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Keywords:

  • blood safety;
  • pathogen inactivation;
  • plasma;
  • platelets;
  • red blood cells

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Plasma components
  5. Platelets
  6. Red blood cells
  7. Predicting the future
  8. Disclosures
  9. References

Although improved donor selection criteria and tests of increasing sensitivity have dramatically reduced the risks of transfusion-transmitted infectious disease, multiple potential means exist for a pathogen to escape detection and injure a recipient: a window period remains in which an infectious donor cannot be detected; some transmissions (e.g. bacterial contamination of platelets) have detection methods that are far from the desired capabilities; and ‘emerging’ pathogens continue to represent a risk to recipients until effective testing strategies are developed and implemented. Pathogen inactivation of labile blood components represents a means of addressing all three of these shortcomings simultaneously as they have for plasma derivatives. Multiple effective means of pathogen inactivation have been validated and put into use for plasma and for platelet components. While not yet universally implemented, these appear to have an acceptable toxicity profile and retain a clinically useful – although slightly diminished – degree of efficacy that is not associated with increased usage. Some of these techniques, such as solvent–detergent treatment of plasma, appear to offer benefits beyond avoidance of infectious disease; in this case, the pooling involved in the process, while creating a risk for dissemination of non-enveloped viruses, appears to reduce the risk of TRALI considerably. Promising systems for pathogen inactivation of red blood cells and whole blood are under development and would complete the spectrum of treatment across all labile components. While some jurisdictions, most notably the United States, interpret the completed clinical trials as not yet presenting adequate benefit to balance perceived risks, the primary impediments to implementation would appear to fall more into the logistic than scientific category. Is there sufficient benefit to warrant implementation of pathogen inactivation for plasma and platelets before red cell treatment is feasible? How can the processes be accomplished while minimizing cost to the system? How will each country’s healthcare system accommodate the inevitably increased expense for this additional production step? What impact will a fully pathogen-inactivated blood supply have on clinicians’ conception of transfusion risk and thus blood utilization? This review provides an overview of data available from clinical trials and attempts to identify a path towards improving transfusion recipient safety.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Plasma components
  5. Platelets
  6. Red blood cells
  7. Predicting the future
  8. Disclosures
  9. References

Blood bankers believe they have achieved remarkable reductions in the risk of serious infectious disease threats through implementation of increasingly specific donor screening criteria and exquisitely sensitive tests. Indeed, the rate of donor positivity for infectious disease markers is orders of magnitude lower than that found in the general population for HIV and HCV in developed nations, and nucleic acid and immunological testing combine to reduce the risks of diseases such as these to extremely low or undetectable levels.

Problems persist with this approach, however, despite its success. Not all recognized pathogen threats have been adequately addressed. For example, the sensitivity of culture to detect bacterial contamination of platelet units is thought to be below 50% [1]. Furthermore, tests to detect the presence of infection in a donor, whether targeting the pathogen directly or targeting an immune response to that pathogen, have a ‘window period’ during which the infection cannot be detected but during which the donor may be infectious. Also, a disease and its transmission must be recognized before definitive counteraction can be implemented, and the development of specific and useful tests requires time. Furthermore, this cycle of recognition and reaction must be repeated for each new pathogen’s threat, increasing the cost of providing safe blood with each turn and inevitably exposing transfusion recipients to undesired risk until effective countermeasures can be brought to bear.

The appearance of West Nile Virus (WNV) in the United States blood supply is a good example of this dilemma: From the recognition of the threat to the safety of the blood supply until the availability of a nucleic acid test (NAT) for WNV (in an investigational format) required only approximately 10 months. Despite this remarkably short time, thousands of transfusion recipients acquired this ‘emerging agent’ during this time, and some died [2]. While the development of a new test was remarkably quick, this speed did not prevent recipient morbidity and mortality.

