In the United States, the risk of transmission of infectious agents through transfusion of blood components (Red Blood Cells, Platelets, and Plasma) and plasma derivatives (clotting factor concentrates, immune globulins, and protein-containing plasma volume expanders) is extremely low. Nevertheless, continued vigilance, including improved surveillance and reporting, is crucial, because no uniform system for transfusion reaction surveillance exists in the United States, and the blood supply remains vulnerable to organisms associated with newly identified or emerging infections. This chapter reviews blood and plasma collection procedures in the United States, factors that have contributed to enhancing the safety of the blood supply, some of the known and emerging infectious agents and related blood safety concerns, and approaches to decreasing the risk of transfusion-transmitted infections.
Blood Components and Plasma Derivatives
Blood collection, preparation, and testing are regulated by the US Food and Drug Administration (FDA). In the United States, whole blood is collected from volunteer donors and separated into components , including Red Blood Cells, Platelets, Plasma, and White Blood Cells. Platelets and, less commonly, Red Blood Cells and Plasma can be collected through apheresis, in which blood passes through a machine that separates blood components and returns uncollected components to the donor. Plasma for transfusion or further manufacturing into plasma derivatives can be prepared from Whole Blood or collected by apheresis. Most Plasma in the United States is obtained from paid donors at specialized collection centers. Plasma derivatives are prepared by pooling plasma from many donors and subjecting the plasma to a fractionation process that separates the desired proteins, including Gamma Globulin and clotting factors.
From an infectious disease standpoint, plasma derivatives differ from blood components in several ways. For economic and therapeutic reasons, plasma from thousands of donors is pooled, and therefore, recipients of plasma derivatives have vastly greater donor exposure than do blood component recipients. However, plasma derivatives are able to withstand vigorous viral inactivation processes that would destroy Red Blood Cells and Platelets. Most recognized infectious organisms, with the notable exception of non-lipid-enveloped viruses and prions, have been shown to be inactivated easily by plasma processing methods. Development and evaluation of various strategies for inactivation of infectious agents are ongoing.
Current Blood Safety Measures
The safety of the blood supply relies on multiple steps, including donor interview and selection, donor screening by serologic tests, screening of collected blood components for markers of infection, inactivation procedures for plasma-derived products, and leukodepletion of certain blood components (see Tables 2.2, and 2.3).1 Blood donors are interviewed to exclude people with a history of exposures or behaviors that increase the risk that their blood will contain an infectious agent. All blood donations are tested routinely for syphilis, hepatitis B virus (HBV), hepatitis C virus (HCV), human T-lymphotropic virus (HTLV) types 1 and 2, and human immunodeficiency virus (HIV) types 1 and 2; selected donations are tested for cytomegalovirus (CMV). Since July 2003, most donations are tested for West Nile virus. Since January 2007, most donations were tested on an investigational basis for Trypanosoma cruzi , the etiologic agent of Chagas disease.
Transfusion-Transmitted Agents: Known Threats and Potential Pathogens
Any infectious agent that has an infectious blood phase potentially can be transmitted by blood transfusion. Factors that influence the risk of transmission by transfusion of an infectious agent and development of clinical disease in the recipient include prevalence and incidence of the agent in donors, duration of hematogenous phase, tolerance of the agent to processing and storage, infectivity and pathogenicity of the agent, and recipient's health status. Table 2.3 lists major known transfusion-transmitted infections and some of the emerging agents under investigation.
HIV, HCV and HBV
The probability of infection in recipients who are exposed to HIV, HCV, or HBV in transfused blood products is approximately 90%. Although blood donations are screened for these viruses, there is a small residual risk of infection resulting almost exclusively from donations collected during the "window period" of infection-the period soon after infection during which a blood donor is infectious but screening results are negative.
To decrease the time period when donor HIV and HCV infection may be undetected, routine nucleic acid amplification (NAA) testing of blood and plasma donations was implemented beginning in 1999 in the United States and is performed on blood and plasma donations. At present, NAA testing for HBV is an optional donor screening test. Various estimates suggest that NAA testing on pooled units can decrease the preantibody seroconversion "window period" from 22 days to 13 to 15 days for HIV and from 70 days to 10 to 29 days for HCV. Mathematical models have been developed to estimate the current very low risks of transfusion transmission of HIV, HCV, and HBV using currently accepted screening policies (Table 2.3).
