As the risks of infectious disease transmission by transfusion

Transcription

1 Noninfectious Complications of Blood Transfusion Anne F. Eder, MD, PhD; Linda A. Chambers, MD Context. Serious noninfectious complications are far more likely to occur than viral disease transmission from blood component transfusion. Objective. To compile a comprehensive list of the noninfectious risks of transfusion, examples of published risk estimates, and summaries of recent information regarding cause, prevention, or management of noninfectious transfusion risks. Data Sources. Information was obtained from peer-reviewed English-language medical journal publications since Conclusions. Early complications, although potentially more serious, usually occur less frequently ( 1 in 1000 transfusions) than late complications, which often affect more than 1% of recipients. Areas of active investigation and discussion include acute hemolytic reactions, transfusion-related acute lung injury, red cell alloimmunization, platelet transfusion refractoriness, and transfusion immunosuppression. Continued effort toward research and education to promote recognition and prevention of noninfectious complications associated with blood components is warranted. (Arch Pathol Lab Med. 2007;131: ) As the risks of infectious disease transmission by transfusion were reduced through the introduction and progressive improvements in donor screening and infectious disease testing during the 1980s and 1990s, the residual risks of noninfectious complications of transfusion have become more apparent. Severe noninfectious complications, although uncommon, now account for most of the significant morbidity and mortality from blood transfusion in developed countries, as surveillance programs in Canada and the United Kingdom document. 1 3 To protect patients, emphasis has been directed at increasing awareness, recognition, and prevention of these noninfectious complications. Patients may still perceive that human immunodeficiency virus transmission is the most likely adverse outcome of transfusion, so it is practical to discuss the residual risk (which is less than 1 in 2 million) as part of informed consent. 3 However, noninfectious complications now far exceed the risk of human immunodeficiency virus or other infectious diseases by orders of magnitude; physicians have a responsibility to explain to the patient the relative risks of noninfectious transfusion hazards as well. In fact, if transfusion mortality is the patient s primary concern, reactions such as transfusion-related acute lung injury (TRALI) and hemolysis from mistransfusion must be included in the informed consent disclosure of the current possible risks of receiving blood. Accepted for publication November 13, From the Biomedical Headquarters, American Red Cross, Washington, DC (Dr Eder); and the Blood Bank of San Bernardino and Riverside Counties, San Bernardino, Calif (Dr Chambers). Dr Chambers is now with Riverside Methodist Hospital, Columbus, Ohio. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Linda A. Chambers, MD, Riverside Methodist Hospital, 3535 Olentangy River Rd, Columbus, OH ( LChamb2@ OhioHealth.com). OBJECTIVE AND DATA SOURCES From the peer-reviewed English language medical journal literature published since 1990, we generated a list of noninfectious complications of transfusion and any reported estimates or measurements of the incidence per unit or transfusion and prevalence in transfusion recipients. Information on the cause, management, and prevention of each risk was summarized. RESULTS Noninfectious complications have been grouped into those that become apparent during or within hours of transfusion (early) and those that begin days to months following transfusion (late) (Table 1). A sample of the reported prevalence rates and frequencies per unit transfused are presented descriptively with each complication. EARLY COMPLICATIONS Febrile Nonhemolytic Transfusion Reactions Febrile nonhemolytic transfusion reactions, characterized by a rise in temperature usually associated with chills or rigors, are believed to be caused by pyrogenic cytokines and intracellular contents that are either released from donor leukocytes after transfusion to a patient with leukocyte-reactive antibodies or infused with the blood component. Because room temperature storage allows more contaminating leukocytes to remain intact, functional, and capable of elaborating pyrogenic cytokines, febrile nonhemolytic transfusion reactions are a particular problem with platelet transfusions. Reactions can be prevented in most patients by reducing the leukocyte contamination level in the blood component, ideally early in the storage period so that both cells and cell contents are removed and the production and accumulation of cytokines is prevented. Most but not all programs report a substantial decrease in the rate of reported febrile nonhemolytic transfusion reactions as a result of converting to exclusive use 708 Arch Pathol Lab Med Vol 131, May 2007 Noninfectious Complications Eder & Chambers

2 Risk Table 1. Febrile nonhemolytic nonseptic transfusion reaction Circulatory (volume) overload Hemolysis of incompatible red blood cells Hemolysis from incompatible plasma Noninfectious Risks of Transfusion* Published Rates Early Complications: Onset During or Within Hours of Transfusion 0.12% of transfusions, all components, all patients 81 ; 1.1% of RBC and 1.7% of apheresis platelet transfusions 4 ; 1 in 1K RBC transfusions 5 ; 0.11% of RBC and 0.13% of platelet pool transfusions 1 ; 2.15% of RBC and 1.58% of apheresis platelet transfusions 82 ; 0.19% of RBC and 0.11% of whole blood derived platelet (per unit) transfusions 6 ; 0.19% of RBC transfusions 7 1.1% of total knee or hip replacement surgery patients 9 ; 1 in 2K RBC and 1 in 6K platelet pool recipients 1 ; fatal events, 1 per 4.5 million 83 1 per 186K RBC transfusions 3 ; 1 in 100K RBC transfusions 12 ; 1 per 13K RBC transfusions 1 ; fatal events, 1 per 1.3 to 1.7 million 83 1 in 46K platelet transfusions at 21% plasma incompatible 84 ; fatal events, 1 per 8 million 83 Transfusion-related acute lung injury 1 in 5K transfusions 22,24 ; 1 in 196K transfusions (possible, probable, or highly likely cases) 2 ; 1 in 1K transfusions 25 ; 1 in 143K RBC and 1 in 16K