Chapter 138: Blood Procurement and Red Cell Transfusion

The United States has a pluralistic system of blood collection rather than the single national system that exists in other developed countries. In the United States during 2011, approximately 15,721,000 units of blood were available for use (Table 138–1). This was a 9 percent decrease from 2008. Approximately 94 percent of the blood was collected in regional blood centers and hospitals collected 7 percent.¹ Less than 1percent of the units donated in the United States were autologous donations or directed donations, that is, blood given by family or friends for a specific patient. Both autologous and directed donations decreased substantially from 2008.¹ Of red cells collected, 97.7 percent of allogeneic, 59.0 percent of autologous, and 72.0 percent of directed donor red cells were transfused to the intended recipient.

All whole blood for transfusion in the United States is donated by unpaid volunteers; however, costs are incurred in the collection, testing, production, and distribution of blood components. Blood banks pass on these costs to hospitals. Some areas of the United States are able to collect more blood than is needed locally and other areas are unable to collect enough blood to meet their local needs. Several inventory-sharing systems are used to move blood around the United States so as to alleviate the shortages.

Blood is considered a drug and all aspects of the selection of donors, collection, processing, testing, preservation, and dispensing are regulated by the FDA. The FDA requirements define the procedures, record-keeping, staff proficiency, specific testing, and donor medical requirements that blood banks must follow. Blood banks meet these requirements using the FDA-defined good manufacturing practices that are similar to those used by pharmaceutical manufacturers.² Additional standards are formulated by the American Association of Blood Banks (AABB), a voluntary organization that accredits blood banks.

Approximately 107 million units of blood are collected annually worldwide. Considerable differences in the availability of blood and blood components throughout the world are related to the extent of development in the country and the country's healthcare system.³ The amount of blood collected in relation to the population ranges from 50 donations per 1000 population in industrialized countries to five to 15 per 1000 population in developing countries and one to five per 1000 population in the least-developed countries.³ Thus, industrialized countries utilize transfused blood products far more commonly. In developed countries, especially Western Europe and parts of Asia, a governmental agency usually oversees the blood collection activities, although the extent to which the government sets requirements and monitors or inspects the blood collection system varies. In developed countries, the basic processes of donor medical screening, blood collection, laboratory testing, and preparation of blood components are similar to the system found in the United States. In virtually all developed countries, blood is donated by volunteers because paid donors are associated with a higher risk of disease transmission.⁴ The basic blood components—red cells, platelets, and plasma—usually are available and apheresis instruments are used to collect platelets. Plasma derivatives such as albumin, coagulation factor VIII, other plasma protein concentrates (coagulation factors or inhibitors, or complement factor-1 inhibitor) and immune globulins are available.

However, in the developing world the blood supply is very limited and components are often not available. Patients may be required to arrange for the blood they need so donors may be friends or family members of patients or even individuals who have been paid by the patient's family to donate the blood needed. Donor screening may not be as extensive, transmissible disease testing may be lacking, and equipment may be reused. These difficulties may be compounded by the presence of endemic transfusion-transmissible diseases for which screening is difficult or expensive and thus not performed as extensively as in more developed countries. Great strides have been made during the last decade primarily from the U.S.-funded President's Emergency Plan for AIDS Relief (PEPFAR) program.⁵ Thus, the availability of blood and its components around the world varies widely, from inadequate supplies and uncertain safety to sophisticated supply systems and component availability equal to or surpassing those of the United States.

The plasma industry is separate from the blood banking system described above. Plasma can be subjected to a fractionation process to produce several medically valuable products referred to as plasma derivatives. Plasma fractionation is performed in manufacturing plants in batches of up to 10,000 L involving the pooling of plasma from a large number of donors. Plasma for manufacture or fractionation into derivatives can be obtained from units of whole blood, but this amount of plasma is inadequate to meet the needs for plasma derivatives. Consequently, large amounts of plasma are obtained by plasmapheresis in which only the plasma and not red cells or platelets are retained from the donor. Individuals can donate plasma up to two times per week and usually are paid because of the more extensive time commitment. This plasma collection system usually is operated by for-profit organizations and functions separately from the system for whole-blood donation.

Approximately 29 million liters of plasma were collected in the United States in 2013. Twenty-six plasma derivatives are approved for licensure by the FDA. Disruption in the sources of plasma or in one manufacturer's plant can have serious consequences and create shortages of certain derivatives.

The remainder of this chapter describes the blood collection system operated by voluntary community organizations to provide cellular and whole-blood–derived components.

Although most Americans will require a blood transfusion at some time in their lives, only about one-third of the U.S. population is eligible to donate blood,⁶ and only a small portion of those actually donate. Blood donors are more likely than the general population to be male, age 30 to 50 years, white, employed, and have more education and higher income.⁷ It is generally believed that the most effective way to get someone to donate blood is to ask him or her personally. Factors such as the convenience of donation, peer pressure, receipt of blood by a family member, and perceived community needs are important factors that are superimposed onto the individual's basic social commitments.

The approach to the selection of blood donors is designed to (1) ensure the safety of the donor and (2) obtain a high-quality blood component that is as safe as possible for the recipient. Some specific steps that are taken to ensure that blood is as safe as possible are the use of only volunteer blood donors; questioning of donors about their general health before their donation is scheduled; obtaining a medical history, including specific risk factors, before donation; conducting a brief physical examination before donation; laboratory testing of donated blood; checking the donor's identity against a donor deferral registry; and providing a method by which the donor can confidentially designate the unit as unsuitable for transfusion after the donation is completed.

HEALTH HISTORY, PHYSICAL EXAMINATION, AND LABORATORY EXAMINATION OF THE BLOOD

The health history is usually done by a computer-assisted self-interview. The questions designed to protect the safety of the donor include whether the donor is under the care of a physician or has a history of cardiovascular or lung disease, seizures, present or recent pregnancy, recent donation of blood or plasma, recent major illness or surgery, unexplained weight loss, unusual bleeding, or is taking medication(s). Some medications may make the donor unsuitable because of the condition requiring the medication, whereas other medications may be potentially harmful to the recipient. Questions designed to protect the safety of the recipient include those related to the donor's general health, history of receipt of growth hormone, and occurrence of or exposure to patients with hepatitis or other liver disease, or a previous diagnosis of HIV or AIDS (or symptoms of AIDS), Chagas disease, babesiosis, or Zika virus. A history also is obtained regarding the injection of drugs; receipt of coagulation factor concentrates; blood transfusion; tattoos; acupuncture; body piercing; receipt of an organ or tissue transplant; recent travel to areas endemic for malaria or Zika virus;⁸ recent immunizations; ingestion of medications (especially aspirin); presence of a major illness or surgery; and previous notice of a positive test for a transmissible disease. In addition, several questions are related to AIDS risk behavior, including whether the potential donor has had sex with anyone with AIDS, given or received money or drugs for sex, (for males) had sex with another male, or (for females) had sex with a male who has had sex with another male.

The physical examination includes determination of the temperature, pulse, blood pressure, weight, and blood hemoglobin (Hgb) concentration. The donor's general appearance is assessed for any signs of illness or the influence of drugs or alcohol. The skin at the venipuncture site is examined for signs of intravenous drug abuse, and local lesions that would make disinfecting the skin difficult and thus lead to contamination of the blood unit during venipuncture.

BLOOD CONTAINERS

Blood must be collected into single-use, sterile, FDA-licensed containers. The containers are made of plasticized material that is biocompatible with blood cells and allows diffusion of gases so as to provide optimal cell preservation. These blood containers are combinations of bags and integral tubing that allow separation of the whole blood into its components in a closed system, thus minimizing the chance of bacterial contamination while making storage of the components for days or weeks possible. Plasticizers from the bags accumulate in red cell components during storage and can be found in tissues of multitransfused patients but also in healthy nontransfused individuals. Although no evidence indicates that transfusion of this material causes clinical problems, containers without plasticizers are now used in some countries.

VENIPUNCTURE AND BLOOD COLLECTION

The blood should be drawn from an area free of skin lesions and the phlebotomy site should be decontaminated. The site is scrubbed with a soap solution, followed by the application of tincture of iodine or iodophor complex solution. The venipuncture is done with a needle that should be used only once in order to prevent contamination. The blood must flow freely and be mixed with anticoagulant frequently as the blood fills the container to prevent the development of small clots. The actual time for collection of 450 to 500 mL usually is approximately 7 minutes and almost always is less than 10 minutes. During blood donation, cardiac output falls slightly but heart rate changes little. A slight decrease in systolic pressure results with a rise in peripheral resistance and diastolic blood pressure.

