction algorithms. Severe hemophilic plasma with or without added Factor VIII (FVIII) was evaluated using commercially available and in-house TG reagents, instruments, and software packages. The inner filter effect (IFE) was induced by spiking elevated amounts of fluorophore 7-amino-4-methylcoumarin (AMC) into plasma prior to the TG experiment. Substrate consumption was modeled by adding decreasing amounts of Z-Gly-Gly-Arg-AMC (ZGGR-AMC) to plasma or performing TG in antithrombin deficient plasma.
    Results: All algorithms corrected the AMC-induced IFE and antithrombin-deficiency induced substrate consumption up to a certain level of either artifact (edge of failure) upon which TG results were not returned or overestimated. TG values in FVIII deficient (FVIII-DP) or supplemented plasma were affected similarly. Normalization of FVIII-DP resulted in a more accurate correction of substrate artifacts than algorithmic methods.
    Conclusions: Correction algorithms may be effective in situations of moderate fluorogenic substrate artifacts inherent to highly procoagulant samples, but correction may not be required under typical conditions for hemophilia treatment studies if TG parameters can be normalized to a reference plasma sample.
    Language English
    Publishing date 2023-10-04
    Publishing country England
    Document type Journal Article
    ZDB-ID 2118392-2
    ISSN 1477-9560
    ISSN 1477-9560
    DOI 10.1186/s12959-023-00549-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Detecting factor XIa in immune globulin products: Commutability of international reference materials for traditional and global hemostasis assays.

    Liang, Yideng / Jackson, Joseph W / Woodle, Samuel A / Surov, Stepan S / Parunov, Leonid A / Scott, Dorothy E / Weinstein, Mark / Lee, Timothy K / Ovanesov, Mikhail V

    Research and practice in thrombosis and haemostasis

    2020  Volume 5, Issue 1, Page(s) 211–222

    Abstract: Background: Activated coagulation factor XIa (FXIa) is an impurity and primary source of procoagulant activity in thrombosis-implicated immune globulin (IG) products. Several assays, of varying quality and precision are used to assess FXIa-like ... ...

    Abstract Background: Activated coagulation factor XIa (FXIa) is an impurity and primary source of procoagulant activity in thrombosis-implicated immune globulin (IG) products. Several assays, of varying quality and precision are used to assess FXIa-like procoagulant activity in units relevant to their respective principles.
    Objectives: To advance unified reporting, we sought to employ the World Health Organization reference reagents (RRs) to present the results of differing methodologies in units of FXIa activity and rank the sensitivity and robustness of these methodologies.
    Methods: RR 11/236 served as a calibrator in several FXIa-sensitive blood coagulation tests: two commercial chromogenic FXIa assays (CAs); a nonactivated partial thromboplastin time (NaPTT); an in-house fibrin generation (FG) assay; an in-house thrombin generation (TG) assay; and an assay for FXIa- and kallikrein-like proteolytic activities based on cleavage of substrate SN13a. Some assays were tested in either normal or FXI-deficient plasma.
    Results: Each method demonstrated a sigmoidal dose-response to RRs. NaPTT was the least sensitive to FXIa and the least precise; our in-house TG was the most sensitive; and the two CAs were the most precise. All methods, except for SN13a, which is less specific for thrombotic impurities, gave comparable (within 20% difference) FXIa activity assignments for IG lots.
    Conclusions: Purified FXIa reference standards support quantitation of FXIa levels in IG products in all tested assay methodologies. This should help to standardize the measurement of thrombotic potentials in IG products and prevent products exhibiting high procoagulant activity from distribution for patient use. Further research is needed to address the effect of IG product-specific matrixes on assay performance.
    Language English
    Publishing date 2020-12-23
    Publishing country United States
    Document type Journal Article
    ISSN 2475-0379
    ISSN (online) 2475-0379
    DOI 10.1002/rth2.12467
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Unifying the mechanism of recombinant FVIIa action: dose dependence is regulated differently by tissue factor and phospholipids.

    Shibeko, Alexey M / Woodle, Samuel A / Lee, Timothy K / Ovanesov, Mikhail V

    Blood

    2012  Volume 120, Issue 4, Page(s) 891–899

    Abstract: Recombinant factor VIIa (rFVIIa) is used for treatment of hemophilia patients with inhibitors, as well for off-label treatment of severe bleeding in trauma and surgery. Effective bleeding control requires supraphysiological doses of rFVIIa, posing both ... ...

