title: Interconnectedness of global hemostasis assay parameters in simultaneously evaluated thrombin generation, fibrin generation and clot lysis in normal plasma.
abstract: BACKGROUND
  Fluorogenic thrombin generation (TG) assays and turbidity-based fibrin generation (FG)- and fibrinolysis (FL)-resistance assays have been sought to assess bleeding and clotting disorders. Theoretically, TG, FG and FL tests should provide overlapping information because thrombin is responsible for FG and induces protection from FL. The relationships between TG, FG and FL parameters remain poorly investigated, partly because existing experimental systems do not permit simultaneous detection of both TG and FG in the same sample of plasma, and are instead tested in separate experiments.
  
  
  OBJECTIVE
  We evaluated the potential benefits of a combined TG/FG/FL assay by testing responses of normal plasma to a wide range of tissue factor (TF) and tissue plasminogen activator (tPA) concentrations. Correlations between multiple parameters extracted from the TG and FG/FL curves were also compared.
  
  
  RESULTS
  Rate of FG correlated well with TG peak height at all TF concentrations, but correlations between TG and FL parameters depended on the TF concentration. Without thrombomodulin, all FG/FL parameters at high TF could be predicted from TG parameters and no FL protection was observed. With thrombomodulin and high TF, TF-dependent FL protection did not correlate with TF-dependent TG. The fluorogenic thrombin substrate did not interfere with optical density readings, and meaningful tPA concentrations did not interfere with TG readings.
  
  
  CONCLUSIONS
  In normal plasma, TG, FG and FL parameters may provide interchangeable information. Evaluation of FL-resistance may provide additional data under special assay conditions, but the value of this information should be studied under disease conditions.
authors.affiliation: Office of Blood Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States of America.
authors.forename: Kevin Z
authors.initials: KZ
authors.lastname: Xin
authors.affiliation: Office of Blood Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Office of Blood Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States of America. Electronic address: mikhail.ovanesov@fda.hhs.gov.
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Ovanesov
mesh_terms: D001777:Blood Coagulation; D001780:Blood Coagulation Tests / Q000379:methods; D005337:Fibrin / Q000378:metabolism*; D005342:Fibrinolysis; D006487:Hemostasis; D006801:Humans; D013917:Thrombin / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000378:metabolism
chemical_list: D005337:Fibrin; D013925:Thromboplastin; D013917:Thrombin; D010959:Tissue Plasminogen Activator
keywords: Fibrin generation; Fibrinolysis; Global hemostasis assay; Overall hemostasis potential; TAFI; Thrombin generation; Tissue factor; Tissue plasminogen activator