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. 2018 Sep 25;2(18):2296-2306.
doi: 10.1182/bloodadvances.2018021931.

Blood manufacturing methods affect red blood cell product characteristics and immunomodulatory activity

Ruqayyah J Almizraq  1 , Philip J Norris  2   3 , Heather Inglis  2 , Somaang Menocha  4 , Mathijs R Wirtz  5   6 , Nicole Juffermans  5   6 , Suchitra Pandey  3   7 , Philip C Spinella  8 , Jason P Acker  1   9 , Jennifer A Muszynski  4
Affiliations

Blood manufacturing methods affect red blood cell product characteristics and immunomodulatory activity

Ruqayyah J Almizraq et al. Blood Adv. .

Abstract

Transfusion of red cell concentrates (RCCs) is associated with increased risk of adverse outcomes that may be affected by different blood manufacturing methods and the presence of extracellular vesicles (EVs). We investigated the effect of different manufacturing methods on hemolysis, residual cells, cell-derived EVs, and immunomodulatory effects on monocyte activity. Thirty-two RCC units produced using whole blood filtration (WBF), red cell filtration (RCF), apheresis-derived (AD), and whole blood-derived (WBD) methods were examined (n = 8 per method). Residual platelet and white blood cells (WBCs) and the concentration, cell of origin, and characterization of EVs in RCC supernatants were assessed in fresh and stored supernatants. Immunomodulatory activity of RCC supernatants was assessed by quantifying monocyte cytokine production capacity in an in vitro transfusion model. RCF units yielded the lowest number of platelet and WBC-derived EVs, whereas the highest number of platelet EVs was in AD (day 5) and in WBD (day 42). The number of small EVs (<200 nm) was greater than large EVs (≥200 nm) in all tested supernatants, and the highest level of small EVs were in AD units. Immunomodulatory activity was mixed, with evidence of both inflammatory and immunosuppressive effects. Monocytes produced more inflammatory interleukin-8 after exposure to fresh WBF or expired WBD supernatants. Exposure to supernatants from AD and WBD RCC suppressed monocyte lipopolysaccharide-induced cytokine production. Manufacturing methods significantly affect RCC unit EV characteristics and are associated with an immunomodulatory effect of RCC supernatants, which may affect the quality and safety of RCCs.

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Residual WBC and platelet counts in RCC produced by different manufacturing methods as measured on day 5 of storage. Data reported for (A) residual white blood cells and (B) residual platelets as scatter dot plots with mean and standard deviation..
Figure 2.
Figure 2.
Hemolysis and supernatant K+of differently manufactured RCC products. Dot plots display (A) percent hemolysis and (B) level of supernatant K+ on day 5 (fresh/white) and day 42 (expired/shaded) of stored and differently manufactured RCC products. Data reported as scatter dot plots with mean and standard deviation. *Significant results (P < .05) in comparison with day 5 values. δSignificant difference (P < .05) compared with the noted blood manufacturing methods.
Figure 3.
Figure 3.
Concentration of EV and subpopulation in RCC products stored for up to 42 days analyzed by the TRPS and flow cytometry systems. (A) EV < 200 nm, (B) EV ≥ 200 nm, (C) total EV, (D) RBC-EV, (E) platelet-EV, and (F) WBC-EV. Data are reported as mean ± standard deviation. *Significant results (P < .05) in comparison with day 5 values. δSignificant difference (P < .05) compared with the noted blood manufacturing methods (n = 8 per blood manufacturing method).
Figure 4.
Figure 4.
Monocyte LPS-induced cytokine production. (A) TNF-α, (B) IL-10, (C) IL-1β, and (D) IL-8 following exposure of RCC supernatant from different RCC manufacturing methods at fresh (day 5/white) and at expiration (day 42/shaded). Significant level in comparison with control (*P < .05; **P < .01; ***P < .001).
Figure 5.
Figure 5.
Monocyte IL-8 production in the absence of LPS stimulation and following exposure to RCC supernatant from different RCC manufacturing methods at fresh (day 5/white) and at expiration (day 42/shaded). *Significant level in comparison with control (***P < .001; ****P < .0001).
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