    Abstract Recombinant factor VIIa (rFVIIa) is used for treatment of hemophilia patients with inhibitors, as well for off-label treatment of severe bleeding in trauma and surgery. Effective bleeding control requires supraphysiological doses of rFVIIa, posing both high expense and uncertain thrombotic risk. Two major competing theories offer different explanations for the supraphysiological rFVIIa dosing requirement: (1) the need to overcome competition between FVIIa and FVII zymogen for tissue factor (TF) binding, and (2) a high-dose-requiring phospholipid-related pathway of FVIIa action. In the present study, we found experimental conditions in which both mechanisms contribute simultaneously and independently to rFVIIa-driven thrombin generation in FVII-deficient human plasma. From mathematical simulations of our model of FX activation, which were confirmed by thrombin-generation experiments, we conclude that the action of rFVIIa at pharmacologic doses is dominated by the TF-dependent pathway with a minor contribution from a phospholipid-dependent mechanism. We established a dose-response curve for rFVIIa that is useful to explain dosing strategies. In the present study, we present a pathway to reconcile the 2 major mechanisms of rFVIIa action, a necessary step to understanding future dose optimization and evaluation of new rFVIIa analogs currently under development.
    MeSH term(s) Blood Coagulation/drug effects ; Blotting, Western ; Enzyme Precursors ; Factor VIIa/pharmacology ; Hemophilia A/drug therapy ; Humans ; Models, Theoretical ; Phospholipids/pharmacology ; Recombinant Proteins/blood ; Recombinant Proteins/pharmacology ; Thrombin/metabolism ; Thromboplastin/pharmacology
    Chemical Substances Enzyme Precursors ; Phospholipids ; Recombinant Proteins ; Thromboplastin (9035-58-9) ; recombinant FVIIa (AC71R787OV) ; Factor VIIa (EC 3.4.21.21) ; Thrombin (EC 3.4.21.5)
    Language English
    Publishing date 2012-05-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2011-11-393371
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 364: Show issues

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  4. Article: Cluster III of Low-Density Lipoprotein Receptor-Related Protein 1 Binds Activated Blood Coagulation Factor VIII

    Kurasawa, James H / Shestopal Svetlana A / Woodle Samuel A / Ovanesov Mikhail V / Lee Timothy K / Sarafanov Andrey G

    Biochemistry. 2015 Jan. 20, v. 54, no. 2

    2015  

    Abstract: Low-density lipoprotein receptor-related protein 1 (LRP) mediates clearance of blood coagulation factor VIII (FVIII). In LRP, FVIII binds the complement-type repeats (CRs) of clusters II and IV, which also bind a majority of other LRP ligands. No ligand ... ...

    Abstract Low-density lipoprotein receptor-related protein 1 (LRP) mediates clearance of blood coagulation factor VIII (FVIII). In LRP, FVIII binds the complement-type repeats (CRs) of clusters II and IV, which also bind a majority of other LRP ligands. No ligand is known for LRP cluster I, and only three ligands, including the LRP chaperone alpha-2 macroglobulin receptor-associated protein (RAP), bind cluster III. Using surface plasmon resonance, we found that in addition to clusters II and IV, activated FVIII (FVIIIa) binds cluster III. The specificity of this interaction was confirmed using an anti-FVIII antibody fragment, which inhibited the binding. Recombinant fragments of cluster III and its site-directed mutagenesis were used to localize the cluster’s site for binding FVIIIa to CR.14–19. The interactive site of FVIIIa was localized within its A1/A3′-C1-C2 heterodimer (HDa), which is a major physiological remnant of FVIIIa. In mice, the clearance of HDa was faster than that of FVIII and prolonged in the presence of RAP, which is known to inhibit interactions of LRP with its ligands. In accordance with this, the cluster III site for RAP (CR.15–19) was found to overlap that for FVIIIa. Altogether, our findings support the involvement of LRP in FVIIIa catabolism and suggest a greater significance of the biological role of cluster III compared to that previously known.
    Keywords antibodies ; binding sites ; blood coagulation ; factor VIII ; ligands ; low density lipoprotein ; metabolism ; mice ; site-directed mutagenesis ; surface plasmon resonance
    Language English
    Dates of publication 2015-0120
    Size p. 481-489.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021%2Fbi5011688
    Database NAL-Catalogue (AGRICOLA)

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    Zs.A 217: Show issues Location:
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  5. Article: Characterization of procoagulant extracellular vesicles and platelet membrane disintegration in DMSO-cryopreserved platelets.