platelet pool transfusions 1 ; fatal events, 1 per million 83 Allergic reaction, mild 1 in 4K components 85 ; 4.8% of platelet transfusions 32 ; 0.41% of RBC and 3% of platelet transfusions 4 Allergic reaction, severe; anaphylactic reaction 1 in 30K transfusions 85 ; 1 in 25K RBC and 1 in 2K platelets 1 Electrolyte abnormalities No published frequencies Coagulation abnormalities No published frequencies Formation of red cell antibodies Secondary complications: Delayed hemolytic transfusion reaction Hyperhemolysis syndrome Hemolytic disease of the fetus and newborn Difficult crossmatching complicating transfusion support Late Complications: Onset Days to Months Following Transfusion 12% of patients and 1 antibody per 210 RBCs transfused, in patients receiving 6 or more RBCs 86 ; 9% of patients and 0.5% per RBC transfused 40 ; 22% of Asian patients with thalassemia after 5 or more years of chronic transfusion 87 ; fatal events, 1 per 1.8 million. 83 Delayed hemolytic transfusion reactions: 1 per 113K RBC transfusions 2 ; 1 in 9K RBC transfusions 43 ; 1 in 5K RBC transfusions 42 ; 1 in 9K RBC transfusions 1 Iron overload Essentially all patients chronically transfused with RBCs 50 Immune suppression Secondary complications: Possible increased infection risk Possible increased mortality Possible increased cancer recurrence Formation of HLA antibodies Secondary complications: Platelet transfusion refractoriness Neonatal alloimmune thrombocytopenia Difficult matching for organ or marrow transplantation Formation of platelet-specific antibodies Platelet transfusion refractoriness Neonatal alloimmune thrombocytopenia Posttransfusion purpura All patients show some immunosuppressive changes in natural killer and lymphocyte subset number, phenotype, and/or function 54, % of cardiac surgery patients 92 ; 7% of leukemia or stem cell transplant patients with universal leukoreduction and 14% without leukoreduction 93 ; 12% of hematology-oncology patients who received multiple transfusions 94 ; 10.6% of all recipients 82 ; 53% of chronically transfused thalassemia patients % of cardiac surgery patients 92 ; 24% of chronically transfused thalassemia patients 95 Graft-versus-host disease Less than 1 per million transfusions 2,10 ; fatal events 1 per 10 million 83 * RBC indicates red blood cell; K, thousand; and HLA, human leukocyte antigen. Assuming use of leukoreduced cellular components unless otherwise indicated. Rates greater than 1 per thousand expressed as percentages; rates less than 1 per thousand expressed as 1 in x with x rounded to the nearest thousand. These complications are clearly not avoided with substitution of autologous transfusion for allogeneic transfusion. of leukoreduced cellular components. 4 8 Febrile reactions are not medically dangerous, but they are uncomfortable for the patient and they necessitate interruption of the transfusion, component wastage, and laboratory investigation to exclude more serious complications (eg, hemolytic and septic reactions) that may also present with fever, chills, and rigors. Circulatory (Volume) Overload Transfusion-associated circulatory overload occurs when the transfusion volume or rate exceeds the ability of the patient s cardiovascular system to handle the additional workload. The incidence is not well documented, but transfusion-induced circulatory overload is thought to be common. In 1 retrospective chart review, 1.1% of elderly surgical patients undergoing total knee or hip replacements had evidence of circulatory overload, sometimes after as few as 1 or 2 units of red blood cells (RBCs). 9 From 25 to 65 cases per recipients have been reported to hemovigilance programs. 1 Acute hypervolemia produces dyspnea, hypoxemia, elevated central venous pressure, rales, and pulmonary edema, which may precipitate congestive heart failure. Pulmonary edema, cardiomegaly, and a distended pulmonary artery are characteristic findings on chest x-ray. The clinical presentation is similar to TRALI, a much less common complication with which it is often confused (Table 2). Unlike TRALI, transfusion-induced circulatory overload is improved with diuresis. The patient s underlying cardiovascular function is a major determinant of risk for volume overload from transfusion. Patients at risk of circulatory overload include those with compromised cardiovascular function, patients already in a volume overload state (eg, renal failure, congestive heart failure), and those for whom the transfusion Arch Pathol Lab Med Vol 131, May 2007 Noninfectious Complications Eder & Chambers 709

3 Table 2. Conditions That Mimic Transfusion-Related Acute Lung Injury With Symptoms and Circumstances That Help Distinguish Them Condition Congestive heart failure, acute left ventricular failure Acute circulatory (volume) overload Pulmonary embolism Rapidly progressive pneumonia (especially viral or fungal) Adult respiratory distress syndrome (ARDS)/ acute lung injury (ALI) Hints* History of congestive heart failure Recent bypass surgery Poor ejection fraction Peripheral edema Pleural effusions on chest x-ray or physical examination Jugular venous distension on physical examination Dilated superior vena cava on ultrasound BNP about 500 pg/ml Pulmonary capillary wedge pressure 18 mm Hg Distended pulmonary artery on chest x-ray Cardiomegaly on chest x-ray Response to diuresis High-volume fluid infusion or transfusion over a short period Elderly or very young patient Increase in systolic blood pressure Pre-existing chronic volume overload state (eg, renal failure, congestive heart failure) Severe chronic anemia Cardiomegaly on chest x-ray Rales on pulmonary auscultation Distended pulmonary artery on chest x-ray Response to diuresis Hypercoagulable state (eg, pregnancy, known thrombophilia syndrome) Immobility Disseminated malignancy No or little pulmonary edema on chest x-ray Fever High white blood cell count Progression of infiltrates on chest x-ray Patchy or lobar pattern of infiltrates on chest x-ray Pre-existing diagnosis of pneumonia Patient at risk for infection (eg, neutropenic) Underlying illness classically associated with ARDS/ALI such as: Sepsis (especially associated with pneumonia) Shock Disseminated intravascular coagulation Multiple trauma Progression or lack of resolution for 1 3 days High mortality * BNP