A 67-year-old woman with a fractured right femur presents for intramedullary nailing under spinal anesthesia. After 45 minutes, she loses 1200 mL of blood and receives 1 unit of designated donor red blood cells (RBCs). Within minutes of initiating transfusion, the patient is shivering and complains of chills, nausea, and difficulty breathing. Her heart rate increases from 84 beats per minute to 128 beats per minute, ST segments are depressed, and the blood pressure decreases from 124/72 mm Hg to 82/46 mm Hg. The urine in the urometer has turned from clear to pink.
Is this a transfusion reaction?
The immediacy of presentation as well as the scope of signs and symptoms indicates that this is an acute hemolytic transfusion reaction. This type of reaction is the most severe immediate transfusion reaction and occurs infrequently. Prior data suggested that acute reactions manifest with an incidence of 1:10,000–1:50,000 units of blood products administered. Newer data suggest a frequency of approximately 1:250,000–1:500,000.
A Canadian hemovigilance study found 11 cases of acute hemolytic transfusions out of 138,605 RBC units given in 2000. Death rates were 25% when <1000 mL was transfused and 44% when >1000 mL of incompatible ABO blood was given.
Are all transfusion reactions immediate?
Immediate transfusion reactions occur within the first 24 hours of administration of blood components. Types of immediate transfusion reactions include acute intravascular hemolytic transfusion reaction (AIHTR) and acute extravascular hemolytic transfusion reaction, allergic transfusion reactions (mild, anaphylactic, anaphylactoid), febrile nonhemolytic transfusion reaction (FNHTR), hypotensive transfusion reaction, bacteria-contaminated or septic transfusion, transfusion-related lung injury (TRALI), heat-induced hemolyzed RBCs, and transfusion-associated circulatory overload (TACO).
Delayed reactions occur after 24 hours and often 3 days to months after transfusion. Types of delayed reactions include delayed extravascular hemolytic, alloimmunization, graft-versus-host disease (GVHD), and infectious (viral, parasitic, and bacterial).
Can all blood products cause transfusion reactions?
All blood products can cause transfusion reactions. The type of transfusion reaction depends on the blood product administered. Only incompatible RBC transfusions cause intravascular or extravascular hemolytic transfusion reactions. Allergic reactions, which are probably the most common transfusion reactions (1%–3% of all transfusions), can occur with RBC, plasma, or platelet transfusions. Allergic reactions usually result from preformed antibodies to plasma proteins. IgE may mediate allergic reactions, and anaphylaxis may occur. Febrile reactions may be produced by stored leukocytes producing increased interleukin (IL)-1 (endogenous pyrogen) or anti-IgA antibodies produced by individuals who are deficient in IgA or an IgA subclass. IL-6, IL-1β, and tumor necrosis factor (TNF)-α, also endogenous pyrogens, have been found to increase in stored platelet concentrates.
What are the etiologies and presentations of transfusion reactions?
Immediate transfusion reactions
Acute intravascular hemolytic transfusion reaction
AIHTR usually occurs intravascularly. Destruction of donor and occasionally recipient RBCs releases free hemoglobin and stroma of destroyed erythrocytes, elaborates cytokines and chemokines, activates complement, reduces oxygen carrying capacity, and causes electrolyte imbalances. This reaction can have devastating results. Morbidity and mortality vary with the amount of blood transfused and the type and amount of antigen and antibody transfused.
The most common cause of AIHTR is ABO incompatibility. High IgM (anti-A, anti-B) antibody titers in the recipient attach to donor erythrocyte antigen. Antibody-coated donor RBCs are referred to as opsonized RBCs. Destruction of these cells and activation of complement lead to acute intravascular hemolysis.
Although ABO antibodies are most often implicated in fatal reactions, antibodies to Rh, Duffy, Kell, Lewis, and Kidd can be just as devastating. In an O-positive individual (with anti-A and anti-B antibodies), the most common antibody is anti-A. Anti-Rh is usually an IgG-mediated reaction that does not generally activate complement. The number of antigenic sites on the RBC varies, with many more ABO antigens (2–8 × 10 5 ) per cell, in contrast to lesser antigens, such as Kell (3–6 × 10 3 per cell). The higher the number of antigens present, the greater the likelihood of complement activation.
Attachment of IgM begins a cascade of events leading to complement activation; cytokine, chemokine (TNF-α, IL-1, IL-6), and kinin production; thrombin generation; tissue factor elaboration; and platelet activation. IgM-induced complement activation as well as sometimes IgG-induced complement activation, leads to anaphylotoxin production composed of complement fragments C3a, C4a, and C5a. Activation of complement components 3, 4, and 5 (particularly C3 and C5) produces cell lysis, degranulation of mast cells, histamine release, smooth muscle contraction, cytotoxic oxygen free radical production, and chemotaxis of leukocytes.