HTLV-1 and HTLV-2
Infections with HTLV are relatively common in certain geographic areas of the world and in specific populations. For example, HTLV-1 is more common in Japan, the Caribbean, and the southern United States, and HTLV-2 is more common in indigenous people of North America, Central America, and South America and among injection drug users in the United States and Europe. HTLV-1 and HTLV-2 are transmitted by transfusion of cellular components of blood but not by plasma or plasma derivatives. The risk of HTLV transmission from screened blood donated during the "window period" has been estimated at 1 per 641 000 units screened. However, transmission of HTLV is less likely to lead to infection than is transmission of HIV, HBV, or HCV, with an approximate 27% seroconversion rate in people in the United States who receive nonleukocyte reduced cellular blood components from infected donors.
Immunocompromised people, including preterm infants, stem cell and solid organ transplant recipients, and others, are at risk of severe, life-threatening illness from transfusion-transmitted CMV. Consequently, in many centers, only blood from donors who lack CMV antibodies is given to people in these categories. Leukoreduction decreases the risk of CMV transmission, because CMV resides in a latent phase within white blood cells.
Blood donations are not screened universally for parvovirus B19, because infection with this virus is common in humans. Seroprevalence rates in adult blood donors range from 29% to 79%. Estimates of parvovirus B19 viremia in blood donors have ranged from 0 to 2.6 per 10 000. Parvovirus, like CMV, usually does not cause severe disease in immunocompetent hosts but may be a threat to certain groups (eg, fetuses of nonimmune pregnant women; people with hemoglobinopathies, such as sickle cell disease and thalassemia; and immunocompromised patients). The risk of transmission of parvovirus B19 from whole blood donations is unknown but thought to be rare. However, pooled plasma derivatives commonly test positive for parvovirus B19 DNA, because parvovirus B19 lacks a lipid envelope, making it resistant to solvent/detergent Treatment. To increase safety, manufacturers of plasma derivatives test plasma minipools for parvovirus DNA and exclude those containing parvovirus above a threshold concentration.
Hepatitis A Virus
As with parvovirus, hepatitis A virus (HAV) lacks a lipid envelope and may survive solvent/detergent Treatment. Infection with HAV leads to a relatively short period of viremia, and a chronic carrier state does not occur. Cases of transfusion-transmitted HAV infection have been reported but are rare. Clusters of HAV infections transmitted from clotting factor concentrates occurred among people with hemophilia in Europe during the early 1990s, in South Africa, and more recently, in the United States.
Non-A Through -E Hepatitis Viruses
A small proportion of people with post-transfusion hepatitis as well as community-acquired hepatitis will have negative test results for all known hepatitis agents. Several other viruses have been evaluated as possible etiologic agents. Although 3 of these viruses-hepatitis G virus/GB virus type C (strain variants of a member of the Flaviviridae family), TT virus (named for the patient from whom the virus was first isolated in Japan), and SEN virus-can be found in blood donors and can be transmitted by transfusion, none of these viruses have been found to be associated with development of post-transfusion hepatitis; hence, technically they are not "hepatitis" viruses. No test has been approved for screening donors for any of these viruses, and no data suggest that such tests would be beneficial.
Human Herpesvirus 8
Human herpesvirus 8 (HHV-8) is associated with Kaposi sarcoma in people with HIV infection, non-HIV Kaposi sarcoma, and certain rare malignant neoplasms. The predominant modes of transmission are male-to-male sexual contact in the United States and close, nonsexual contact in Africa. Because HHV-8 DNA has been detected in peripheral blood mononuclear cells and serum specimens, there is concern that HHV-8 could be transmitted through blood and blood products. Serologic evidence of HHV-8 infection has been associated with receipt of transfused and nonleukoreduced blood components as well as with injection drug use. However, HHV-8 transmission has not been detected in some studies of small numbers of recipients of blood from known HHV-8-seropositive donors. Among people with exposure to blood and blood products (eg, people with hemophilia), HHV-8 seroprevalence generally is comparable with that among healthy, HIV-seronegative people. Research on larger populations of recipients of blood or blood products from HHV-8-positive people will be needed to evaluate more completely this risk. An Epidemiology study in Uganda, where HHV-8 is endemic, has provided evidence that HHV-8 can be transmitted by blood transfusion.
