Effect of tranexamic acid incorporated in fibrin sealant clots on the cell behavior of neuronal and nonneuronal cells

Abstract

Fibrin sealants are commonly used for hemostasis following surgery on various types of tissues. Aprotinin, an effective fibrinolysis inhibitor, is one of the components in some fibrin sealant products currently available. Tranexamic acid (tAMCHA) is another fibrinolysis inhibitor and is used as an alternative to aprotinin. Recent studies on fibrin sealant products containing tAMCHA indicate that it may be responsible for various adverse reactions when used in neurological applications. To determine a possible mechanism for such adverse reactions, we examined the effect of tAMCHA on the behavior of neuronal and nonneuronal cells using in vitro assays. The data indicate that different concentrations of tAMCHA incorporated in fibrin clots had no effect on the initial cell adhesion of either proliferative cells (glial cells and fibroblasts) or nonproliferative cells (neuronal cells) to the fibrin clots. Moreover, a high concentration of tAMCHA (300-450 mM) incorporated in the fibrin clots increased glial and fibroblast proliferation on fibrin clots. However, because tAMCHA is known to leach out of the fibrin clots, we have also examined the effect of solubilized tAMCHA in a growth medium on cells seeded on matrix-coated surfaces. A high concentration (300-450 mM) of tAMCHA detached all cell types from matrix-coated dishes. Our model suggests that tAMCHA in fibrin clots has no adverse effect on cells bound to the fibrin clots; however, tAMCHA leaching out from the fibrin clots reduces adhesion of adjacent cells bound to their natural extracellular matrix. Thus, a high concentration of tAMCHA should not be used as a fibrinolysis inhibitor in fibrin sealant products, especially in neurosurgery.

Effects of Hemostatic Agents on Fibroblast Cells

“…LDH levels were significantly higher in the fibrin glue group when compared with the tAMCHA group and higher when compared with the ABStreated group, which is in correlation with the findings of Cox et al 22 who have stated that t-AMCHA is not cytotoxic. Our SEM findings of apoptotic cells in the tAMCHA-treated groups at both time intervals also confirm their results concluding that t-AMCHA used as a fibrinolysis inhibitor has adverse effects on tissue healing.…”

“…22 In our study, we have found that the number of cells were significantly lower in the Tranexamic acidtreated group when compared with the control group in the both time intervals. They have observed a decrease in adhesion between the cells and detachment from the matrix-coated dishes, leading to an increased cell proliferation rate.…”

Comparison of structure, strength and cytocompatibility of a fibrin matrix supplemented either with tranexamic acid or aprotinin

“…However, we could not verify that cells recover or readhere after incubation in fresh culture medium without t‐AMCA (data not shown). Furthermore, our experiments revealed significant reduction of cellular viability due to incubation with t‐AMCA already within 100 min, compared to 3 days in the other report 22…”

“…The concentrations of t‐AMCA, however, achieved due to intravenous administration are in the range of 20–500 μg/mL,21 which is three orders of magnitude less than the concentrations in a commercial fibrin sealant (95 mg/mL). Similarly, reduced proliferation and detachment was already shown earlier for neuronal cells and fibroblasts seeded on polyethyleneimine‐coated culture dishes 22. However, we could not verify that cells recover or readhere after incubation in fresh culture medium without t‐AMCA (data not shown).…”

Topical moistening of mastectomy wounds with diluted tranexamic acid to reduce bleeding: randomized clinical trial

“…TXA inhibits plasminogen, which is ubiquitous in tissue matrix and has numerous functions beyond the cleavage of fibrin. Studies have suggested that TXA may affect cell adhesion, and inhibition of TXA on tumour growth and spread was investigated in the 1970s and 1980s. The authors made the unexpected observation in a previous study that prolonged exposure to high concentrations of topical TXA caused lack of re‐epithelialization, and even epithelial detachment, in an ex vivo human skin wound model.…”