++
Adverse reactions to transfused blood components occur despite multiple tests, inspections, and checks. Fortunately, the most common reactions are not life threatening, although serious reactions can present with mild symptoms and signs. Some reactions can be reduced or prevented by modified (filtered, washed, or irradiated) blood components. When an adverse reaction is suspected, the transfusion should be stopped and reported to the blood bank for investigation.
++
Transfusion reactions may result from immune and nonimmune mechanisms. Immune-mediated reactions are often due to preformed donor or recipient antibody; however, cellular elements may also cause adverse effects. Nonimmune causes of reactions are due to the chemical and physical properties of the stored blood component and its additives.
++
Transfusion-transmitted viral infections are increasingly rare due to improved screening and testing. As the risk of viral infection is reduced, the relative risk of other reactions increases, such as hemolytic transfusion reactions and sepsis from bacterially contaminated components. Pretransfusion quality assurance improvements further increase the safety of transfusion therapy. Infections, like any adverse transfusion reaction, must be brought to the attention of the blood bank for appropriate studies (Table 12-3).
++
+++
IMMUNE-MEDIATED REACTIONS
+++
Acute hemolytic transfusion reactions
++
Immune-mediated hemolysis occurs when the recipient has preformed antibodies that lyse donor erythrocytes. The ABO isoagglutinins are responsible for the majority of these reactions. However, alloantibodies directed against other RBC antigens, i.e., Rh, Kell, and Duffy, are responsible for more fatal hemolytic transfusion reactions.
++
Acute hemolytic reactions may present with hypotension, tachypnea, tachycardia, fever, chills, hemoglobinemia, hemoglobinuria, chest and/or flank pain, and discomfort at the infusion site. Monitoring the patient’s vital signs before and during the transfusion is important to identify reactions promptly. When acute hemolysis is suspected, the transfusion must be stopped immediately, intravenous access maintained, and the reaction reported to the blood bank. A correctly labeled posttransfusion blood sample and any untransfused blood should be sent to the blood bank for analysis. The laboratory evaluation for hemolysis includes the measurement of serum haptoglobin, lactate dehydrogenase (LDH), and indirect bilirubin levels.
++
The immune complexes that result in RBC lysis can cause renal dysfunction and failure. Diuresis should be induced with intravenous fluids and furosemide or mannitol. Tissue factor released from the lysed erythrocytes may initiate DIC. Coagulation studies including prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and platelet count should be monitored in patients with hemolytic reactions.
++
Errors at the patient’s bedside, such as mislabeling the sample or transfusing the wrong patient, are responsible for the majority of these reactions. The blood bank investigation of these reactions includes examination of the pre- and posttransfusion samples for hemolysis and repeat typing of the patient samples; direct antiglobulin test (DAT), sometimes called the direct Coombs test, of the posttransfusion sample; repeating the cross-matching of the blood component; and checking all clerical records for errors. DAT detects the presence of antibody or complement bound to RBCs in vivo (Fig. 12-1).
++
+++
Delayed hemolytic and serologic transfusion reactions
++
Delayed hemolytic transfusion reactions (DHTRs) are not completely preventable. These reactions occur in patients previously sensitized to RBC alloantigens who have a negative alloantibody screen due to low antibody levels. When the patient is transfused with antigen-positive blood, an anamnestic response results in the early production of alloantibody that binds donor RBCs. The alloantibody is detectable 1–2 weeks following the transfusion, and the posttransfusion DAT may become positive due to circulating donor RBCs coated with antibody or complement. The transfused, alloantibody-coated erythrocytes are cleared by the reticuloendothelial system. These reactions are detected most commonly in the blood bank when a subsequent patient sample reveals a positive alloantibody screen or a new alloantibody in a recently transfused recipient.
++
No specific therapy is usually required, although additional RBC transfusions may be necessary. Delayed serologic transfusion reactions are similar to DHTR, because the DAT is positive and alloantibody is detected; however, RBC clearance is not increased.
+++
Febrile nonhemolytic transfusion reaction
++
The most frequent reaction associated with the transfusion of cellular blood components is a febrile nonhemolytic transfusion reaction (FNHTR). These reactions are characterized by chills and rigors and a ≥1°C rise in temperature. FNHTR is diagnosed when other causes of fever in the transfused patient are ruled out. Antibodies directed against donor leukocyte and HLA antigens may mediate these reactions; thus, multiply transfused patients and multiparous women are felt to be at increased risk. Although anti-HLA antibodies may be demonstrated in the recipient’s serum, investigation is not routinely done because of the mild nature of most FNHTR. The use of leukocyte-reduced blood products may prevent or delay sensitization to leukocyte antigens and thereby reduce the incidence of these febrile episodes. Cytokines released from cells within stored blood components may mediate FNHTR; thus, leukoreduction before storage may prevent these reactions.
