The precise risk of an adverse reaction is difficult to estimate; many reactions may be wrongly attributed to the patient's underlying illness, and approximately half of all transfusions are given to anesthetized patients in the operating rooms where reactions may be blunted or more difficult to recognize. The incidence of some adverse reactions has fallen in the past decade due to changes in component handling. Adverse reactions may occur soon after a transfusion begins, as seen with acute hemolytic reactions or acute lung injury, or within days to weeks of a transfusion, as seen with delayed hemolytic reactions.59 Fortunately, the majority of acute transfusion reactions are mild and manageable. Many of the reported transfusion-related fatalities involve human errors which may be as much as 1:18,000 transfusions.
IMMEDIATE TRANSFUSION REACTIONS
In general, immediate transfusion reactions are more dangerous than delayed reactions. Severe complications, including death, can on rare occasions develop within a few minutes of initiating transfusion. Close attention and early vital sign assessments are recommended at the beginning and within 15 minutes of starting a transfusion.
Acute Hemolytic Transfusion Reactions
Acute hemolytic transfusion reactions (AHTRs) are almost always caused by the immune-mediated destruction of ABO-incompatible transfused blood. ABO incompatible transfusions are estimated to occur in one in 38,000 to one in 70,000 RBC transfusions.60 Isohemagglutinins can activate the complement and coagulation systems. C3a and C5a can activate white blood cells to release inflammatory cytokines (interleukin [IL]-1, IL-6, IL-8, and tumor necrosis factor-alpha [TNF-α]), contributing to fever, hypotension, wheezing, chest pain, nausea, and vomiting.61 The presence of antigen-antibody complexes and activated complement on donor RBCs may lead to bradykinin generation. This can increase capillary permeability and arteriolar dilatation causing a fall in systemic blood pressure. Activation of factor XII may initiate the coagulation cascade with formation of thrombin and lead to disseminated intravascular coagulation. Renal failure may also develop as a result of ischemia, hypotension, antigen-antibody complex deposition, and thrombosis. Although rare, AHTRs can also be seen because of other blood group antibodies, particularly those in the Kidd blood group system.
Clinical Presentation The most common presenting symptom is fever with or without chills or rigors. In mild cases, this may be accompanied with abdominal, chest, flank, or back pain, whereas dyspnea, hypotension, hemoglobinuria, and eventually shock can be seen in severe cases. Bleeding, caused by the consumptive coagulopathy, can occur. Hematuria can be the first sign of intravascular hemolysis, particularly in anesthetized or unconscious patients. The severity of AHTR is extremely variable and usually depends on the rate and total volume of blood administered. Approximately 47 percent of the recipients of ABO incompatible blood show no effects, even after receiving a whole unit, 41 percent show symptoms of AHTR, and mortality is approximately 2 percent.59,60
Laboratory Evaluation Laboratory evaluation involves checking for technical and identification errors, examine a posttransfusion specimen for hemolysis, and perform a DAT to detect antibody-coated red cells. If AHTR is strongly suspected, repeat ABO and Rh typing of the patient and the transfused blood and repeat antibody screen and crossmatch may be helpful. A negative DAT occurs in rare cases when all transfused RBCs are lysed.
Management Immediate discontinuation of transfusion should always be the first step in any transfusion reaction. Maintaining vascular access with slow infusion of normal saline, monitoring vital signs, and assessing urine output are key early steps. A blood specimen should be collected immediately for laboratory evaluation. The component bag should be returned to the blood bank. If severe hemolysis has occurred, therapy focuses on management of hypotension, coagulation disorders, and renal function. A urine output of approximately 100 mL/h for 24 hours should be maintained in adults without contraindications. In simple cases, normal saline infusion may be sufficient; however, diuretics may be necessary in some cases. Intravenous administration of furosemide (40 to 80 mg) promotes diuresis and improves blood flow to the renal cortex. In severe cases of hypotension, intravenous dopamine, which dilates renal vasculature and increases cardiac output, can be used. Patients with coagulopathy and active bleeding may require administration of platelets, fresh-frozen plasma, or cryoprecipitate.
Prevention The most common basis for AHTRs is a clerical error resulting from mistakes in identifying the patient, labeling the pretransfusions sample, or identifying the correct red cell unit for the patient.60-62
Febrile Nonhemolytic Transfusion Reactions
A febrile nonhemolytic transfusion reaction (FNHTR) is defined, arbitrarily, as a temperature increase of 1°C or more during or up to 4 hours after transfusion. Other possible symptoms include increases in respiratory rate, anxiety, and, more unusually, nausea or vomiting.
