DISCOVERIES 2014, Jan-Mar, 2(1): e11 DOI: 10.15190/d.2014.3 Transfusion in the 21st Century

REVIEW Article

Blood Transfusion in the 21st Century

Mark T. Friedman1,*, Vaidehi Avadhani1, Sandra Gilmore2, Emilio Madrigal1

1Department of Pathology, and Transfusion Services, 2Blood Management, Bloodless Medicine and Surgery, Mount Sinai Health System, St. Luke’s, Roosevelt, and Beth Israel Hospitals, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA Corresponding author: Mark T. Friedman, DO, Mount Sinai Roosevelt Hospital, Medical Director of Blood Bank and Transfusion Service, 1000 Tenth Avenue, New York, NY 10019. Phone: 212-523-7242; Fax: 212- 523-6394; [email protected].

Submitted: March 11, 2014; Published after revision: March 31, 2014; Citation: Friedman MT, Avadhani V, Gilmore S, Madrigal E. in the 21st Century. Discoveries 2014, Jan-Mar; 2(1): e11. DOI: 10.15190/d.2014.3

ABSTRACT implement appropriate patient blood management Blood transfusion is a common procedure in the strategies. This review will examine these issues hospital setting, and the safety of the blood supply along with newer blood safety technological has been vastly improved over the past few decades innovations and further highlight contributing largely due to improvements in screening for viral studies from our institutions. transmissible diseases, especially human immunodeficiency virus (HIV) and viral hepatitis. Keywords: Blood substitutes; factor concentrates; However, more recent efforts to improve blood hemovigilance; patient blood management; safety have focused on non-transmissible disease education; transfusion safety. risks such as transfusion-related acute lung injury (TRALI), non-viral transmissible diseases such as Abbreviations bacterial contamination of blood products American Association of Blood Banks (AABB); Centers (especially components which are stored at for Disease Control and Prevention (CDC); room temperature) and Chagas disease (a parasitic Cytomegalovirus (CMV); Food and Drug Administration disease caused by Trypanosoma cruzi), and prion (FDA); Hemoglobin-based oxygen carriers (HBOC’s); transmissible agents (e.g., variant Creutzfeldt-Jakob Human immunodeficiency virus (HIV); Human disease, also known as the agent of mad cow leukocyte antigen (HLA); Patient blood management (PBM); Perfluorocarbons (PFC’s); Serious Hazards of disease) as well as more recently-recognized Transfusion (SHOT); The Joint Commission (TJC); transmissible viral disease risks such as West Nile Transfusion-associated graft-vs-host disease (TA- virus. Appropriate blood utilization has also come GVHD); Transfusion-related acute lung injury (TRALI); under more intense scrutiny in recent times due to Transfusion-related immunomodulation (TRIM); United healthcare costs and the recognition that many Kingdom (U.K.); Variant Creutzfeldt-Jakob disease blood transfusions are given under circumstances in (vCJD). which the benefit to the patients is unclear and may be potentially harmful due to the above risks as well SUMMARY as the emerging concept that blood transfusions 1. Introduction may cause long-term damage to the immune system 2. Safety of the blood supply resulting in worse patient morbidity and mortality 3. Quality of the blood supply outcomes. Toward that end, accreditation agencies 4. Transfusion medicine education such as the Joint Commission and the American 5. Patient blood management Association of Blood Banks (AABB) are 6. Future technology advocating for healthcare organizations to 7. Concluding remarks www.discoveriesjournals.org/discoveries 1 Blood Transfusion in the 21st Century

1. Introduction with the fact that published transfusion guidelines have been updated over the years to reflect a more Blood transfusion is one of the most common conservative approach to blood utilization9,10, procedures performed in hospitals. Accordingly, it clinicians have been slow to adopt these transfusion was reported that there were nearly 15 million practices and in many cases, transfusion practices and units transfused in remain inconsistent even amongst physicians of the the United States alone in 2008, representing a same specialty practicing within a localized region nearly 6% increase in transfusions from the prior or even within the same institution11. This review surveyed year of 20061. This is because anemia is a will further discuss issues surrounding blood common comorbidity that can be found in a variety utilization, including the safety and quality of the of patients, including patients with cancer, patients blood supply and patient blood management. undergoing surgical procedures or hemodialysis,