++
Urticarial reactions are related to plasma proteins found in transfused components. Mild reactions may be treated symptomatically by temporarily stopping the transfusion and administering antihistamines (diphenhydramine, 50 mg orally or intramuscularly). The transfusion may be completed after the signs and/or symptoms resolve. Patients with a history of allergic transfusion reaction should be premedicated with an antihistamine. Cellular components can be washed to remove residual plasma for the extremely sensitized patient.
+++
Anaphylactic reaction
++
This severe reaction presents after transfusion of only a few milliliters of the blood component. Symptoms and signs include difficulty breathing, coughing, nausea and vomiting, hypotension, bronchospasm, loss of consciousness, respiratory arrest, and shock. Treatment includes stopping the transfusion, maintaining vascular access, and administering epinephrine (0.5–1 mL of 1:1000 dilution subcutaneously). Glucocorticoids may be required in severe cases.
++
Patients who are IgA-deficient, <1% of the population, may be sensitized to this Ig class and are at risk for anaphylactic reactions associated with plasma transfusion. Individuals with severe IgA deficiency should therefore receive only IgA-deficient plasma and washed cellular blood components. Patients who have anaphylactic or repeated allergic reactions to blood components should be tested for IgA deficiency.
+++
Graft-versus-host disease
++
Graft-versus-host disease (GVHD) is a frequent complication of allogeneic stem cell transplantation, in which lymphocytes from the donor attack and cannot be eliminated by an immunodeficient host. Transfusion-related GVHD is mediated by donor T lymphocytes that recognize host HLA antigens as foreign and mount an immune response, which is manifested clinically by the development of fever, a characteristic cutaneous eruption, diarrhea, and liver function abnormalities. GVHD can also occur when blood components that contain viable T lymphocytes are transfused to immunodeficient recipients or to immunocompetent recipients who share HLA antigens with the donor (e.g., a family donor). In addition to the aforementioned clinical features of GVHD, transfusion-associated GVHD (TA-GVHD) is characterized by marrow aplasia and pancytopenia. TA-GVHD is highly resistant to treatment with immunosuppressive therapies, including glucocorticoids, cyclosporine, antithymocyte globulin, and ablative therapy followed by allogeneic bone marrow transplantation. Clinical manifestations appear at 8–10 days, and death occurs at 3–4 weeks after transfusion.
++
TA-GVHD can be prevented by irradiation of cellular components (minimum of 2500 cGy) before transfusion to patients at risk. Patients at risk for TA-GVHD include fetuses receiving intrauterine transfusions, selected immunocompetent (e.g., lymphoma patients) or immunocompromised recipients, recipients of donor units known to be from a blood relative, and recipients who have undergone marrow transplantation. Directed donations by family members should be discouraged (they are not less likely to transmit infection); lacking other options, the blood products from family members should always be irradiated.
+++
Transfusion-related acute lung injury
++
Transfusion-related acute lung injury (TRALI) is the most common cause of transfusion related fatalities. The recipient develops symptoms of hypoxia (Pao2/FIo2 <300 mmHg) and signs of noncardiogenic pulmonary edema, including bilateral interstitial infiltrates on chest x-ray, either during or within 6 h of transfusion. Treatment is supportive, and patients usually recover without sequelae. TRALI usually results from the transfusion of donor plasma that contains high-titer anti-HLA class II antibodies that bind recipient leukocytes. The leukocytes aggregate in the pulmonary vasculature and release mediators that increase capillary permeability. Testing the donor’s plasma for anti-HLA antibodies can support this diagnosis. The implicated donors are frequently multiparous women. The transfusion of plasma from male and nulliparous women donors reduces the risk of TRALI. Recipient factors that are associated with increased risk of TRALI include smoking, chronic alcohol use, shock, liver surgery (transplantation), mechanical ventilation with >30 cmH2O pressure support and positive fluid balance.
+++
Posttransfusion purpura
++
This reaction presents as thrombocytopenia 7–10 days after platelet transfusion and occurs predominantly in women. Platelet-specific antibodies are found in the recipient’s serum, and the most frequently recognized antigen is HPA-1a found on the platelet glycoprotein IIIa receptor. The delayed thrombocytopenia is due to the production of antibodies that react to both donor and recipient platelets. Additional platelet transfusions can worsen the thrombocytopenia and should be avoided. Treatment with intravenous immunoglobulin may neutralize the effector antibodies, or plasmapheresis can be used to remove the antibodies.
