OC 47.4 - The role of factor XIII in modulating the efficacy of tranexamic acid on fibrinolysis and fibrin structure in cellular and cell-free environments

Background: Red blood cells (RBCs) are abundant in thrombi and play a crucial role in influencing lytic susceptibility of clots. Tranexamic acid (TXA) is widely used to reduce bleeding in various medical conditions. Previously we have shown that there is synergism between TXA and RBCs in inhibiting fibrinolysis. Factor XIII (FXIII) crosslinks fibrin to enhance thrombus stability and retains RBCs within clots.

Aims: To study whether FXIII impacts the efficacy of TXA on the inhibition of fibrinolysis.

Methods: A global viscoelastic lysis test (ClotPro) was conducted to examine the impact of FXIII on fibrinolysis in the presence of RBCs and TXA in purified fibrin clots. Plasminogen activation was measured using fluorescent plasmin substrate layered onto preformed fibrin surfaces, along with tissue-type plasminogen activator. Combinations of 10 µg/mL recombinant FXIIIA, 0-128µM TXA, and 30%(v/v) RBCs were tested with or without FXIII inhibitor (6µM, ZED1301). Scanning electron microscopy (SEM) was used to study the structure of artificial clots and determine fiber thickness.

Results: In cell-free fibrin clots FXIIIA did not significantly affect lysis time (LT) regardless of the presence of TXA. In clots containing RBCs, LT was prolonged by FXIIIA, and this effect was even more pronounced in the presence of TXA: 11.6±1.2% LT prolongation without TXA vs. 18.6±1.9% at 128 µM TXA, (n=8).
The inhibitory effect of TXA on plasminogen activation was not enhanced by FXIIIA in cell-free clots, whereas in the presence of RBCs, the inhibition of plasminogen activation was about 3-fold stronger compared to TXA alone.
In SEM samples, FXIIIA resulted in thinning of fibers, while TXA thickened fibers in all experimental setups. In the presence of RBCs and TXA, FXIII-inhibition caused more pronounced fiber thickening compared to cell-free clots.

Conclusion(s): Factor XIII contributes to the action of TXA in a cellular environment by enhancing its anti-fibrinolytic synergism with red blood cells.