Table 3 Translational advantages and points to consider about platelet extracellular vesicles (p-EVs) made from allogeneic platelet concentrates (PCs) for regenerative medicine or as drug-delivery system (DDS)

Supply

• Allogenic single-donor or pooled PCs collected by blood establishments following GMPs

• Autologous PCs obtained from a patient using plateletpheresis collection procedure (or alternatively whole blood collection)

• Allogeneic PCs are a known cellular product on the WHO Model List of Essential Medicines

• Platelets are concentrated 3–fivefold in PCs compared to their basal level in the blood circulation, providing a concentrated cellular source for EV production

• Outdated PCs, no longer suitable for transfusion, can be a source of p-EVs, therefore not competing with transfusion needs. If needed, allogeneic PC collection dedicated to p-EV preparation is technically feasible

• PCs can be used fresh, or alternatively stored frozen and used directly as source material to generate and isolate p-EVs

• The lack of ex vivo expansion to generate p-EVs facilitates clinical translation

Pathogen safety

• Donors of allogeneic PCs are screened and donations are tested by serological and/or NAT to limit the risks of TTI (e.g., HIV, HBV, and HCV)

• PCs can be subjected to licensed photochemical treatments to inactivate most bacteria, viruses, and parasites

• The collection process and storage of PCs are conducted under aseptic conditions using dedicated licensed single-use medical devices. There is a residual incidence of bacterial contamination of approximately 1 in 2000 in PCs occurring during venipuncture

• Risks of viral contamination (due to window phase donations of known and tested viruses or emerging, untested, viruses) cannot be excluded. The risk is approximately 1 in 1–2 million when PCs are collected from healthy donors in countries with a regulated blood system

• p-EVs made from pools of multiple donations should preferably be prepared from pathogen-reduced PCs

• The lack of a nucleus in platelets makes it feasible to use photochemical treatments designed to alter nucleic acids and inactivate blood-borne pathogens

Immunological safety

• The PC material should be tested for the presence of platelet antigens to avoid alloimmunization by recipients

• Platelets express antigens (e.g., ABO, HLA class 1, or HPA antigens) that can cause alloimmunization in incompatible recipients. These antigens may be present on p-EVs and may potentially be clinically significant

• Leukoreduction of PCs decreases risks of contamination of p-EV preparations by leukocytes expressing HLA class I and HLA class II

Procoagulant activity

• PCs are collected in the presence of a citrate anticoagulant solution and stored for up to 5 to 7 days following licensed procedures intended to minimize platelet activation

• Generation methods of p-EVs may generate p-EVs with exacerbated procoagulant activity. Process validation and quality control tests can be used to check the prothrombogenic activity of p-EVs