Usually 500 mL is collected. The blood is mixed with 63 to 70 mL of anticoagulant composed of citrate, phosphate, and dextrose (CPD). The amount of blood withdrawn must be within prescribed limits so as to maintain the proper ratio with the anticoagulant; otherwise, the blood cells may be damaged and/or anticoagulation may be unsatisfactory.

An untoward reaction occurs after approximately 2 to 5 percent of blood donations, but, fortunately, most of the reactions are not serious. Donors who have reactions are more likely to be younger, unmarried, have a higher predonation heart rate and lower diastolic blood pressure, lower weight, female, and first-time or infrequent donors. Donors who experience a reaction are less likely to donate in the future.

The most common reactions to blood donation are weakness, cool skin, and diaphoresis.⁹ More extensive, but still moderate, reactions are dizziness, pallor, hypertension, and bradycardia.¹⁰ Bradycardia usually is considered a sign of a vasovagal reaction rather than hypotensive or cardiovascular shock, where tachycardia would be expected. In a more severe form, a vasovagal reaction may progress to loss of consciousness, convulsions, and involuntary passage of urine or stool. Other reactions include nausea and vomiting; hyperventilation, sometimes leading to twitching or muscle spasms; hematoma at the venipuncture site; convulsions; and serious cardiac difficulties. Such serious reactions are rare. Injury of the brachial nerve and resulting pain and/or paresthesia may occur as a result of needle puncture of the nerve or compression from a hematoma.

Donors are advised to drink extra fluids to replace lost blood volume and to avoid strenuous exercise for the remainder of the day of donation. The latter advice is given to prevent fainting and to minimize the possibility of hematoma development at the venipuncture site. Some donors are subject to lightheadedness or even fainting if they change position quickly. Therefore, donors are advised not to return to work for the remainder of the day if they have an occupation where fainting would be hazardous to themselves or others.

AUTOLOGOUS DONOR BLOOD

Autologous blood for transfusion can be obtained by preoperative donation, acute normovolemic hemodilution, intraoperative salvage, and postoperative salvage, but only preoperative donation is discussed here. Most commonly, this situation occurs with elective surgery. Autologous blood accounts for a very low level (<1 percent) of the United States' blood supply.¹

If patient candidates for autologous blood donation meet the usual FDA criteria for blood donation, their blood can be used for other patients if the original autologous donor has no need for the blood. However, this practice is not allowed by AABB standards and is usually not relevant because most patients do not meet the FDA donation criteria. If the autologous donor does not meet the FDA criteria for blood donation, the blood must be specially labeled, segregated during storage, and discarded if it is not used by that specific patient. Thus, the autologous blood donation should be collected only for procedures with a substantial likelihood that the blood will be used. Without this type of planning, a very high rate of wastage of autologous blood is observed, estimated at 59 percent in 2011.¹ Thus, the cost of autologous blood is high.

No age or weight restrictions exist for autologous donation. Pregnant women can donate, but this practice is not recommended routinely because these patients rarely require transfusion. The autologous donor's Hgb may be lower (11 g/dL) than that required for routine donors (12.5 g/dL), although usually only 2 to 4 units of blood can be obtained before the Hgb falls below 11 g/dL. Autologous blood donors can be given erythropoietin and iron to increase the number of units of blood they can donate,^11,12 although this strategy has not been shown to reduce the need for allogeneic donor blood. Reactions in autologous donors are similar to allogeneic donors and are related to first-time donation, female gender, lower age, and lower weight.

Autologous blood must be typed for ABO and Rh antigens. If the unit is to be shipped to another facility for transfusion, it must be tested for transmissible diseases similar to allogeneic blood. If any of the transmissible disease tests are positive, the unit must be labeled with a biohazard label.

DIRECTED DONOR BLOOD

Directed donors are friends or relatives who wish to give blood for a specific patient because the patient hopes those donors will be safer than the regular blood supply. However, directed donors do not have a lower incidence of transmissible disease markers¹³ and thus do not support a realistic rationale for these donations. Because the blood becomes part of the community's general blood supply if it is not used for the originally intended patient, directed donors must meet all the usual FDA requirements for routine blood donation.

PATIENT-SPECIFIC DONATION

In a few situations, appropriate transfusion therapy involves collecting blood from a particular donor for a particular patient. Examples are donor-specific transfusions prior to kidney transplantation, maternal platelets for a fetus projected to have neonatal alloimmune thrombocytopenic purpura (NATP), or family members of a patient with a rare blood type. Usually, these donors must meet all the usual FDA requirements, except that they may donate as often as every 3 days so long as the Hgb remains above the normal donor minimum of 12.5 g/dL. An exception is donation of maternal platelets for a neonate with NATP. Patient-specific donated units must undergo all routine laboratory testing.

THERAPEUTIC BLEEDING

Blood can be collected as part of the therapy of diseases such as polycythemia vera or primary hemochromatosis. Usually such blood is not used for transfusion because the donors do not meet the FDA standards for donor health. As the genetic basis of hemochromatosis has become better understood, blood removed from these patients appears to be safe and red cells from patients with hemochromatosis are normal during blood bank storage,¹⁴ and although a blood collection program can operate successfully, this has not gained general acceptance.

Blood components can be obtained by apheresis rather than prepared from whole blood. In apheresis, the donor's anticoagulated whole blood is passed through an instrument in which they use centrifugation to separate the blood components. Red cells, platelets, granulocytes, blood stem cells, mononuclear cells, and plasma can be obtained by apheresis.

PLATELETPHERESIS

In the United States, approximately 92 percent of platelet concentrates are produced by plateletpheresis (see Table 138–1). Plateletpheresis requires approximately 90 minutes, during which approximately 4000 to 5000 mL of the donor's blood is processed through the blood cell separator. The process results in a platelet concentrate with a volume of approximately 200 mL and containing approximately 4.0 × 10¹¹ platelets and less than 0.5 mL red cells. Currently manufactured blood cell separators produce a platelet concentrate that contains less than 5 × 10⁶ leukocytes and thus can be considered leukocyte reduced. Following plateletpheresis, the donor's platelet count declines by approximately 30 percent but returns to preplateletpheresis levels in approximately 4 days.

COLLECTION OF RED CELLS BY APHERESIS

Chronic shortages of group O red cells stimulated interest in the use of apheresis for collecting the equivalent of 2 units of red cells from some donors, especially group O.¹⁵ In 2011, 1,978,000 units of red cells were collected by apheresis.¹ The collection procedure is similar to other apheresis procedures, except that red cells are retained rather than returned to the donor. The red cells usually have a very high hematocrit (Hct) as they are removed from the instrument, but an additive solution is incorporated and the red cells can be stored for the usual 42 days. Red cells obtained by apheresis have the same characteristics as those produced from whole blood. Because 2 U of red cells are removed, donors may donate only every 4 months.

LEUKAPHERESIS

Leukapheresis has been used to produce a granulocyte concentrate for transfusion therapy of infections unresponsive to antibiotics. Because the efficiency of granulocyte extraction from whole blood is less than for platelets, the leukapheresis procedure involves processing 6500 to 8000 mL of donor blood for approximately 3 hours. To increase the separation of granulocytes from other blood components, hydroxyethyl starch is added to the blood-cell–separator flow system. In addition, glucocorticoids and granulocyte colony-stimulating factor (G-CSF) have been administered to granulocyte donors to increase the granulocyte count and the granulocyte yield.¹⁶

PLASMAPHERESIS

Plasmapheresis is used to obtain plasma for manufacture of derivatives but not plasma for transfusion. Plasmapheresis usually can be performed in approximately 30 minutes and produces up to 750 mL of plasma. Because few red cells are removed, the procedure can be repeated up to two times per week, so theoretically a donor could provide a large amount of plasma. Because of the nature and possible frequency of plasma donation, special donor criteria apply.

The selection of donors for apheresis uses the same criteria as for whole-blood donation with some additional donor requirements. No more than 15 percent of the donor's blood should be extracorporeal during apheresis; thus, the donor's size is considered when making decisions about specific apheresis procedures or instruments to be used. The platelet count must be monitored for frequent donors. Because a plateletpheresis concentrate would be the sole source of platelets for the transfusion, the donor must not have taken aspirin for at least 3 days.

The amount of blood components removed from apheresis donors must be monitored. Not more than 200 mL of red cells per 2 months or approximately 1500 mL of plasma per week can be removed. The laboratory testing of donors and apheresis components for transmissible diseases is the same as for whole-blood donation. Thus, the likelihood of disease transmission from apheresis components is the same as from whole blood.