The concept of inactivating pathogens present in blood represents a wholly different approach that could lead to the proverbial ‘paradigm shift’ in our efforts to provide a safe blood supply. Threats that have already been addressed by effective screening and testing measures, e.g. HIV, HCV, and WNV, provide little motivation for development of pathogen inactivation (PI) systems as little residual risk remains and large amounts of effort and resources (i.e. money) would need to be directed at reducing these risks further with little tangible benefit for recipients. However, there remain many threats for which effective screening and testing measures are yet to be developed [3]. Their continued threat poses unwanted risk for recipients and, ironically, undesirable consequences for blood collectors who must defer many donors using imprecise methods (e.g. malarial deferral of US vacationers to Mexican ‘malarial areas’ [4]) or employ expensive yet insensitive methods to detect bacterial contamination while interdicting less than half of affected units [1]. Indeed, had PI been in place prior to the advent of WNV in North America, there never would have been a need to develop a test to detect infectious donors as any contaminated units would have been rendered free of infectious virions.

As we move beyond the threats we have been considering for several decades in Europe and North America to ‘newer’ ones, including dengue virus, Ebola virus, chikungunya virus, and Trypanosoma cruzi, just to name a few, the impossibility of achieving a reliably safe blood supply by always ‘chasing after’ the ‘next new agent’ becomes very clear. The role of PI in the blood system would then, primarily, be to reduce risks we have not been able to address adequately through other means and potentially interdict new ones before they became apparent while, at the same time, providing an additional layer of safety against the most-feared viruses we have already addressed successfully [5].

Licensure and acceptance of PI systems requires that they achieve useful degrees of infectivity reduction in a practical system that creates a manageable or acceptable amount of damage to the efficacy of the blood component and an acceptable or commensurate risk of complications for the recipient. The achievement of 4–6 log10 reduction in pathogen infectivity is recognized likely to be associated with some loss of cellular viability or effectiveness as well as loss of some degree of plasma procoagulant activity. However, the lack of complete delineation of the clinical impact of blood transfusions and concerns about the untoward effects of transfusion of ‘traditional’ components complicate the assessment of PI-treated components even before the possibility of entirely new or substantially increased previous risks with PI are considered. The developers of PI systems have spent and continue to spend unprecedented amounts of money (for blood component development) in an attempt to minimize the negative aspects of PI treatments while maximizing treatment effectiveness and ease of use. While they have achieved much over the previous two decades, many issues remain to be resolved completely or their origins to be entirely understood, and these uncertainties form the basis of continued regulatory scepticism and implementation reluctance. The importance of these concerns can – and has been and will be – debated, and the urgency of their resolution will seem to increase as we come closer to the development of PI for red cells.

(Space limitations preclude providing full details of all the PI techniques mentioned below and inclusion of consideration of prion-related disease. Readers are encouraged to refer to other sources [3,6,7] for more information about procedures and efficiency of inactivation and the risks of transfusion-transmitted diseases.)

Plasma components

  1. Top of page
  2. Abstract
  3. Introduction
  4. Plasma components
  5. Platelets
  6. Red blood cells
  7. Predicting the future
  8. Disclosures
  9. References

Initial efforts in PI were directed at plasma derivatives as the large pool sizes involved created the greatest risk for recipient exposure. Successful development of techniques, particularly solvent–detergent (SD) treatment, that could remove (enveloped) viruses yet maintain procoagulant activity encouraged the adaptation of the approach to plasma for transfusion.

Solvent–detergent plasma, first introduced almost 20 years ago, has been implemented as the standard (or one of several) PI plasmas in multiple countries [8]. SD plasma has never transmitted an enveloped virus through over 6 million units, and, because of the pooling and thus dilution involved in the process, is recognized to have reduced the risk of TRALI to virtually zero. Allergic reactions to plasma have also been reported at a 40-fold lower rate with SD plasma, < 1/50 000 units [9]. Because of concerns of the dissemination of non-enveloped viruses, pools are screened by NAT for Hepatitis A and Parvovirus B-19, and minimum antibody levels are required in each pool to ensure that contamination remains below levels associated with infectivity [10]. Incubation with a prion-binding ligand gel in addition to the reduction inherent in the SD process leads to more than a 5 log10 reduction of PrPSc [11]. (OctaplasLG®, Octapharma, Lachen, Switzerland) A ‘universal plasma’ without detectable anti-A or anti-B activity remains in the final stages of development and licensure. SD plasma units offer the additional benefit of uniform size and content, although procoagulant concentrations are 10–20% lower than in untreated plasma. These reductions do not appear to be associated with substantial increases in usage, although this may be attributable in part to many of the applications of plasma being in clinical situations where it is unlikely to offer much benefit to the recipient [12]. The prelicensure clinical trials of SD plasma were focused on replacement of congenital factor deficiencies and plasma exchange in thrombotic thrombocytopenic purpura (TTP). In the former situation, the expected rises and half-lives of the factor levels were documented. SD plasma is very effective in the therapy of TTP as ADAMTS-13 activity is preserved in the product, and there is a relative deficiency of high-molecular weight von Willebrand factor multimers.