indicates B-natriuretic peptide. Congestive heart failure is a chronic volume overload state, because heart failure induces fluid retention as a compensatory mechanism. The overlap in findings and symptoms with acute volume overload unrelated to heart failure is therefore not unexpected. volumes are relatively high compared with the patient s intravascular volume (eg, elderly patients and small children). Patients with severe, but compensated, chronic anemia are also at significant risk of circulatory overload if aggressively transfused to increase hemoglobin and hematocrit. In some cases, a single unit may be sufficient to trigger respiratory distress. If a patient is at risk of volume overload, the rate of transfusion should be slowed or the component should be divided into smaller aliquots and given for a longer period. Hemolysis of Incompatible Red Cells Acute hemolytic transfusion reactions typically occur in the setting of accidental transfusion of ABO incompatible red cells and account for a significant proportion of all transfusion-related deaths. 10 Acute intravascular hemolysis is less often caused by immunoglobulin (Ig) M antibodies other than anti-a and anti-b isohemagglutinins or complement-fixing IgG alloantibodies in the recipient, such as anti-p k, anti-vel, and rarely antibodies with Lewis (anti-le a ), Kidd (anti-jk a, anti-jk b ), and Kell (anti-k1) specificities. 11 Complement activation by hemolytic antibodies causes osmotic lysis of red cells in the peripheral circulation through the formation of the terminal pore complex composed of complement factors C5 to 9 on the red cell membrane. Intravascular hemolysis produces the hallmark features of ABO incompatible transfusion hemoglobinemia and hemoglobinuria. Complement activation also generates anaphylotoxins, inflammatory cytokines, histamines, bradykinin, and vasoactive amines, which produce fever, hypotension, wheezing, chest pain, nausea and vomiting, and disseminated intravascular coagulation. Renal failure, shock, and circulatory collapse may ultimately ensue. Acute hemolytic reactions usually result from to the failure to properly identify the intended transfusion recipient, either at the time of initial phlebotomy for pretransfusion testing or prior to administering the red cell unit. 12 The incidence of ABO incompatible transfusions is not known but has been estimated to occur in 1 in to 1 in red cell transfusions. 1,12 These rates derive from voluntary reporting of transfusion errors or surveillance programs, which likely underestimate the true frequency due to a failure to recognize or report such events. The Institute of Medicine recognized medication errors as a serious public health problem and attributed more than 7000 deaths to 710 Arch Pathol Lab Med Vol 131, May 2007 Noninfectious Complications Eder & Chambers

4 medication errors in 1993 alone. 13 Since 2005, the Joint Commission on Accreditation of Healthcare Organizations has designated accurate patient identification as their top National Patient Safety Goal. The Joint Commission on Accreditation of Healthcare Organizations recommends using at least 2 patient identifiers (neither to be the patient s room number) whenever administering medications or blood products, taking blood samples and other specimens for clinical testing, or providing treatments or procedures. 14 Similarly, the College of American Pathologists requires accredited programs to ensure that all blood samples used for compatibility testing are labeled at the time of specimen collection with the patient s first and last name, unique identification number, and date of collection. College of American Pathologists accredited programs must also have a policy and documented procedure for blood administration that includes positive identification of transfusion recipients and blood components. 15 Several hospitals have focused on redesigning the transfusion process to incorporate barcodes or radiofrequency identification technology as part of an integrated health information system to reduce the risk of mistransfusion. 16 Additional strategies include the use of a designated team of specially trained nurses to carry out all transfusions and pretransfusion specimen collection, frequent monitoring of blood administration practice, repeat determination of the patient s ABO group at the bedside before transfusion, and physical barriers to transfusion such as a locked transport bag that requires matching the patient s wristband information with the component. The severity of the reaction to ABO-incompatible blood is extremely variable and usually reflects the rate and the volume administered. Nearly half (47%) of the recipients of incompatible red cells suffer no ill effects even after receiving a full unit, 41% experience an acute hemolytic transfusion reaction, and about 2% die as a result. 2,12 Treatment of an acute hemolytic transfusion reaction is supportive (eg, hydration, furosemide, dopamine) and aimed at maintaining renal perfusion, blood pressure, and cardiac function. Hemolysis From Incompatible Plasma There have been fewer than 20 case reports published of hemolytic reactions due to transfusion of plasma-incompatible platelets to non group O patients. 17,18 All have involved group O platelets. Most have occurred with group A patients, apheresis components, and donors whose anti-a titers (saline and/or anti-human globulin) were greater than 1:1000. Although millions of group O platelets have been transfused, the number given to non group O patients is unknown. It is fair to say, however, that hemolysis from plasma-incompatible platelet transfusion is a rare event and probably occurs about as often as, for example, an overt delayed hemolytic transfusion reaction (DHTR) following red cell transfusion. Some transfusion medicine experts have suggested removing plasma (volume reduction) or measuring the anti- A or anti-b titer (whichever is relevant to the recipient s blood type) to ensure it is less than a selected level (eg, 1:256) before giving a group O platelet to a non group O patient. 