Apheresis donors can experience the same kind of reactions as whole-blood donors. In addition, apheresis donors experience a higher incidence of paresthesias, probably because of the infusion of citrate (that may affect calcium levels) used to anticoagulate the donor's blood while it is in the cell separator. This type of reaction is managed by slowing the blood flow rate through the instrument, which slows the rate of citrate infusion. In leukapheresis, donors can be given glucocorticoid and/or G-CSF to increase the granulocyte count, and the sedimenting agent hydroxyethyl starch is used in the cell separator to improve the granulocyte yield. When G-CSF and glucocorticoids are used, approximately 60 percent of donors experience side effects, usually myalgia, arthralgia, headache, or flu-like symptoms.¹⁶ The major side effect of hydroxyethyl starch is blood volume expansion manifested by headache and/or hypertension.

Each unit of whole blood or each apheresis component undergoes a standard battery of tests, including those for blood type, red cell antibodies (including ABO, Rh, minor antigens), and transmissible diseases (Table 138–2). Additional tests, such as those for cytomegalovirus (CMV) antibodies, may be done. During the last few years, testing for West Nile virus and Trypanosoma cruzi have been added. Babesia is another transfusion transmissible disease¹⁷ for which a donor screening test has been developed. It is not clear whether routine testing will be introduced.

Ironically, the improvements in blood safety have occurred at a time of the public's increased fear of transfusion and the more cautious use of blood components by physicians. Each step in the overall process of donor evaluation and testing adds to blood safety in important ways, and the medical history is important as illustrated by the 90 percent reduction in HIV infectivity from the use of donor-selection criteria identifying HIV risk behavior.¹⁸ Tests for transmissible diseases further reduce the proportion of infectious donors.¹⁹ Donor deferral registries detect individuals who previously were deferred as blood donors but who for various reasons attempt to donate again. Currently, the risk of acquiring a transfusion-transmitted disease ranges from one per 150,000/unit for hepatitis B to one per 2,135,000/unit for HIV (Table 138–3). Thus, although the blood supply is safer than ever, transfusion is not risk free and should be undertaken only after careful consideration of the patient's clinical situation and specific blood component needs.

Red blood cell (RBC) transfusions are indicated to increase oxygen carrying capacity in anemic patients. While oxygen extraction and delivery may be measured using invasive procedures, these methods are not available in most clinical settings. As a result, the decision to transfuse RBCs is often based on Hgb or Hct value(s).

Transfusing RBCs to a critically anemic patient will increase the oxygen-carrying capacity; however, the utility of RBC transfusions in an asymptomatic patient with a Hgb between 6 and 10 g/dL is less clear. Most of the large, prospective, randomized controlled studies looking at RBC usage and transfusion triggers did not specifically address the question of increased oxygen-carrying capacity at various Hgb/Hct levels. Instead they used the more practical markers of mortality, end-organ dysfunction, or adverse events to determine the efficacy and safety of restrictive (low Hgb threshold) versus liberal (higher Hgb threshold) transfusion strategies.

RED BLOOD CELL TRANSFUSION THRESHOLDS

The Transfusion Requirements in Critical Care (TRICC) trial was the first adequately powered study to compare a restrictive and liberal strategy for RBC transfusions in critically ill patients.²³ A total of 838 ICU patients were randomized into two groups: a liberal arm, which maintained Hgb concentrations between 10 and 12 g/dL and gave transfusions when the Hgb concentration fell below 10 g/dL; and a restrictive arm, which maintained Hgb levels between 7 and 9 g/dL and used a Hgb value of 7 g/dL as the trigger for transfusion. The exclusion criteria included age younger than 16 years; active blood loss at the time of enrollment; admission after a routine cardiac procedure; chronic anemia; imminent death; and others. Thirty-day mortality from all causes was the primary outcome measure. Secondary outcomes included 60-day mortality, death during hospitalization, and multiple-organ dysfunction (MOD). The severity of a patient's illness was classified using the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. This and other patient characteristics were statistically similar in the two study arms. This study was designed as an equivalency trial, and overall found similar results in the two groups for 30-day mortality (18.7 vs. 23.3 percent; p = 0.11), as well as for the secondary outcomes. Thirty-day mortality rates among patients in the restrictive transfusion arm who were less acutely ill (APACHE II ≤20) (8.7 vs. 16.1 percent; p = 0.03), or were younger than 55 years old (5.7 vs. 13.0 percent; p = 0.02). The restrictive group also received fewer transfusions (54 percent) than the liberal group. The authors concluded that “a restrictive strategy is as least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients.…”

Studies conducted after the TRICC trial have used various categories of high-risk patients to better define RBC transfusion thresholds in these populations (Table 138–4). Studies have focused on patients with upper gastrointestinal bleeding, cardiovascular risk factors, orthopedic surgery patients and other populations that usually require a large number of RBC transfusions. All studies followed the basic structure of the TRICC trial, randomizing patients into a restrictive versus liberal arm. Most studies also used mortality or end-organ dysfunction as end points.

A total of 899 patients with an upper gastrointestinal bleed were randomized so that the restrictive arm had a transfusion threshold of 7 g/dL versus a Hgb level of 9 g/dL for the liberal arm.²⁴ Death from any cause within the first 45 days was the primary outcome, and the rate of further bleeding and in-hospital complications were used as secondary outcomes. The two patient groups had similar characteristics, including equivalent numbers and grades of cirrhosis. The results of this study also favored a restrictive transfusion strategy. The probability of survival at 6 weeks was higher in the restrictive strategy group (p = 0.02) and the risk of further bleeding was lower (p = 0.01). Overall adverse events were also lower in the restrictive group when compared to the liberal transfusion arm (p = 0.02). The rate of survival was slightly higher in the restrictive group compared to the liberal group for patients with peptic ulcers (hazard ratio, 0.70; 95 percent confidence interval [CI], 0.26 to 1.25); and was significantly higher in patients with cirrhosis and Child-Pugh class A or B disease (hazard ratio, 0.30; 95 percent CI, 0.11 to 0.85). No difference was found for cirrhosis patients and Child-Pugh class C disease (hazard ratio 1.04; 95 percent CI, 0.45 to 2.37). As with the TRICC study, a highly significant difference in transfusion rates was reported. In the restrictive arm, 51 percent of patients did not receive a transfusion, compared to 15 percent of patients in the liberal arm who did not receive RBC transfusions (p <0.001). These two major trials demonstrated that a 7 g/dL Hgb threshold was safe for a variety of critically ill patients.

RED BLOOD CELL TRANSFUSIONS FOR CARDIOVASCULAR PATIENTS

Moderate anemia may lead to increased rates of myocardial ischemia and infarction in patients with cardiovascular risk factors. Several studies were designed to test whether lower transfusion thresholds were deleterious in this patient population. A subgroup analysis of the TRICC trial found that patients with cardiovascular disease had similar outcomes in the restrictive and liberal cohorts; however, the rate of patients suffering from acute pulmonary edema was significantly higher in the liberal transfusion arm.²⁵

The Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair (FOCUS trial) compared the transfusion thresholds of 10 g/dL versus less than 8 g/dL in patients who were status post–hip fracture repair and had cardiovascular risk factors.²⁶ The trial enrolled 2016 patients older than 50 years of age who were randomized into the restrictive or liberal transfusion threshold group. The primary outcome was death or an inability to walk across a room without human assistance on 60-day followup. Secondary outcomes included in-hospital myocardial infarction, unstable angina, or death for any reason. The liberal transfusion strategy, when compared with the restrictive strategy, did not reduce rates of death or inability to walk independently at 60-day followup or reduce in-hospital morbidity in elderly patients at high cardiovascular risk. The rates of in-hospital complications were similar in the two groups.

The Transfusion Requirements After Cardiac Surgery (TRACS) trial randomized patients who underwent cardiac surgery with cardiopulmonary bypass into a liberal (Hct ≥30 percent) or restrictive (Hct ≥24 percent) strategy for RBC transfusions.²⁷ This noninferiority study found similar rates of 30-day all-cause mortality and severe morbidity. The number of transfused RBC units was found to be an independent risk factor for complications or death at 30 days.

Taken together, the evidence points to a Hgb threshold of 8 g/dL as a safe level to maintain most patients with a history of cardiovascular disease. Patients with acute coronary syndrome continue to be an important exception for which current data is insufficient to support any guidance.

RED BLOOD CELL TRANSFUSIONS FOR ORTHOPEDIC PATIENTS

The FOCUS trial, discussed above (see “Red Blood Cell Transfusions for Cardiovascular Patients”), specifically identified patients with cardiovascular risk factors undergoing hip repair.²⁶ Other studies with orthopedic patients looked at more general outcome measures such as ability to ambulate after hip surgery. One prospective study found a significant association between anemia and a decreased ability to walk independently before the anemia was corrected.²⁸ However, a second prospective study found no differences in postoperative functional mobility or length of stay when comparing patients maintained on restrictive (8 g/dL) or liberal (10 g/dL) transfusion strategies.²⁹ However, the liberal transfusion group had few cardiovascular complications and lower mortality when compared to the restrictive group. The authors concluded that a liberal transfusion strategy does not increase ambulation scores but that a restrictive strategy should be treated with caution in elderly high-risk hip fracture patients.

