Identification of Patients at Low Risk for Recurrent Venous Thromboembolism by Measuring Thrombin Generation

Hron, Gregor; Kollars, Marietta; Binder, Bernd R.; Eichinger, Sabine; Kyrle, Paul A.

doi:10.1001/jama.296.4.397

Cited by 342 publications

(244 citation statements)

References 23 publications

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“…Although studies have demonstrated significant correlations between TGA parameters and both hemostatic defects [22] and primary and recurrent thrombosis [9, 23–25], the assay has not yet received regulatory approval for clinical use from either the U.S. Food and Drug Administration or European Medicines Agency, in part due to difficulties with assay standardization. In particular, thrombin generation measurements are highly sensitive to pre-analytical variables, including the method of blood collection and plasma isolation (tube style, presence or absence of contact pathway inhibitors, centrifugation speeds and freezing methods), and analytical variables (tissue factor level, lipid concentration, use or not of calibrators) [26].…”

Section: Thrombin Generation Assaysmentioning

confidence: 99%

Global assays of hemostasis

Brummel‐Ziedins

Wolberg

2014

Current Opinion in Hematology

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Purpose of review There exists an imbalance between our understanding of the physiology of the blood coagulation process and the translation of this understanding into useful assays for clinical application. As technology advances, the capabilities for merging the two areas have become more attainable. Global assays have advanced our understanding of the dynamics of the blood coagulation process beyond end point assays and are at the forefront of implementation in the clinic. Recent findings We will review recent advances in the main global assays with a focus on thrombin generation that have potential for clinical utility. These assays include direct (thrombogram, whole blood, purified systems) and indirect empirical measures of thrombin generation (thromboelastography) and mechanism-based computational models that use plasma composition data from individuals to generate thrombin generation profiles. Summary Empirical thrombin generation assays (direct and indirect) and computational modeling of thrombin generation have greatly advanced our understanding of the hemostatic balance. Implementation of these types of assays and visualization approaches in the clinic potentially will provide a basis for the development of individualized patient care. Advances in both empirical and computational global assays have made the goal of predicting pre-crisis changes in an individual’s hemostatic state one step closer.

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Section: Thrombin Generation Assaysmentioning

confidence: 99%

Global assays of hemostasis

Brummel‐Ziedins

Wolberg

2014

Current Opinion in Hematology

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“…Chromogenic assays require the utilization of defibrinated plasma samples in the analysis due to increased interference from the resulting turbidity when fibrinogen is added to the assay. Fluorogenic assays are more sensitive allowing for the use of smaller sample sizes compared to their chromogenic counterparts, however, there is no direct linear correlation between the fluorescence signal and thrombin activity [28].…”

Section: Introductionmentioning

confidence: 99%

Poly(methyl methacrylate) microchip affinity capillary gel electrophoresis of aptamer–protein complexes for the analysis of thrombin in plasma

et al. 2008

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Thrombin generation in blood serves as an important marker for various hemostasis-related diseases and conditions. Analytical techniques currently utilized for determining the thrombin potential of patients rely primarily on the enzymatic activity of thrombin. Microfluidic-based ACE using fluorescently labeled aptamers as affinity probes could provide a simple and efficient technique for the real-time analysis of thrombin levels in plasma. In this study, aptamers were used for the analysis of thrombin by affinity microchip CGE. The CGE used a poly(methyl methacrylate) (PMMA) microfluidic device for the sorting of the affinity complexes with a linear polyacrylamide (LPA) serving as the sieving matrix. Due to the fact that the assay was run under nonequilibrium electrophoresis conditions, the presence of the sieving gel was found to stabilize the affinity complex, providing improved electrophoretic performance compared to free-solution electrophoresis. Two fluorescently labeled aptamer affinity probes, HD1 and HD22, which bind to exosites I and II, respectively, of thrombin were investigated. With an electric field strength of 300 V/cm, two well-resolved peaks corresponding to free aptamer and the thrombin-aptamer complex were obtained in less than 1 min of separation time with a run-to-run and chip-to-chip reproducibility (RSD) of migration times <10% using both aptamers. HD22 affinity assays of thrombin produced baseline-resolved peaks with favorable efficiency due to its higher binding affinity, whereas HD1 assays showed poorer resolution of the free aptamer and complex peaks. HD22 was used in determining the level of thrombin in human plasma. Assays were performed directly on plasma that was diluted to 10% v/v. Thrombin was successfully analyzed by microchip CGE at a concentration level of 543.5 nM for the human plasma sample.

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“…Such a role ascribed to thrombin has been examined, with elevated endogenous thrombin potential (ETP) and peak thrombin levels demonstrated in venous thromboembolism and acute coronary artery disease and speculated in ischaemic stroke [12, 15–17]. There is increasing speculation about dissimilar trend in thrombin generation kinetics in VTE which showed elevated ETP and PTG, when compared to coronary artery disease with elevated lag time and time to peak [15, 18–20]. Such discordant trend has been suggested in stroke of different aetiological types [16, 21].…”

Section: Introductionmentioning

confidence: 99%

Thrombin Generation in Acute Ischaemic Stroke

Balogun

Roberts

Patel

et al. 2016

Stroke Research and Treatment

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Introduction. Stroke remains a global leading cause of death and disability. Traditional description of plasma biology in the aftermath of acute ischaemic stroke favours development of hypercoagulability, resulting from complex interplay between plasma and endothelial factors. However, no single assay measures the overall global coagulation process. We postulate that thrombin generation would assist in identifying coagulation abnormalities after acute stroke. Aim. To investigate the coagulation abnormalities after acute ischaemic stroke using thrombin generation. Methods. We evaluated thrombin generation, measured with calibrated automated thrombography in stroke of different aetiological types (n = 170) within 48 hours of symptoms onset (baseline) and in the second week (time 2) and in normal healthy volunteers (n = 71). Results. Two-point thrombin generation assays showed prolonged lag time and time to peak at baseline (3.3 (2.9, 4.0) versus 3.6 (3.2, 4.7); p = 0.005) and (3.3 (2.9, 4.0) versus 3.6 (3.2, 4.7); p = 0.002), respectively, and at time 2 (3.5 (2.9, 4.2) versus 4.0 (3.1, 4.9); p = 0.004) and (5.9 (5.3, 6.6) versus 6.8 (5.8, 7.7) p = 0.05), respectively, in cardioembolic stroke (n = 39), when compared to noncardioembolic stroke (n = 117). The result was reproduced in multiple comparisons between acute ischaemic stroke subgroups and normal healthy volunteers. Endogenous thrombin potential and peak thrombin did not indicate hypercoagulability after acute ischaemic stroke, and thrombolytic therapy did not affect thrombin generation assays. Conclusion. Our findings suggest that thrombin generation in platelet poor plasma is not useful in defining hypercoagulability in acute ischaemic stroke. This is similar to observed trend in coronary artery disease and contrary to other hypercoagulable states.

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Identification of Patients at Low Risk for Recurrent Venous Thromboembolism by Measuring Thrombin Generation

Abstract: Measurement of thrombin generation identifies patients at low risk for recurrent VTE.

Cited by 342 publications

References 23 publications

Global assays of hemostasis

Global assays of hemostasis

Poly(methyl methacrylate) microchip affinity capillary gel electrophoresis of aptamer–protein complexes for the analysis of thrombin in plasma

Thrombin Generation in Acute Ischaemic Stroke

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