Acute Hemolytic Transfusion Reactions
Immune-mediated hemolysis occurs when the recipient has preformed antibodies that lyse donor erythrocytes. The anti-A or anti-B antibodies are responsible for the majority of these reactions. However, alloantibodies directed against other RBC antigens, i.e., Rh, Kell, and Duffy, are responsible for fatal hemolytic transfusion reactions as well.
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. 109-1).
Direct and indirect Coombs test. The direct Coombs (antiglobulin) test detects the presence of antibodies (or complement) on the surface of erythrocytes. The indirect Coombs (antiglobulin) test detects antibodies in the serum that may bind to donor erythrocytes. RBC, red blood cell. (Adapted from https://commons.wikimedia.org/wiki/File:Coombs_test_schematic.png.)
Delayed Hemolytic and Serologic 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, as 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 FNHTRs. 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 leukocytes within stored blood components may mediate FNHTR; thus, leukoreduction before storage may prevent these reactions. Likewise, cytokines and chemokines released from platelets components, released during storage may also mediate FNHTR.
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 may be premedicated with an antihistamine. Cellular components can be washed to remove residual plasma for the extremely sensitized patient. Most of the allergic presentation may not depend on preformed antibodies and may be attributable to biological response modifiers triggering histamine and serotonin release from platelets and leukocytes.
This severe allergic 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. Of note, the importance of the allergic risk associated with IgA deficiency may be overestimated and is currently debated.
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 posttransfusion.
TA-GVHD can be prevented by irradiation of cellular components (minimum of 2500 cGy) before transfusion to patients at risk. Recently, pathogen inactivation technologies have shown to prevent TA-GVHD as well. 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
TRALI is among 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. Anti-HLA class I and anti-human neutrophil antigen (HNA) antibodies can be involved as well. 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 and platelets 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 cm H20 pressure support and positive fluid balance.
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 RBC 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.