Factor XIII and Tranexamic Acid But Not Recombinant Factor VIIa Attenuate Tissue Plasminogen Activator-Induced Hyperfibrinolysis in Human Whole Blood

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 Vila (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)), rFVIla (final concentration: 1.6 mu g . mL(-1)), TA (final concentration: 0.33 mg . mL(-1)), or saline. Coagulation was analyzed by rotational thromboelastometry (ROTEM (R)) using the clot lysis index (CLI) after 45 and 60 minutes in extrinsically activated assays, with (FIBTEM (R)) and without (EXTEM (R)) 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 rFVIla (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 rFVIla 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). CONCLUSION: In thromboelastometric assays using whole blood, only TA, FXIII, and PCC significantly inhibited r-tPA-evoked hyperfibrinolysis whereas rFVIla had no effect. We also found that the effects of exogenous FXIII were dependent on the presence of functional platelets. (Anesth Analg 2012;114:1182-8)