Pathogen-reduction systems for blood components: The current position and future trends
ABSTRACT The current multi-layered interventional approaches to blood safety have dramatically reduced the risk of viral contamination of blood components. Nowadays most of the residual transfusion transmitted infections (TTI) occur as the result of the interval between the time the donor is infected and the moment at which tests are capable of detecting the agent, the so called "window period" which has been considerably reduced by the increased sensitivity of nucleic acid testing (NAT). However, the residual risk of bacterial contamination and the unexpected appearance of some other emerging pathogens, almost every five years, are still of major concern to the public, politicians, regulatory agencies and place immense pressures on the organisations responsible for the provision of safe blood and its components. In view of these bleak scenarios, the use of human blood as a raw biological source is inherently unsafe, and screening/testing alone cannot exclude all the potential human pathogens; hence we need to put in place some sort of safer alternatives and/or additional preventative safety measures. Recently, several substitutes (alternatives) to virtual blood components have been developed and tried. Moreover, various mechanical methods such as cell washing and leukofiltration have been implemented as additional preventative safety measures but with limited success in abrogating the risk of transfusion transmitted cell-associated agents. The most promising approaches, so far, are methods that target pathogen nucleic acids (Methylene blue; Psolaren and Riboflavin UV light treatment). These procedures have undergone considerable in vitro studies to ensure their extremely high safety margins in terms of toxicity to the cells or to the recipients. In essence, while the technology of targeting nucleic acid to stop viral proliferation is common to the above three strategies, in practice these procedures differ in terms of operational, physicochemical and biological characteristics; including the potential impacts of their metabolites and photo-adducts; their effects on the spectrum of pathogens affected and the log reductions in culture infective studies. Accordingly, any strategy that involves addition of an extraneous agent or physicochemical manipulation of blood must balance the benefits of pathogen reduction against the loss or alteration to the cells and plasma functional integrity, short and long term toxicity to the cells and to the recipients, as well as the risk to the personnel involved and the community at large. Moreover, it must be noted that each method will have a different profile of adverse reactions and may differ in terms of the risk to particularly vulnerable groups of patients, requiring in depth clinical trials, while taking into consideration the cost benefit of the final process. Newer diagnostic procedures must be in place to establish the storage stability of products that have undergone pathogen inactivation, in particular tests reflecting the release of platelet-derived cytokines, cellular apoptosis or microvesiculation and their role in immunosupressiveness. This overview aims to provide an update on the continual improvements in blood component safety, in particular using methods that target pathogen nucleic acid. Emphasis is placed on methylene blue light treatment (MBLT) and Intercept or Mirasol PRT systems for platelets and plasma. The status of pathogen reduction of whole blood and red cells is also highlighted, though the progress in this area has been virtually stopped after the finding of antibody development in the clinical trial.
- SourceAvailable from: Anirban Sen Gupta
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- "10.1016/j.biomaterials.2012.09.074 Fig. 3. Representative data from various design approaches mimicking the aggregation functionality of natural platelets: (A) Fg-coated albumin microcapsules (Synthocytes), when administered in thrombocytopenic rabbits, resulted in significant reduction [D and B] of surgical abdominal incision wound bleeding, compared to administration of uncoated microcapsules [,] or just saline  [reproduced with permission from ; (B) Injection of polymeric nanoparticles surface-decorated with various RGD peptides linked via 4600 MW PEG spacers significantly reduced bleeding time in a rat femoral artery injury model, compared to injection of saline or coagulation factor FVII [reproduced with permission from ; (C) Liposomal vesicles decorated with H-12 peptide showed enhancement of aggregation [B] of active platelets on collagen from thrombocytopenic blood, compared to vesicles without peptide modification [C] or just saline [:] [reproduced with permission from ; (D) Further refinement of the H-12-decorated liposome design by encapsulating platelet agonist ADP in the liposomes enabled enhancement of platelet aggregation [B] compared to ADP-loaded liposomes with no H-12 decoration [,] [reproduced with permission from ; (E) Injection of albumin microparticles decorated with Fg-mimetic H-12 peptide showed reduction [B] of tail vein bleeding time in rats compared to injection of saline [C] [reproduced with permission from ; (F) Liposomes decorated with a GPIIb-IIIa-selective cyclic RGD peptide significantly enhanced aggregation of 'activated' platelets but showed minimum effect on resting platelets [reproduced with permission from . "
