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An adverse effect of blood transfusion occurs in approximately 3% of transfusions in the United States. These complications of transfusion can be classified as immunologic, infectious, or due to the chemical or physical characteristics of blood components.
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Immunologic Reactions
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Hemolytic Transfusion Reactions
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Although HTRs are much discussed, they are fortunately quite uncommon, reflecting the efficacy of the serologic and procedural techniques in place to prevent their occurrence. Although HTRs occur with less than 0.1% of the units transfused in the United States, they can be life-threatening. It bears noting that fatal, acute HTR due to ABO incompatibility is a more frequent adverse outcome of transfusion than infection with HIV or HCV, and it is more often the result of patient or sample misidentification than to serologic mishaps or exotic blood types.
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An adverse effect of blood transfusion occurs in an estimated 3.0% to 3.5% of transfusions in the United States. These complications of transfusion can be classified as immunologic, infectious, or due to the chemical or physical characteristics of blood components.
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HTRs are mediated by antibodies directed against alloantigens present on transfused RBCs. Most alloantibodies to RBC antigens, other than the AB isoagglutinins, develop in response to exposure to allogeneic RBCs by transfusion or maternal–fetal hemorrhage. There are hundreds of RBC antigens comprising more than 50 systems. Fortunately, only a small proportion of these have clinical significance. In addition to the AB isoagglutinins, antibodies to antigens in the Rh, Kell, Duffy, Kidd, and MNSs systems are responsible for the preponderance of HTRs. Identification of these alloantibodies, by the techniques discussed above, is important because the degree and severity of hemolysis differs among them.
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HTRs can be either acute, occurring within 24 hours of transfusion, or delayed, in a reaction that appears 5 to 7 days (range 3-21 days) after the transfusion. Acute reactions are usually more severe than their delayed counterparts, and occur in patients who already have antibodies to RBC alloantigens when they are transfused with RBCs bearing those target antigens. The most severe acute HTRs are due to ABO incompatibility because the AB isoagglutinins are present at a substantial titer and fix complement efficiently, being largely IgM. The A and/or B antigen sites are also abundant on RBCs (typically 1-2 × 106 antigen sites per cell). Antibodies to antigens in the Kell, Kidd, and Duffy systems also have been responsible for acute HTR.
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Patients with an acute HTR typically present with temperature elevation, an important point, because they might initially be mistaken for a febrile-nonhemolytic transfusion reaction (FNHTR; discussed later). Nausea, vomiting, hypotension, low back pain, and substernal pressure may also signal the occurrence of acute hemolysis. Hemolysis is generally intravascular in this setting. The hemoglobin released into the plasma from the lysed RBCs is apparent as hemoglobinemia (red plasma rather than yellow) and hemoglobinuria (red urine that remains red after centrifugation). Disseminated intravascular coagulation and systemic hemodynamic instability may be triggered by the hemolysis. Together with the direct toxic effects of cell-free hemoglobin on the tubular cells of the kidney, these conditions are responsible for the impaired kidney function that often accompanies acute intravascular hemolysis. Therapy is largely supportive, but preservation of renal function is critical, and is often accomplished through the use of intravenous hydration and diuretics.
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Delayed HTRs occur in 2 situations. In one, the patient is exposed to a foreign RBC alloantigen by transfusion and mounts a primary immune response. As the amount of antibody in the plasma increases, hemolysis may ensue. The second situation in which a delayed response may occur is when a patient is reexposed to an alloantigen to which he or she was sensitized in the past by previous transfusion or pregnancy (anamnestic response). Even if the alloantibody to this antigen is not detectable prior to the transfusion, exposure to the alloantigen can stimulate an anamnestic response. Antibodies to Kidd and Rh antigens are frequently responsible for such reactions. Hemolysis is typically extravascular in delayed HTR with the only clinical and laboratory signs being a decrease in the hemoglobin level, a rise in the bilirubin level, a low-grade temperature, and a feeling of malaise. When no hemolysis can be detected in a delayed HTR, the reaction is called a delayed serologic (rather than hemolytic) transfusion reaction.