    Tegegn, Tseday Z / De Paoli, Silvia H / Orecna, Martina / Elhelu, Oumsalama K / Woodle, Samuel A / Tarandovskiy, Ivan D / Ovanesov, Mikhail V / Simak, Jan

    Journal of extracellular vesicles

    2016  Volume 5, Page(s) 30422

    Abstract: Background: Freezing is promising for extended platelet (PLT) storage for transfusion. 6% DMSO cryopreserved PLTs (CPPs) are currently in clinical development. CPPs contain significant amount of platelet membrane vesicles (PMVs). PLT-membrane changes ... ...

    Abstract Background: Freezing is promising for extended platelet (PLT) storage for transfusion. 6% DMSO cryopreserved PLTs (CPPs) are currently in clinical development. CPPs contain significant amount of platelet membrane vesicles (PMVs). PLT-membrane changes and PMV release in CPP are poorly understood, and haemostatic effects of CPP PMVs are not fully elucidated. This study aims to investigate PLT-membrane alterations in CPPs and provide comprehensive characterization of CPP PMVs, and their contribution to procoagulant activity (PCA) of CPPs.
    Methods: CPPs and corresponding liquid-stored PLTs (LSPs) were characterized by flow cytometry (FC), fluorescence polarization (FP), nanoparticle tracking analysis (NTA), electron microscopy (SEM, TEM), atomic force microscopy (AFM) and thrombin-generation (TG) test.
    Results: SEM and TEM revealed disintegration and vesiculation of the PLT-plasma membrane and loss of intracellular organization in 60% PLTs in CPPs. FP demonstrated that 6% DMSO alone and with freezing-thawing caused marked increase in PLT-membrane fluidity. The FC counts of annexin V-binding PMVs and CD41a(+) PMVs were 68- and 56-folds higher, respectively, in CPPs than in LSPs. The AFM and NTA size distribution of PMVs in CPPs indicated a peak diameter of 100 nm, corresponding to exosome-size vesicles. TG-based PCA of CPPs was 2- and 9-folds higher per PLT and per volume, respectively, compared to LSPs. Differential centrifugation showed that CPP supernatant contributed 26% to CPP TG-PCA, mostly by the exosome-size PMVs and their TG-PCA was phosphatidylserine dependent.
    Conclusions: Major portion of CPPs does not show activation phenotype but exhibits grape-like membrane disintegration with significant increase of membrane fluidity induced by 6% DMSO alone and further aggravated by freezing-thawing process. DMSO cryopreservation of PLTs is associated with the release of PMVs and marked increase of TG-PCA, as compared to LSPs. Exosome-size PMVs have significant contribution to PCA of CPPs.
    Language English
    Publishing date 2016-05-04
    Publishing country Sweden
    Document type Journal Article
    ZDB-ID 2683797-3
    ISSN 2001-3078
    ISSN 2001-3078
    DOI 10.3402/jev.v5.30422
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Correction of microplate location effects improves performance of the thrombin generation test.

    Liang, Yideng / Woodle, Samuel A / Shibeko, Alexey M / Lee, Timothy K / Ovanesov, Mikhail V

    Thrombosis journal

    2013  Volume 11, Issue 1, Page(s) 12

    Abstract: Background: Microplate-based thrombin generation test (TGT) is widely used as clinical measure of global hemostatic potential and it becomes a useful tool for control of drug potency and quality by drug manufactures. However, the convenience of the ... ...

