Most plasma used for manufacturing plasma-derived medicinal products (PDMPs) such as albumin, immunoglobulin (Ig), and clotting factors is obtained from source plasma collected via plasmapheresis, the majority of which is contributed by the United States (US). While the demand for PDMPs continues to rise, it remains unclear whether high-frequency plasmapheresis, such as the twice-weekly plasma donation allowed in the US, may have any (long-term) adverse health effects on the donor. To investigate the frequency at which plasma can be donated without harm to the donor, the current systematic review explores the impact of plasma donation frequency on cardiovascular health, protein depletion, and adverse events in healthy plasma donors. We asked the following research question: What is the impact of plasmapheresis frequency (Intervention) on the safety or health (Outcome) of healthy donors (Population)? Six databases (PubMed, Embase, Web of Science, CINAHL, the Cochrane Library, and Transfusion Evidence Library), two clinical trial registries (ICTRP and clinicaltrials.gov), and the PROSPERO database were searched. Four observational and two experimental studies were included, and one ongoing randomized controlled trial was identified. The results showed that very high-frequency donation (twice per week) may result in a clinically relevant decrease in ferritin and bring IgG levels below the EDQM-defined lower threshold of 6 g/l. However, the evidence is of low to very low certainty, and solid conclusions are hindered by the healthy donor effect and methodological limitations of the included studies. In order to determine a safe threshold donation frequency that minimizes any possible harmful effect on the donor, more high-quality prospective cohort studies and experimental studies are thus needed. In the meantime, we argue for a precautionary approach and suggest that a sustainable and stable plasma supply may better rely on a large number of voluntary donors donating at a lower frequency (up to two donations per month), rather than on a small number of donors donating at a high frequency.

The authors have declared no competing interest.

Funding: this work was funded by the EU4Health Programme of the European Union ("project 101056988/SUPPLY"). The content of this manuscript represents the views of the authors only and is their sole responsibility; it cannot be considered to reflect the views of the European Commission and/or the European Health and Digital Executive Agency (HaDEA) or any other body of the European Union. The European Commission and the Agency do not accept any responsibility for use that may be made of the information it contains. In addition, this work was co-funded by the Foundation for Scientific Research of the Belgian Red Cross. Belgian Red Cross-Flanders is responsible for supplying adequate quantities of safe blood products to hospitals in Flanders and Brussels on a continuous basis and is reimbursed for this activity.

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