Opsonized RBCs are phagocytized, in particular by macrophages and less so by monocytes. These cells degranulate, releasing histamine, serotonin, proinflammatory cytokines and chemokines (including TNF-α and kallikrein), and activated bradykinin. This process causes hypotension and capillary leak, producing direct and reflex tachycardia, renal dysfunction, and often respiratory distress. TNF-α, which is produced during hemolysis, also leads to endothelial tissue factor release and extrinsic followed by intrinsic coagulation cascade activation, thrombin generation, and platelet activation; this contributes to disseminated intravascular coagulopathy (DIC) seen with AIHTR.
Free hemoglobin binds to endothelial nitric oxide, preventing the action of endothelial relaxing factor and leads to renovascular vasoconstriction. Norepinephrine release, owing to hypotension induced by bradykinin, serotonin, and histamine, leads to further vasoconstriction. Destroyed red cell stroma induces further vasoconstriction and clogs microtubules. IL-1, IL-1 receptor antagonist, and IL-6 activation of genes also occurs, leading to RBC autoantibody and alloantibody production, which may have a part in delayed hemolytic transfusion reaction (DHTR) and the degree to which extravascular hemolysis occurs.
Acute extravascular hemolytic transfusion reaction
Acute extravascular hemolytic transfusion reaction generally involves non-ABO antigen groups. They are most commonly associated with Rh group incompatibility. Complement either is not activated or attaches only to C3b receptors, without activation to C3a or C5a receptors. There is no intravascular RBC destruction. Extravascular removal of opsonized RBCs occurs either by the spleen (C3b) or liver (IgG). The direct antibody test (DAT) becomes positive (as it does with AIHTR) from alloantibodies binding to incompatible erythrocytes. The hematocrit and haptoglobin levels decrease slowly, but hemoglobinemia or hemoglobinuria is rare. A low-grade fever may be produced by cytokine release or IL-1 production.
Febrile nonhemolytic transfusion reaction
FNHTR, the most common type of transfusion reaction, is related to the presence of donor leukocytes in transfused blood products (particularly RBCs and platelets). Typically, there is a 1° C (usually <2° C) increase in temperature. Febrile reactions >2° C are usually associated with transfusion of bacterial contaminated blood products.
FNHTR can occur immediately or several hours after transfusion (usually within 4 hours) and usually resolves within 48 hours. Chills, subjective feelings of cold, or rigors often accompany the febrile reaction. These symptoms may be present in the absence of increased temperature. Other conditions that produce this constellation of symptoms include AIHTR, acute extravascular hemolytic transfusion reaction, anaphylactic reactions, anaphylactoid reactions, and TRALI. Other symptoms include headache, myalgias, nausea, and nonproductive cough.
FNHTR is mediated by recipient alloantibodies against donor leukocytes. These leukocytes release cytokines, and platelets release proinflammatory cytokines (IL-1, IL-6, IL-8, and TNF-α), all of which act on the hypothalamus producing febrile reactions.
Prestorage leukoreduction of RBC and platelet units has markedly reduced the incidence of FNHTR. Before the practice of prestorage leukoreduction, temperature elevation occurred in 43%–75% of transfusions. Patients experiencing a previous febrile reaction have a 12.5% chance of having another and should be given leukocyte-depleted units.
Allergic transfusion reaction
Allergic transfusion reactions occur in about 1% of all transfusions. Manifestations range from the most common mild reaction (e.g., urticaria, pruritus, swelling, rash) to the relatively rare anaphylactoid and anaphylactic reactions. Allergic reactions are due to release of histamine when donor plasma proteins attach to preformed IgE or IgG antibodies on mast cells in sensitized individuals. Histamine may also be infused from stored blood products. Allergic reactions are more likely to occur with fresh frozen plasma transfusions. However, a reaction can occur with RBC and platelet transfusions because there is plasma in these blood products as well.
Anaphylactic reactions consist of bronchospasm, severe hypotension, tachycardia, urticaria, and possibly laryngeal edema. Awake patients may also complain of dyspnea, chest pain, nausea, and vomiting. This reaction occurs most commonly in IgA-deficient individuals, who are sensitized by exposure to “foreign” IgA proteins from previous transfusions or pregnancy, or individuals lacking in other plasma proteins, such as haptoglobin. Anaphylactoid reactions usually occur with a larger volume of transfusion, are less severe, and are often proportionate to the volume infused.