West Nile Virus
West Nile virus (WNV) has been shown to be transmitted through blood transfusions. To reduce transfusion-associated transmission, blood collection agencies have implemented NAA testing for WNV. Blood collection agencies primarily use an algorithm starting with minipools of donation samples. Donations making up a reactive minipool are retested individually and removed from the blood supply if results still are positive. If there is evidence of local epidemic WNV transmission, local blood collection agencies switch to individual donation testing to improve the sensitivity of finding blood donations containing WNV. These steps have reduced but not eliminated the risk of WNV transmission via blood products. Cases of WNV disease in patients who have received blood transfusions within 28 days before illness onset should be reported promptly to the Centers for Disease Control and Prevention (CDC) through state and local public health authorities. Serum and tissue samples should be retained for later studies. In addition, cases of WNV disease diagnosed in people who have donated blood within 2 weeks before the onset of illness should be reported promptly.
Although major advances in blood safety have been made, bacterial contamination of blood products remains an important cause of transfusion reaction. Bacterial contamination can occur during collection, processing, and transfusion of blood components.
Platelets are stored at room temperature, which can facilitate growth of contaminating bacteria. Bacterial contamination of blood products previously was underestimated. The predominant bacterium that contaminates Platelets is Staphylococcus epidermidis. Bacillus species; more virulent organisms, such as Staphylococcus aureus ; and various gram-negative bacteria, including Salmonella and Serratia species, also have been reported. Transfusion reactions attributable to contaminated Platelets potentially are underrecognized, because episodes of bacteremia with skin organisms are common in patients requiring Platelets, and the link to the transfusion may not be suspected.
On March 1, 2004, the AABB (formerly known as the American Association of Blood Banks) adopted a new standard that requires member blood banks and transfusion services to implement measures to detect and limit bacterial contamination of all Platelet components. As a result, most apheresis platelets are screened using liquid culture methods, while pooled platelets generally are screened using less-sensitive methods. All widely used detection methods have been reported to fail, so no method is failsafe. The American Red Cross has estimated that current culture methods may detect only 50% of bacterial contamination. Hospitals should ensure that protocols are in place to communicate results of bacterial contamination, both for quarantine of components from individual donors and prompt Treatment of any transfused recipients. Post-transfusion notification of appropriate personnel is required if cultures identify slow-growing bacteria after product release or transfusion. If bacterial contamination of a component is suspected, the transfusion should be stopped immediately, the unit should be saved for further testing, and blood cultures should be obtained from the recipient. Bacterial isolates from cultures of the recipient and unit should be saved for further investigation. The AABB should be consulted for management guidance (www.aabb.org/) . In 2007, the FDA cleared for marketing a rapid test to screen for bacterial contamination of Platelets before transfusion (www.fda.gov/bbs/topics/NEWS/2007/NEW01702.html) .
Red Blood Cell units are much less likely than are Platelets to contain bacteria at the time of transfusion, because refrigeration kills or inhibits growth of many bacteria. However, certain bacteria, most notably gram-negative organisms, such as Yersinia enterocolitica , may contaminate Red Blood Cells, because they survive cold storage. Cases of septic shock and death attributable to transfusion-transmitted Y enterocolitica and other gram-negative organisms have been documented.
Reported rates of transfusion-associated bacterial sepsis have varied widely depending on study methodology and microbial detection methods used. A prospective, multisite study (the Assessment of the Frequency of Blood Component Bacterial Contamination Associated with Transfusion Reaction [BaCon] Study) estimated the rate of transfusion-transmitted sepsis to be 1 in 100 000 units for single-donor and pooled Platelets and 1 in 5 million units for Red Blood Cells. Other studies that did not require matching bacterial cultures and/or molecular typing of both the component and the recipient's blood, as in the BaCon Study, or which included less severe recipient reactions in addition to sepsis have found higher rates of infection.
Several parasitic agents have been reported to cause transfusion-transmitted infections, including malaria, Chagas disease, babesiosis, toxoplasmosis, and leishmaniasis. Increasing travel to and immigration from areas with endemic infection have led to a need for increased vigilance in the United States. Babesiosis and toxoplasmosis are endemic in the United States.