++
A recipient may become alloimmunized to a number of antigens on cellular blood elements and plasma proteins. Alloantibodies to RBC antigens are detected during pretransfusion testing, and their presence may delay finding antigen-negative cross-match-compatible products for transfusion. Women of childbearing age who are sensitized to certain RBC antigens (i.e., D, c, E, Kell, or Duffy) are at risk for bearing a fetus with hemolytic disease of the newborn. Matching for D antigen is the only pretransfusion selection test to prevent RBC alloimmunization.
++
Alloimmunization to antigens on leukocytes and platelets can result in refractoriness to platelet transfusions. Once alloimmunization has developed, HLA-compatible platelets from donors who share similar antigens with the recipient may be difficult to find. Hence, prudent transfusion practice is directed at preventing sensitization through the use of leukocyte-reduced cellular components, as well as limiting antigenic exposure by the judicious use of transfusions and use of SDAPs.
+++
NONIMMUNOLOGIC REACTIONS
++
Blood components are excellent volume expanders, and transfusion may quickly lead to transfusion-associated circulatory overload (TACO). Dyspnea with PaO2 <90% on room air, bilateral infiltrates on chest x-ray, and systolic hypertension are found with TACO. Brain natriuretic peptide (BNP) is often elevated (>1.5) compared with pretransfusion levels. Monitoring the rate and volume of the transfusion and using a diuretic can minimize this problem.
++
Refrigerated (4°C) or frozen (−18°C or below) blood components can result in hypothermia when rapidly infused. Cardiac dysrhythmias can result from exposing the sinoatrial node to cold fluid. Use of an in-line warmer will prevent this complication.
++
RBC leakage during storage increases the concentration of potassium in the unit. Neonates and patients in renal failure are at risk for hyperkalemia. Preventive measures, such as using fresh or washed RBCs, are warranted for neonatal transfusions because this complication can be fatal.
++
Citrate, commonly used to anticoagulate blood components, chelates calcium and thereby inhibits the coagulation cascade. Hypocalcemia, manifested by circumoral numbness and/or tingling sensation of the fingers and toes, may result from multiple rapid transfusions. Because citrate is quickly metabolized to bicarbonate, calcium infusion is seldom required in this setting. If calcium or any other intravenous infusion is necessary, it must be given through a separate line.
++
Each unit of RBCs contains 200–250 mg of iron. Symptoms and signs of iron overload affecting endocrine, hepatic, and cardiac function are common after 100 units of RBCs have been transfused (total-body iron load of 20 g). Preventing this complication by using alternative therapies (e.g., erythropoietin) and judicious transfusion is preferable and cost effective. Chelating agents, such as deferoxamine and deferasirox, are available, but the response is often suboptimal.
+++
Hypotensive reactions
++
Transient hypotension may be noted among transfused patients who take angiotensin-converting enzyme (ACE) inhibitors. Because blood products contain bradykinin that is normally degraded by ACE, patients on ACE inhibitors may have increased bradykinin levels that cause hypotension in the recipient. The blood pressure typically returns to normal without intervention.
++
Transfusion of allogeneic blood is immunosuppressive. Multiply transfused renal transplant recipients are less likely to reject the graft, and transfusion may result in poorer outcomes in cancer patients and increase the risk of infections. Transfusion-related immunomodulation is thought to be mediated by transfused leukocytes. Leukocyte-depleted cellular products may cause less immunosuppression, although controlled data are unlikely to be obtained as the blood supply becomes universally leukocyte depleted.
+++
INFECTIOUS COMPLICATIONS
++
The blood supply is initially screened by selecting healthy donors without high-risk lifestyles, medical conditions, or exposure to transmissible pathogens, such as intravenous drug use or visiting malaria endemic areas. Multiple tests performed on donated blood to detect the presence of infectious agents using nucleic acid amplification testing (NAAT) or evidence of prior infections by testing for antibodies to pathogens and sterility of platelet products further reduce the risk of transfusion-acquired infections.
+++
Hepatitis C virus (HCV)
++
Blood donations are tested for antibodies to HCV and HCV RNA. The risk of acquiring HCV through transfusion is now calculated to be approximately 1 in 2,000,000 units. Infection with HCV may be asymptomatic or lead to chronic active hepatitis, cirrhosis, and liver failure.
+++
Human immunodeficiency virus type 1 (HIV-1)
++
Donated blood is tested for antibodies to HIV-1, HIV-1 p24 antigen, and HIV RNA using NAAT. Approximately a dozen seronegative donors have been shown to harbor HIV RNA. The risk of HIV-1 infection per transfusion episode is 1 in 2,000,000. Antibodies to HIV-2 are also measured in donated blood. No cases of HIV-2 infection have been reported in the United States since 1992.
