↓ Figure 1. Theorized effects of cfDNA on the
transfusion recipient. The impact of transfused cfDNA on the recipient may vary widely depending on
factors such as cfDNA concentration, the recipient’s genomic background and lifestyle, and the
cellular origin of the cfDNA. It is hypothesized that cfDNA bound to histones may evade DNase
degradation and potentially integrate into the host genome. This integration could influence gene
regulation by promoting transcriptional activation or silencing. cfDNA has also been associated with
genomic instability in theoretical models. If not effectively cleared by the immune system, donor cfDNA
may contribute to enhanced immune activation, potentially triggering responses linked to transplant
rejection or the activation of pathways involving tumor suppressor genes, oncogenes, or Toll-like
receptors. cfDNA: cell-free DNA; CpG: cytosine-phosphate-guanine; TLR: Toll-like receptor.
↓ Figure 2. Potential sources of donor-derived
cfDNA in transfused blood. Donor blood may contain various sources of cfDNA, including DNA from white
blood cells, stem cells, NETs, dietary DNA (e.g., from GMOs), nuclear DNA, and mt-cfDNA. These fragments
can persist in the recipient’s circulation post-transfusion, despite leukoreduction, and may
contribute to downstream immunologic or epigenetic effects. cfDNA: cell-free DNA; cfDNA-mt:
mitochondrial cell-free DNA; GMOs: genetically modified organisms; NETs: neutrophil extracellular
traps.