Additive solutions for RBC storage: - PowerPoint Presentation

Additive solutions for RBC storage:AS-1, AS-3, AS-5 & AS-7 Stephanie N. David, MD8.19.15

OutlineHistory & introduction of additive solutionsComparing additive solutions used today AS-7Additive solution use in neonatesCurrent VUMC practice of selecting different AS for pediatric vs. adults

History1970s: Saline-adenine-glucose (SAG)1981: addition of mannitol  SAGM No new RBC additive solutions have been licensed for use for over 20 years…until now! Blood Transfus 2012; 10 Suppl 2: s7-11

Importance of Additive SolutionsDuring storage, RBCs undergo complex and progressive accumulation of changes—RBC storage lesion

RBC storage lesionsMorphological changesSlowed metabolism with decrease in concentration of ATP Acidosis with decrease in concentration of 2,3-diphosphoglycerate (2,3-DPG)increased affinity of hemoglobin for oxygen decreased capacity of rbcs to release oxygen Blood Transfus 2010; 8:82-8.

RBC storage lesions continuedLoss of function of cation pumps Oxidative damage with changes to structure of RBCsApoptotic changes Loss of parts of the membranes through vesiculation Blood Transfus 2010; 8:82-8.

Potential consequences of RBC storage lesionsCompromise safety and efficacy of RBCsReduce capacity to carry and release O2Promote release of potentially toxic intermediates Free hemoglobin can act as source of reactive oxygen species Increased capacity of RBCs to adhere to endothelium Enhanced thrombogenic or pro-inflammatory potential Blood Transfus 2010; 8:82-8.

Complex inter-relationships difficult to predict how RBCs respond to different storage conditions Blood Transfus 2012: 10 Suppl 2: s7-11 RBC biochemistry RBC cytoskeletal structure RBC membrane proteins

Standard requirements for patenting new AS in USA Level of hemolysis: below threshold of 0.8% at the end of the storage periodSurvival rate of transfused cells: >75% at 24 hours after transfusion Blood Transfus 2010; 8:82-8.

Anticoagulant/Preservative solutionsAcid Citrate Dextrose (ACD): 21 day storageCitrate-phosphate-dextrose (CPD) & Citrate-phosphate-dextrose-dextrose (CP2D): 21 day storage Citrate-phosphate-dextrose-adenine (CPDA-1) : 35 day storage Similar to CPD but + 17.3 mg adenine

Additive Solutionsshelf life: 42 daysAS-1: AdsolAS-3: Nutricel AS-5: Optisol AS-7: SOLX

Preparation of RBCs with AS Blood collected in CPD or CP2D Spun Mixed with 110 mL AS for 500 mL collections (100mL for 450 mL collections)  product with HCT 55-65% http://www.bloodcenters.org/docs/Use_of_Additive_Solutions_in_Neonatal_Red_Cell_Transfusions_-_Morvarid_Mayeri.pdf

http://www.aabb.org/ CIRCULAR OF INFORMATION FOR THE USE OF HUMAN BLOOD AND BLOOD COMPONENTS. 2013

AS-7 (SOLX)Alkaline Previously called EAS-81 (Experimental AS-81)Designed to improve RBC metabolism during storage by increasing the range and capacity of pH buffering by adding phosphate and bicarbonateApril 19, 2013 - First AS approved by FDA in US in >20 years! Approved for RBC storage at 1-6C for up to 42 days after collection Transfusion. 2015 March; 55: 491-498 http://www.fda.gov/biologicsbloodvaccines/bloodbloodproducts/approvedproducts/newdrugapplicationsndas/ucm352625.htm

Transfusion. 2015 March; 55: 491-498.

Study design & MethodsStorage quality measured in prospective, randomized and three-center trial Subjects randomly assigned to have whole blood collected and processed into RBC and plasma components stored in one of 3 ways:Control: processed within 8 hours and stored in AS-1 at 1-6°C for 42 days (n =60) Test: processed within 2 hours and stored in AS-7 at 1-6°C for up to 56 days ( n =60) Test: Processed within 8 hours and stored in AS-7 at 1-6°C for up to 56 days ( n =60) Transfusion. 2015 March; 55: 491-498.

Transfusion. 2015 March; 55: 491-498.

