CAN THE TISSUE FACTOR EXPRESSION USED AS A PREDICTIVE VALUE TO DETERMINE THE THROMBOEMBOLIC RISK OF MSC THERAPIES?

Abstract

<h3>Background</h3> Although thromboembolism is a rarely reported event in mesenchymal stem cell (MSC) intravascular administration-based therapies, studies have been suggested that the tissue factor (TF/CD142) expression increases the risk for clot formation in a dose-dependent manner. For this reason, this study aimed to evaluate whether the expression levels of TF can be used as a predictive value to determine the risk for thromboembolism. <h3>Methods</h3> The thrombogenic potential of human immature dental pulp stem cells (hIDPSCs), in two proportional doses to clinically tested doses (1 × 10⁶/Kg of body weight and 20 × 10⁶/patient), and with different TF-positive cell percentages (0.2 to 60% of TF-positive cells), was evaluated using the rotational thromboelastometry (ROTEM). The percentual of TF-positive cells was correlated with the clotting time (CT). <h3>Results</h3> Our results showed that all cells, independently of the TF-positive cell percentages, reduced the CT when compared with the controls (plasma with saline), being not verified statistically significant differences among the CTs of cells expressing among 0.2 to 60% of TF. These results were also confirmed by the Pearson's correlation (R=0.06), which did not indicate a statistical correlation between the TF expression and CT. Additionally, we verified that HUVEC cells (TF-negative), in these even doses, had a CT statistically identical to the hIDPSCs. However, the CT of both HUVEC and hIDPSCs increased following the addition of enoxaparin. <h3>Conclusion</h3> Our results provide evidence that despite the TF is recognized as a key activator of extrinsic via of coagulation; the TF expression does not necessarily increase the risk for thromboembolism. Considering that previous studies suggesting that the TF expression can elicit the clot formation were based on ROTEM, and that they did not include a TF-negative cell as an additional control, we hypothesized that the CT reduction described can be elicited by the cell lysis, resulted from the rotational movement of the piston into the cup, leading to the exposure of phosphatidylserine phospholipids, which are the main activator of intrinsic via of coagulation cascade. Thus, the ROTEM's results do not reflect a predictive value for clinical studies. Despite this data, the prophylactic administration of anticoagulants such as enoxaparin reduces expressively clot formation.