19 Others simply limit the number of incompatible group O platelets given to a patient in a 24-hour period. Alternatively, because clinical consequences are rare, some do not take preventive interventions but do consider platelets as a possible source of incompatible antibody if evidence of hemolysis develops. At a minimum, transfusing physicians and transfusionists should be aware that hemolytic reactions are a possible risk of platelet transfusions as well as red cell transfusions. Transfusion-Related Acute Lung Injury Transfusion-related acute lung injury, characterized by acute respiratory distress, occurs in all age groups, both sexes, and all clinical settings. 20,21 All standard blood components and intravenous immunoglobulin (IVIG) have been implicated in TRALI although frozen plasma (eg, fresh frozen plasma) is overrepresented and platelets are underrepresented in the reported cases. 22,23 Transfusionrelated acute lung injury is a clinical syndrome with the following features and findings: 1. Abrupt onset in association with transfusion. Symptoms usually begin during transfusion, often during administration of the component ultimately implicated in the case. 2. Severe hypoxemia. For example, oxygen saturation less than 90% on room air would document a degree of hypoxemia sufficient to support a clinical diagnosis of TRALI. 3. Chest x-ray showing bilateral infiltrates characteristic of pulmonary edema. Because there are many other causes of acute onset of hypoxemia (eg, pulmonary embolism, myocardial infarction, pneumonia, aspiration, pulmonary hemorrhage, arrhythmia, bronchospasm), it is difficult to narrow the differential diagnosis to TRALI and its closely related conditions, acute lung injury and adult respiratory distress syndrome (ARDS), without demonstrating pulmonary edema on a chest x-ray. Therefore, a chest x-ray is fundamental to the evaluation of a possible TRALI reaction, the same way a repeat antibody screen and direct antiglobulin test on a postreaction sample would be a routine component of the evaluation of a suspected DHTR. 4. Absent findings of circulatory overload. Signs of circulatory overload include an acute significant (eg, 30 mm Hg or more) rise in systolic blood pressure, elevated central venous or pulmonary capillary wedge pressure, jugular venous distension, pulmonary rales on physical examination, cardiomegaly on chest x-ray, positive fluid balance, and improvement with diuresis. Patients with known congestive heart failure or renal failure are particularly susceptible to circulatory overload. B-natriuretic peptide is a 32 amino acid polypeptide secreted by the cardiac myocytes, in response to ventricular expansion and pressure overload. A B-natriuretic peptide level greater than about 500 pg/ml or a posttransfusion-to-pretransfusion B-natriuretic peptide ratio greater than 2.0 strongly supports a diagnosis of volume overload and not TRALI No preexisting acute lung injury or ARDS. Because the chest x-ray findings and clinical features of acute lung injury or ARDS are indistinguishable from those of TRA- LI, it is not possible at this time to separate exacerbations of pre-existing acute lung injury or ARDS from TRALI. In 2004, a case definition of TRALI was developed at an international consensus conference, which included each of these 5 items. 24 Participants recommended that TRALI onset in association with transfusion be taken to mean onset during or within 6 hours of transfusion. Terminology was standardized: Characteristic findings in conjunction with other conditions known to cause acute lung injury or ARDS, such as sepsis, shock, or pneumonia, would Arch Pathol Lab Med Vol 131, May 2007 Noninfectious Complications Eder & Chambers 711

5 be termed a case of possible TRALI. In a patient with no such underlying condition, the clinical diagnosis of TRALI could be made. There are 2 active hypotheses of the pathophysiology of TRALI. The most widely accepted is that TRALI results from endothelial damage when leukocyte-reactive antibodies, usually with human leukocyte antigen (HLA) class I or class II specificity, are transfused and activate antigen-positive neutrophils in the pulmonary capillaries. 20,22 Antibodies with neutrophil or monocyte antigen specificity are less often implicated. Female donors sensitized as a result of pregnancy are most often identified as the source of the causative transfusion. The second hypothesis is that patients, as a result of their disease or treatment, are in an inflammatory alert state in which neutrophils are assembled and primed in the pulmonary capillary beds. 25 An appropriate second challenge is sufficient to fully activate the neutrophils causing endothelial damage. In this model, lipids that accumulate in cellular blood components during storage provide the second challenge. Neither hypothesis fully predicts what is observed epidemiologically. For example, about 20% of blood components contain HLA antibodies, yet TRALI is a rare transfusion complication. 26 In lookback investigations for donors who have been discovered to have HLA antibodies capable of mediating TRALI (usually after they have been implicated in an index case), other transfusion recipients who were known positive for the corresponding antigen did not develop pulmonary symptoms when transfused with components that would have contained incompatible antibodies. 27 On the other hand, the lipid model does not explain why frozen plasma is overrepresented in reported cases of TRALI. Under the lipid hypothesis, TRALI should occur most often with older red cell and platelet transfusions, with no particular association with the sex or parity of the donor. At a minimum, uncharacterized features of the patient, antibody, and blood component must determine whether or not TRALI develops. The diagnosis of TRALI does not hinge on testing for the presence or absence of HLA or granulocyte antibodies in the donors of the transfused blood products. Transfusion-related acute lung injury is a clinical diagnosis that may or may not be supported by the findings in the involved blood components and donors. This means that the evaluation of the patient at the hospital must be performed methodically if the rest of the case investigation is going to be meaningful. The significance of HLA or granulocyte antibodies in the donors can be assessed only if the HLA or granulocyte typing of the patient is known. Therefore, donor testing should probably be reserved for those cases in which patient phenotyping will be performed