patients with autoimmune or bone marrow disorders 2. Safety of the blood supply (such as myelodysplastic syndrome), patients with congenital anemia (such as sickle cell anemia and Over the years, the safety of the blood supply has thalassemia), trauma patients, obstetrical patients, dramatically improved. Early efforts to reduce risk and patients with nutritional deficiencies, such as focused on reliance on volunteer donors while iron deficiency. While it is certainly known that screening out donors with high-risk behavior, such anemia can have adverse effects on patients, as male-to-male sex, for human immunodeficiency particularly in cardiovascular and neurocritical care virus (HIV) and viral hepatitis (hepatitis B and patients2-4, what is becoming more evident is that hepatitis C) as well as the implementation of correction of anemia via blood transfusion is not highly-sensitive testing to reduce the infectious beneficial to many patients, and in fact, may be window period, that is, the time between exposure more harmful, unless the patient is acutely to viral infection and ability of the blood test to symptomatic (e.g., shortness of breath, low blood detect the virus when the donor may be infectious pressure, rapid heart rate, dizziness, or chest pain) though the test result is negative. Such strategies from the anemia. Thus, it is considered problematic have reduced the risk of HIV and hepatitis C that many blood transfusions are administered transmission through blood to about 1 in 2 million unnecessarily, driving up healthcare costs, (or roughly the equivalent of the risk of getting expending a valuable resource (i.e., blood struck by lightning)12. More recently, testing for components) in short supply (because only a West Nile virus and Chagas disease (Trypanosoma minority of eligible blood donors in the U.S. give cruzi) has been added to address those emerging blood), and exposing patients to all the risks and transmissible disease threats to the blood complications (like fluid and iron overload) of supply13,14, and standards were adopted for reducing blood transfusions. Hèbert et al. published their the risk of bacterial contamination of platelet landmark study 15 years ago which demonstrated components (which must be stored at room the lack of benefit of a liberal transfusion strategy temperature to maintain platelet hemostatic over that of a restrictive one in critical care function)15. Still, there remain transmissible disease patients5. Since then, additional studies have been risks that are not tested for owing to the fact that published demonstrating similar outcomes in other U.S. Food and Drug Administration (FDA)- patient populations such as elderly patients approved testing is unavailable. Perhaps most undergoing orthopedic (e.g., hip replacement) problematic in the U.S. is babesiosis, a parasitic surgery, pediatric patients, and patients with agent that infects red blood cells à-la malaria but gastrointestinal bleeding6-8. Despite these data that is endemic in the northeastern U.S.; supportive of restrictive transfusion strategies along transmission of babesiosis through blood has been reported16, and the FDA may consider Although blood transfusions are commonly implementation of testing in the near future. Yet used to treat anemia, restrictive transfusion another transmissible agent for which testing is practices (i.e., fewer transfusions) have been unavailable is variant Creutzfeldt-Jakob disease shown to be as effective if not better than liberal (vCJD, the prion agent of bovine spongiform transfusion practices. encephalopathy or mad cow disease); human cases have been attributed to transfusion of blood