FNHTRs are one of the most commonly encountered transfusion reactions occurring in approximately 0.12 to 0.5 percent of RBC units transfused, and are more likely to occur following transfusion of platelets than RBCs. Leukocyte reduction decreases the incidence of FNHTRs with both whole-blood derived and apheresis platelets.
Clinical Presentation Fever is triggered by the action of cytokines (e.g., IL-1, IL-6, TNF-α). This may be the result of activation of donor leukocytes by anti-HLA or other antibodies in the recipient, activation of recipient leukocyte and endothelial cells by transfused donor leukocytes or plasma constituents, or by the passive transfer of cytokines or CD40 ligand (CD154) that accumulated in the unit during storage.
Fever should not be solely attributed to FNHTR until other potential life-threatening transfusion reactions or patient-related factors have been excluded. Past transfusion reaction history should be reviewed to determine if additional measures should be implemented for future transfusions.
Laboratory Evaluation The laboratory investigation should concentrate on ruling out a septic transfusion reaction. A Gram stain is not a highly sensitive technique in this setting, but may be used to rule-in bacterial contamination. Rapid qualitative immunoassay tests (e.g., Verax or BacTx) are highly sensitive for most commonly encountered bacterial contaminants and may be used in lieu of Gram stain to screen implicated platelet units. In cases with a high index of suspicion, the unit should be cultured. If all results are negative and the patient's presentation is consistent with a mild FNHTR, no additional testing is required.
Management FNHTRs are typically benign, and usually resolve completely within 1 to 2 hours after the transfusion is discontinued. The remainder of the transfused unit and a posttransfusion blood sample from the patient should be sent to the laboratory for investigation. Antipyretics may be administered to shorten the duration of the fever and provide analgesia. Acetaminophen 325 to 650 mg orally for adults or 10 to 15 mg/kg/dose orally for children is effective for this purpose.
Transfusing leukoreduced RBCs and/or platelets stored in additive solution will significantly reduce the risk of FNHTRs.63 Premedication with antipyretics (acetaminophen) is not helpful.64,65
Allergic Transfusion Reactions
These are a common adverse reaction of transfusion therapy, ranging from mild forms characterized by localized pruritus and/or urticaria, to severe anaphylactic or anaphylactoid reactions. The mild forms of allergic transfusion reaction (ATR) occur in 1 to 3 percent of transfusions of plasma-rich components (i.e., platelets/fresh-frozen plasma) and in 0.1 to 0.3 percent for red cells. Severe anaphylactic reactions are much less frequent and estimated at one in 20,000 to 50,000 transfusions.7
The majority of ATRs are immediate (type 1) hypersensitivity reactions, mediated by preformed IgE antibodies binding to soluble proteins present within donor plasma.66 Severe anaphylactic reactions may occur after transfusion of blood products to IgA-deficient patients who have anti-IgA antibodies. Most patients labeled as IgA deficient still have low levels of the immunoglobulin (2 to 4 mg/dL) and will not produce anti-IgA antibodies. The rare patient with complete IgA deficiency (<0.05 mg/dL) may develop anti-IgA antibodies and thus might experience anaphylaxis with transfusion. Anaphylactoid reactions are similar to anaphylaxis but clinically less severe and caused by non–IgE-mediated activation of mast cells.
Clinical Presentation ATRs usually begin during or within an hour of starting a transfusion, but may not become evident until several hours later. Common findings include urticaria, rash, pruritus, and flushing. More severe reactions occur sooner and may include angioedema, chest tightness, dyspnea, cyanosis, hoarseness, stridor, or wheezing. In addition, gastrointestinal symptoms such as abdominal pain, nausea, vomiting, and diarrhea may also occur. Unlike other acute transfusion reactions, fever is usually absent. Anaphylaxis occurs immediately after starting the transfusion. Symptoms can include bronchospasm, angioedema, respiratory distress, nausea, vomiting, abdominal cramps, diarrhea, shock, and loss of consciousness.
Laboratory Evaluation There is no need for laboratory investigation with simple urticarial and/or localized pruritus. However, the incident should be reported to the blood bank to update the patient's record for any future transfusions. In anaphylactic reactions, the patient should be tested for complete IgA deficiency; however, a history of anaphylactic reactions mandate use of washed red cells and platelets and avoidance of plasma transfusions regardless of the results of these tests.
Management Most ATRs are mild, self-limited and respond well to transfusion discontinuation and, if indicated, administration of antihistamine (diphenhydramine hydrochloride, usually orally). In cases limited to urticaria, the transfusion may be resumed immediately after symptoms resolve. However, transfusion should never be resumed when there is a severe reaction. In acute anaphylaxis, fluid resuscitation may be needed to maintain blood pressure followed by administration of subcutaneous or intramuscular epinephrine (0.3 mL of 1:1000 dilution), as well as airway management and intensive care. In case of shock, a higher concentration of intravenous epinephrine (3 to 5 mL of a 1:10,000 dilution) can be administered. Steroids are usually not helpful in acute crises.