Both day 42 & 56 AS-7—within the levels considered sufficient to maintain RBC viability ATP recoveries (assessed as % of ATP at prestorage level) were significantly higher in AS-7 than AS-1 Transfusion. 2015 March; 55: 491-498. AS-1 Day 42 AS-7 Day 42 AS-7 Day 56 Intracellular RBC ATP concentration μmol/g Hb 4.4 ± 0.7  3.6 ± 0.8 4.3 ± 0.7  3.9 ± 0.7 4.3 ± 0.7  3.1 ± 0.8 AS-1<8 hr storageAS-7<2 hr storage AS-76-8 hr storageATP recovery (%)At day 4282.5 ± 14.693.7 ± 17.989.5 ± 13.7ATP

Morphology index AS-1 <8 hr storage AS-7 <2 hr storage AS-7 6-8 hr storage Morphology index Day 42 69 ± 8 81 ± 8 80 ± 6.6 Morphology index Day 56 79 ± 7 77 ± 7 Shed microvesicle protein (mg / dL ) 28.9 ± 18.2 At day 42 16.8 ± 11.3 At day 5616.8 ± 11.3At day 56 Transfusion. 2015 March; 55: 491-498.By day 56, AS-7 maintained 10% higher morphology indices than day 42 AS-1 Day 56 AS-7 RBCs contained 40% less shed microvesicle protein than day 42 AS-1 RBCs

Hemolysis in AS-1 units is significantly higher than AS-7 at 42 days Transfusion. 2015 March; 55: 491-498. AS-1 Day 42 AS-7 Day 42 AS-7 Day 56 Hemolysis (%) 0.39 ± 0.21 0.29 ± 0.11 0.42 ± 0.17 AS-7 Day 42 AS-7 Day 56 Recovery (%) 88 ± 5 82 ± 3 All units stored for 42 days had recoveries > 75% RBCs stored in AS-7 for 42 days had higher 24-hr in vivo recovery than historic controls (82 +/- 7%) in current AS AS-7 at 56 days maintains 24-hr recoveries over the minimal FDA requirements

Summary of AS-1 vs AS-7Improved biochemical status Decreased vesicle formationReduced hemolysis Increased in vivo recovery at conventional and prolonged period of storage Transfusion. 2015 March; 55: 491-498.

Red cell transfusions in neonatesTraditionally, used fresh CPDA-1 units (<7 days)Initially concern for using AS due to mannitol (AS-1, AS-5) & adenine additives Also concern about hyperkalemia, acidosis and decreased function of older red cells Transfusion 1996;36:873-878 Transfusion and Apheresis Science 24 (2001):111-115

AS use in neonates Strauss RG, Burmeister LF, Johnson K, et al. AS-1 red cells for neonatal transfusions: a randomized trial assessing donor exposure and safety. Transfusion. 1996;36(10):873-878 Red cells stored in AS-1 <42 days from single donor vs red cells stored in CPDA-1 stored <7 days No significant differences in: Pre-transfusion and post-transfusion blood chemistries Renal and hepatic chemistries Minimized donor exposure Similar conclusions for AS-3 study (2000) Jain R, Jarosz C. Safety and efficacy of AS-1 red blood cell use in neonates. Transfusion and Apheresis Science. 2001;24(2):111–115. Compared to storage in CPDA-1, found no clinical or laboratory evidence that AS-1 RBCs had any deleterious effects J Pediatr 2000. 136: 215–219

Variability in Preparation, Storage, and Processing of Red Blood Cell Products for Extremely Low Birth Weight Infants: A Blood Bank Survey for the Transfusion of Prematures (TOP) Trial Josephson CD, Friedman D, Pizzini DS, et al. For small volume transfusions (< 20 ml/kg) 11/29 sites exclusively use CPD/CPDA storage solutions 6/29 sites use only additive solutions 12/29 sites use a combination of solutions. 17/22 sites, make aliquots from a RBC unit until expiration 6/29 sites do not use dedicated units until expiration; they select another donor when the unit ages 5 to 28 days old

RBC transfusion in neonatesFor small-volume transfusions: Aliquots of same parent bag in AS to minimize donor exposure AS-3 over AS-1 if concern about mannitol AS-5?

Large volume transfusions in neonatesEvidence for use of AS is not well established No randomized controlled trialsAbstract from Eder et al. at CHOP – “Comparison of CPDA vs. AS Red Cell Transfusion to Infants on ECMO”AS-1 & AS-3 tolerated as well as CPDA-1 units Comparable post-transfusion lab values ( Hct , Na, K, glc , Ca)

Current VUMC practice of selecting a different AS for pediatric versus adults?

Questions?