and the clinical presentation is consistent with TRALI or possible TRALI. Conditions that can be mistaken for TRALI and hints that the mimicking condition may be present are presented in Table 2. Because TRALI is defined at this time by the presence and absence of a small number of clinical features, the transfusion service evaluation of a suspected case must be directed at documenting these features. The clinical care team may already have obtained some of the needed evaluations while treating the patient. Proper evaluation of a patient suspected of having TRALI may require the following: Chest x-ray (to document presence of pulmonary edema) Oxygen saturation (or other measure of oxygenation) Posttransfusion B-natriuretic peptide (or other objective evidence of lack of volume overload such as whether rales are present, whether the pulmonary artery is dilated on chest x-ray, or whether jugular venous distension is present on physical examination) HLA class I and II phenotype (to evaluate the significance of any antibodies detected in donors) if donor testing by the blood center if planned When faced with a report of a possible TRALI case, most blood centers base their investigation on the leukocyte antibody model and investigate the donor for HLA class I and perhaps class II antibodies. To absolutely implicate a particular donor, the leukocyte-reactive antibody should be shown to be incompatible with the patient either because the patient is positive for the corresponding antigen (eg, donor serum contains anti HLA-B12 and patient is B12 positive) or because a leukocyte crossmatch between the patient and donor is positive. 28 Allergic Reactions Allergic reactions are characterized by cutaneous and constitutional symptoms, and different terms (minor, anaphylactoid, anaphylactic) have been used to describe the severity of the symptoms. The term anaphylactoid is applied to reactions with symptoms similar to anaphylaxis but which are not mediated by IgE. 29 Cutaneous manifestations of minor allergic transfusion reactions include pruritus, urticarial lesions (hives), erythema, flushing, and angioedema. 29 In clinical practice, anaphylactic and anaphylactoid reactions may be clinically indistinguishable, and an alternate classification scheme combines the two under the term major allergic reactions. These are characterized by prominent constitutional symptoms including hypotension, dyspnea, stridor, wheezing, chest pain, and tachycardia. Gastrointestinal symptoms (nausea, vomiting, diarrhea) may also develop. Major allergic reactions can be catastrophic, resulting in shock, cardiac arrest, and death. The treatment approach is guided by the severity of the reaction, directed at alleviating symptoms or supporting cardiac and respiratory function. Minor allergic transfusion reactions are common and more likely to occur with platelet, plasma, or plasma-derivative transfusion than with red cells. 1 Fortunately, major allergic reactions to blood transfusion are rare; only 8 deaths in a 9-year period were attributed to transfusioninduced anaphylaxis, although severe allergic reactions to blood components may have played a role in the death of other critically ill patients. 1,10 The best-characterized examples of anaphylactic transfusion reactions occur in IgA-deficient ( 0.05 mg/dl) patients with IgG class-specific anti-iga who receive plasma or IVIG. 29 Most allergic reactions to transfusion, however, are not related to IgA deficiency or anti-iga, which is detectable in 20% to 40% of healthy individuals. Antihaptoglobin was responsible for more reactions than anti-iga in Japan, and other implicated antigens include C4 (Chido/Rogers blood group antigens), but the cause of most reactions is not known. 30,31 Other candidate antigens in immediate allergic reactions include plasma proteins; chemicals used to sterilize administration tubing, such as eth- 712 Arch Pathol Lab Med Vol 131, May 2007 Noninfectious Complications Eder & Chambers

6 ylene oxide; or drugs taken by the donor prior to donation, such as penicillin. Platelet membrane-derived microparticles present in plasma-containing blood components may be the cause of some allergic reactions. Resuspending platelets in a nonprotein-containing storage solution instead of fresh frozen plasma eliminated allergic reactions while the rates of allergic reactions for nonmanipulated platelets and prestorage leukoreduced platelets were 4.1% and 4.8%, respectively. 32 Leukoreduction did not reduce the incidence of allergic reactions associated with platelet transfusion in other studies as well, suggesting that cytokines released from white blood cells during storage are probably not the cause. Patients at risk of allergic reactions include those who have had prior allergic reactions to transfusion and those who are taking -adrenergic blocking agents and angiotensin-converting enzyme inhibitors. Recurrent, minor allergic reactions may be prevented by premedication with antihistamines; moderate to severe reactions may also require premedication with corticosteroids. If a severe allergic reaction or anaphylactic reaction is linked to anti- IgA, efforts should be made to limit exposure to plasmacontaining products, wash cellular components, and obtain IgA-deficient components for transfusion. Further consultation with an allergist or immunologist for patients who have had severe allergic reactions to transfusion may be informative. Metabolic and Coagulation Abnormalities Metabolic and coagulation abnormalities can develop following transfusion of a relatively large volume per body weight, with rapid administration, or in patients with certain underlying medical conditions. The metabolic abnormalities are due to biochemical changes that occur in blood components during storage or to constituents of the preservative, anticoagulant, and additive solutions. The coagulation abnormalities develop because of dilution of the patient s blood with platelet- and coagulation factorpoor RBCs. Blood components contain citrate as the anticoagulant, which chelates calcium ions. When transfused, citrate can produce a transient decrease in the recipient s plasma ionized calcium concentration causing prolongation of the QT interval, decreased left ventricular function, hypotension, hypomagnesemia, and