Simultaneous thrombin and plasmin generation capacities in normal and abnormal states of coagulation and fibrinolysis in children and adults

Simpson, Mindy L.; Goldenberg, Neil A.; Jacobson, Linda; Bombardier, C.; Hathaway, William E.; Manco‐Johnson, Marilyn J.

doi:10.1016/j.thromres.2010.12.011

Cited by 52 publications

(52 citation statements)

References 19 publications

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“…The simplest turbidimetric methods report time to 50% lysis, but later developments were aimed at generating a global figure for patient fibrinolytic capacity. The introduction of fluorogenic substrates has developed from thrombin generation assays (TGAs) , but fibrinolysis is explored in the presence of two substrates sensitive to thrombin or plasmin, added to separate wells run in parallel or in the same well . These TGA‐like assay systems have been explored to identify what factors regulate thrombin and plasmin generation and probe the relationships between clotting and lysis.…”

Section: Euglobulin Plasma Whole Bloodmentioning

confidence: 99%

Measuring fibrinolysis: from research to routine diagnostic assays

Longstaff

2018

Journal of Thrombosis and Haemostasis

134

123

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SummaryDevelopment and standardization of fibrinolysis methods have progressed more slowly than coagulation testing and routine high‐throughput screening tests for fibrinolysis are still lacking. In laboratory research, a variety of approaches are available and are applied to understand the regulation of fibrinolysis and its contribution to the hemostatic balance. Fibrinolysis in normal blood is slow to develop. For practical purposes plasminogen activators can be added to clotting plasma, or euglobulin prepared to reduce endogenous inhibitors, but results are complicated by these manipulations. Observational studies to identify a ‘fibrinolysis deficit’ have concluded that excess fibrinolysis inhibitors, plasminogen activator inhibitor 1 (PAI‐1) or thrombin‐activatable fibrinolysis inhibitor (TAFI), zymogen or active enzyme, may be associated with an increased risk of thrombosis. However, results are not always consistent and problems of adequate standardization are evident with these inhibitors and also for measurement of fibrin degradation products (D‐dimer). Few methods are available to investigate fibrinolysis under flow, or in whole blood, but viscoelastic methods (VMs) such as ROTEM and TEG do permit the contribution of cells, and importantly platelets, to be explored. VMs are used to diagnose clinical hyperfibrinolysis, which is associated with high mortality. There is a debate on the usefulness of VMs as a point‐of‐care test method, particularly in trauma. Despite the difficulties of many fibrinolysis methods, research on the fibrinolysis system, taking in wider interactions with hemostasis proteins, is progressing so that in future we may have more complete models and better diagnostic methods and therapeutics.

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Section: Euglobulin Plasma Whole Bloodmentioning

confidence: 99%

Measuring fibrinolysis: from research to routine diagnostic assays

Longstaff

2018

Journal of Thrombosis and Haemostasis

134

123

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“…Refinement of preclinical and clinical variables must be validated using samples from well-defined cohorts of patients with coagulopathy to ensure the sensitivity and predictive value of the assay readouts. Another area of active investigation with modifications of this technology is the simultaneous measurement of thrombin and plasmin generation and its relationship to clinical phenotypes [32–34]. …”

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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“…Reported clinical manifestations include abnormal epistaxis, oral bleeding with injury or dental extractions, haematoma formation, maenorrhagia, haemorrhagic ovarian cysts, haemorrhage in pregnancy and intracranial bleeding with injury. 19,20 The NHA was used to evaluate simultaneous thrombin and plasmin generation in five patients with PLGD and ten patients with complete PAI-1 deficiency who carry the same homozygous frameshift mutation. 15 Heterozygous PAI-1 deficiency is not associated with abnormal bleeding, even after haemostatic challenge.…”

Section: Introductionmentioning

confidence: 99%

Thrombin and plasmin generation in patients with plasminogen or plasminogen activator inhibitor type 1 deficiency

et al. 2019

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Introduction Deficiencies of plasminogen and plasminogen activator inhibitor type 1 (PAI‐1) are rare disorders of fibrinolysis. Current laboratory assays for analysis of activity of plasminogen and PAI‐1 do not provide an accurate correlation with clinical phenotype. Methods The Nijmegen Hemostasis Assay (NHA) was used to simultaneously measure thrombin and plasmin generation in 5 patients with plasminogen deficiency (PLGD) and 10 patients with complete PAI‐1 deficiency. Parameters analysed included: lag time ratio, thrombin peak time ratio, thrombin peak height, thrombin potential (AUC), fibrin lysis time, plasmin peak height and plasmin potential. Parameters were expressed as a percentage compared to a reference value of 53 healthy normal controls. Results Patients with PLGD demonstrated a short lag time and thrombin peak time, with normal thrombin peak height but an increased AUC. Plasmin generation was able to be detected in only one (23% plasminogen activity) of the five PLGD patients. All ten PAI‐1 deficient patients demonstrated a short lag and thrombin peak time, low thrombin peak height with normal AUC. Plasmin generation revealed an increased plasmin peak and plasmin potential; interestingly, there was a large variation between individual patients despite all patients having the same homozygous defect. Conclusion Patients with either PLGD or PAI‐1 deficiency show distinct abnormalities in plasmin and thrombin generation in the NHA. The differences observed in the propagation phase of thrombin generation may be explained by plasmin generation. These results suggest that disorders of fibrinolysis also influence coagulation and a global assay measuring both activities may better correlate with clinical outcome.

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Simultaneous thrombin and plasmin generation capacities in normal and abnormal states of coagulation and fibrinolysis in children and adults

Cited by 52 publications

References 19 publications

Measuring fibrinolysis: from research to routine diagnostic assays

Measuring fibrinolysis: from research to routine diagnostic assays

Global assays of hemostasis

Thrombin and plasmin generation in patients with plasminogen or plasminogen activator inhibitor type 1 deficiency

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