The incidence of transfusion-associated malaria has decreased over the last 30 years in the United States. During the last decade, the rate has ranged from 0 to 0.18 cases per million units transfused-that is, no more than 1 to 2 cases per year. Most cases are attributed to infectious donors who have immigrated to the United States rather than people born in the United States who traveled to areas with endemic infection. Plasmodium falciparum is the species most commonly transmitted. Prevention of transfusion-transmitted malaria relies on interviewing donors for risk factors related to residence in or travel to areas with endemic infection or previous Treatment for malaria. Donation should be delayed until 3 years after either completing Treatment of malaria or living in a country where malaria is found and 12 months after returning from a trip to an area where malaria is found. There is no approved laboratory test to screen donated blood for malaria.
Chagas Disease (see American Trypanosomiasis)
The immigration of millions of people from areas with endemic T cruzi infection (parts of Central America, South America, and Mexico) and increased international travel have raised concern about the potential for transfusion-transmitted Chagas disease. To date, fewer than 10 cases of transfusion-transmitted Chagas disease have been reported in North America. However, studies of blood donors likely to have been born in or to have traveled to areas with endemic infection have found antibodies to T cruzi in as many as 0.5% of people tested. Although recognized transfusion transmissions of T cruzi in the United States have been rare, in some areas of the United States, the prevalence of Chagas disease estimated by detection of antibodies, appears to have increased in recent years. Screening for Chagas disease by donor history has not been adequately sensitive or specific. In December 2006, the FDA licensed a test for T cruzi (www.fda.gov/bbs/topics/NEWS/2006/NEW01524.html) . The American Red Cross tested approximately 150 000 samples from areas of the United States where some blood donors were expected to have undiagnosed Chagas disease and found that 61 donors were repeatedly reactive for antibodies to T cruzi (www.cdc.gov/mmwr/preview/mmwrhtml/mm5607a2.htm) . The AABB offered recommendations to member facilities regarding appropriate use of the test. The American Red Cross and Blood Systems, Inc began screening all blood donations in January 2008. As of November 2007, the FDA concluded that the test offers an important new safety measure and is expected to issue specific guidance for appropriate use of the test for all blood donations.
The most commonly reported transfusion-associated tickborne infection in the United States is babesiosis. More than 30 cases of transfusion-induced babesiosis have been documented; most were attributed to Babesia microti , but the WA1-type Babesia parasite also has been implicated. Babesia organisms are intracellular parasites that infect red blood cells. However, at least 4 cases have been associated with receipt of Platelets, which often contain a small number of red blood cells. Although most infections are asymptomatic, Babesia infection can cause severe, life-threatening disease, particularly in elderly or splenectomized patients. Severe infection can result in hemolytic anemia, thrombocytopenia, and renal failure. Surveys using indirect immunofluorescent antibody assays in areas of Connecticut and New York with highly endemic infection have revealed seropositivity rates for B microti in approximately 1% and 4%, respectively. In a study of blood donors in Connecticut, 19 (56%) of 34 seropositive donors had positive results for nucleic acid, as determined by polymerase chain reaction (PCR) assay. Blood from 3 (20%) of 15 donors with positive PCR assay results was infectious when inoculated into hamsters, and infection was transmitted to recipients of blood from approximately 1 in 4 donors with positive PCR assay results.
No licensed test is available to screen donors for Babesia organisms. Donors with a history of babesiosis are deferred indefinitely from future donation. Although people with acute illness or fever are not eligible to donate, infected people commonly are asymptomatic or experience only mild and nonspecific clinical symptoms. In addition, Babesia species can cause asymptomatic infection for months and even years in untreated, otherwise healthy people. Questioning donors about recent tick bites has been shown to be ineffective, because donors who are seropositive for antibody to tickborne agents are no more likely than seronegative donors to recall tick bites.
Transmissible Spongiform Encephalopathies: Prion Disease
Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease
Creutzfeldt-Jakob disease (CJD) and Variant CJD (vCJD) are fatal neurologic illnesses caused by unique infectious agents known as prions (see Transmissible Spongiform Encephalopathies).
The risk of transmitting most forms of CJD through blood has been considered theoretical. No cases of CJD resulting from receipt of blood transfusion from donors who later developed sporadic, familial, or iatrogenic forms of CJD have been documented, and case-control studies have not found an association between receipt of blood and development of CJD.