cardiac arrhythmias. Patients with liver failure or premature infants with immature liver function are most susceptible because citrate is removed by metabolism to bicarbonate by the liver. Usually, hypocalcemia does not require treatment other than slowing the rate of the transfusion although susceptible patients may require empiric calcium replacement. Potassium accumulates in the supernatant of whole blood and red cell units during storage at 1 C to6 C, because of the impaired function of the adenosine triphosphate pump. Gamma irradiation accelerates the potassium leakage. Although the concentration may be high in the supernatant of stored blood compared with physiologic levels, the total amount of potassium infused in usual transfusion volumes usually is not clinically significant. For example, several studies have demonstrated the safety of red cells stored to their expiration date for up to 20 ml/kg transfusions to infants (equivalent to about 3 units to an adult). 33,34 The vast majority of transfusions to even critically ill infants are not associated with any significant change in serum potassium or adverse reaction. 35 However, rapid infusion of large volumes ( 20 ml/kg) of stored red cells can lead to fatal hyperkalemia in infants, children, and, very rarely, adults. 36,37 Cardiac arrest attributed to hypocalcemia and hyperkalemia has also been reported with direct transfusion of blood components into the central venous circulation. 38 Patients with oliguric renal failure, significant hepatic dysfunction, or tenuous cardiac function are at increased risk for these complications. Both hypoglycemia and hyperglycemia have been reported in association with transfusions to neonates. Neonates often require continuous glucose infusion of 4 to 8 mg/kg/min to maintain euglycemia. Hypoglycemia may develop if glucose infusions are discontinued during transfusion. Transfusions may also be associated with transient hyperglycemia from the glucose in the preservative/anticoagulant solution, which may be followed by insulin release and rebound hypoglycemia after the transfusion. It is usually asymptomatic and may go unrecognized if the infant is not monitored. Hypoglycemic episodes are more frequently observed with transfusions of citrate phosphate dextrose adenine 1 RBCs than additive solution RBCs (eg, AS-1, AS-3) because of the lower dextrose concentration in the citrate phosphate dextrose adenine 1 preservative/anticoagulant formulation. The management of coagulopathy in patients requiring massive transfusion is considerably more challenging in both the surgical and trauma settings. Massive transfusion is usually defined as transfusion of greater than 10 units of blood in an adult or replacement of 1 blood volume (70 ml/kg in adults, ml/kg in neonates) in 24 hours. In the controlled setting of elective surgical procedures, the primary effect of massive transfusion is a decrease in fibrinogen concentration. 39 In the trauma setting, a complex coagulopathy results from hypothermia, shock, tissue anoxia and damage, and disseminated intravascular coagulation in addition to hemodilution of platelets and plasma procoagulant factors from massive transfusion of red cells and asanguinous fluids. 39 Hypothermia is further aggravated if red cell components are transfused rapidly soon after removal from refrigerated storage (4 C 6 C) without warming. If the patient s body temperature falls to less than 35 C, the prothrombin time and partial thromboplastin time are prolonged and platelet function is impaired. General considerations for restoring and maintaining hemostasis during massive transfusion include giving sufficient numbers of RBCs to ensure adequate oxygen delivery, platelet transfusion to maintain the count greater than / L, plasma transfusion to replace plasma factors, and cryoprecipitate to provide fibrinogen. Treatment strategies must be adapted to the patient s individual circumstances and guided by baseline and periodic assessment of laboratory parameters (prothrombin time, partial thromboplastin time, platelet count, fibrinogen) during resuscitation, as much as possible. LATE COMPLICATIONS Red Cell Alloimmunization and Delayed Hemolysis Red cell antibodies are detectable in up to 2.6% of the general population, at higher rates among individuals who have been previously transfused, and rarely among infants younger than 4 months. 40,41 The prevalence among different patient groups varies from 18% to 47% in patients with sickle cell anemia, 5% to 11% in patients with thalassemia, and 20% in previously transfused patients Arch Pathol Lab Med Vol 131, May 2007 Noninfectious Complications Eder & Chambers 713

7 without underlying hematologic or oncologic diagnoses. 40 The risk of red cell antibody formation depends on a myriad of factors including the patient s underlying illness, genetic predisposition, immune status, degree and duration of antigen exposure (eg, total number of transfusions), and degree of antigen disparity with the blood donor. Acute hemolytic transfusion reactions due to non-abo incompatibility are largely prevented with accurate antibody identification and component phenotyping during compatibility testing. However, recently transfused red cells may become incompatible if red cell antibodies quickly develop because of transfusion in a previously sensitized patient (anamnestic response). The incidence of this delayed incompatibility was estimated as 1 in 1500 red cell units at a tertiary-care medical center. 42 Despite the coincidence of antigen-positive transfused red cells and incompatible antibody, investigation often reveals no evidence of accelerated red cell destruction; in these cases, the findings have been termed a delayed serologic transfusion reaction. 