Prevention Patients with a history of mild ATRs should not be premedicated with an antihistamine, as this does not reduce the overall risk of ATRs.65 Platelets stored in additive solution may be used to reduce the risk of a reaction. In IgA-deficient patients with a history of anaphylaxis to transfusion, components from IgA-deficient donors are sometimes available.63
Transfusion-Related Acute Lung Injury
Transfusion-related acute lung injury (TRALI) is a syndrome of acute hypoxia attributable to noncardiogenic pulmonary edema that occurs within 6 hours of a transfusion.67,68 TRALI has been the leading cause of transfusion-related fatalities for several years.
There are two main hypotheses regarding the capillary leak seen in TRALI. The two-hit hypothesis states that underlying patient factors act as a necessary first hit, leading to adherence of primed neutrophils to the pulmonary endothelium. The second hit is caused by mediators within the transfused component, which activate pulmonary neutrophils, which, in turn, damage the endothelium.68 The mediators are often antibodies specific for either class II HLA or for human neutrophil antigens (HNAs). There are also cases in which no antibody was detected, which are thought to be a result of proinflammatory mediators, bioactive lipids, and CD40 ligand that accumulate in the blood product during storage.69 Despite reports of a direct correlation between storage time of cellular blood components and TRALI, this mechanism remains controversial.
Specific patient factors (first hits) that are associated with a greater risk of TRALI include patients on mechanical ventilation, sepsis, chronic alcohol abuse, severe liver disease, hematologic malignancy, and others. It is not known whether the risk is determined by the patient's condition, or by a greater transfusion requirement. The two-hit hypothesis accounts for critically ill patients who develop TRALI; however, there are reports of TRALI in reasonably healthy patients. This observation led to the threshold model of TRALI.70 In this paradigm, a threshold, or tipping point, must be surpassed to induce TRALI. A healthy patient may develop TRALI when transfused with a high titer of antibody. Conversely, a critically ill patient with primed neutrophils can be tipped into TRALI with a lower titer of antibody.
Clinical Presentation and Differential Diagnosis It is often impossible to fully distinguish TRALI from other causes of respiratory distress. The typical presentation of TRALI is the sudden development of dyspnea, severe hypoxemia (O2 saturation <90 percent in room air) hypotension, and fever that develop within 6 hours of transfusion and usually resolves with supportive care within 48 to 96 hours. Although hypotension is considered one of the important signs in diagnosing TRALI, hypertension can occur in some cases.
In addition to new or worsening oxygen desaturation, TRALI is characterized by chest x-ray findings of bilateral diffuse patchy pulmonary densities without cardiac enlargement. TRALI can be ruled out as the sole cause of pulmonary failure by the presence of rales and jugular venous distention on physical exam and/or dilated pulmonary arteries on chest x-ray, which are evidence of congestive heart failure with or without transfusion-associated circulatory overload (TACO). Transient leukopenia, which follows the reaction within few hours, can also distinguish TRALI from TACO.
Management Supportive care is the mainstay of therapy in TRALI, including oxygen supplementation and aggressive respiratory support plus intravenous fluid and vasopressors for hypotension, if indicated. It has been suggested that diuretics, which are indicated in TACO management, are not efficacious and should be avoided in TRALI. Glucocorticoids may provide benefit.
Prevention HLA alloimmunization has been directly correlated with the number of times a woman is pregnant and plasma from multiparous women has been implicated as a risk factor in TRALI. To reduce this risk, blood banks attempt to collect plasma from males, nulliparous females, and/or females tested and found to be negative for HLA antibodies. After blood collection centers implemented TRALI mitigation strategies, the incidence of TRALI dropped from an estimate of one in 4000 transfusions, to approximately one in 12,000.71 Nonetheless, TRALI continues to be the leading cause of transfusion-related fatalities.
Pooled plasma may also be used for TRALI mitigation because antibody titers drop due to dilution. No cases of TRALI resulting from transfusion of pooled solvent detergent treated plasma have been reported.72,73
Transfusion-Associated Circulatory Overload
TACO occurs when patients are unable to effectively process the expansion in intravascular volume from a blood transfusion. Circulatory overload may be the consequence of the infusions rates, the volume of infused blood product, and/or an underlying cardiac, renal, and/or pulmonary pathology. The fluid volume transfused may be less important than the infusion flow rate and the patient's ability to process the fluid.