Nevertheless, because blood of animals with a number of naturally acquired and experimental transmissible spongiform encephalopathies (TSEs) may be infective, concerns have remained about the theoretical risk of transmitting CJD by blood transfusion. Since 1987, the FDA has recommended that certain people at increased risk of having CJD be deferred as blood donors. Concern increased after 4 reports of transfusion-transmitted vCJD (see next paragraph). People with signs of CJD or who are at increased risk of other forms of CJD (eg, receipt of pituitary-derived growth hormone or dura mater transplant or family history of CJD) should be deferred from donation. In addition, if postdonation information reveals that a donor should have been deferred because of increased CJD risk, in-date Whole Blood and components, including unpooled Plasma remaining from previous donations, should be retrieved and discarded; if those units already have been distributed, a biological product deviation report should be submitted to the FDA by the blood establishment. However, since 1998, withdrawal of plasma derivatives no longer has been recommended in that situation, because epidemiologic and laboratory data suggest that most plasma derivatives are much less likely to transmit TSE agents than are blood components, because Plasma undergoes extensive processing during fractionation.
In 1996, cases of a new clinically and histopathologically distinct variant form of CJD (vCJD) first were reported in the United Kingdom. The agent causing this new TSE is believed to be the same as that of bovine spongiform encephalopathy (BSE). BSE in cattle first was recognized in the United Kingdom in 1986 and later in more than 20 other countries.
Transmission of vCJD to 4 elderly people in the United Kingdom presumptively has been attributed to transfusions years earlier with nonleukoreduced Red Blood Cells from healthy donors who became ill with vCJD 16 months to 3.5 years after the donations. Three of the recipients had typical vCJD, and a fourth had evidence of preclinical or subclinical infection. The asymptomatic incubation periods in the clinically ill recipients lasted from 6.3 to 8.5 years; the patient with evidence of preclinical infection died of an unrelated illness approximately 5 years after receiving the implicated transfusion. Recipients of blood components from other donors later diagnosed with vCJD remain under surveillance in the United Kingdom and France. As a precaution, authorities in the United Kingdom have notified recipients of plasma derivatives that they also may be at increased risk of vCJD; the magnitude of that risk is uncertain, and at the time of this writing, no case of vCJD has been attributed to Treatment with a plasma derivative.
In the United States, the following categories of potential blood and plasma donors are deferred indefinitely: people who received a blood or blood component transfusion in the United Kingdom after January 1, 1980, when the BSE epidemic is believed to have begun; people who have lived in the United Kingdom for any combined period of 3 months or more from the beginning of 1980 until the end of 1996 (after which rigorous food protection measures were implemented fully throughout the United Kingdom); people who spent a total of 5 years or more in most other European countries (excluding countries of the former Soviet Union) from 1980 to the present; people injected with bovine insulin, unless it is confirmed that the insulin was not manufactured from cattle in the United Kingdom; and military personnel, civilian employees, and dependents who resided or worked on US military bases from 1980 through the end of 1990 in northern Europe or the end of 1996 in southern Europe (as defined by the US Department of Defense). Policies regarding CJD donor deferral may change, and blood and Plasma programs are expected to remain informed about such changes, which are announced promptly by trade organizations and the FDA.
Improving Blood Safety
A number of strategies have been proposed or implemented to further decrease the risk of transmission of infectious agents through blood and blood products. Various safety strategies are as follows.
Elimination of Infectious Agents
Virtually all Plasma derivatives, including Immune Globulin Intravenous (IGIV) and clotting factors, are treated to eliminate infectious agents that may be present despite screening measures. Methods used for this include wet and dry heat and Treatment with a solvent/detergent. Solvent/detergent-treated pooled Plasma for transfusion no longer is marketed in the United States, but methods of treating single-donor Plasma are under study. Solvent/detergent Treatment dissolves the lipid envelope of HIV, HBV, and HCV but is not effective against non-lipid-enveloped viruses, such as HAV and parvovirus B19. Transmission of HIV through administration of IGIV never has been documented.
Because of the fragility of Red Blood Cells and Platelets, pathogen inactivation is more difficult. However, several methods have been developed, such as addition of psoralens followed by exposure to ultraviolet A, which binds nucleic acids and blocks replication of bacteria and viruses. Clinical trials of these treated components are underway.
Leukoreduction, whereby filters are used to remove donor white blood cells, is performed increasingly in the United States. Benefits of this process include decreasing febrile transfusion reactions related to white blood cells and their products and decreasing the immune modulation associated with transfusion. Leukoreduction also decreases cell-associated agents (eg, intracellular viruses, such as CMV, Epstein-Barr virus, HHV-8, and HTLV). Several countries have adopted this practice.