+++
Hepatitis B virus (HBV)
++
Donated blood is screened for HBV using assays for hepatitis B surface antigen (HbsAg). NAAT testing is not practical because of slow viral replication and lower levels of viremia. The risk of transfusion-associated HBV infection is several times greater than for HCV. Vaccination of individuals who require long-term transfusion therapy can prevent this complication.
+++
Other hepatitis viruses
++
Hepatitis A virus is rarely transmitted by transfusion; infection is typically asymptomatic and does not lead to chronic disease. Other transfusion-transmitted viruses—TT virus, SEN virus, and GB virus C—do not cause chronic hepatitis or other disease states. Routine testing does not appear to be warranted.
+++
West nile virus (WNV)
++
Transfusion-transmitted WNV infections were documented in 2002. This RNA virus can be detected using NAAT; routine screening began in 2003. WNV infections range in severity from asymptomatic to fatal, with the older population at greater risk.
++
This ubiquitous virus infects ≥50% of the general population and is transmitted by the infected “passenger” WBCs found in transfused PRBCs or platelet components. Cellular components that are leukocyte-reduced have a decreased risk of transmitting CMV, regardless of the serologic status of the donor. Groups at risk for CMV infections include immunosuppressed patients, CMV-seronegative transplant recipients, and neonates; these patients should receive leukocyte-depleted components or CMV seronegative products.
+++
Human T lymphotropic virus (HTLV) type 1
++
Assays to detect HTLV-1 and -2 are used to screen all donated blood. HTLV-1 is associated with adult T cell leukemia/lymphoma and tropical spastic paraparesis in a small percentage of infected persons. The risk of HTLV-1 infection via transfusion is 1 in 641,000 transfusion episodes. HTLV-2 is not clearly associated with any disease.
++
Blood components and pooled plasma products can transmit this virus, the etiologic agent of erythema infectiosum, or fifth disease, in children. Parvovirus B19 shows tropism for erythroid precursors and inhibits both erythrocyte production and maturation. Pure red cell aplasia, presenting either as acute aplastic crisis or chronic anemia with shortened RBC survival, may occur in individuals with an underlying hematologic disease, such as sickle cell disease or thalassemia (Chap. 11). The fetus of a seronegative woman is at risk for developing hydrops from this virus.
+++
Bacterial contamination
++
The relative risk of transfusion-transmitted bacterial infection has increased as the absolute risk of viral infections has dramatically decreased.
++
Most bacteria do not grow well at cold temperatures; thus, PRBCs and FFP are not common sources of bacterial contamination. However, some gram-negative bacteria can grow at 1–6°C. Yersinia, Pseudomonas, Serratia, Acinetobacter, and Escherichia species have all been implicated in infections related to PRBC transfusion. Platelet concentrates, which are stored at room temperature, are more likely to contain skin contaminants such as gram-positive organisms, including coagulase-negative staphylococci. It is estimated that 1 in 1000–2000 platelet components is contaminated with bacteria. The risk of death due to transfusion-associated sepsis has been calculated at 1 in 17,000 for single-unit platelets derived from whole blood donation and 1 in 61,000 for apheresis product. Since 2004, blood banks have instituted methods to detect contaminated platelet components.
++
Recipients of transfusion contaminated with bacteria may develop fever and chills, which can progress to septic shock and DIC. These reactions may occur abruptly, within minutes of initiating the transfusion, or after several hours. The onset of symptoms and signs is often sudden and fulminant, which distinguishes bacterial contamination from an FNHTR. The reactions, particularly those related to gram-negative contaminants, are the result of infused endotoxins formed within the contaminated stored component.
++
When these reactions are suspected, the transfusion must be stopped immediately. Therapy is directed at reversing any signs of shock, and broad-spectrum antibiotics should be given. The blood bank should be notified to identify any clerical or serologic error. The blood component bag should be sent for culture and Gram stain.
+++
Other Infectious Agents
++
Various parasites, including those causing malaria, babesiosis, and Chagas’ disease, can be transmitted by blood transfusion. Geographic migration and travel of donors shift the incidence of these rare infections. Other agents implicated in transfusion transmission include dengue, chikungunya virus, variant Creutzfeldt-Jakob disease, A. phagocytophilum, and yellow fever vaccine virus, and the list will grow. Tests for some pathogens are available, such as T. cruzi, but not universally required, whereas others are being developed (B. microti). These infections should be considered in the transfused patient in the appropriate clinical setting.