The method of production of SD plasma used in Europe differs slightly from that initially developed and licensed in the United States. The latter form was associated with unwanted thromboses when used in large volumes in some patients undergoing procedures such as liver transplantation [13]. Although a causal effect was never proven, there was concern that the lower Protein S and citrate levels in the US product may have allowed a pathologic degree of activation of the clotting cascade. Although the issue of unexpected thromboses (plus high price and other marketing decisions) led to the discontinuation of production of SD plasma in the United States, it remains licensed there but not marketed. Similarly, hyperfibrinolysis (occasionally fatal) has been reported using the European product in liver transplantation, possibly attributable to low plasmin inhibitor levels during the period of no hepatic activity [14,15].

The antiviral properties of methylene blue (MB), known for decades, have been applied to plasma in a single-unit PI format (Theraflex®; MacoPharma, Lille, France). It is activated by visible light and, in some systems, is removed after treatment by adsorption filtration. Freezing the plasma prior to treatment reduces intracellular genome carriage that might be less-effectively treated, although leucocyte reduction filtration is also employed to reduce intracellular virus transmission potential.

MB treatment appears to reduce the activity of most procoagulant proteins 10–15%, and fibrinogen and Factor VIII 25–35% [6,16]. (This does not apparently prevent the production of cryoprecipitate that meets regulatory expectations for fibrinogen content, albeit at lower fibrinogen concentration [17].) Although coagulation assays of MB plasma are prolonged, treated fibrinogen retains its ability to interact with platelet receptors (GP IIb/IIIa), a key part of the clotting mechanism [18]. Thrombin generation capacity has been reported to be reduced with MB plasma in a manner that did not correlate with procoagulant concentrations nor correct with the addition of fibrinogen [15,19]. However, Cardigan and colleagues demonstrated by thromboelastography that although thrombin generation and clot formation were slower, the strength of the clot was unaffected by MB treatment of plasma [20]. There have been conflicting reports whether implementation of MB plasma use resulted in increased – or unchanged – use of plasma, cryoprecipitate, and plasma derivatives [15,21–23]. MB treatment has been reported to require twice as many plasma exchanges in treatment of TTP and result in a twofold increase in the rate of recurrence [24].

Although the MB plasma product has generally been regarded as safe, some concerns have recently surfaced through the French haemovigilance system. Since the introduction of its use in 2007, it has been associated with 11 severe allergic reactions, including one death. A safety alert has been sent to all physicians, and this PI component is being used primarily in acute-need situations (personal communication, Georges Andreu, November 2009).

Ultraviolet-activated photochemicals developed for PI of platelet components, including amotosalen and riboflavin, have also been used for treatment of plasma. (An adsorption step is included in the PI process using amotosalen.) Both systems treat single units.

Riboflavin-based PI treatment (Mirasol®; CaridianBCT Biotechnologies, Lakewood, CO, USA) yields plasma with approximately 20% reduction in procoagulant activity except for about a 20–30% reduction in fibrinogen, Factor VIII and Factor XI; coagulation inhibitors and ADAMTS-13 activity are preserved [25,26]. Although the product has been CE-marked, there are, as yet, few published reports of clinical trials involving its use.

Plasma treated with amotosalen and UV light (Intercept® plasma, Cerus, Concord, CA, USA) has seen wider use with over 20 000 units transfused. Treatment of volunteers who had been coumadinized showed Intercept® plasma and autologous plasma to yield similar corrections of Factor VII with unchanged pharmacokinetics [27]. This plasma retained anticoagulant protein activity and demonstrated approximately 80–90% the procoagulant activities found in fresh plasma [28]. The levels of α2 antiplasmin and Factor XI are usually found to be reduced by the greatest amounts. This form of inactivated plasma worked well in treating congenitally deficient patients with the observation, however, that Factors I, II and XIII had shorter half-lives [29]. In these previously multiply transfused individuals, mild skin rashes were noted in 25% of patients, urticaria in 57% and mild bronchospasm in 11%. Many of these reactions may represent an immunological response to the congenitally deficient protein. In routine use in over 3000 general hospital patients, amotosalen-treated plasma was associated with reaction rates of 0·11% per transfusion and 0·25% per patient [30]. Similarly, 121 patients with acquired coagulopathy because of liver disease had responses with Intercept® plasma similar to those following FFP administration with no increase in reported complications or reactions [31]. The clinical course of 35 patients randomized to receive plasma exchange with Intercept® or regular plasma were not different [32]. Cryoprecipitate has also been reported to be prepared with acceptable fibrinogen levels from Intercept® plasma [33].

