Intravenous administration of mesenchymal stromal cells leads to a dose-dependent coagulopathy and is unable to attenuate acute traumatic coagulopathy in rats

Abstract

Background: Mesenchymal stromal cells (MSCs) express surface tissue factor (TF), which may affect hemostasis and detract from therapeutic outcomes of MSCs if administered intravenously. In this study, we determine a safe dose of MSCs for intravenous (IV) administration and further demonstrate the impact of IV-MSC on acute traumatic coagulopathy (ATC) in rats.

Methods: Tissue factor expression of rat bone marrow-derived mesenchymal stromal cell (BMSC) or adipose-derived mesenchymal stromal cell (AMSC) was detected by immunohistochemistry and enzyme-linked immunosorbent assay. The coagulation properties were measured in MSC-treated rat whole blood, and blood samples were collected from rats after IV administration of MSCs. Acute traumatic coagulopathy rats underwent polytrauma and 40% hemorrhage, followed by IV administration of 5 or 10 million/kg BMSCs (BMSC-5, BMSC-10), or vehicle at 1 hour after trauma.

Results: Rat MSCs expressed TF, and incubation of rat BMSCs or AMSCs with whole blood in vitro led to a significantly shortened clotting time. However, a dose-dependent prolongation of prothrombin time with reduction in platelet counts and fibrinogen was found in healthy rat treated with IV-MSCs. Bone marrow-derived mesenchymal stromal cells at 5 million/kg or less led to minimal effect on hemostasis. Mesenchymal stromal cells were not found in circulation but in the lungs after IV administration regardless of the dosage. Acute traumatic coagulopathy with prolonged prothrombin time was not significantly affected by 5 or 10 million/kg BMSCs. Intravenous administration of 10 million/kg BMSCs led to significantly lower fibrinogen and platelet counts, while significantly higher levels of lactate, wet/dry weight ratio, and leukocyte infiltration in the lung were present compared with BMSC-5 or vehicle. No differences were seen in immune or inflammatory profiles with BMSC treatment in ATC rats, at least in the acute timeframe.

Conclusion: Intravenous administration of MSCs leads to a risk of coagulopathy associated with a dose-dependent reduction in platelet counts and fibrinogen and is incapable of restoring hemostasis of rats with ATC after polytrauma and hemorrhagic shock.