43 The diagnosis of a DHTR requires clinical or laboratory evidence that the newly discovered red cell alloantibody is actually causing hemolysis (eg, fever, falling hematocrit, and jaundice). Only a subset of cases of delayed incompatibility actually results in a DHTR. Implicated antibodies in DHTRs are typically IgG reactive at 37 C that fix complement (C3d) on red cells, and Duffy (Fy a ) and Kidd (Jk a ) antibodies are more likely to cause delayed hemolytic reactions than other antibody specificities. The progressive removal of portions of the red cell membrane by phagocytic cells in the spleen results in the appearance of spherocytes in the peripheral circulation. Accelerated destruction of transfused red cells is also evident by reticulocytosis, unconjugated hyperbilirubinemia, and increased serum lactate dehydrogenase. Prolonged intervals between the initial and subsequent red cell transfusion predispose to DHTRs because the antibody titer may decrease so that it is no longer detectable in routine pretransfusion screening tests. Delayed hemolytic transfusion reactions occur 2 days to 2 weeks after re-exposure to the implicated antigen and are associated with mild hemolysis of transfused red cells in most clinical settings. In some instances, however, the apparent loss of circulating red cells exceeds what would be expected if only the antigen-positive transfused red cells were cleared from the peripheral blood. Bystander hemolysis of the patient s own red cells as well as transfused red cells may result from complement activation and deposition of C3d on autologous red cells. In patients with sickle cell disease, DHTRs may present as acute pain syndrome and may result in severe life-threatening anemia due to profound bystander hemolysis, formation of red cell autoantibodies, and suppressed erythropoiesis. This syndrome has also been called hyperhemolysis or the hemolytic transfusion reaction syndrome in patients with sickle cell disease. 44,45 Potentially fatal hyperhemolysis has also been reported in patients with other hematologic diagnoses. 46 Standard blood bank practices are designed to prevent DHTRs by accurate record keeping of prior red cell alloantibodies and avoidance of re-exposure to implicated red cell antigens for all future transfusions. As a further precaution in repeatedly and chronically transfused patients, investigation should include obtaining an accurate patient history regarding previous transfusions at other institutions and any clinically significant serologic findings. Primary red cell alloimmunization may be prevented by avoiding unnecessary transfusions and by minimizing the potential for blood group antigen incompatibility between the blood donor and transfusion recipient. Because patients with sickle cell disease are at the greatest risk of serious transfusion complications and are often dependent on long-term red cell transfusion, additional measures are warranted to prevent red cell alloimmunization and prevent DHTRs. Recent clinical practice guidelines advocate that all patients with sickle cell disease should have their extended red cell antigen phenotype (ABO, Rh, Kell, Kidd, Duffy, Lewis, and MNSs blood group systems) determined before they start transfusion therapy, and they should receive ABO/Rh type-specific units that are phenotypically matched for C, E, and K1. 47,48 More extensive antigen matching is recommended for those patients who develop red cell alloantibodies. Strategies to increase African American donor recruitment and to direct this blood to patients with sickle cell disease decreases the probability of antigenic mismatches, facilitates the identification of phenotypically matched units, and may further reduce the risk of alloimmunization. Prophylactic red cell antigen matching for patients with sickle cell disease is not widely practiced, however, according to a recent College of American Pathologists survey. 49 Most transfusion services (743/1182 respondents) do not routinely perform phenotype testing of patients with sickle cell anemia for antigens other than ABO and D. 49 Alloimmunized pediatric transfusion recipients are managed at these centers by providing specific antigennegative red cells only after identification of alloantibodies, although this approach is not consistent with the current expert recommendations. Iron Overload An inevitable complication of long-term transfusion is iron overload because there is no physiologic means of eliminating the additional transfused heme iron. 50 Iron homeostasis is tightly regulated through intestinal absorption. About 10% of the normal 10 to 20 mg of dietary iron is absorbed each day, which is sufficient to balance the 1 to 2 mg of daily iron losses from desquamation of epithelial cells. Most of the iron in the body is recycled when old red cells are taken out of the circulation. A unit of red cells for transfusion contains about 250 mg of iron, which quickly exceeds the body s ability to handle the additional iron so that iron accumulates in reticuloendothelial cells and parenchymal cells causing end-organ damage. The most significant damage occurs to the hepatic, cardiac, and endocrine systems, and complications can be fatal if iron balance is not restored. Even with significant and ongoing iron accumulation, patients usually continue to feel well until end-organ damage has occurred, although abdominal discomfort, lethargy, and fatigue are common but nonspecific complaints. Mild to moderate hepatomegaly develops early as iron accumulates in parenchymal cells, followed by fibrosis and cirrhosis. Dyspnea with exertion and peripheral edema indicate significant cardiac compromise and reflect advanced iron loading. Although iron chelation therapy is effective, patient compliance is often poor with the primary regimen of subcutaneous infusions of deferoxamine, which must be given for 8 to 12 hours daily, when the patient may not perceive any ill effects or symptoms of iron overload. The first oral iron chelator was recently approved, but it is not 714 Arch Pathol Lab Med Vol 131, May 2007 Noninfectious Complications Eder & Chambers

