Risks associated with red blood cell transfusions: potential benefits from application of pathogen inactivation

Kleinman, Steve; Stassinopoulos, Adonis

There are two conceptual approaches to obtaining PI-RBCs (Fig. 3) . WB can be separated into components and then PI can be applied to the RBCs, or PI treatment can be applied to the WB unit. The PI-WB unit can be transfused as WB or, alternatively, could subsequently undergo further processing to produce components; 99 the latter approach has the logistic advantage of producing multiple PI components from a single PI application. However, if the WB unit is stored before processing, this approach may require compromises since component storage requirements are conflicting and will be difficult to satisfy simultaneously (e.g., RBCs and WB are stored refrigerated, PLTs at RT, and plasma frozen). In developed countries, targeted blood component therapy for specific indications has been standard practice for many decades. Specialized storage containers have been tailored to each component and additive solutions developed to optimize quality and extend shelf life. 100 Furthermore, individual-component PI technology is compatible with apheresis component collection, which has become an important part of the blood supply chain. 101 In contrast, in countries with little infrastructure or in acute trauma situations (particularly in military conflicts), the need for WB transfusion is greater and suggests the value of the application of PI to WB units. 102, 103 Two methods are in commercial development for supplying PI-RBC products: WB photochemical inactivation using riboflavin and ultraviolet (UV) light (Mirasol System) 104 and RBC chemical inactivation using S-303 and glutathione (GSH; Intercept System). 105 In addition, use of the S-303 and GSH system to treat WB is being pursued for the developing world. 106 The basic characteristics of the two systems are summarized in Fig. 4 . The riboflavin and UV WB system utilizes the same riboflavin dose and illuminator as for plasma and PLT PI, but uses a much higher UV dose, corresponding to a significantly longer illumination time (Fig. 4) . 104 The S-303 and GSH system, now in its second generation, utilizes a chemical system featuring a fast-acting compound (S-303) that reacts with nucleic acid bases to form stable adducts and cross-links with a mode of action similar to the Intercept systems for PLTs and plasma, but without the use of an illuminator. 105 To minimize nonspecific reactions with molecules in the extracellular domain, GSH is included in the process. Because of its size, GSH does not penetrate cell or viral membranes, so when added to the RBC unit, it remains exclusively in the extracellular space. This allows quenching of extracellular reactions without a significant impact on pathogen and WBC inactivation. The modifications present in the secondgeneration system were implemented to reduce the formation of immunogenic adducts on the surface of PI-RBCs. [107] [108] [109] The second-generation system uses the same dose of the active ingredient S-303, a buffered version of the quencher GSH at 10-fold higher concentration for improved quenching, and includes an exchange step after the overnight incubation that allows the effective removal of proteins and electrolytes from the RBC supernatant. 109, 110