Treatment of plasma with UVC light alone, without addition of a photoinactivator, has also been reported to produce inactivation of many viruses, although HIV incompletely, when accompanied with vigorous agitation [34]. Reduction of procoagulant activities of 10–20% (Factor XI to 29%) have been reported, but no clinical trials have yet been reported using this PI component.

Platelets

  1. Top of page
  2. Abstract
  3. Introduction
  4. Plasma components
  5. Platelets
  6. Red blood cells
  7. Predicting the future
  8. Disclosures
  9. References

Three procedures for photoinactivation have reached or are approaching clinical application. They share the use of UV light, although at different wavelengths and exposures, and they also share similar untoward effects on platelet physiology. However, these appear to leave the components with sufficient viability and haemostatic effectiveness to allow them to achieve the necessary clinical effectiveness.

Published in vitro studies suggest that exposure to UV light is the primary, albeit not sole, cause of changes during PI treatment [35–37]. All of the techniques currently available or under development appear to lead to acceleration of energy production with expected secondary changes such as increased lactate production [38]. The metabolic changes appear to be more pronounced in amotosalen- than riboflavin-treated platelets where the former appear to show some impairment of mitochondrial-based respiratory energy production and lower ATP levels late in storage [35]. At the same time, PI treatments appear to induce some degree of platelet activation. This would usually be thought of as contributing to the platelet ‘storage lesion’, but sheer-induced adhesion may be better maintained in riboflavin-treated than untreated platelets [39]. All together, these changes combine to reduce in vivo recovery and survival in normal subjects by 12–20%, and patient trials have demonstrated corresponding decreases in 1 and 24 h CCI measurements that are very similar between these two PI methods.

Although long-term transfusion studies have not been undertaken in humans, it appears that the treatments that inactivate pathogens also affect the function and replication of leucocytes [40,41], reducing alloimmunization to leucocyte-borne antigens [42] and preventing the replication of transfused leucocytes that is requisite for development of graft-versus-host disease [43,44]. This raises the potential for implementation of PI technologies to simplify the preparation and administration of platelet units to recipients susceptible to these complications.

Ultimately, the ‘proof of the pudding’ for a platelet component is its ability to prevent and treat haemorrhage, and two techniques have been subjected to trials with this or the increase in the patient’s platelet count as the end-point. The first of these, the euroSPRITE trial, used the corrected platelet count increment (CCI1hr) as its primary outcome measure [45]. This was no different with platelets treated with amotosalen and UV light (Intercept®) when compared to untreated platelets. However, as the PI process resulted in fewer platelets being transfused, the PI platelet recipients required a proportionately larger number of platelet units to be transfused and reached their transfusion threshold again more quickly. The SPRINT trial in the United States followed the bleeding outcomes in 645 patients randomized to either control platelets or those treated with amotosalen and UV light [46]. As before, the patients in the PI group received fewer platelets per transfusion (3·7 PI vs. 4·0 × 1011 control; P < 0·001) and, not surprisingly, more transfusions (8·4 vs. 6·2; P < 0·001). Although the CCIs were lower in the PI group, comparison of CCIs among patients receiving similar doses of platelets indicated no difference. The primary outcome measure, the proportion of patients experiencing Grade 2 (or greater) bleeding, was not different between the groups nor was the time to such a bleeding episode. Although many patients experienced an adverse event at some time during the course of their illness, the frequency of any significant event did not appear to be different except for that of respiratory distress (which was noted in five patients in the PI group and none in the control group). An independent panel of pulmonologists reviewed the records of all 148 patients with any report of a breathing problem without knowledge of the group to which the subject had been assigned, and this reassessment could document no difference in pulmonary outcomes between the two groups [47]. This assessment matches that derived from haemovigilance reporting in European countries that have implemented this PI treatment for platelets where excess respiratory difficulties have not been noted. [48]. Days of Grade 2 bleeding were also higher in the SPRINT PI group (3·2 vs. 2·5 d (P = 0·02; median = 1 for both), but a careful analysis of a Belgian implementation experience has failed to indicate any increased use of red cells in patients receiving PI platelets in a routine manner [49].