www.discoveriesjournals.org/discoveries 2 Blood Transfusion in the 21st Century

components in the United Kingdom17. To address implemented by most hospital transfusion services, this, prospective blood donors in the U.S. who have such as the requirement for a second sample to traveled for a defined period of time to the U.K. confirm the ABO prior to crossmatch (cumulative 3 month travel between 1980 and and strict blood administration policies for bedside 1996) or western Europe (cumulative 5 years patient identification at the time of transfusion. between 1980 and present) are currently excluded; Nevertheless, TRALI and group ABO-incompatible however, this is problematic as a number of transfusion occurrence estimates remain much otherwise-eligible blood donors are unable to greater than for transmission of HIV and hepatitis donate, representing a small but not insignificant and are amongst the highest causes of transfusion- loss of U.S. blood donors18. Transfusion- related fatalities21,22. Transfusion-associated graft- transmitted cases of hepatitis E virus have also been vs.-host disease (TA-GVHD) is yet another non- reported outside of the U.S., though testing for this infectious complication of transfusion that is fatal23. agent is not currently performed either19. However, though it is preventable through blood As the risk of transmissible disease through component irradiation which inactivates the blood transfusion has decreased, non-infectious causative immune cells (T4 lymphocytes), risks have become more prominent. Transfusion- clinicians do not always order, or otherwise provide related acute lung injury (TRALI), defined as the patient’s condition to alert the hospital blood edema or fluid collection in the lungs during or bank to prepare, irradiated blood for their at-risk shortly (within 6 hours) after transfusion not patients (those who are immunocompromised or causally-linked to heart failure or other cause of have certain conditions like leukemia or Hodgkin’s lung injury unrelated to transfusion such as disease). Most hospital blood banks do not pneumonia, has been shown to be largely a result of routinely maintain large inventories of irradiated antibodies to white blood cell antigens (known as blood since the irradiation process reduces the human leukocyte antigen [HLA] antibodies) in storage shelf life of the red blood cell products, nor female donors (because of exposure to HLA during do they have a blood irradiator device onsite which pregnancy); as a result, the use of plasma requires a significant amount space and carries a components (which contain the HLA antibodies) very high level of security concern to protect the from females has been restricted in the U.S. unless radiation source24. Finally, in addition to all the the female donor is known not to have ever been above risks, blood transfusion can lead to the pregnant or is otherwise tested for the causative formation of unexpected alloantibodies to red blood HLA antibodies since last pregnancy20. Transfusion cell antigens (i.e., non-ABO antibodies such as of group ABO-incompatible blood is another non- antibodies to the ) in infectious risk that has gained more recognition recipients which can make future blood transfusions over time and is almost always due to human error even more difficult in the way of finding such as error in collection of the crossmatch sample compatible blood and result in hemolytic reactions (i.e., the sample is collected from the wrong patient (because of incompatibility related to the though labeled with the correct patient’s unexpected antibodies) as well as carrying the identification) or in patient identification at the time added risk in females of childbearing age of causing of blood transfusion (i.e., blood correctly severe complications, even fetal death, during crossmatched but given to wrong patient). pregnancy (i.e., hemolytic disease of the fetus and Strategies to reduce this risk have been newborn)25. In order to further improve blood safety • Improved donor screening and across the nation, the U.S. Biovigilance Network, a transmissible disease testing, particularly collaboration between the U.S. Department of for HIV and hepatitis C, vastly increased Health and Human Services, including the Centers the safety of the blood supply. for Disease Control and Prevention (CDC), and organizations that collect and transfuse blood, • More recent efforts to increase safety have launched the National Hemovigilance Program in largely focused on noninfectious risks and 201026. The U.S. program followed that of many bacterial contamination of blood products. other developed countries, including France (where it was set into law by 1993) and the U.K.’s Serious www.discoveriesjournals.org/discoveries 3 Blood Transfusion in the 21st Century

Figure 1: Transfusion safety schematic

Hazards of Transfusion (SHOT) program (which recurrence.”27 However, many hospital transfusion began in 1996)27. The International Hemovigilance services across the U.S. have been slow to join the Network defines hemovigilance as “surveillance reporting system which remains voluntary, limiting procedures covering the whole transfusion chain, its effectiveness. Transfusion services are required, from collection of blood and its components to however, to report serious reactions, especially follow-up of recipients, intended to collect and those that result in fatality, to the FDA as well as to assess information on unexpected or undesirable their local department of health in a number of effects resulting from the therapeutic use of labile states28-30. A transfusion safety schematic is blood products and to prevent their occurrence or presented in Figure 1. www.discoveriesjournals.org/discoveries 4 Blood Transfusion in the 21st Century

