Development, validation, and potential applications of biotinylated red blood cells for posttransfusion kinetics and other physiological studies: evidenced‐based analysis and recommendations

Abstract

The current reference method in the United States for measuring in vivo population red blood cell (RBC) kinetics utilizes chromium-51 ( Cr) RBC labeling for determining RBC volume, 24-hour posttransfusion RBC recovery, and long-term RBC survival. Here we provide evidence supporting adoption of a method for kinetics that uses the biotin-labeled RBCs (BioRBCs) as a superior, versatile method for both regulatory and investigational purposes. RBC kinetic analysis using BioRBCs has important methodologic, analytical, and safety advantages over Cr-labeled RBCs. We critically review recent advances in labeling human RBCs at multiple and progressively lower biotin label densities for concurrent, accurate, and sensitive determination of both autologous and allogeneic RBC population kinetics. BioRBC methods valid for RBC kinetic studies, including successful variations used by the authors, are presented along with pharmacokinetic modeling approaches for the accurate determination of RBC pharmacokinetic variables in health and disease. The advantages and limitations of the BioRBC method-including its capability of determining multiple BioRBC densities simultaneously in the same individual throughout the entire RBC life span-are presented and compared with the Cr method. Finally, potential applications and limitations of kinetic BioRBC determinations are discussed.

Reexamination of the chromium‐51–labeled posttransfusion red blood cell recovery method

“…However, these methods are also predicted to suffer from measurement error. Nonetheless, of these, the biotin‐labeling method has several advantages, including that it does not suffer from errors due to hemodilution/hemoconcentration . In addition, because the biotin label does not elute from RBCs, it allows for a more accurate measurement of RBC life span, which cannot be measured by transfusing an entire unit of unlabeled RBCs.…”

Improved quantitative detection of biotin‐labeled red blood cells by flow cytometry

“…The fate of transfused RBCs has traditionally been measured radiometrically by labeling a fraction of the transfused cells with the gamma emitter 51 Cr . This method has many shortcomings . Since the gamma emitter 51 Cr, in the form of sodium chromate, is noncovalently associated with intracellular proteins, blood samples collected and assayed for gamma emissions must be corrected for both 51 Cr half‐life (28 days) and spontaneous chromium leak from the labeled cells.…”

“…20 This method has many shortcomings. 21 Since the gamma emitter 51 Cr, in the form of sodium chromate, is noncovalently associated with intracellular proteins, blood samples collected and assayed for gamma emissions must be corrected for both 51 Cr half-life (28 days) and spontaneous chromium leak from the labeled cells. Further, chromium is distributed differentially and has different elimination kinetics in various body tissues; the biologic half-life of 51 Cr in bone is 1000 days.…”

Blood donor component‐recipient linkages: is there fire where there is smoke?

“…Other novel approaches could include the use of biotinylated RBCs to quantify posttransfusion recovery and survival of RBCs from smokers compared to nonsmokers. [34][35][36] Additional studies could link "vein-to-vein databases" with in vitro hemolysis, genomic data, and metabolomic data to study the RBC quality of cotinine-positive units. The Recipient Epidemiology and Donor Evaluation Study (REDS-III) RBC-Omics study examined poststorage osmotic and oxidative hemolysis of leukoreduced RBC samples from a diverse group of blood donors, including a subset with a history of tobacco use.…”

“…In parallel, markers of intravascular hemolysis (e.g., haptoglobin, plasma‐free hemoglobin, or lactate dehydrogenase) or extravascular hemolysis (e.g., non‐transferrin bound iron or indirect bilirubin) would provide compelling evidence that smaller changes in hemoglobin levels after transfusion were due to increased hemolysis or clearance of cotinine‐positive RBC units. Other novel approaches could include the use of biotinylated RBCs to quantify posttransfusion recovery and survival of RBCs from smokers compared to nonsmokers …”