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Reactions to Plasma Components
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Hypersensitivity Reactions—Allergic and Anaphylactic Transfusion Reactions
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Allergic reactions occur in approximately 1% to 3% of patients receiving blood products containing plasma. In most cases, these hypersensitivity reactions are a host response to foreign plasma proteins in the donor blood components. The vast majority of these reactions consist of hives, pruritus, and erythema, and can be managed with antihistamines or steroids. More serious responses such as bronchospasm, laryngeal edema, gastrointestinal disturbance (nausea, vomiting, cramps, and diarrhea), and hypotension (anaphylactoid reaction) are much less frequent. IgA-deficient patients with anti-IgA antibodies in their plasma are at risk for serious reactions including frank anaphylaxis if exposed to IgA in a transfused blood component. If transfusion is required, these patients should be provided with components from IgA-deficient donors, or, in an elective situation, store their own components for later use. Washing packed RBC can effectively remove IgA. Patients who are IgA deficient, but who do not have anti-IgA, do not require special preparations, but should be observed closely during transfusion.
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White Blood Cell Reactions
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Febrile-nonhemolytic Transfusion Reactions
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These reactions are among the most common transfusion-related complications and accompany approximately 1% to 3% of transfusions of cellular components. They are more common in multiply transfused patients and with nonleukoreduced cellular components. An FNHTR usually presents with a temperature elevation of 1°C or more, during or shortly after a transfusion (usually within 1-2 hours), that is unlikely to be associated with the patient's underlying disease or therapy. The temperature elevation is often accompanied by chills, rigors, and generalized discomfort, and in some patients, nausea and vomiting as well. The majority of these reactions are mild and do not persist for more than 8 hours. Antipyretics may be administered, and occasionally meperidine may be required to treat severe rigors. These reactions have long been considered to be the product of antileukocyte antibodies present in the recipient's plasma, reacting with WBCs or WBC fragments in the transfused product. There may, however, be other etiologies for the FNHTRs, including the presence of cytokines released by lymphocytes in the donated unit during storage.
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Febrile-nonhemolytic transfusion reactions are among the most common transfusion-related complications and accompany 1% to 3% of transfusions of cellular components.
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Transfusion-associated Graft Versus Host Disease (TA-GVHD)
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Immunocompetent T lymphocytes present in cellular blood components may engraft in an immunoincompetent transfusion recipient, particularly if cellular immunity is compromised. The engrafted, allogeneic T cells mount an alloimmune response to cells in the skin and gastrointestinal tract, similar to what occurs in hematopoietic stem cell transplant-associated GVHD. However, in transfusion-associated GVHD, the donor T cells attack the host cells in the bone marrow as well, making this complication of transfusion lethal in most cases. Fortunately, T lymphocytes in cellular blood components can be inactivated by exposure to gamma irradiation, which effectively prevents this complication. Patients at risk for this rare complication include those undergoing hematopoietic progenitor cells (HPC) transplantation or who have hematologic malignancies. Low-birth-weight infants, infants born with hemolytic disease of the newborn, and fetuses receiving intrauterine transfusions are also at risk. Patients with congenital T-cell immunodeficiencies (eg, Wiskott–Aldrich and diGeorge syndromes) have also developed this complication. Cellular components from blood relative donors are also routinely irradiated to prevent TA-GVHD that may occur in the circumstance when the donor is homozygous for an HLA haplotype shared with the transfusion recipient. In this situation, the transfused T cells remain immunologically invisible to the otherwise immunocompetent host and, rather than being cleared, they engraft and attack the host because they recognize the mismatched host haplotype antigens as foreign. Most of the reports of TA-GVHD in other patients, such a those with solid tumors or who were undergoing surgery, predate the awareness of this 1-way haplotype match, which is the most likely explanation for the occurrence of this event in these immunocompetent patients.
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Transfusion-related Acute Lung Injury (TRALI)
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TRALI is characterized by the development of acute respiratory distress, hypoxia, and bilateral infiltrates on chest x-ray, often accompanied by fever and hypotension, during or within 6 hours of completion of a transfusion. To meet the current working definition of TRALI, there must be no preexisting form of acute lung injury or other risk factors such as sepsis, aspiration, or pneumonia. Most patients recover completely with supportive care, which may include mechanical ventilation, and the pulmonary infiltrates usually resolve within 2 to 4 days without long-term sequelae. However, there is a 5% mortality rate. This complication has been attributed to the presence of antileukocyte antibodies in the plasma of donor blood (often from females with a history of pregnancy) that react with the recipient's WBCs. This results in the formation of immune complexes that are trapped in the pulmonary vasculature and lead to alveolar edema. At present, various steps are being taken to reduce the incidence of TRALI, including making FFP from predominately male donors or donors with no history of pregnancy or transfusion, or by testing for HLA antibodies.