More recently, two trials of amotosalen-treated platelets led to different conclusions. An independently funded trial in the Netherlands has raised questions about their clinical utility [50]. The reduction in CCI noted with PI in this study paralleled that seen in the SPRINT study. Episodes of bleeding (including Grade 1) were reported more frequently in patients receiving PI platelets. However, the number of protocol violations reported and the premature cessation of the study may make interpretation and application of this small study difficult. Publication of a full report will be required to understand the import of this clinical trial. However, a multicentre trial across several European countries at Day 6 or 7 of storage demonstrated non-inferiority in CCI (meaning documentation of less than a 30% difference with treated platelets) [51]. The group receiving PI platelets did not show a decreased time to next transfusion nor an increase in a computed haemostatic score.

In a recently completed study with 110 platelets using the Mirasol® technology of riboflavin + UV [52], there was a 31% decrease in the primary outcome measure, CCI1h, with the treated platelets. However, there was no difference in observed bleeding (in any WHO grade), and the intertransfusion interval (2·2 vs. 2·3 d) was not lengthened. There was also no significant difference in the number of adverse events between the two groups (although one patient in the treatment group had a fatal intracerebral haemorrhage).

Treatment of platelets with UV light alone (MacoPharma) has not yet proceeded to a clinical trial stage. Treatment with 500 J/m2 of UVC light (254 nm) appears to produce useful inactivation of many model viruses and bacteria but relatively little (∼ 1 log10) effect on HIV [53,54]. The technique appears to depend on creation of thin-layer exposure of component, induced by agitation [55]. Similar types of up-regulation of glycolytic activity and platelet activation during storage to other forms of photoinactivator-based PI have been documented. Interestingly, less annexin-V binding appears to occur after treatment [51], but whether this will correlate with better recovery and survival remains to be investigated in vivo.

Recently, the bacteriocidal effects of various novel antimicrobial peptides have been evaluated as a means of reducing bacterial risk in platelets. Some of these short polypeptides would appear to have the ability to inactivate the load of bacteria found early in the storage period [56]. Although there may be some increased platelet activation during storage with such polypeptides, other biochemical functions appear unperturbed [57]. These compounds’ effects would appear to be limited to bacterial pathogens, but such threats today comprise the largest risk to platelet recipients.

Red blood cells

  1. Top of page
  2. Abstract
  3. Introduction
  4. Plasma components
  5. Platelets
  6. Red blood cells
  7. Predicting the future
  8. Disclosures
  9. References

The approach of activating a chemical compound with light is hampered in red cell components because of haemoglobin’s absorption spectrum. Thus, a chemical that could be activated on the pH change when encountering the blood component, S-303, was developed by Cerus to avoid the need to initiate the PI treatment via light. Although the recovery and survival of treated red cells appeared to be only minimally reduced by this technique, the creation of antibodies against treated red cells (actually, directed against an acridine-like moiety deposited on the red cell surface by the active compound) forced reformulation of the treatment protocol to include higher concentrations of the quencher, glutathione. Additional work was also undertaken to create the optimal biochemical environment to sustain posttransfusion red cell physiology. Initial results from a radiolabeled autologous reinfusion study have been reported as meeting FDA requirements [58].

(A similar problem of neoantigen formation plagued the application of PEN110, Inactine®, as a red cell PI method. Its development was ultimately abandoned.)

Another approach, that of inactivation using riboflavin in whole blood, is also under active development. UV illumination occurs in the range 280–350 nm (peak: 313 nm). This appears able to inactivate model viruses of interest as well as leucocytes in the unit. The treated red cells, in a baboon model, did not appear to suffer from shortened recovery nor alloantibody formation [59]. Plasma procoagulant activities were maintained except at the highest energy levels. The technique is currently undergoing refinement through initial trials in normal subjects to assess recovery and survival [60].