Hypotensive transfusion reaction
A hypotensive transfusion reaction, in which the systolic or diastolic blood pressure decreases at least 30 mm Hg within the first few minutes of a blood transfusion, may be the result of contact activation (intrinsic coagulation pathway) and generation of bradykinin and other kinins. Septic transfusions, anaphylaxis, TRALI, and acute hemolytic transfusion reactions may also manifest in this manner. Awake patients may experience facial flushing, nausea, abdominal pain, shock, and respiratory distress.
Bradykinin acts on kinin receptors of blood vessel endothelium leading to hypotension and edema formation from intracellular fluid leaking. Because angiotensin-converting enzyme breaks down bradykinin, this reaction is most often seen in patients taking angiotensin-converting enzyme inhibitors. Contact activation can occur with the use of blood warmers, with the use of some leukoreduction filters, and from prostate glandular kininogen.
Bacteria-contaminated or septic transfusion
Because of improved viral contamination detection, most infectious transfusion reactions are caused by bacterial contamination of transfused blood products. Individuals may present with mild fever or frank sepsis leading to hypotension, respiratory distress, acute kidney failure, DIC, and circulatory collapse. Septic transfusions are usually associated with an increase of >2° C in temperature. Absence of hemoglobinemia (and hemoglobinuria) distinguishes this reaction from AIHTR.
Blood product contamination may occur from asymptomatic donors who later develop infection; transmission of donor skin flora into the collection system; contamination of collection bags, which then contaminate phlebotomists; and bacterial contamination of water baths used to thaw blood component units. Blood donations are declined from individuals with temperatures >37.5° C, or who present with infectious symptoms such as upper respiratory symptoms and diarrhea.
There is a higher incidence of transmitted bacterial infections from platelets that are stored at room temperature (22° C) than RBCs (stored between 1° C and 6° C). The longer the storage time (>5 days), the greater the risk of bacterial infection. Although the U.S. Food and Drug Administration limits platelet storage to 5 days, platelets are still the most common cause of transfusion-transmitted bacterial infections. Sepsis may occur from any contaminated blood component transfusion.
Some bacteria, such as Pseudomonas , Enterobacter , and Yersinia , can grow at the low temperatures used for RBC storage. Staphylococcus aureus , Staphylococcus epidermidis , Streptococcus species, and gram-negative organisms can contaminate blood components. Salmonella has been reported as a contaminant in platelets.
Transfused bacteria or endotoxins or both can lead to sepsis, with release of proinflammatory cytokines and interleukins (IL-1, TNF-α) as well as complement activation; this produces the clinical picture of sepsis. Interleukin and cytokine interaction with endothelial smooth muscle locally produces nitric oxide, which leads to the refractory hypotension of sepsis. Sudden development of hypotension and rigors in awake patients or hypotension and DIC symptoms in anesthetized patients suggests a bacteria-contaminated transfusion. The incidence of septic transfusions has decreased by the routine use of bacterial monitoring systems, some of which detect oxygen consumption of blood components.
Transfusion-related lung injury
The incidence of TRALI is 1:1000–1:4500 transfusions. Although uncommon, TRALI is the leading cause of transfusion morbidity and accounts for 47% of transfusion-related deaths. It can occur with a transfusion of any blood-derived product, although more commonly with platelets and plasma. There is a higher incidence with blood component transfusion donated from multiparous women (because of their exposure to fetal blood) or from individuals who received multiple transfusions in the past. Despite supportive measures and aggressive ventilatory support, there is a 5%–10% mortality rate.
TRALI is any noncardiogenic pulmonary edema occurring within 6 hours of a transfusion. It is associated with chills, hypoxemia, and fever. Bilateral pulmonary infiltrates are seen on chest x-ray, and severe pulmonary insufficiency may develop similar to adult respiratory distress syndrome. In mild cases, there is dyspnea, with spontaneous resolution of symptoms. Most patients (approximately 70%) require intubation and mechanical ventilation. The lung injury is usually transient, with return of preevent oxygenation levels within 72–96 hours, although occasionally this may take a week to resolve. Under general anesthesia, it may be difficult to differentiate TRALI from acute hemolytic reaction, hypotensive reaction, anaphylactic reaction, septic transfusion, and transfusion-associated circulatory overload.
