title: Factor XIII and tranexamic acid but not recombinant factor VIIa attenuate tissue plasminogen activator-induced hyperfibrinolysis in human whole blood.
abstract: BACKGROUND
  Hyperfibrinolysis is a pathological state that often results in depletion of coagulation factors and platelets and can contribute to bleeding. Factor XIII (FXIII) and thrombin activatable fibrinolysis inhibitor have key roles in protecting clots against fibrinolysis. We tested the hypotheses that FXIII concentrate, prothrombin complex concentrate (PCC), recombinant factor VIIa (rFVIIa), and tranexamic acid (TA) inhibit fibrinolysis to different degrees, and that platelets contribute to antifibrinolysis.
  
  
  METHODS
  Hyperfibrinolysis was induced by addition of recombinant tissue plasminogen activator (r-tPA) (final concentration: 100 ng · mL(-1)) to citrated whole blood obtained from 13 healthy volunteers. To assess inhibition of fibrinolysis, we added to the assays FXIII-A(2)B(2) (0.42 U · mL(-1)), PCC (0.42 U · mL(-1)), rFVIIa (final concentration: 1.6 μg · mL(-1)), TA (final concentration: 0.33 mg · mL(-1)), or saline. Coagulation was analyzed by rotational thromboelastometry (ROTEM®) using the clot lysis index (CLI) after 45 and 60 minutes in extrinsically activated assays, with (FIBTEM®) and without (EXTEM®) inhibition of platelet function by cytochalasin D.
  
  
  RESULTS
  After r-tPA-evoked fibrinolysis (CLI45: median 78%; 72/85.5, 25th/75th percentile), FXIII (90%; 82.5/96, P = 0.025), PCC (89%; 74/91, P = 0.0465), and TA (94%; 92/96, P = 0.001) but not rFVIIa (79%; 72/86.5, P = 1.0) significantly attenuated the decrease in CLI. Similarly, CLI60 increased only with FXIII (66%; 33/90.5, P = 0.017) and TA (90%; 89/92, P = 0.001) compared with r-tPA alone (21%; 7/59). After abolition of platelet function by cytochalasin D, only TA (95%; 89/97.5, P = 0.0025) and PCC (84%; 70.5/90, P = 0.0305) but not FXIII or rFVIIa significantly increased CLI45 and CLI60 (TA: 89%; 84.5/96, P = 0.01 and PCC: 55%; 29.5/60, P = 0.0405) compared with r-tPA alone (CLI45: 59%; 40.5/72.5 and CLI60: 10%; 0/30).
  
  
  CONCLUSIONS
  In thromboelastometric assays using whole blood, only TA, FXIII, and PCC significantly inhibited r-tPA-evoked hyperfibrinolysis whereas rFVIIa had no effect. We also found that the effects of exogenous FXIII were dependent on the presence of functional platelets.
authors: Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen & Universitätsklinikum Essen, Essen, Germany. Daniel.Dirkmann@uni-duisburg-essen.de
authors: Daniel
authors: D
authors: Dirkmann
authors: Klaus
authors: K
authors: Görlinger
authors: Caroline
authors: C
authors: Gisbertz
authors: Fabian
authors: F
authors: Dusse
authors: Jürgen
authors: J
authors: Peters
mesh_terms: D000328:Adult; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D001779:Blood Coagulation Factors / Q000494:pharmacology; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D015638:Cytochalasin D / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D015942:Factor VIIa / Q000494:pharmacology*; D005176:Factor XIII / Q000494:pharmacology*; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D008297:Male; D015539:Platelet Activation / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000097:blood*; D014148:Tranexamic Acid / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000933:Antifibrinolytic Agents; D001779:Blood Coagulation Factors; D011994:Recombinant Proteins; D015638:Cytochalasin D; C025667:prothrombin complex concentrates; D014148:Tranexamic Acid; D005176:Factor XIII; C103587:recombinant FVIIa; D015942:Factor VIIa; D010959:Tissue Plasminogen Activator