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Posttransfusion Purpura (See the Section “Bleeding Disorders” in Chapter 11)
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This rare complication occurs in patients who lack a common platelet antigen (often HPA-1A) and have developed an alloantibody by exposure through prior transfusion or pregnancy. When reexposed to HPA-1A by transfusion of a platelet product or an RBC product containing contaminating platelets, these patients appear to develop an anamnestic response and become severely thrombocytopenic 7 to 10 days later. Paradoxically, the patient's own platelets, which are HPA-1A negative, are also cleared. Several explanations have been offered including the observation that there is an initial IgM response that reacts with GP IIb–IIIa (essentially a platelet autoantibody) but then “matures” with the production of an IgG with anti-HPA-1A specificity. The reaction is self-limiting, but may be complicated by severe hemorrhage. Steroids and intravenous immunoglobulin have been used successfully to manage this immunologic reaction.
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Transfusion-related acute lung injury is characterized by the development of acute respiratory distress, hypoxia, and bilateral infiltrates on chest x-ray, often accompanied by fever and hypotension, during or within 6 hours of completion of a transfusion.
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Refractoriness to Platelet Transfusions
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Patients may become sensitized to leukocyte and platelet antigens through transfusion or pregnancy. Transfused platelets may be cleared rapidly when given to a patient who has preformed antibodies directed at foreign platelet antigens or HLA Class I molecules, which are also expressed on the platelet membrane. As a result, it may be extremely difficult to elevate the platelet count in such patients. A patient is considered to be refractory to platelet transfusion if the increment measured between 15 and 60 minutes after the platelet transfusion is lower than expected on 2 occasions. Note that counts done several hours afterward are not useful for determining which patients are immunologically refractory. The posttransfusion count may be corrected for the number of platelets administered and the patient's body surface area (the “corrected count increment”) as follows:
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Here the default for number of platelets transfused is: 1 unit whole blood-derived platelets = 5.5 ×1010 platelets; 1 unit apheresis platelets = 3 ×1011 platelets.
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A corrected count increment of <7500 is a strong evidence of immunologic refractoriness. Note that other causes of refractoriness should be ruled out, among them: active bleeding, fever, sepsis, splenomegaly (splenic sequestration), disseminated intravascular coagulation, marrow transplantation, antibiotics (eg, vancomycin), IV amphotericin B, thrombotic thrombocytopenic purpura, idiopathic or immune thrombocytopenic purpura, and heparin-induced thrombocytopenia.
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Patients with immunologic refractoriness may respond well to platelets from donors who lack the HLA antigens corresponding to the patient's HLA alloantibodies (or to platelets that are HLA matched) or to platelets that have been chosen by platelet crossmatching.
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Leukocytes in the transfused unit appear to be necessary for stimulating the immune response to both platelet and leukocyte antigens. Alloimmunization may be prevented by transfusion of cellular components from which leukocytes have been removed, usually by passage of the product through a filter that retains the leukocytes. Patients who are likely to need extensive platelet transfusion support (eg, for HPC transplants or hematologic malignancies) often receive leukoreduced cellular components to reduce the likelihood of alloimmunization.
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Nonimmunologic Reactions
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Complications Created by the Physical Characteristics of Blood
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Transfusion of small volumes of cold blood may be associated with minor discomfort. This complication can be averted by using blood warmers or blankets. In the setting of massive transfusion, however, the rapid transfusion of large amounts of blood that is at 1°C to 10°C contributes to hypothermia. Hemostasis is impaired when the circulating blood is below 37°C and in extreme situations, cardiac dysrhythmias and arrest may occur. In this setting, the use of high-throughput blood warmers is warranted.
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Transfusion-associated Circulatory Overload (TACO)
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Volume overload is a relatively common but often overlooked complication of transfusion. Patients with congestive heart failure or renal failure, the very young, and the very old are particularly at risk. It should be suspected in a patient who complains of dyspnea, orthopnea, cough, or chest pain, during or soon after transfusion, particularly if there are signs of hypoxia, rales, tachycardia, or hypertension. Supplemental oxygen and diuresis may be required. Future transfusions should be carried out slowly and perhaps with the aid of a diuretic.