3. Quality of the blood supply practices continue to be principally based upon individual clinical experience35. In fact, assessment Efforts have been put forth to improve the quality of overall transfusion medicine knowledge in our of the blood supply in other areas. One major own hospital facilities showed poor baseline improvement resulted when the system of labeling knowledge amongst physicians across different blood components converted from Codabar specialties and training levels35. As previously symbology to the ISBT 128 system which has the commented on in a published editorial, lack of advantage of being a global system that is unique, transfusion medicine knowledge may possibly be comprehensive, and more accurate in its coding the greatest obstacle toward making transfusion method31. A second major improvement has practices more consistent and in line with published resulted from the trend toward universal guidelines and evidence-based medicine36. leukoreduction, or depletion of white blood cells, from blood components. However, universal 5. Patient blood management leukoreduction in the U.S. has lagged behind Europe and Canada which implemented Patient blood management (PBM), as defined by leukoreduction much earlier partly in response to the AABB, is “an evidence-based, multidisciplinary the risk of vCJD transmission (vCJD has been approach to optimizing the care of patients who reported to be closely associated with the buffy-coat might need transfusion. PBM encompasses all or white blood cell layer of blood though more aspects of patient evaluation and clinical recent evidence has shown infectivity in plasma and management surrounding the transfusion decision- red blood cells)32. White blood cells, considered making process, including the application of contaminants of red blood cell and platelet appropriate indications, as well as minimization of components, pose complications related to febrile blood loss and optimization of patient red cell mass. transfusion reactions, alloimmunization (i.e., PBM can reduce the need for allogeneic blood formation of HLA antibodies which can lead to transfusions and reduce health-care costs, while transplant rejection), and transmission of some ensuring that blood components are available for pathogens like cytomegalovirus (CMV, a common the patients who need them.”37 In addition to the herpes virus that may cause complications like AABB, the Joint Commission (TJC), a major pneumonia in some at-risk patients such as those organization that accredits healthcare organizations who are immunocompromised). Yet it is unclear (formerly known as the Joint Commission on what impact leukoreduction at the time of collection Accreditation of Healthcare Organizations or (i.e., pre-storage leukoreduction), which removes JCAHO), has drafted its own set of guidelines for about 99% of the white blood cells and prevents PBM certification38. Previously, though, TJC buildup of white cell products (known as cytokines) published a set of blood management performance during storage, will have on the mitigation of measures that hospital transfusion services could transfusion-related immunomodulation (TRIM). opt to use to improve their processes surrounding TRIM is the concept that blood transfusions weaken transfusion39. Measure PBM-02 RBC Transfusion the immune system in recipients and increase the Indication39 was in part developed around published risk of postoperative infections and cancer data from our hospitals showing a significant recurrence33. Finally, there is some evidence that correlation between lack of transfusion transfusion of older (greater than 14 days in documentation in the patient medical record and storage) blood products compared with fresher ones failure to justify the transfusion as clinically (less than 14 days in storage) may also increase the necessary40. Transfusion services employ this risk of poorer hospital outcomes in some patient measure to evaluate their blood utilization populations34. practices41, and we are currently planning a follow-

4. Transfusion medicine education PBM strategies such as: preoperative anemia management, use of surgical techniques to Unfortunately, in light of the above risks and minimize blood loss, or recover shed blood complications of blood transfusion, clinicians (intraoperative cell salvage), can minimize the continue to receive little to no formal training in appropriate use of blood products and their need for blood transfusions.

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up analysis in our own facilities. We further intravenous use, limiting their effectiveness due to published data from our hospital facilities low PFC content such that high concentrations of concerning Measure PBM-01 Transfusion supplemental oxygen must be given in order to Consent39 demonstrating that information discussed achieve a therapeutic effect. Fluosol-DA (Green with patients prior to transfusions tended to focus Cross Corp., Osaka, Japan/Alpha Therapeutic, Los on the benefits of transfusion (namely, correction of Angeles, CA), a first-generation PFC, received anemia, which as noted above, may not actually be FDA approval in 1989 for use in coronary balloon a benefit unless symptomatic) along with minor angioplasty but was withdrawn from the market just risks (such as febrile and allergic reactions) while 5 years later since it was found to be cumbersome omitting discussion of more significant risks such to store (requiring frozen storage) and prepare for as hemolytic (incompatible blood) reactions, therapeutic use as well as the fact that TRALI, volume overload, and transmission of HIV improvements in angioplasty catheter technology and hepatitis C42. PBM-01 is an important measure eliminated the need for Fluosol45,46. Second in that AABB standards require transfusion consent generation PFC’s, which have higher PFC content, and in that the Institute of Medicine, in naming such as Oxygent (Alliance Pharmaceutical Corp., patient centeredness (defined as “providing care La Jolla, CA) and Oxyfluor (Hemagen, Inc., St. that is respectful of and responsive to individual Louis, MO) were subsequently developed and patient preferences, needs, and values, and ensuring tested but have not been approved by the FDA45,46. that patient values guide all clinical decisions”) as HBOC’s, on the other hand, are manufactured from one of its 6 core attributes of a high-quality human or bovine hemoglobin, and at least one healthcare system, encourages dialogue between recombinant (genetically-engineered) product was physicians and patients in the decision-making developed45,47. However, the main obstacle to the 43 process . Blood substitutes, really oxygen therapeutic