    Abstract Background: Microplate-based thrombin generation test (TGT) is widely used as clinical measure of global hemostatic potential and it becomes a useful tool for control of drug potency and quality by drug manufactures. However, the convenience of the microtiter plate technology can be deceiving: microplate assays are prone to location-based variability in different parts of the microtiter plate.
    Methods: In this report, we evaluated the well-to-well consistency of the TGT variant specifically applied to the quantitative detection of the thrombogenic substances in the immune globulin product. We also studied the utility of previously described microplate layout designs in the TGT experiment.
    Results: Location of the sample on the microplate (location effect) contributes to the variability of TGT measurements. Use of manual pipetting techniques and applications of the TGT to the evaluation of procoagulant enzymatic substances are especially sensitive. The effects were not sensitive to temperature or choice of microplate reader. Smallest location effects were observed with automated dispenser-based calibrated thrombogram instrument. Even for an automated instrument, the use of calibration curve resulted in up to 30% bias in thrombogenic potency assignment.
    Conclusions: Use of symmetrical version of the strip-plot layout was demonstrated to help to minimize location artifacts even under the worst-case conditions. Strip-plot layouts are required for quantitative thrombin-generation based bioassays used in the biotechnological field.
    Language English
    Publishing date 2013-07-05
    Publishing country England
    Document type Journal Article
    ISSN 1477-9560
    ISSN 1477-9560
    DOI 10.1186/1477-9560-11-12
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Cluster III of low-density lipoprotein receptor-related protein 1 binds activated blood coagulation factor VIII.

    Kurasawa, James H / Shestopal, Svetlana A / Woodle, Samuel A / Ovanesov, Mikhail V / Lee, Timothy K / Sarafanov, Andrey G

    Biochemistry

    2015  Volume 54, Issue 2, Page(s) 481–489

    Abstract: Low-density lipoprotein receptor-related protein 1 (LRP) mediates clearance of blood coagulation factor VIII (FVIII). In LRP, FVIII binds the complement-type repeats (CRs) of clusters II and IV, which also bind a majority of other LRP ligands. No ligand ... ...

    Abstract Low-density lipoprotein receptor-related protein 1 (LRP) mediates clearance of blood coagulation factor VIII (FVIII). In LRP, FVIII binds the complement-type repeats (CRs) of clusters II and IV, which also bind a majority of other LRP ligands. No ligand is known for LRP cluster I, and only three ligands, including the LRP chaperone alpha-2 macroglobulin receptor-associated protein (RAP), bind cluster III. Using surface plasmon resonance, we found that in addition to clusters II and IV, activated FVIII (FVIIIa) binds cluster III. The specificity of this interaction was confirmed using an anti-FVIII antibody fragment, which inhibited the binding. Recombinant fragments of cluster III and its site-directed mutagenesis were used to localize the cluster's site for binding FVIIIa to CR.14-19. The interactive site of FVIIIa was localized within its A1/A3'-C1-C2 heterodimer (HDa), which is a major physiological remnant of FVIIIa. In mice, the clearance of HDa was faster than that of FVIII and prolonged in the presence of RAP, which is known to inhibit interactions of LRP with its ligands. In accordance with this, the cluster III site for RAP (CR.15-19) was found to overlap that for FVIIIa. Altogether, our findings support the involvement of LRP in FVIIIa catabolism and suggest a greater significance of the biological role of cluster III compared to that previously known.
    MeSH term(s) Animals ; Binding Sites ; Factor VIII/chemistry ; Factor VIII/metabolism ; Factor VIIIa/chemistry ; Factor VIIIa/metabolism ; LDL-Receptor Related Protein-Associated Protein/metabolism ; Low Density Lipoprotein Receptor-Related Protein-1/chemistry ; Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; Mice ; Mice, Inbred BALB C ; Protein Binding ; Protein Interaction Mapping ; Protein Multimerization ; Recombinant Proteins/chemistry ; Recombinant Proteins/metabolism
    Chemical Substances LDL-Receptor Related Protein-Associated Protein ; Low Density Lipoprotein Receptor-Related Protein-1 ; Recombinant Proteins ; Factor VIIIa (72175-66-7) ; Factor VIII (9001-27-8)
    Language English
    Publishing date 2015-01-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1108-3
    ISSN 1520-4995 ; 0006-2960
    ISSN (online) 1520-4995
    ISSN 0006-2960
    DOI 10.1021/bi5011688
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 217: Show issues Location:
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  8. Article: Cluster III of Low-Density Lipoprotein Receptor-Related Protein 1 Binds Activated Blood Coagulation Factor VIII

    Kurasawa, James H. / Shestopal Svetlana A.author / Woodle Samuel A.author / Ovanesov Mikhail V.author / Lee Timothy K.author / Sarafanov Andrey G.author
    Language English
    Document type Article
    Database AGRIS - International Information System for the Agricultural Sciences and Technology

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