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Chemical Complications
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Each unit of packed RBC contains approximately 200 mg of iron. Chronic RBC transfusion can overwhelm the body's mechanisms for eliminating excess iron, resulting in iron accumulation in various tissues. An individual who has received 100 or more units of RBCs (20 g of iron) is at risk to develop various complications of iron overload including cardiac dysrhythmias, pancreatic failure (“bronze diabetes”), and liver function abnormalities. Tissue iron can be mobilized and excreted using chelating agents such as desferroxamine or deferasirox. Chelation therapy is a slow process and is more effective if deployed well before tissue accumulation of iron is extensive.
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Volume overload is a relatively common but often overlooked complication of transfusion. Patients with congestive heart failure or renal failure, the very young, and the very old are particularly at risk.
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Potassium leaks out of RBCs during storage as ATP levels decline and the ATPase-dependent Na+/K+ pump activity diminishes. Once the banked RBCs are transfused, they transport glucose, restore their ATP levels, and take up the K+ that was lost during storage. In the short term, however, each unit of RBCs might contain as much as 6 mmol of extracellular K+ at the time of expiration. There have been a handful of reports of neonates, or patients with renal failure receiving large volumes of banked blood, who have developed life-threatening cardiac dysrhythmias. Neonates usually receive RBC units that have been stored for less than 1 week and have not yet accumulated much extracellular K+. Washing RBC is also an effective means of removing extracellular K+, although it is very rarely required.
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Citrate is the anticoagulant used in the collection of all blood products and is therefore transfused with the blood product into the patient. It is present in the plasma. Hence, most of it ends up in platelet and plasma products while there is relatively little in RBC products. Citrate is metabolized by every nucleated cell of the body, but in circumstances where large volumes of banked blood are being infused rapidly, as in massive transfusion, the rapid influx of citrate may overwhelm the body's metabolic capacity, leading to an accumulation in the patient's plasma. Most patients can receive up to 1 unit of FFP every 6 minutes without evidence of citrate toxicity. Patients with liver failure metabolize citrate more slowly, however, and are particularly susceptible. The accumulating citrate chelates calcium, causing the ionized calcium levels to drop and producing perioral tingling and extremity paresthesias. In extreme circumstances, it may produce severe hypo(ionized)calcemia that can lead to cardiac dysrhythmias.
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Depletion of 2,3-Diphosphoglycerate (2,3-DPG)
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With increasing storage time of RBCs, the intracellular level of 2,3-DPG decreases, producing a left shift of the oxyhemoglobin dissociation curve. Once banked RBCs are transfused, they restore the levels of 2,3-DPG over a period of 24 to 48 hours. It has been suggested that the high oxygen affinity of the hemoglobin in the 2,3-DPG-deficient banked RBCs might impair oxygen delivery, particularly to neonates. As a result, it has become a general practice to transfuse neonates with RBCs that have been banked less than 1 week. However, most of the literature demonstrating unfavorable outcomes for neonates receiving older units was based on studies with RBC storage systems in which maintenance of 2,3-DPG levels was not as effective as it is using the current systems.
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Infectious Complications (See the Section “Infectious Disease Testing”)
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The Classic Pathogens
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Transfusion transmission of the hepatitis viruses and the retroviruses has been substantially reduced through the interventions of donor education, screening on the basis of medical history and risk behaviors, and testing, including the use of highly sensitive techniques based on amplification of viral genetic nucleic acids. The residual risk of HIV or HCV infection through transfusion is in the range of 1 event per 1 to 2 ×106 units transfused. Viral transmission by pooled plasma products has also been largely eliminated by the use of robust viral inactivation techniques or replacement with recombinant proteins.
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Transfusion transmission of the hepatitis viruses and the retroviruses has been substantially reduced through the interventions of donor education, screening on the basis of medical history and risk behaviors, and testing.
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The Current Significant Pathogens
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At the present time, bacterial contamination of blood components is the most significant infectious complication of transfusion in developed countries, in terms of both the number of transmitted infections and the number of fatalities. It has been estimated that in the United States, approximately 1 in 500,000 units of RBCs, or 1 in 10,000 to 20,000 units of platelets, is associated with transfusion-transmitted sepsis. The organisms most frequently associated with septic RBC transfusions are psychrophilic gram-negative bacteria such as Yersinia enterocolitica and Pseudomonas spp., as well as Enterobacter spp. and Serratia spp. Platelet units have been reported to transmit gram-positive cocci (Streptococcus aureus, S. epidermidis, and Staphylococcus spp.) as well as gram-negative organisms (Klebsiella spp., Serratia spp., Salmonella spp., and Enterobacter spp.). The sources of these bacteria are thought to be skin commensals picked up and introduced into the blood donation with the venipuncture, or less commonly, cryptic bacteremia in clinically healthy donors. Even if the inoculum is quite small, blood provides a superb culture medium, particularly when stored at room temperature, as is the case for platelets. Although donors are now questioned specifically about antibiotic use, the health history is neither a sensitive nor a specific screening tool. The implementation of tests to screen platelet products for evidence of bacterial contamination was discussed above and is now routine.