The population in the FOCUS trial was elderly, high-risk cardiovascular patients; the finding of an 8 g/dL Hgb threshold for RBC transfusions may not be generalizable to the remaining lower-risk orthopedic patient population. However, until adequately powered studies are conducted in these populations, applying the 8 g/dL trigger is the safest approach for lower risk patients. While a Hgb of 8 g/dL is safe for orthopedic patients, the quality-of-life studies indicate that a higher Hgb allows for faster recovery.

RED BLOOD CELL TRANSFUSIONS FOR NEUROLOGICALLY IMPAIRED PATIENTS

No large scale, prospective randomized trial has been done regarding the safety and efficacy of transfusion practice in neurocritically ill patients. The lack of large studies led to a systematic review of six studies that had a combined total of 537 patients.³⁰ The Hgb triggers in these studies ranged from 7 to 10 g/dL in restrictive groups, to 9.3 to 11.5 g/dL in higher Hgb groups. While some studies reported shorter lengths of stay in the lower Hgb groups, the systematic review found insufficient evidence to guide transfusion practice in neurocritically ill patients.

RED BLOOD CELL TRANSFUSIONS FOR PEDIATRIC PATIENTS

Clinical trials of transfusion triggers for pediatric patients fall into two basic categories: general studies of critically ill pediatric patients and studies focused on high-risk neonates. The Transfusion Strategies for Patients in Pediatric Intensive Care Units (TRIPICU) trial and its affiliated subanalyses represent the major data set covering the pediatric population ranging from 3 days old to 14 years of age.³¹ The trial enrolled 626 patients who had Hgb less than or equal to 9.5 during their first 7 days in the pediatric ICU. The restrictive arm used a Hgb threshold of 7 g/dL, versus the liberal threshold of 9.5 g/dL. The restrictive group received significantly fewer transfusions yet multiple-organ dysfunction syndrome (MODS) and mortality were almost identified in the two arms of the study. Thus, for critically ill children, a Hgb threshold of 7 g/dL could decrease transfusion requirements without increasing adverse outcomes.

Three subgroup analyses were conducted with the TRIPICU data. One study analyzed postoperative patients,³² the second looked at pediatric patients after cardiac surgery,³³ and the third examined patients with sepsis.³⁴ All three found no significant differences between new or progressive MODS or 28-day mortality in the restrictive and liberal groups. However, all three studies suffered from small sample size and could not draw strong conclusions because of insufficient power.

Trials in the neonate population have focused on premature babies and infants of very low birth weight. Unlike the clinical trials in adults, where the results of all studies found that a restrictive transfusion approach was as good as, or possibly superior to a liberal transfusion strategy, the results from clinical trials in neonates were mixed. One trial enrolled 100 preterm infants with birth weights between 500 and 1300 g.³⁵ The transfusion thresholds in the restrictive and liberal arms were dependent upon the infant's age and respiratory status and varied from 22 to 34 percent in the low group to 30 to 46 percent in the high group. In each age group the transfusion threshold levels decreased with improving clinical status, as indicated by the level of respiratory support required. In either arm of the study, additional RBC transfusions could be given at the discretion of the attending neonatologist based on a set of predetermined circumstances. Infants in the restrictive arm of the study were more likely to have intraparenchymal brain hemorrhage or periventricular leukomalacia and also had more frequent episodes of mild and severe apnea. The liberal arm received more RBC transfusions; however, donor exposure was similar in both groups. The authors concluded that a restrictive transfusion practice may be harmful to preterm infants.

The largest trial of transfusion practice in preterm infants was the Premature Infants in Need of Transfusion (PINT) study.³⁶ This randomized trial asked whether extremely-low-birth-weight infants transfused at different Hgb thresholds had different rates of survival or morbidity at discharge. A total of 451 infants, each weighing less than 1000 g at birth, were randomized into a low or high Hgb threshold group. The thresholds ranged from 6.8 g/dL to 11.5 g/dL in the low group and 7.7 g/dL to 13.5 g/dL in the high group. The actual threshold was determined by a combination of age and presence or absence of respiratory support. There was no statistically significant difference between the two groups in terms of death before home discharge or survival with severe morbidity. In addition, fewer infants received one or more transfusions in the low threshold group. The authors concluded that maintaining extremely-low-birth-weight infants at a higher Hgb threshold conferred no benefit.

A Cochrane review of transfusion in neonates concluded that a restrictive approach resulted in a modest reduction in exposure to transfusion, but did not appear to have a significant impact on death or major morbidities (Table 138–5).³⁷

SICKLE CELL DISEASE

Transfusion therapy is indicated for sickle cell patients suffering from stroke, acute chest syndrome, acute exacerbations of anemia, and other complications. Regular transfusions also significantly reduce the recurrence of cerebral infarcts in children with sickle cell disease (SCD).³⁸ Transfusions are usually not necessary to correct baseline anemia or alleviate vasoocclusive crises. Because transfusion also creates complications, such as iron overload, transfusion reactions, alloimmunization, and delayed hemolytic transfusion reactions, clinicians should take particular care when considering transfusions for sickle cell patients.

Chronic transfusion can lead to a high rate of RBC alloimmunization in patients with SCD. Rates ranged from 18 to 47 percent, which is significantly higher than found in the general U.S. population (0.5 to 1.5 percent),³⁹ or the highly transfused hematology-oncology population (9 to 15 percent). The reasons for this high rate include number of transfusions, age at first transfusion, the inflammatory milieu created by SCD,⁴⁰ and the different RBC antigens present in donors of mostly European descent versus sickle cell patients of African ancestry.

The multiple antibodies specific for RBC antigens can cause delayed hemolytic transfusion reactions (DHTRs).⁴¹ DHTRs may be difficult to recognize, because some occur without any detectable antibody present, and with a negative direct antiglobulin test (DAT).⁴² In addition, some DHTRs occur without obvious clinical signs of hemolysis.⁴¹ Severe cases of DHTR result in the hyperhemolysis syndrome, defined by a drop in the patient's Hgb to a level lower than the pretransfusion value. This steep decline in Hgb suggests hemolysis of autologous cells, as well as the transfused allogeneic RBCs.

Transfusion services may attempt to ameliorate the alloimmunization rate by prophylactically matching donor and patient for Rh (antigens D, C, c, E, e) and Kell antigens. A few will also provide an extended phenotype match for the common Kidd, Duffy and S antigens. Both strategies reduce alloimmunization, yet even with matched transfusions, SCD patients continue to form RBC antibodies at rates up to 58 percent of chronically transfused and 15 percent of episodically transfused SCD patients.⁴¹ Most of these antibodies were made against Rh antigens, and more than half occurred in patients who received RBCs phenotypically matched for the corresponding Rh antigen. The likely explanation for this seeming paradox is that SCD patients have variant RH genes. In fact, high resolution RH genotyping showed variant alleles in 87 percent of the subjects.^41,43

THALASSEMIA

Thalassemia major patients are chronically transfusion dependent. Over time, this will lead to iron overload, and can result in RBC alloimmunization. No clinical trial has been staged to find the optimal transfusion threshold for patients with thalassemia; however, the consequences of anemia can be severe and must be balanced with the risks of transfusion. Transfusing to maintain a Hgb of 10 g/dL is considered sufficient to suppress erythropoiesis, thereby averting the bone deformities and other sequelae of this disease; however, some transfusion regimens call for a pretransfusion minimum of greater than 10 g/dL, with a posttransfusion goal of more than 15 g/dL. Thalassemia intermedia patients have more varied transfusion requirements, in keeping with the wide clinical presentation of this disease. If transfusion therapy is clinically indicated, the transfusion recommendations are similar to those for thalassemia major (Chap. 48).

TRANSFUSION SUPPORT

The duration and specificity of transfusion support for hematopoietic stem cell transplantation (HSCT) patients depends upon the disease, the source of the stem cells, the preparative regimen applied prior to transplant, and patient factors during the post-transplant recovery period. Human leukocyte antigen (HLA) matching remains an important predictor of success with HSCT. As a result, the ABO barrier is often crossed when searching for the best HLA match between donor and patient. Crossing the ABO barrier has little or no effect upon overall outcomes; however, transfusion difficulties can arise due to antigenic incompatibility between the transplanted cells and the patient.