Predicting the future

  1. Top of page
  2. Abstract
  3. Introduction
  4. Plasma components
  5. Platelets
  6. Red blood cells
  7. Predicting the future
  8. Disclosures
  9. References

Being able to transfuse blood components with no risk of pathogen transmission remains a viable goal, but one that still has challenges ahead of it. Questions about side-effects of PI platelets need to be resolved, and the (minimal if not none-existent) impact of PI on platelet usage and maintained patient outcomes as reported from several European centres need to be confirmed. The development of a PI system for RBCs that maintains their viability and function still remains a major hurdle. Finally, adjustment of systems to accommodate the increased cost of PI needs to be accomplished. (Recent steps to allow treatment of double apheresis units or larger pools of whole blood-derived platelets, for example, are examples of ways of reducing the financial impacts of routine implementation.)

As these issues are addressed, perhaps a revisioning of the ‘goal line’ would be helpful. As it is clear that PI treatments have some detrimental effects on the efficacy of the components and raise some issues about potential toxicities (i.e. untoward events) for some recipients, these must be balanced with the benefits. Indeed, the targets are no longer the ‘traditional’ ones (e.g. HIV, HCV), as sensitive testing has essentially removed them from the risk/benefit equation. Preventing the spread of a virus that has not yet been identified or recognized as a threat may not make a compelling argument for implementation or even balance the regulatory equation of risk vs. benefit. For platelets, the driver is likely to be bacterial contamination as this is a risk that persists in large measure despite diligent attempts to reduce it. The traditional requirement of 6 log10 reduction may actually far exceed the practical need for additional assurance given current testing protocols for known viral pathogens already addressed by testing, and reduction of the intensity of PI treatment (through less UV exposure, for example) might reduce the unwanted effects on efficacy or even reduce the potential for the development of new risks while retaining sufficient pathogen reduction to allow introduction to prove a meaningful increment in recipient safety with respect to bacterial contamination. The experience gained from such introductions in some countries may inform decisions regarding expansion of the PI products’ application as well as provide direction for further research regarding how to modify processes to bring greater benefit (at less risk) for other recipient populations.

The resolution of safety and efficacy issues of PI components may prompt us to consider some of the basic tenets of our clinical trials. Does tracking posttransfusion CCIs tell us anything clinically useful when the PLADO study [61] documented that half-dose prophylactic platelet transfusions provided the same clinical outcome? What value are CCIs at 1 h, primarily a ‘recovery’ surrogate, when most platelet transfusions are given prophylactically? What value are CCIs at 24 h, more of a ‘survival’ parameter, but one greatly affected by the patient’s condition? Do these parameters have the sensitivity and specificity to be clinically meaningful? How can we hope to assess a low-frequency complication of a new blood component when comparing it to the consequence of an infection we have not yet named? What margin of inferiority in CCI or days to Grade 2 bleeding is acceptable vs. avoidance of Dengue fever or an as-yet-unrecognized threat? When facing these questions, will we remember the stark terror faced by blood bankers and recipients alike in the early 1980s when we realized a fatal, dreaded disease was being transmitted by transfusion and there was little that could be done?

When milestones to allow broad regulatory approval and routine implementation of PI are reached, will we see a dramatic rise in transfusion rates? Certainly concerns about viral infection have had a notable effect on transfusion rates over the years, and removal of these concerns through introduction of PI might be predicted to unleash accelerated demand for transfusion. However, in the intervening years, as the appearance of HIV in the blood supply and the recognition of the long-term impacts of HCV infection combined to reduce the growth in transfusion demand in many countries, new, non-infectious concerns regarding transfusion have surfaced. The necessary or best dose for prophylactic platelet transfusion may be less than commonly used [61], and, indeed, prophylactic transfusions may not provide the presumed benefit [62]. The red cell storage lesion has also come under scrutiny with concerns that increased storage time may induce unwanted outcomes in certain recipient groups. While PI may be welcomed by many as obliterating a long-standing threat, it is not this threat to recipients that is currently perceived as the greatest. Thus while the implementation of PI will allow us all to ‘breathe easier’, it may not open the floodgates of transfusion. Rather, it may just allow greater focus on other risks and questions in transfusion, and there will remain continued calls for judicious use of what will remain a scarce and (even more) expensive medical resource.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Plasma components
  5. Platelets
  6. Red blood cells
  7. Predicting the future
  8. Disclosures
  9. References
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