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Clotting: An Added Consideration for Intravenous Infusion of Stem Cell Therapies?

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Review of “Clinical Cellular Therapeutics Accelerate Clot Formation” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Intravenous infusion represents an oft-used delivery route for stem cell therapeutics; however, unwanted interactions between blood and the cell population employed can induce significant incidences of clotting. Increased clotting has the potential to reduce the regenerative output of stem cell therapies, but more importantly, this process may also increase the risk of deleterious side effects. Both in vitro and in vivo  assessments of interactions between human mesenchymal stem cells (MSCs) and blood have demonstrated that the expression of tissue factor (TF), a pro-clotting component [1], accelerates clot formation and reduces therapeutic efficacy [2, 3], although we lack a fuller understanding of the clotting potential of other therapeutically-relevant stem cell populations. 

Now, in a new STEM CELLS Translational Medicinearticle, researchers led by Charles S. Cox Jr. (McGovern Medical School at the University of Texas Health Science Center, USA) have established that a wide range of stem cells differentially promote clot formation via varying levels of TF expression, thereby advocating for the implementation of clotting activator analysis in safety assessments for stem cell therapies [4].

George et al. established that bone marrow mononuclear cells, multipotent adult progenitor cell (MAPC) donors, and MSCs derived from bone marrow, adipose, amniotic fluid, umbilical cord from over thirty patients all displayed widely varying proclotting activities that correlated with cell-surface TF expression. Of note, adipose- and amniotic fluid-derived MSCs exhibited the highest levels of TF and accelerated clot formation to the highest level of all cells tested using thromboelastography and calibrated thrombograms. However, the authors discovered that treatment with an anti-TF antibody reduced clotting for some cell types, although analysis of amniotic fluid- and bone marrow-derived MSCs suggested the involvement of an additional clotting mechanism for these cell types. 

Overall, George et al. establish that expression of TF by various therapeutically relevant cell types may enhance clotting following intravenous infusion, potentially leading to reduced therapeutic effects and unwanted side effects. Therefore, they advise the consideration of TF levels as a safety measure for the approximately 800 active clinical trials employing cell/stem cell therapies in the clinic in the United States.

For more on the clotting potential of therapeutically relevant cell types and a possible means to solve this problem, stay tuned to the Stem Cells Portal.

References

  1. Drake TA, Morrissey JH, and Edgington TS, Selective cellular expression of tissue factor in human tissues. Implications for disorders of hemostasis and thrombosis. Am J Pathol 1989;134:1087-97.
  2. Christy BA, Herzig MC, Montgomery RK, et al., Procoagulant activity of human mesenchymal stem cells. Journal of Trauma and Acute Care Surgery 2017;83:S164-S169.
  3. Moll G, Rasmusson-Duprez I, von Bahr L, et al., Are Therapeutic Human Mesenchymal Stromal Cells Compatible with Human Blood? STEM CELLS 2012;30:1565-1574.
  4. George MJ, Prabhakara K, Toledano-Furman NE, et al., Clinical Cellular Therapeutics Accelerate Clot Formation. STEM CELLS Translational Medicine 2018;7:731-739.