Transfusion support can be divided into the pre- and posttransplantation periods. Prior to an HSCT, an immunocompetent patient (e.g., aplastic anemia, hemoglobinopathies) is capable of mounting an immune response to transfusions, leading to alloimmunization against HLA antigens present on the surface of leukocytes. Leukoreduction reduces alloimmunization rates, but sufficient white blood cells remain in the unit for alloimmunization to occur. Antibodies against HLA contribute to delayed engraftment and graft rejection in some patient populations.⁴⁴ As a result, pretransplantation transfusions in immunocompetent patients should be avoided, as they are associated with increased graft failure rates.^45,46 RBC transfusions can be minimized by using a Hgb trigger of 8 g/dL for stable patients.⁴⁷

Patients who are immunocompromised, either because of their disease, or from chemotherapy, are less likely to become immunized to foreign antigens. Nonetheless, using leukoreduced products to minimize the risk of alloimmunization is still recommended. Extra care must also be taken if the stem cell donation comes from a blood relative. In this situation family members should not give directed blood donations prior to transplantation, as this may lead to alloimmunization against major and/or minor HLA antigens that are present in the transplant organ. In addition, all RBC and platelet transfusions should be irradiated as the risk for transfusion-associated graft-versus-host disease (TA-GVHD) is high in HSCT patients (see section Transfusion-Associated-Graft-versus-Host Disease below for more in-depth discussion of TA-GVHD).

RBC engraftment is difficult to assess, but may be defined by the appearance of 1 percent reticulocytes in the peripheral blood, or as the day of the last RBC transfusion, with no transfusion given in the following 30 days. In general, engraftment time is shortest when hematopoietic progenitor cells are obtained by apheresis (HPC-A), and greatest when hematopoietic progenitor cells are obtained from umbilical cords (HPC-C) are used; however, considerable patient-to-patient variability exists. Prolonged engraftment directly translates into higher transfusion rates for RBCs and platelets.

When an ABO incompatible transplant is used, group O red cells are used to avoid incompatibility issues. The ABO type of plasma products may be different from the red cell type (Table 138–6). Once the patient begins to produce “donor-type” erythrocytes, their blood type should be reassessed. The decision to switch a patient's blood type is highly variable across institutions. In our hospital, when a patient is RBC transfusion independent for 100 days, and no incompatible isohemagglutinins against the new RBC phenotype can be detected in two consecutive blood samples, the patient's native blood type is switched to the donor type for future transfusions.

TRANSFUSION-RELATED COMPLICATIONS

There are transfusion-related complications that are specific to, or more frequently seen, in the HSCT population. Some of these complications arise when lymphocytes within the transplant are activated against the recipient; these include TA-GVHD and passenger lymphocyte syndrome (PLS). Another complication, pure red cell aplasia (PRCA), occurs when the patient's residual antibodies attack the transplanted red cells. Standard transfusion reactions, such as allergic or febrile nonhemolytic reactions, are frequently seen in this heavily transfused patient population; however, these “standard” transfusion reactions are discussed more fully later in this chapter in the section Adverse Effects of Red Cell Transfusions.

Major and Minor ABO Mismatches

Complications from ABO incompatibility depend upon whether a major or minor ABO mismatch is present (see Table 138–6). A major mismatch occurs when the transplant contains RBCs that are incompatible with the recipient's plasma. Conversely, a minor mismatch is present when the donor plasma contains isohemagglutinins against the recipient's RBCs. Bidirectional transplants (e.g., group A transplant into group B recipient) carry both major and minor mismatches.

Major ABO Mismatch When a major ABO mismatched transplant is given, immediate hemolysis may occur during the infusion. This complication is more commonly seen when the HSCT is derived from marrow, because more red cells are present; however, RBC depletion techniques have effectively eliminated this complication. Because HPC-A units contain a minimal volume of RBCs (8 to 15 mL), clinically significant cases of immediate hemolysis have not been identified.⁴⁸ Most HPC-C units are RBC-depleted prior to cryopreservation, and the residual erythrocytes lyse during cryopreservation, therefore immediate hemolysis is not a problem with cord blood transplants.

Preformed antibodies against non-ABO RBC antigens can remain in a recipient's peripheral circulation for many weeks after transplantation. These antibodies may cause lysis when engrafted cells begin to produce new RBC. Also chimeric patients may develop antibodies against ABO or non-ABO RBC antigens, resulting in delayed hemolysis. When recipients have isohemagglutinins specific for the ABO type of the transplant, delayed erythrocyte engraftment and PRCA may ensue. This is seen most frequently when group O patients receive a group A transplant, or with bidirectional mismatches. PRCA develops when anti-ABO antibodies destroy erythrocyte progenitor cells in the marrow.

Minor Mismatches When lymphocytes within the HSCT recognize the recipient RBCs as foreign, antibodies may be produced that are specific for ABO or minor RBC antigens. This PLS usually presents 7 to 14 days after the transplant with the abrupt onset of hemolysis. The hemolysis ranges from mild to severe, and may be intra- or extravascular, depending upon the nature of the antibody involved. These “passenger lymphocytes” are reported most frequently in transplants that use a group O donor with a group A recipient.⁴⁹ Antibodies against minor RBC antigens are less frequently reported, and cause less-severe hemolysis.⁴⁹

In cases involving the ABO system, the Hgb level may drop precipitously. The laboratory signs of intravascular hemolysis, that is, hemoglobinemia, hemoglobinuria and an elevated lactate dehydrogenase (LDH) should be used to follow the course of disease. In most cases a DAT will be positive, unless all antibody bound cells have already been lysed. The hemolysis can persist as long as incompatible RBCs are present, but usually subsides within 5 to 10 days.⁴⁹

Nonmyeloablative conditioning regimens carry a greater risk for PLS than when full ablation is used. Because HPC-A preparations carry a greater lymphocyte load when compared to hematopoietic cell concentrate-marrow (HPC-M) and hematopoietic cell concentrate-cord (HPC-C) collections, recipients of peripheral blood stem cells are at an increased risk of developing PLS. The authors are not aware of a case of PLS that has been reported with an umbilical cord stem cell transplant. Maintaining graft-versus-host disease (GVHD) prophylaxis with only a T-cell inhibitor, such as cyclosporine, without an accompanying B-cell inhibitor, is also considered a risk factor.

Transfusion-Transmitted Cytomegalovirus

CMV infection continues to be a serious complication following HSCTs. Most CMV infections are likely the result of reactivation of virus from a previous infection rather than acquisition of a new strain. However, in CMV-antibody–negative patients there is a risk of developing a transfusion-transmitted de novo CMV infection. To reduce this risk, one may use CMV-antibody-negative blood, or leukocyte-reduced components. A large controlled trial and a meta-analysis from 2007 showed that leukocyte-reduced components are as effective as antibody-negative components in preventing transfusion-transmitted CMV.^50,51 Two additional studies support the safety of using only leukoreduced blood in preventing transfusion transmission of CMV.^52,53 Both studies found 0 percent risk of transfusion-transmitted CMV infection. Nonetheless, the overall risk of transfusion transmission of CMV in leukoreduced components is not zero. CMV DNA was found in 44 percent of newly seropositive blood donors, and the overall prevalence of CMV DNA was 0.13 percent in nearly 32,000 donations.⁵⁴ While blood products could be obtained from donors with a longstanding history of CMV-positive serology, a more practical approach is to screen donated blood for CMV DNA or immunoglobulin (Ig) M antibodies, although we believe that the use of leukoreduced blood components is adequate.

Transfusion-Associated Graft-Versus-Host Disease

All HSCT patients should receive irradiated components from the time of initiation of conditioning chemotherapy, and for at least 1 year following transplantation to prevent TA-GVHD. However, many centers continue to provide irradiated products for the life of the patient. The British Committee for Standards in Haematology (BCSH) recommends that allogeneic transplant recipients should receive irradiated components for 6 months posttransplantation, or until the patient's lymphocyte count is greater than 1 × 10⁹/L; however, if chronic GVHD is present, then irradiated products should be given indefinitely.⁵⁵ Autologous transplant patients should begin receiving irradiated components from the time of initiation of conditioning chemotherapy, but can revert to nonirradiated components 3 months after the transplantation. If autologous transplant patients received total-body irradiation, then the BCSH recommends extending the use of irradiated products for 6 months after the transplantation.