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Cytomegalovirus (CMV) is a ubiquitous member of the herpes virus family to which approximately 30% to 60% of adults in developed countries have been exposed. CMV can be transmitted by transfusion of blood components that contain leukocytes, such as packed RBCs and platelets. Although primary infection rarely produces serious disease in immunologically intact hosts, it is associated with systemic infection in immunocompromised patients who are CMV-seronegative. The following groups of patients have been shown to be susceptible to transfusion-transmitted CMV primary infection and disease and should receive CMV reduced-risk cellular blood components:
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Premature, low-birth-weight (<1200 g) neonates
CMV-seronegative pregnant women (including those undergoing intrauterine transfusions)
CMV-seronegative recipients of, or candidates for, hematopoietic or solid organ transplants
CMV-seronegative, HIV-infected patients
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CMV reduced-risk blood components can be obtained by screening donors for CMV antibody (IgG) that indicates past exposure, or by removing the leukocytes that contain latent CMV by filtration with leukocyte reduction filters. These 2 approaches have been shown to be equally effective in preventing transfusion-transmitted CMV infection. Only cellular components need to be CMV reduced-risk, since intact mononuclear cells are required to transmit CMV.
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The blood supply will always be vulnerable to the introduction of new pathogens into the donor population. In some instances, the pathogen may truly be a new organism, or one that has recently acquired the ability to infect humans, such as the SARS virus, various strains of avian flu, and the bovine prion responsible for variant Creutzfeldt–Jakob disease. Population shifts in response to natural or man-made catastrophes, or simply travel for business or pleasure, spread pathogens from 1 part of the world to another, such as the West Nile virus, Plasmodium spp., and Trypanosoma spp. In some circumstances, questioning donors about exposure to a pathogen or a history of a characteristic illness, or the rapid development of a screening test has been an effective means of interdicting transfusion transmission of a new infectious agent. However, an effective response is more difficult in the circumstance where the organism has not been identified, its biology is unique, the routes of transmission are not well understood, or the clinical effects are not well defined. As a result, work continues to develop pathogen inactivation technology that would be suitable for cellular blood components.
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Transfusion Reaction Workup
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If a reaction is suspected, the transfusion must be stopped immediately while maintaining venous access, and the patient must be assessed. Emergent airway and hemodynamic issues should be dealt with immediately and appropriate measures taken to alleviate the patient's major symptoms and concerns. If the assessment reveals that the patient's only symptoms are cutaneous manifestations of hypersensitivity (flushing, pruritus, and urticaria), then the transfusion may be resumed under careful observation. In all other situations, the transfusion of that unit should be stopped and a clerical check should be performed to verify that the correct unit (ie, one labeled for that patient) has been administered. A transfusion reaction form should be filled out and a new blood bank specimen should be drawn from the patient. The transfusion reaction form, the unit involved, and the new specimen should be returned to the blood bank for evaluation. A posttransfusion urine specimen should also be obtained and sent for urinalysis.
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If a reaction is suspected, the transfusion must be stopped immediately while maintaining intravenous access, and the patient must be assessed.
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The blood bank will perform a clerical check, and compare the posttransfusion specimen with the pretransfusion specimen used for compatibility testing for the appearance of hemolysis or hyperbilirubinemia. The ABO and Rh type of the posttransfusion specimen will be determined to confirm that the pretransfusion specimen was indeed from this patient and that the ABO and Rh type of the unit that was being transfused was appropriate. A direct antiglobulin test is also performed on the posttransfusion specimen looking for antibody-coated RBC (ie, donor cells coated with recipient alloantibody) indicating an immune-based HTR. Any findings suggestive of an HTR trigger a more extensive investigation in the blood bank. If the workup rules out a hemolytic reaction, transfusion may resume.