Blood Aging, Safety, and Transfusion: Capturing the “Radical” Menace

Division of Hematology, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland 20892, USA.
Antioxidants & Redox Signaling (Impact Factor: 7.41). 10/2010; 14(9):1713-28. DOI: 10.1089/ars.2010.3447
Source: PubMed


Throughout their life span, circulating red blood cells (RBCs) transport oxygen (O(2)) primarily from the lungs to tissues and return with carbon dioxide (CO(2)) from respiring tissues for final elimination by lungs. This simplistic view of RBCs as O(2) transporter has changed in recent years as other gases, for example, nitric oxide (NO), and small molecules, such as adenosine triphosphate (ATP), have been shown to either be produced and/or carried by RBCs to perform other signaling and O(2) sensing functions. In spite of the numerous biochemical and metabolic changes occurring within RBCs during storage, prior to, and after transfusion, perturbations of RBC membrane are likely to affect blood flow in the microcirculation. Subsequent hemolysis due to storage conditions and/or hemolytic disorders may have some pathophysiological consequences as a result of the release of Hb. In this review, we show that evolution has provided a multitude of protection and intervention strategies against free Hb from "cradle" to "death"; from early biosynthesis to its final degradation and a lot more in between. Furthermore, some of the same naturally occurring protective mechanisms can potentially be employed to oxidatively inactivate this redox active protein and control its damaging side reactions when released outside of the RBC.

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Available from: Elena Karnaukhova, Dec 20, 2014
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    • "Exogenous sources of free heme include red blood cell (RBC) preparations during storage (Buehler et al., 2011), heme-based therapeutics (such as Panhematin, hemin for injection, and heme arginate) that are used for the treatment of porphyrias (Tenhunen and Mustajoki, 1998; Siegert and Holt, 2008), and Hb-based blood substitutes (Alayash, 2014). In the circulation, the free heme redox toxicity is mitigated by several innate defense mechanisms, including heme sequestration by plasmatic major heme scavengers hemopexin, albumin, and some other proteins (Ascenzi et al., 2005; Buehler et al., 2011). A1M, also known as protein HC, has emerged among anti-oxidative defense mechanisms as a tissue housekeeping protein which is capable of capturing heme and free radicals (Allhorn et al., 2002; Åkerström et al., 2007; Olsson et al., 2012; Åkerström and Gram, 2014), as well as reducing oxidative lesions (Allhorn et al., 2005; Olsson et al., 2008; Rutardottir et al., 2013). "
    Frontiers in Physiology 12/2014; 5(465):1-11. · 3.53 Impact Factor
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    • "The metabolic changes that occur in RBCs during storage have been extensively studied (Brewer et al., 1976; Strauss et al., 1980; Messana et al., 2000; reviewed in Hess and Greenwalt, 2002; Kanias and Acker, 2010; Buehler et al., 2011; Hess, 2014). RBCs lack mitochondria and are completely dependent on glycolysis for their energy requirements. "
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    ABSTRACT: Stored blood components are a critical life-saving tool provided to patients by health services worldwide. Red cells may be stored for up to 42 days, allowing for efficient blood bank inventory management, but with prolonged storage comes an unwanted side-effect known as the "storage lesion", which has been implicated in poorer patient outcomes. This lesion is comprised of a number of processes that are inter-dependent. Metabolic changes include a reduction in glycolysis and ATP production after the first week of storage. This leads to an accumulation of lactate and drop in pH. Longer term damage may be done by the consequent reduction in anti-oxidant enzymes, which contributes to protein and lipid oxidation via reactive oxygen species. The oxidative damage to the cytoskeleton and membrane is involved in increased vesiculation and loss of cation gradients across the membrane. The irreversible damage caused by extensive membrane loss via vesiculation alongside dehydration is likely to result in immediate splenic sequestration of these dense, spherocytic cells. Although often overlooked in the literature, the loss of the cation gradient in stored cells will be considered in more depth in this review as well as the possible effects it may have on other elements of the storage lesion. It has now become clear that blood donors can exhibit quite large variations in the properties of their red cells, including microvesicle production and the rate of cation leak. The implications for the quality of stored red cells from such donors is discussed.
    Frontiers in Physiology 06/2014; 5:214. DOI:10.3389/fphys.2014.00214 · 3.53 Impact Factor
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    • "Free heme appears in plasma primarily because of in vivo hemolysis of the red blood cell (RBC) due to hemolytic disorders, or during RBC storage under certain conditions. It can also be released from hemoglobin-based oxygen therapeutics, or heme-based therapeutics intended for the treatment of porphyrias [6]. In vivo, the redox toxicity associated with free heme in the circulation is controlled by several defense mechanisms, including heme scavenging by plasma proteins. "
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    ABSTRACT: Background Heme is a unique prosthetic group of various hemoproteins that perform diverse biological functions; however, in its free form heme is intrinsically toxic in vivo. Due to its potential toxicity, heme binding to plasma proteins is an important safety issue in regard to protein therapeutics derived from human blood. While heme binding by hemopexin, albumin and α1-microglobulin has been extensively studied, the role of other plasma proteins remains largely unknown.Methods We examined two acute-phase plasma proteins, haptoglobin (Hp) and alpha-1 proteinase inhibitor (α1-PI) for possible interactions with heme and bilirubin (BR), the final product of heme degradation, using various techniques: UV/Vis spectroscopy, fluorescence, circular dichroism (CD), and surface plasmon resonance (SPR).ResultsAccording to our data, Hp exhibits a very weak association with both heme and BR; α1-PI's affinity to BR is also very low. However, α1-PI's affinity to heme (KD 2.0 × 10− 8 M) is of the same order of magnitude as that of albumin (1.26 × 10− 8 M). The data for α1-PI binding with protoporphyrin IX (PPIX) suggest that the elimination of the iron atom from the porphyrin structure results in almost 350-fold lower affinity (KD 6.93 × 10− 6 M), thus indicating that iron is essential for the heme coordination with the α1-PI.Conclusions This work demonstrates for the first time that human α1-PI is a heme binding protein with an affinity to heme comparable to that of albumin.General significanceOur data may have important implications for safety and efficacy of plasma protein therapeutics.
    Biochimica et Biophysica Acta (BBA) - General Subjects 12/2012; 1820(12):2020–2029. DOI:10.1016/j.bbagen.2012.09.012 · 4.38 Impact Factor
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