Patients awaiting a solid-organ transplant should have minimal exposure to allogeneic blood products to reduce the risk of alloimmunization. Leukoreduced components contain sufficient white blood cells to immunize a patient against class I and class II HLA molecules. The risk of sensitization from a blood transfusion ranges from 2 to 21 percent.⁵⁶ Sensitization may increase the extent of alloimmunization, which contributes to delays in finding a compatible organ for transplantation. In fact, patients who have been transfused have an 11 percent reduction in the likelihood of ever receiving a renal transplant.⁵⁶ Attempts to reduce alloimmunization by matching blood donors and patients⁵⁷ or matching for the DR locus have shown no consistent reduction.⁵⁸ Using a Hgb of 7 g/dL as a safe threshold for transfusions can minimize exposure. In some patients the use of erythropoiesis-stimulating agents (ESA) may help decrease the number of RBC transfusions; however, ESAs are contraindicated in patients with a history of malignancy or stroke.

The precise risk of an adverse reaction is difficult to estimate; many reactions may be wrongly attributed to the patient's underlying illness, and approximately half of all transfusions are given to anesthetized patients in the operating rooms where reactions may be blunted or more difficult to recognize. The incidence of some adverse reactions has fallen in the past decade due to changes in component handling. Adverse reactions may occur soon after a transfusion begins, as seen with acute hemolytic reactions or acute lung injury, or within days to weeks of a transfusion, as seen with delayed hemolytic reactions.⁵⁹ Fortunately, the majority of acute transfusion reactions are mild and manageable. Many of the reported transfusion-related fatalities involve human errors which may be as much as 1:18,000 transfusions.

IMMEDIATE TRANSFUSION REACTIONS

In general, immediate transfusion reactions are more dangerous than delayed reactions. Severe complications, including death, can on rare occasions develop within a few minutes of initiating transfusion. Close attention and early vital sign assessments are recommended at the beginning and within 15 minutes of starting a transfusion.

Acute Hemolytic Transfusion Reactions

Acute hemolytic transfusion reactions (AHTRs) are almost always caused by the immune-mediated destruction of ABO-incompatible transfused blood. ABO incompatible transfusions are estimated to occur in one in 38,000 to one in 70,000 RBC transfusions.⁶⁰ Isohemagglutinins can activate the complement and coagulation systems. C3a and C5a can activate white blood cells to release inflammatory cytokines (interleukin [IL]-1, IL-6, IL-8, and tumor necrosis factor-alpha [TNF-α]), contributing to fever, hypotension, wheezing, chest pain, nausea, and vomiting.⁶¹ The presence of antigen-antibody complexes and activated complement on donor RBCs may lead to bradykinin generation. This can increase capillary permeability and arteriolar dilatation causing a fall in systemic blood pressure. Activation of factor XII may initiate the coagulation cascade with formation of thrombin and lead to disseminated intravascular coagulation. Renal failure may also develop as a result of ischemia, hypotension, antigen-antibody complex deposition, and thrombosis. Although rare, AHTRs can also be seen because of other blood group antibodies, particularly those in the Kidd blood group system.

Clinical Presentation The most common presenting symptom is fever with or without chills or rigors. In mild cases, this may be accompanied with abdominal, chest, flank, or back pain, whereas dyspnea, hypotension, hemoglobinuria, and eventually shock can be seen in severe cases. Bleeding, caused by the consumptive coagulopathy, can occur. Hematuria can be the first sign of intravascular hemolysis, particularly in anesthetized or unconscious patients. The severity of AHTR is extremely variable and usually depends on the rate and total volume of blood administered. Approximately 47 percent of the recipients of ABO incompatible blood show no effects, even after receiving a whole unit, 41 percent show symptoms of AHTR, and mortality is approximately 2 percent.^59,60

Laboratory Evaluation Laboratory evaluation involves checking for technical and identification errors, examine a posttransfusion specimen for hemolysis, and perform a DAT to detect antibody-coated red cells. If AHTR is strongly suspected, repeat ABO and Rh typing of the patient and the transfused blood and repeat antibody screen and crossmatch may be helpful. A negative DAT occurs in rare cases when all transfused RBCs are lysed.

Management Immediate discontinuation of transfusion should always be the first step in any transfusion reaction. Maintaining vascular access with slow infusion of normal saline, monitoring vital signs, and assessing urine output are key early steps. A blood specimen should be collected immediately for laboratory evaluation. The component bag should be returned to the blood bank. If severe hemolysis has occurred, therapy focuses on management of hypotension, coagulation disorders, and renal function. A urine output of approximately 100 mL/h for 24 hours should be maintained in adults without contraindications. In simple cases, normal saline infusion may be sufficient; however, diuretics may be necessary in some cases. Intravenous administration of furosemide (40 to 80 mg) promotes diuresis and improves blood flow to the renal cortex. In severe cases of hypotension, intravenous dopamine, which dilates renal vasculature and increases cardiac output, can be used. Patients with coagulopathy and active bleeding may require administration of platelets, fresh-frozen plasma, or cryoprecipitate.

Prevention The most common basis for AHTRs is a clerical error resulting from mistakes in identifying the patient, labeling the pretransfusions sample, or identifying the correct red cell unit for the patient.^60-62

Febrile Nonhemolytic Transfusion Reactions

A febrile nonhemolytic transfusion reaction (FNHTR) is defined, arbitrarily, as a temperature increase of 1°C or more during or up to 4 hours after transfusion. Other possible symptoms include increases in respiratory rate, anxiety, and, more unusually, nausea or vomiting.

FNHTRs are one of the most commonly encountered transfusion reactions occurring in approximately 0.12 to 0.5 percent of RBC units transfused, and are more likely to occur following transfusion of platelets than RBCs. Leukocyte reduction decreases the incidence of FNHTRs with both whole-blood derived and apheresis platelets.

Clinical Presentation Fever is triggered by the action of cytokines (e.g., IL-1, IL-6, TNF-α). This may be the result of activation of donor leukocytes by anti-HLA or other antibodies in the recipient, activation of recipient leukocyte and endothelial cells by transfused donor leukocytes or plasma constituents, or by the passive transfer of cytokines or CD40 ligand (CD154) that accumulated in the unit during storage.

Fever should not be solely attributed to FNHTR until other potential life-threatening transfusion reactions or patient-related factors have been excluded. Past transfusion reaction history should be reviewed to determine if additional measures should be implemented for future transfusions.

Laboratory Evaluation The laboratory investigation should concentrate on ruling out a septic transfusion reaction. A Gram stain is not a highly sensitive technique in this setting, but may be used to rule-in bacterial contamination. Rapid qualitative immunoassay tests (e.g., Verax or BacTx) are highly sensitive for most commonly encountered bacterial contaminants and may be used in lieu of Gram stain to screen implicated platelet units. In cases with a high index of suspicion, the unit should be cultured. If all results are negative and the patient's presentation is consistent with a mild FNHTR, no additional testing is required.

Management FNHTRs are typically benign, and usually resolve completely within 1 to 2 hours after the transfusion is discontinued. The remainder of the transfused unit and a posttransfusion blood sample from the patient should be sent to the laboratory for investigation. Antipyretics may be administered to shorten the duration of the fever and provide analgesia. Acetaminophen 325 to 650 mg orally for adults or 10 to 15 mg/kg/dose orally for children is effective for this purpose.

Transfusing leukoreduced RBCs and/or platelets stored in additive solution will significantly reduce the risk of FNHTRs.⁶³ Premedication with antipyretics (acetaminophen) is not helpful.^64,65

Allergic Transfusion Reactions

These are a common adverse reaction of transfusion therapy, ranging from mild forms characterized by localized pruritus and/or urticaria, to severe anaphylactic or anaphylactoid reactions. The mild forms of allergic transfusion reaction (ATR) occur in 1 to 3 percent of transfusions of plasma-rich components (i.e., platelets/fresh-frozen plasma) and in 0.1 to 0.3 percent for red cells. Severe anaphylactic reactions are much less frequent and estimated at one in 20,000 to 50,000 transfusions.⁷

The majority of ATRs are immediate (type 1) hypersensitivity reactions, mediated by preformed IgE antibodies binding to soluble proteins present within donor plasma.⁶⁶ Severe anaphylactic reactions may occur after transfusion of blood products to IgA-deficient patients who have anti-IgA antibodies. Most patients labeled as IgA deficient still have low levels of the immunoglobulin (2 to 4 mg/dL) and will not produce anti-IgA antibodies. The rare patient with complete IgA deficiency (<0.05 mg/dL) may develop anti-IgA antibodies and thus might experience anaphylaxis with transfusion. Anaphylactoid reactions are similar to anaphylaxis but clinically less severe and caused by non–IgE-mediated activation of mast cells.

Clinical Presentation ATRs usually begin during or within an hour of starting a transfusion, but may not become evident until several hours later. Common findings include urticaria, rash, pruritus, and flushing. More severe reactions occur sooner and may include angioedema, chest tightness, dyspnea, cyanosis, hoarseness, stridor, or wheezing. In addition, gastrointestinal symptoms such as abdominal pain, nausea, vomiting, and diarrhea may also occur. Unlike other acute transfusion reactions, fever is usually absent. Anaphylaxis occurs immediately after starting the transfusion. Symptoms can include bronchospasm, angioedema, respiratory distress, nausea, vomiting, abdominal cramps, diarrhea, shock, and loss of consciousness.