8 effective in all patients. Red cell exchange transfusion can be used as an alternative transfusion therapy for some patients with sickle cell disease and has been shown to reduce iron accumulation and reverse iron overload in some chronically transfused patients. 51 Disadvantages of red cell exchange include the need for more donor blood and increased donor exposures, as well as the requirement for a central venous catheter if peripheral venous access is not adequate for the apheresis procedure. Immune System Effects Blood transfusion is essentially administration of a liquid allogeneic transplant. It induces profound short- and long-term changes in the cellular immunologic profile of the transfusion recipient, some of which are stimulatory, others of which are immunosuppressive. 52,53 Transfusion has been found to cause release of a variety of cytokines, prostaglandins, interleukins, complement fragments, and neutrophil contents. Although the exact nature of the effects vary depending on the study, the net changes always reflect a down-regulated immune system It remains debated, however, whether or not the durable changes are medically important and, if so, which elements in the transfused blood component mediate the effects (eg, the contaminating leukocytes or all of the transfusion) and the degree to which interventions (eg, prestorage leukoreduction, use of autologous blood) mitigate these effects. Clinical studies of the association of blood transfusion with complications that might reflect immunosuppression have produced conflicting results. Some investigators have reported higher rates of postoperative infections, multiorgan failure, cancer reoccurrence, and mortality in patients who were transfused compared with patients who were not transfused Others have found no differences The obvious difficulty in assigning these outcomes to transfusion is confirming that the transfused and untransfused patient groups were otherwise comparable in terms of their underlying disease, treatment, and comorbidity factors that undoubtedly affect the likelihood of complications and mortality. In some, but not all, of the studies of transfusion-mediated immunosuppression, meticulous care was taken to control and correct for other factors that may have influenced the observations and conclusions. In early analyses, the transfusions were not leukoreduced, whereas they were in later reports, although the immunosuppression associated with transfusion does not appear to be mediated solely by donor leukocytes because it was not prevented by high-efficiency leukoreduction of the blood component and the effects of transfusion remain in later investigations using leukoreduced blood. 62 In most studies, the transfusion indications were not strictly controlled, introducing another important opportunity to have inadvertently moved the sicker patients into the transfused cohort. The literature remains inconclusive to most readers. There is one important prospective randomized study among the various, mostly observational, studies of adverse outcomes from transfusion that should be known to each institution s transfusion practice committee (or its equivalent) for lessons it may hold regarding transfusion immune suppression and outcomes. Between November 1994 and November 1997, Hebert et al 65 in Canada followed 838 critical care patients at 25 hospitals receiving red cells to maintain their hemoglobins either in the 10 to 12 g/dl range (liberal) or in the 7 to 9 g/dl range (restrictive). All of the outcomes evaluated intensive care unit mortality, hospital mortality, 30-day mortality, 60-day mortality, multiple organ dysfunction score, intensive care unit length of stay, and hospital length of stay favored the restrictive transfusion group. The differences in mortality were magnified for those patients who were younger than 55 years and less critically ill (Acute Physiology and Chronic Health Evaluation II score 20) to the point that there would be an estimated 1 additional death for every 13 patients if a liberal, rather than a restrictive, transfusion strategy were in use. 66 The details of the complications and fatalities in the 2 groups are provided in the report. All patients were transfused, so there is no untransfused cohort for comparison. As would be expected in a critical care population, the outcome profiles are complex. The restrictive transfusion group, which received an average of 2.6 units of red cells compared with 5.6 units of red cells to the liberal transfusion group, did indeed have lower rates of bacteremia and ARDS but had higher rates of pneumonia, catheterrelated sepsis, and septic shock, although all differences were statistically insignificant. Most of the deaths were preceded by cardiac events and/or multiorgan failure; the liberal transfusion group simply had more of the same types of fatal events. Whether or not it was differences in transfusion immune suppression that were at the core of the differences in outcome or whether some other unintended negative effect of transfusion or another unrecognized uncontrolled variable was at play is unknown. Formation of HLA and Platelet-Specific Antibodies Platelet transfusions are frequently given to cancer patients with chemotherapy- or radiation-induced thrombocytopenia, and as a result, platelet-reactive antibodies directed against class I HLA or platelet-specific antigens, such as human platelet antigen 1a, may develop. The antibodies appear as early as 10 days, but generally in 21 to 28 days, after primary exposure and 4 days after reexposure to the antigen in patients previously sensitized through transfusion or pregnancy. The risk of alloimmunization is related to the underlying disease and the immunosuppressive effects of treatment regimens. The risk can be lowered by reducing the leukocyte content of platelet components to less than per unit. 33,67 70 Limiting donor exposures by providing leukocyte-reduced apheresis platelet units does not offer additional benefit over leukocyte-reduced pooled platelets derived from whole blood. Platelet antibodies are one cause of platelet refractoriness, a condition in which platelet transfusion fails repeatedly to adequately increase the patient s platelet count. More common consumptive causes of refractoriness include fever, infection, drugs, bleeding, splenomegaly, and disseminated intravascular coagulation. Under ideal clinical conditions, the expected platelet increment to either whole blood derived (4 6 units for an average adult patient) or apheresis platelets (1 unit for an average adult patient) is / L to / L per transfusion, or / L to / L per unit of whole blood derived platelets. The response is more accurately evaluated by calculating the corrected platelet count increment. Platelets may be destroyed rapidly by platelet antibodies, as evidenced by an unchanged or a minimally affected platelet count 10 to 60 minutes after the transfusion. In Arch Pathol Lab Med Vol 131, May 2007 Noninfectious Complications Eder & Chambers 715