ABSTRACT: Platelet transfusion is routinely used for treating bleeding complications in patients with hematologic or oncologic clotting disorders, chemo/radiotherapy-induced myelosuppression, trauma and surgery. Currently, these transfusions mostly use allogeneic platelet concentrates, while products like lyophilized platelets, cold-stored platelets and infusible platelet membranes are under investigation. These natural platelet-based products pose considerable risks of contamination, resulting in short shelf-life (3-5 days). Recent advances in pathogen reduction technologies have increased shelf-life to ∼7 days. Furthermore, natural platelets are short in supply and also cause several biological side effects. Hence, there is significant clinical interest in platelet-mimetic synthetic analogs that can allow long storage-life and minimum side effects. Accordingly, several designs have been studied which decorate synthetic particles with motifs that promote platelet-mimetic adhesion or aggregation. Recent refinement in this design involves combining the adhesion and aggregation functionalities on a single particle platform. Further refinement is being focused on constructing particles that also mimic natural platelet's shape, size and elasticity, to influence margination and wall-interaction. The optimum design of a synthetic platelet analog would require efficient integration of platelet's physico-mechanical properties and biological functionalities. We present a comprehensive review of these approaches and provide our opinion regarding the future directions of this research.Biomaterials 10/2012; 34(2). DOI:10.1016/j.biomaterials.2012.09.074 · 8.56 Impact Factor
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- "Other advantages are that it preserves the morphological and functional integrity of platelets, does not damage red cells and has a broad spectrum of action on viruses(8,22). According to the study by Seghatchian & Souza(9), it has the disadvantage that it may lead to formation of antibodies against red cells. "
ABSTRACT: The aim of this study was to conduct a systematic review on the photoinactivators used in hemotherapy, with action on viral genomes. The SciELO, Science Direct, PubMed and Lilacs databases were searched for articles. The inclusion criterion was that these should be articles on inactivators with action on genetic material that had been published between 2000 and 2010. The key words used in identifying such articles were "hemovigilance", "viral inactivation", "photodynamics", "chemoprevention" and "transfusion safety". Twenty-four articles on viral photoinactivation were found with the main photoinactivators covered being: methylene blue, amotosalen HCl, S-303 frangible anchor linker effector (FRALE), riboflavin and inactin. The results showed that methylene blue has currently been studied least, because it diminishes coagulation factors and fibrinogen. Riboflavin has been studied most because it is a photoinactivator of endogenous origin and has few collateral effects. Amotosalen HCl is effective for platelets and is also used on plasma, but may cause changes both to plasma and to platelets, although these are not significant for hemostasis. S-303 FRALE may lead to neoantigens in erythrocytes and is less indicated for red-cell treatment; in such cases, PEN 110 is recommended. Thus, none of the methods for pathogen reduction is effective for all classes of agents and for all blood components, but despite the high cost, these photoinactivators may diminish the risk of blood-transmitted diseases.03/2012; 34(3):231-5. DOI:10.5581/1516-8484.20120056
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- "Plainly given its essential nature, there are fewer potential toxicity problems with riboflavin than with completely synthetic xenobiotics . The photochemistry associated with riboflavin, breaking down into lumiflavin and lumichrome  is well understood, and the photoproducts, each of which is also a photosensitiser, are non-toxic to humans . Riboflavin and its breakdown products interact with DNA, making this system attractive in the photodisinfection of blood and blood products . "
ABSTRACT: The onset of the HIV pandemic led both to significant alterations in blood collection and screening practice and to the development of more sophisticated methods of inactivation of infectious agents from the blood supply. Photodynamic (i.e. light activated) pathogen inactivation is one such method currently in limited use in various European states. The approach is based on the generation of a burst of reactive oxygen and nitrogen species, resulting in the activation of several cell death mechanisms. However, its application to tropical pathogens is perhaps less appreciated, despite the fact that the efficacies of photoantimicrobial agents such as methylene blue were originally reported following screening against organisms such as Trypanosoma cruzi and viruses such as those responsible for dengue and yellow fever. Since the objective of pathogen inactivation is to remove both established and emerging infective agents, it is necessary for photoantimicrobial agents to be broad-spectrum in activity. While this is demonstrable in plasma and platelet fractions, the application to red blood cells is currently under investigation.Photodiagnosis and photodynamic therapy 09/2011; 8(3):240-8. DOI:10.1016/j.pdpdt.2011.04.001 · 2.01 Impact Factor