Laboratory Evaluation There is no need for laboratory investigation with simple urticarial and/or localized pruritus. However, the incident should be reported to the blood bank to update the patient's record for any future transfusions. In anaphylactic reactions, the patient should be tested for complete IgA deficiency; however, a history of anaphylactic reactions mandate use of washed red cells and platelets and avoidance of plasma transfusions regardless of the results of these tests.

Management Most ATRs are mild, self-limited and respond well to transfusion discontinuation and, if indicated, administration of antihistamine (diphenhydramine hydrochloride, usually orally). In cases limited to urticaria, the transfusion may be resumed immediately after symptoms resolve. However, transfusion should never be resumed when there is a severe reaction. In acute anaphylaxis, fluid resuscitation may be needed to maintain blood pressure followed by administration of subcutaneous or intramuscular epinephrine (0.3 mL of 1:1000 dilution), as well as airway management and intensive care. In case of shock, a higher concentration of intravenous epinephrine (3 to 5 mL of a 1:10,000 dilution) can be administered. Steroids are usually not helpful in acute crises.

Prevention Patients with a history of mild ATRs should not be premedicated with an antihistamine, as this does not reduce the overall risk of ATRs.⁶⁵ Platelets stored in additive solution may be used to reduce the risk of a reaction. In IgA-deficient patients with a history of anaphylaxis to transfusion, components from IgA-deficient donors are sometimes available.⁶³

Transfusion-Related Acute Lung Injury

Transfusion-related acute lung injury (TRALI) is a syndrome of acute hypoxia attributable to noncardiogenic pulmonary edema that occurs within 6 hours of a transfusion.^67,68 TRALI has been the leading cause of transfusion-related fatalities for several years.

There are two main hypotheses regarding the capillary leak seen in TRALI. The two-hit hypothesis states that underlying patient factors act as a necessary first hit, leading to adherence of primed neutrophils to the pulmonary endothelium. The second hit is caused by mediators within the transfused component, which activate pulmonary neutrophils, which, in turn, damage the endothelium.⁶⁸ The mediators are often antibodies specific for either class II HLA or for human neutrophil antigens (HNAs). There are also cases in which no antibody was detected, which are thought to be a result of proinflammatory mediators, bioactive lipids, and CD40 ligand that accumulate in the blood product during storage.⁶⁹ Despite reports of a direct correlation between storage time of cellular blood components and TRALI, this mechanism remains controversial.

Specific patient factors (first hits) that are associated with a greater risk of TRALI include patients on mechanical ventilation, sepsis, chronic alcohol abuse, severe liver disease, hematologic malignancy, and others. It is not known whether the risk is determined by the patient's condition, or by a greater transfusion requirement. The two-hit hypothesis accounts for critically ill patients who develop TRALI; however, there are reports of TRALI in reasonably healthy patients. This observation led to the threshold model of TRALI.⁷⁰ In this paradigm, a threshold, or tipping point, must be surpassed to induce TRALI. A healthy patient may develop TRALI when transfused with a high titer of antibody. Conversely, a critically ill patient with primed neutrophils can be tipped into TRALI with a lower titer of antibody.

Clinical Presentation and Differential Diagnosis It is often impossible to fully distinguish TRALI from other causes of respiratory distress. The typical presentation of TRALI is the sudden development of dyspnea, severe hypoxemia (O₂ saturation <90 percent in room air) hypotension, and fever that develop within 6 hours of transfusion and usually resolves with supportive care within 48 to 96 hours. Although hypotension is considered one of the important signs in diagnosing TRALI, hypertension can occur in some cases.

In addition to new or worsening oxygen desaturation, TRALI is characterized by chest x-ray findings of bilateral diffuse patchy pulmonary densities without cardiac enlargement. TRALI can be ruled out as the sole cause of pulmonary failure by the presence of rales and jugular venous distention on physical exam and/or dilated pulmonary arteries on chest x-ray, which are evidence of congestive heart failure with or without transfusion-associated circulatory overload (TACO). Transient leukopenia, which follows the reaction within few hours, can also distinguish TRALI from TACO.

Management Supportive care is the mainstay of therapy in TRALI, including oxygen supplementation and aggressive respiratory support plus intravenous fluid and vasopressors for hypotension, if indicated. It has been suggested that diuretics, which are indicated in TACO management, are not efficacious and should be avoided in TRALI. Glucocorticoids may provide benefit.

Prevention HLA alloimmunization has been directly correlated with the number of times a woman is pregnant and plasma from multiparous women has been implicated as a risk factor in TRALI. To reduce this risk, blood banks attempt to collect plasma from males, nulliparous females, and/or females tested and found to be negative for HLA antibodies. After blood collection centers implemented TRALI mitigation strategies, the incidence of TRALI dropped from an estimate of one in 4000 transfusions, to approximately one in 12,000.⁷¹ Nonetheless, TRALI continues to be the leading cause of transfusion-related fatalities.

Pooled plasma may also be used for TRALI mitigation because antibody titers drop due to dilution. No cases of TRALI resulting from transfusion of pooled solvent detergent treated plasma have been reported.^72,73

Transfusion-Associated Circulatory Overload

TACO occurs when patients are unable to effectively process the expansion in intravascular volume from a blood transfusion. Circulatory overload may be the consequence of the infusions rates, the volume of infused blood product, and/or an underlying cardiac, renal, and/or pulmonary pathology. The fluid volume transfused may be less important than the infusion flow rate and the patient's ability to process the fluid.

The incidence of TACO is difficult to ascertain, as there are inconsistent case definitions, passive reporting systems and poor clinical recognition. Approximately 1 percent of orthopedic patients developed TACO postoperatively, compared to 6 percent of patients in an ICU setting.⁷⁴ Reports of TACO have surged as awareness has increased. Active surveillance also increases the number of cases. In one institution the historical prevalence rate from 6 years of passive reporting was one in 1566 from plasma transfusions. After 1 month of active surveillance the prevalence rate jumped to one in 68.⁷⁵

TACO is seen more in younger and advanced age patients.⁷⁶ Additional risk factors include female sex, a history of congestive heart failure, hemodialysis, mechanical ventilation, recent vasopressors, and positive fluid balance.⁷⁷

Clinical Presentation Symptoms of TACO may include dyspnea, orthopnea, cough, headache, and hypoxemia, which are not specific. However, signs such as rales, hypertension, and jugular vein distention may differentiate TACO from TRALI. These signs and symptoms usually present within 2 hours of the onset of transfusion, but may be up to 6 hours or even 24 hours after the onset of transfusion.

Laboratory Evaluation Oxygen saturation may decrease along with the partial pressure of oxygen in the arterial blood. New bilateral infiltrates on chest x-ray is characteristic for TACO; however, it is also seen in TRALI. Elevated levels of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are both useful markers for TACO, but NT-proBNP may be more useful as it has a longer in vivo and in vitro half-life. Unfortunately neither peptide was found to be useful in distinguishing TACO from TRALI in critically ill patients.⁷⁸

Management Once TACO is suspected, intravenous fluids should be restricted, followed by the administration of supplemental oxygen and a diuretic, if not contraindicated. Placing the patient in a sitting position can also be helpful. In severe cases, mechanical ventilation may be required.

If a patient is at risk for TACO and blood transfusion is imperative, blood should be administered slowly at a rate of 1 to 4 mL/kg/h. Most blood banks can also reduce the transfusion volume by splitting the blood product into smaller volumes if the transfusion is going to last longer than 4 hours. Close monitoring of the patient's vital signs throughout the transfusion may also help in decreasing the development of TACO.

Transfusion-Related Sepsis

Transfusion-related sepsis when it occurs is usually from platelet units that are stored at room temperature. Red cells, stored at refrigerator temperatures, are very rarely contaminated by unusual cold-growing organisms (e.g., Yersinia, Serratia, Pseudomonas). The rate of fatal transfusion-transmitted bacteremia from red cells has been estimated to be 0.13 per million units transfused in the United States.²⁰

Clinical Presentation The infusion of large numbers of Gram-negative microorganisms may lead to fever (>38.5°C), rigors, marked hypotension, abdominal pain, vomiting, diarrhea, and the development of profound shock. Gram-positive contaminants may cause fever and rigors, but are not associated with the severe symptoms produced by Gram-negative toxins.

Laboratory Evaluation Rapid diagnosis usually may be made via Gram stain of the residual donor blood; however, a culture of the transfused component is necessary.