Decreasing Exposure to Blood Products
Current screening policies have decreased the risk of transfusion associated infections dramatically, but blood products remain a source of known and potentially unknown infection agents.
Alternatives to Human Blood Products
Many alternatives to human blood products have been developed. Established alternatives include recombinant clotting factors for patients with hemophilia and factors such as erythropoietin used to stimulate red blood cell production. Physicians should use the lowest erythropoiesis-stimulating agent (ESA) dose that will increase the hemoglobin level gradually to a concentration not exceeding 12 g/dL. Increased risks of death and serious cardiovascular and thrombotic events have been described when ESAs were administered to achieve a target hemoglobin concentration greater than 12 g/dL in people with chronic kidney failure and surgical candidates. These adverse safety outcomes and shortened time to tumor progression have been observed in certain patients with cancer with chemotherapy-related anemia, such as people with advanced head and neck cancer receiving radiation therapy and metastatic breast cancer.
Other agents currently in clinical trials include hemoglobin-based oxygen carriers, Red Blood Cell substitutes, such as human hemoglobin extracted from Red Blood Cells, recombinant human hemoglobin, animal hemoglobin, and various oxygen-carrying chemicals.
Another means of decreasing recipient exposure is autologous transfusion. Blood may be donated by the patient several weeks before a surgical procedure (preoperative autologous donation) or, alternatively, donated immediately before surgery and replaced with a volume expander (acute normovolemic hemodilution). In either case, the patient's blood can be reinfused if needed. Autologous blood is not completely risk free, because bacterial contamination may occur.
Blood recycling techniques (autotransfusion) also are in this category. During surgery, blood lost by the patient may be collected, processed, and reinfused to the patient.
Surveillance For Transfusion-transmitted Infection
Transfusion-transmitted infection surveillance is crucial and must be coupled with the capacity to investigate reported cases rapidly and to implement measures needed to prevent additional infections. The AABB and CDC have begun a collaboration to develop a blood transfusion adverse event module in the National Healthcare Safety Network, a voluntary prospective surveillance system. Serious adverse reactions and product problems should be reported to the manufacturer (or, alternatively, to the supplier for transmission to the manufacturer). Health care professionals also may report such information directly to the FDA through MedWatch. This can be done by telephone (1-800-FDA-1088), fax (1-800-FDA-0178), Internet (www.fda.gov/medwatch/report/hcp.htm) , or mail (see MedWatch). Voluntary reporting is considered vital for monitoring product safety.
Organ And Tissue Transplantation
More than 25 000 organ and 2 000 000 tissue transplantations (eg, musculoskeletal allografts, cornea, and skin) and numerous cell therapy infusions (eg, bone marrow and peripheral stem cell transplants) occur each year in the United States. The proliferation of these products also has increased the opportunities for transmission of infectious pathogens, including bacteria, viruses, and parasites. Transmission of Chagas disease, Mycobacterium tuberculosis , lymphocytic choriomeningitis virus, rabies, WNV, HIV, and HCV have been reported through organ transplantation.
In 2005, the FDA final rule, Current Good Tissue Practice for Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), became effective. The purpose of this rule is to improve the safety of HCT/Ps by preventing introduction, transmission, and spread of communicable disease through transplantation of HCT/Ps.1 The Joint Commission adopted some of these standards, which will apply to accredited organizations that store or use tissue. In addition, The Transplantation Transmission Sentinel Network is a system under development to facilitate recognition of adverse events associated with transplanted allografts (organs, tissues, and eyes). Along with receiving mandatory reports of adverse events from HCT/P establishments that manufacture tissue, the FDA encourages direct voluntary reporting through its MedWatch program by using MedWatch Form FDA-3500 (available at www.fda.gov/medwatch). Additional information about the FDA and HCT/Ps is available at www.fda.gov/cber/tiss.htm.
a . For additional information, see Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine. First of two parts: blood transfusion. N Engl J Med . 1999;340(7):438-447; and Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine. Second of two parts: blood conservation. N Engl J Med . 1999;340(7):525-533. [PMID:10021474]
b . Other transfusion-transmitted agents include Toxoplasma gondii and leishmanial species.
1 . Centers for Disease Control and Prevention. Notice to Readers: FDA Rule for Current Good Tissue Practice for Human Cells, Tissues, and Cellular and Tissue-Based Products. MMWR Morb Mortal Wkly Rep . 2005;54(19):490
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