The incidence of TACO is difficult to ascertain, as there are inconsistent case definitions, passive reporting systems and poor clinical recognition. Approximately 1 percent of orthopedic patients developed TACO postoperatively, compared to 6 percent of patients in an ICU setting.74 Reports of TACO have surged as awareness has increased. Active surveillance also increases the number of cases. In one institution the historical prevalence rate from 6 years of passive reporting was one in 1566 from plasma transfusions. After 1 month of active surveillance the prevalence rate jumped to one in 68.75
TACO is seen more in younger and advanced age patients.76 Additional risk factors include female sex, a history of congestive heart failure, hemodialysis, mechanical ventilation, recent vasopressors, and positive fluid balance.77
Clinical Presentation Symptoms of TACO may include dyspnea, orthopnea, cough, headache, and hypoxemia, which are not specific. However, signs such as rales, hypertension, and jugular vein distention may differentiate TACO from TRALI. These signs and symptoms usually present within 2 hours of the onset of transfusion, but may be up to 6 hours or even 24 hours after the onset of transfusion.
Laboratory Evaluation Oxygen saturation may decrease along with the partial pressure of oxygen in the arterial blood. New bilateral infiltrates on chest x-ray is characteristic for TACO; however, it is also seen in TRALI. Elevated levels of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are both useful markers for TACO, but NT-proBNP may be more useful as it has a longer in vivo and in vitro half-life. Unfortunately neither peptide was found to be useful in distinguishing TACO from TRALI in critically ill patients.78
Management Once TACO is suspected, intravenous fluids should be restricted, followed by the administration of supplemental oxygen and a diuretic, if not contraindicated. Placing the patient in a sitting position can also be helpful. In severe cases, mechanical ventilation may be required.
If a patient is at risk for TACO and blood transfusion is imperative, blood should be administered slowly at a rate of 1 to 4 mL/kg/h. Most blood banks can also reduce the transfusion volume by splitting the blood product into smaller volumes if the transfusion is going to last longer than 4 hours. Close monitoring of the patient's vital signs throughout the transfusion may also help in decreasing the development of TACO.
Transfusion-related sepsis when it occurs is usually from platelet units that are stored at room temperature. Red cells, stored at refrigerator temperatures, are very rarely contaminated by unusual cold-growing organisms (e.g., Yersinia, Serratia, Pseudomonas). The rate of fatal transfusion-transmitted bacteremia from red cells has been estimated to be 0.13 per million units transfused in the United States.20
Clinical Presentation The infusion of large numbers of Gram-negative microorganisms may lead to fever (>38.5°C), rigors, marked hypotension, abdominal pain, vomiting, diarrhea, and the development of profound shock. Gram-positive contaminants may cause fever and rigors, but are not associated with the severe symptoms produced by Gram-negative toxins.
Laboratory Evaluation Rapid diagnosis usually may be made via Gram stain of the residual donor blood; however, a culture of the transfused component is necessary.
Management Septic shock from transfusion of contaminated blood should be managed as for septic shock from other causes and is not discussed further here.
DELAYED TRANSFUSION REACTIONS
Delayed Hemolytic Transfusion Reactions
DHTRs occur when a previously immunized patient receives red cells containing the corresponding antigen but are compatible in the crossmatch because of a low titer of circulating alloantibody. DHTRs occur in 0.2 to 2.6 percent of patients. It is vanishingly rare in infants younger than 4 months of age, and more common in chronically transfused patients.
Approximately 30 to 40 percent of alloantibodies become undetectable months to years after their initial identification. However, a patient previously immunized by transfusion or pregnancy may develop a secondary immune response after reexposure to a blood group antigen. Decreasing Hct or failure to see the typical 1 g/dL Hgb/3 percent Hct increment following transfusion may be noted within several days to weeks of a blood transfusion, as well as an unexplained fever. Hemolysis from DHTR is typically extravascular, without dramatic clinical symptoms and signs, although some classes of IgG bind complement and will cause intravascular hemolysis. Hemolysis in DHTRs is usually mild and gradual, however, when antibodies are produced against antigens in the Kidd blood system, the hemolysis may be rapid, intravascular, and may be severe.
The usual evidence of hemolysis is seen. The appearance of spherocytes and reticulocytes on peripheral blood film, increases in total and unconjugated bilirubin, and increased LDH. The DAT is usually positive but may be negative if all the transfused RBCs have been eliminated from the circulation. The antibody screen is usually positive and the antibody can be identified. No specific management is usually needed as these reactions are usually subtle and clinically silent. In cases of intravascular hemolysis, clinical support measures are similar to those described for an acute hemolytic transfusion reaction. If transfusion is necessary donor red cells negative for the offending antigen may be selected.
Posttransfusion purpura is a rare immune-mediated disorder that is discussed in greater detail in Chap. 139.