Management Septic shock from transfusion of contaminated blood should be managed as for septic shock from other causes and is not discussed further here.

DELAYED TRANSFUSION REACTIONS

Delayed Hemolytic Transfusion Reactions

DHTRs occur when a previously immunized patient receives red cells containing the corresponding antigen but are compatible in the crossmatch because of a low titer of circulating alloantibody. DHTRs occur in 0.2 to 2.6 percent of patients. It is vanishingly rare in infants younger than 4 months of age, and more common in chronically transfused patients.

Approximately 30 to 40 percent of alloantibodies become undetectable months to years after their initial identification. However, a patient previously immunized by transfusion or pregnancy may develop a secondary immune response after reexposure to a blood group antigen. Decreasing Hct or failure to see the typical 1 g/dL Hgb/3 percent Hct increment following transfusion may be noted within several days to weeks of a blood transfusion, as well as an unexplained fever. Hemolysis from DHTR is typically extravascular, without dramatic clinical symptoms and signs, although some classes of IgG bind complement and will cause intravascular hemolysis. Hemolysis in DHTRs is usually mild and gradual, however, when antibodies are produced against antigens in the Kidd blood system, the hemolysis may be rapid, intravascular, and may be severe.

The usual evidence of hemolysis is seen. The appearance of spherocytes and reticulocytes on peripheral blood film, increases in total and unconjugated bilirubin, and increased LDH. The DAT is usually positive but may be negative if all the transfused RBCs have been eliminated from the circulation. The antibody screen is usually positive and the antibody can be identified. No specific management is usually needed as these reactions are usually subtle and clinically silent. In cases of intravascular hemolysis, clinical support measures are similar to those described for an acute hemolytic transfusion reaction. If transfusion is necessary donor red cells negative for the offending antigen may be selected.

Posttransfusion Purpura

Posttransfusion purpura is a rare immune-mediated disorder that is discussed in greater detail in Chap. 139.

One of the most common complications of chronic RBCs transfusion is iron overload, which is further discussed in the chapters on congenital hemoglobinopathies (Chaps. 48 and 49).

Most cases of TA-GVHD are associated with HSCT. TA-GVHD is a very rare complication that occurs when a susceptible patient is exposed to viable lymphocytes introduced in a blood transfusion. This can occur when transfusions from close relatives or other unintentionally genetically matched donors are administered to severely immunocompromised recipients. The immunocompromised recipient is incapable of “rejecting” or mounting an attack against the lymphocytes in the transfused blood. In addition, cases of TA-GVHD have been reported in recipients with an intact immune system.^22,21

TA-GVHD may present with maculopapular rash, fever, watery diarrhea, liver dysfunction, and marrow failure within 8 to 10 days of transfusion. The mortality rate in is approximately 90 percent and the downhill course often rapid.

RBC, platelet, and granulocyte units all contain some lymphocytes and therefore carry a risk of TA-GVHD; plasma and cryoprecipitate are acellular and therefore pose no risk. To prevent TA-GVHD, lymphocytes within a blood component must be eliminated or disabled. Leukoreduction is not sufficient, as it reduces, but does not completely eliminate white blood cells. Frozen units may also carry a risk, as the lymphocytes may survive. Gamma and X-ray irradiation of components are effective prophylaxis for TA-GVHD.⁷⁹ A dose of at least 2500 centigray to the center of a cellular blood component and 1500 centigray throughout the unit leaves lymphocytes intact but unable to proliferate. This simple precaution prevents TA-GVHD.

Irradiation at the indicated dose appears to damage the red cell membrane. The damage does not affect the oxygen carrying capacity of the erythrocyte, but does allow potassium to leak from the cell. The level of extracellular potassium has been shown to increase with storage time. As a result, red cells may be stored for only 28 days after irradiation.

In the United States, RBC may be stored in additive solution for up to 42 days. The criteria used to determine storage limits are based on in vivo recovery and in vitro hemolysis data. During storage, RBC units develop a progressive “storage lesion.” Some of these changes include an increase in free Hgb which acts as a nitric oxide scavenger; a reduction in 2,3-bisphophosglyceric acid (2,3-BPG), which leads to increased oxygen affinity/decreased oxygen delivery; an increase in hydrogen ions in the supernatant causing a drop in the pH; an increase in microvesicles in the supernatant, creating a procoagulant effect and reduced RBC membrane deformability. Each of these changes is a dynamic process, with some occurring on the first day of blood storage, and others taking days or weeks to be evident. Aspects of the storage lesion have been demonstrated in vivo using healthy volunteers who are transfused with autologous units that are stored for widely divergent time periods. In three of these controlled experiments, no differences were found in pulmonary function,⁸⁰ nitric oxide-mediated hyperemic response to ischemia,⁸¹ or cognitive function.⁸² A fourth volunteer study found significant differences with in vivo iron-related parameters and signs of hemolysis when fresh and older units were compared.⁸³

The clinical relevance of these in vitro and in vivo studies is not clear. Some of the in vitro findings are reversed within 24 to 48 hours of transfusion, and no adverse effects were reported in the volunteers used for the in vivo studies; however, they were healthy and may be more able to withstand insults to their system. Multiple retrospective and prospective studies have looked for an association between the storage age of a RBC unit and clinical outcomes. In one study,⁸⁴ in more than 5000 cardiac surgery patients receiving more than 18,000 units of RBCs, patients receiving blood that was stored for longer than 2 weeks were at a significantly higher risk of postoperative complications as well as short-term and long-term survival. Subsequently, a large number of retrospective studies and a smaller number of prospective studies were performed. A recent review summarizing the findings of 32 studies reported that 18 found a detrimental effect from prolonged RBC storage, while 14 studies did not.^85,86 It is notable that the four prospective randomized trials included in the review found no significant ill effect. A meta-analysis of 21 studies, either observational studies or randomized controlled trials, found that use of older stored blood is associated with a significantly increased risk of death.⁸⁶

The question of higher risk from transfusion of older units continues to be studied in multiple, large prospective clinical trials. These studies are being conducted with ICU and cardiac surgery patients, among others. Until the results of these studies are available, no changes to practice should be made based on the available data.

Patient blood management (PBM) is an evidence-based, systematic and multifaceted approach to optimizing the care of patients who might need transfusion. The risks associated with unnecessary transfusions, coupled with the rising cost of blood have helped fuel the growth of PBM efforts. PBM was recently adopted by the World Health Organization as the new standard of care, and the AABB has issued guidelines and other tools designed to help hospitals implement a PBM program. A comprehensive PBM program includes (1) hospital-wide guidelines for evidence-based use of blood components, (2) early assessment and correction of preoperative anemia, and (3) application of a variety of techniques to minimize perioperative blood loss.

Guidelines for transfusion have been published by multiple medical professional societies, and can serve as a useful starting point for hospitals; however, the evidence for Hgb thresholds was developed in selected patient populations and does not always apply in all clinical situations. Combining evidence with a clinical assessment is necessary when deciding if a transfusion is indicated. Adding decision support tools into computerized physician order entry systems can remind clinicians of guidelines and safety considerations when ordering blood.⁸⁷ These systems have been shown to reduce blood use and decrease costs associated with transfusions.⁸⁸ Auditing transfusion orders may reveal patterns of blood utilization that can be corrected with education.

Preoperative anemia is associated with adverse outcomes in surgery.^89-91 Anemia levels act as an inverted sliding scale, with higher mortality seen in patients with lower preoperative Hgb. The effect of blood loss on mortality was also more pronounced in patients with lower versus higher preoperative Hgb values. When preexisting comorbidities and other confounders were considered, preoperative anemia continued to be independently associated with adverse outcomes after cardiac and noncardiac surgery. Even relatively mild preoperative anemia was shown to be an independent risk factor for higher early mortality in cardiac surgeries,⁹⁰ and for 30-day morbidity and mortality in patients undergoing major noncardiac surgery.⁹¹

Given the risks of preoperative anemia, both patients and hospitals may benefit from a preoperative anemia assessment program for all surgical patients. When possible, this assessment should be undertaken 28 days before surgery, to correct anemia with oral iron when possible, and IV iron or erythropoietin when necessary and not contraindicated. Hematologists should be consulted for cases of refractory anemia.

Perioperative blood management is the third pillar of a strong PBM program. Blood sparing surgical techniques and anesthesiology-based blood conservation tools should be used whenever possible. Minimizing perioperative blood loss reduces the need for RBC transfusion and the length of hospital stay.⁹² Together the combination of a restrictive transfusion strategy, preoperative anemia correction and perioperative blood management has been shown to reduce RBC transfusions, decrease adverse events and reduce hospital costs.⁹²