agents, though in development for many years 6. Future technology are not approved for use in the U.S. and Although PBM strategies should optimize and in cannot replace the need for blood. many instances minimize the use of blood success of HBOC’s has been the fact that cell-free transfusions as such strategies gain prominence in hemoglobin is quite toxic, causing increased hospitals throughout the U.S. over time, the need vasoconstriction and vascular resistance leading to for blood will be ever present largely because of an hypertension (due to scavenging of nitric oxide aging population that is expanding and undergoing along the endothelial lining of the blood vessels more medical procedures, including cardiothoracic where NO normally promotes vascular dilatation) surgery, joint replacement, transplant surgery, and damage to the kidneys as well as hemodialysis, and cancer treatment (chemo- and gastrointestinal, hepatic, pancreatic, and radiation therapy), which will require transfusion neurological side effects47. In addition, HBOC’s support in many cases. Yet the promise of blood have a rather short plasma half-life and have altered substitutes, also known as “artificial blood”, which oxygen-binding properties45. Manufacturers have are really oxygen therapeutic agents rather than introduced various alterations to their proprietary complete substitutes for blood, has proven to be HBOC’s in order to stabilize the cell-free quite elusive. Development of a therapeutic oxygen hemoglobin and circumvent these problems carrier, which ideally would be readily available, including, intramolecular crosslinking, universally compatible, pathogen free, cost efficient polymerization, pegylation, pyridoxilation, and with minimal side effects and a long shelf life, has encapsulation45,46. As such, an impressive array of taken two forms over the years: perfluorocarbon HBOC’s have been in development, including emulsions (PFC’s) and hemoglobin-based oxygen PolyHeme (Northfield Laboratories, Evanston, IL), carriers (HBOC’s)44,45. PFC’s are chemically-inert, Hemolink (Hemosol, Mississauga, Ontario, colorless, clear liquids that have the ability to Canada), HemAssist (Baxter Healthcare, Deerfield, dissolve large volumes of gases, including oxygen IL), PHP (Apex Bioscience, Research Triangle 44 and carbon dioxide . However, PFC’s are also Park, NC), Hemospan (Sangart, San Diego, CA), water insoluble and must be emulsified for PEG-Hemoglobin (Enzon, Piscataway, NJ), www.discoveriesjournals.org/discoveries 6 Blood Transfusion in the 21st Century

Table 1: Factor Concentrates Licensed in the United States*

Hemopure (Biopure, Cambridge, MA), Oxyglobin of difficulty in finding compatible blood. However, (Biopure), and Optro (Somatogen, Boulder, CO), other applications may include use as a cardioplegic but none have achieved FDA approval, though oxygen solution for open heart surgery, for Hemopure has been approved for use in South treatment of ischemia in myocardial infarction and Africa since 200145. In the end, it is likely that, if stroke patients, and as sensitizers to oxygenate solid and when a so called is approved tumors for increased response to chemo- or by the FDA, the indications will be limited to radiotherapy45. In other technology, artificial extreme trauma or to situations in which blood (i.e., platelet substitutes) have been under transfusion may not be possible because of religious development, but such development is still in the objection (as in Jehovah’s Witnesses who refuse early stages48. Pathogen-inactivated cellular transfusion with typical blood products) or because components, such as Cerus Corporation’s www.discoveriesjournals.org/discoveries 7 Blood Transfusion in the 21st Century

INTERCEPT Blood System (Cerus Corp., Concord, in controlling the bleeding into the brain55. CA)49 have also not been fully developed as of yet Nevertheless, off-label use for recombinant factor while solvent-detergent-treated plasma has recently VIIa and other concentrates persists with significant been reintroduced to the U.S. market, albeit by a costs, uncertain benefits, and possible different manufacturer (Octaplas, Octapharma AG, thomboembolic risks due to the high-clotting Lachen, Switzerland)50, after withdrawal of an potency of these products. earlier product, Plas+SD (VITEX, Watertown, MA) a decade ago after the FDA issued a Black Box 7. Concluding remarks warning contraindicating its use in liver transplant patients and those with severe liver disease (it must be noted here that Octaplas is manufactured using a Should all possible blood safety different process and does not have such initiatives, no matter how remote the contraindication)51. Where technology perhaps has risk, be implemented at any cost? been most successful is in the development of factor concentrates. Both human plasma-derived and recombinant factor concentrates are available for Transfusion medicine continues to evolve with use today to treat hemophilia and other coagulation improvements in the quality and safety of blood disorders (see Table 1). Unfortunately, because components to minimize transfusion risks. human plasma-derived factor concentrates are Educating clinicians to follow appropriate manufactured from pooled plasma from thousands transfusion practices under established blood of donors, many of the early (1970’s-1980’s) management protocols is also of high importance, hemophilia factor concentrates were tainted with particularly since the accrediting agencies (AABB HIV and hepatitis leading to the deaths of many and TJC) will hold hospitals more accountable for hemophiliacs. By the mid 1980’s, however, heat their transfusion practices and in the light that treatment and later other viral-inactivation steps newer, more potent, and more costly blood such as solvent-detergent treatment were products, such the factor concentrates noted above, incorporated into the manufacturing processes of are becoming much more available and in demand. the plasma-derived concentrates along with The search for a blood substitute continues but will improved donor screening and transmissible disease likely have only limited applications when finally testing52. Recombinant factor VIII and factor IX approved. Though many advances have been made products became available in the 1990’s; since then, in the field of transfusion medicine to date, a other recombinant factors have been approved number of questions remain incompletely answered, (Table 1). These concentrates, though, are much such as the benefits vs. risks of more restrictive more costly than conventional blood products transfusion practices in higher-risk patients (i.e., (costing on average several thousand dollars per those with underlying cardiovascular disease), the dose vs. several hundred dollars for a typical dose risks of transfusing older vs. fresher blood, the long [several units] of transfused plasma). Yet more term risks of blood transfusion on the immune problematic is the clinical use of these products for system (TRIM), and the best practices to prevent the treatment of conditions for which there is little established risks such as TRALI as well as to no evidence of benefit and for which they were questions about emerging risks. Further studies will not intended for use by the FDA (i.e., off-label use). be necessary and in some cases are ongoing to As an example, recombinant factor VIIa provide insight into these and other issues (NovoSeven RT, Novo Nordisk, Bagsvaerd, surrounding the transfusion of blood products. Denmark), intended for use in certain patients with Ultimately though, we could not agree more with hemophilia53, was used for treatment of Menitove et al.56 who advocate for a risk-based intracerebral bleeding after one study published in decision-making approach toward blood safety, the New England Journal of Medicine showed noting that “some safety initiatives promising data54. Enthusiasm for such use cost more than 10 times the currently accepted diminished, however, after a follow-up study failed threshold of up to $100,000/quality-adjusted life to demonstrate a survival benefit even though the year gained for other medical interventions” in the study did demonstrate effectiveness of the product drive to attain a zero-risk blood supply. www.discoveriesjournals.org/discoveries 8 Blood Transfusion in the 21st Century

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oxygen carriers, platelet substitutes, recombinant 53. Novo Nordisk. NovoSeven RT prescribing clotting factors, and others. Artif Cells Blood Substit information.http://www.novo-pi.com/novosevenrt. Immobil Biotechnol. 2006;34:537-550. PMID: pdf Accessed on March 6, 2014. 17090427. 54. Mayer SA, Brun NC, Begtrup K, et al. Recombinant 49. Cerus Press Release Details. Cerus and Grifols to activated factor VII for acute intracerebral collaborate on INTERCEPT Red Cell kit hemorrhage. N Engl J Med. 2005;352:777-785. development. Cerus Corporation, 6/2/2009. PMID: 15728810. http://www.cerus.com/Investors/Press-Releases/ 55. Mayer SA, Brun NC, Begtrup K. Efficacy and safety Press-Release-Details/2009/Cerus-and-Grifols-to- of recombinant activated factor VII for acute Collaborate-on-INTERCEPT-Red-Cell-Kit- intracerebral hemorrhage. N Engl J Med. 2008; 358: Development/default.aspx Accessed on March 28, 2127-2137. PMID: 18480205. 2014. 56. Menitove JE, Leach Bennett J, Tomasulo P, Katz 50. Hellstern P, Solheim BG. The use of solvent/ LM. How safe is safe enough, who decides and detergent treatment in pathogen reduction of plasma. how? From a zero-risk paradigm to a risk-based Transfuse Med Hemother. 2011;38:65-70. PMID: decision making. Transfusion. 2014;54:753-757. 21779207. PMID: 24617628. 51. U.S. Food and Drug Administration. Safety Alert: PLAS+SD (Pooled Plasma, (Human) Solvent Detergent Treated). March 29, 2002. http://www. DISCOVERIES is a peer-reviewed, open access, fda.gov/Safety/MedWatch/SafetyInformation/Safety AlertsforHumanMedicalProducts/ucm155086.htm online, multidisciplinary and integrative journal, Accessed on March 28, 2014. publishing high impact and innovative manuscripts 52. Lusher JM. Hemophilia: from plasma to from all areas related to MEDICINE, BIOLOGY recombinant factors. American Society of and CHEMISTRY; © 2014, Applied Systems .http://www.hematology.org/publication s/50-years-in-hematology/4737.aspx

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