TRALI probably occurs as a two-step process. In many cases, it develops in patients with preexisting conditions (e.g., recent surgery, malignancy, infections). These preexisting conditions cause neutrophil priming, allowing them to marginate and sequester along the pulmonary vasculature. The second step occurs when transfused blood activates these primed leukocytes and cytotoxic granules are released. Cytotoxic substances disrupt endothelium resulting in interstitial and alveolar edema. The mechanism involves transfused lipids, granulocytes, major antibodies, or platelet-derived proinflammatory mediators (CD40) reacting with sequestered recipient leukocytes. However, TRALI can also occur with fresh frozen plasma transfusions that have no cellular components.
Transfusion-associated circulatory overload
Rapid administration of blood products may result in TACO. Individuals at particular risk are patients with preexisting cardiac disease or renal insufficiency. TACO may manifest as congestive heart failure with dyspnea, oxygen desaturation, circulatory overload, jugular venous distention, increasing central vascular pressures (central venous pressure, pulmonary capillary wedge pressure), and tachycardia.
In a nonbleeding patient, transfusion rates should be limited to 2–3 mL/kg/hour and less in patients with cardiovascular compromise. TACO may easily occur with rapid transfusion devices, when active bleeding has stopped and aggressive transfusion continues.
Other acute transfusion reactions
Rapid transfusion with multiple units of older RBCs can lead to intravascular hyperkalemia. This condition usually occurs when administered blood is near the end of its expiration date, and large volumes have been transfused. A review of U.S. combat patients in Iraq demonstrated that 7 units of RBCs were needed to increase potassium (K + ) concentrations transiently to >5.5 mEq/L. As storage time increases, there is a linear increase of K + concentration in the supernatant. RBCs have a K + concentration of 2 mEq/L, which increases to 45 mEq/L over 42 days of storage, using citrate-phosphate-dextrose (CPD) preservative. Sodium-adenine-glucose-mannitol is used in Canada and Great Britain. CPD or CPD with adenine is commonly used in the United States.
Other factors predisposing to hyperkalemia include hypovolemia, small patient size, amount of blood transfused, and prior irradiation of transfused blood. The increase in K + appears to be transient and is often normal several hours after transfusion. Techniques to limit the increase of K + include use of in-line K + scavenging filters, RBC washing (by the blood bank or more expeditiously with a cell saver), infusing through larger bore intravenous catheters, and insulin-dextrose treatment.
Massive transfusions have been associated with transient increases in citrate levels. Citrate is normally metabolized in the liver. Large volumes of RBCs, reduced liver perfusion or function, and hypothermia impair citrate metabolism leading to increased citrate levels. Citrate binds calcium and magnesium leading to hypocalcemia and hypomagnesemia, which can impair cardiac function and produce coagulopathy.
Delayed transfusion reactions
Delayed hemolytic transfusion reaction
DHTR usually occurs 3–10 days after transfusion and is usually mild. It occurs more commonly extravascularly but can occur intravascularly as well. DHTR is usually due to an amnestic antigen-antibody response. The recipient, after exposure to RBC antigen (previous transfusion or pregnancy), develops antibodies whose levels decrease over time and are undetectable the next time crossmatching is performed. When the recipient is reexposed to the RBC antigen, a secondary immune response is triggered, and antibody levels increase with a more rapid and larger reaction than occurred during the first exposure, lysing donor RBCs; this usually occurs in the spleen and reticuloendothelial system, and it results in a less severe reaction and is self-limiting. This response most commonly occurs in the Rh group. The most common presentation is a low-grade temperature, increasing bilirubin, and unexplained decreasing hemoglobin. A newly positive DAT is diagnostic.
GVHD may occur 8–10 days after transfusion, although it is more commonly seen with bone marrow transplantation. It more commonly occurs in immunocompromised patients, in whom unopposed donor lymphocytes attack recipient tissues. It can be seen in organ transplant recipients and neonates who had a blood exchange transfusion. It can also occur in immunocompetent recipients who are transfused blood from first-degree relatives. The mechanism of GVHD is that both the donor and the recipient have similar human leukocyte antigen haplotypes. The recipient does not reject the donor lymphocytes, but the donor recognizes the recipient as having foreign cells and initiates an immune response. Irradiation is the only effective method to reduce the incidence of GVHD.
Bone marrow is frequently involved resulting in aplasia. Involvement of the liver and skin is often unrecognized. Patients frequently die from bleeding diatheses and infections within several weeks.
Delayed acquired transfusion-transmitted infection
Delayed acquired transfusion-transmitted infections include the hepatitis viruses B and C, cytomegalovirus, and human immunodeficiency virus (HIV). Modern screening techniques employed by blood banks have significantly reduced the incidence of these transfusion-transmitted infections. At the present time, the American Association of Blood Banks reports the risk of acquiring hepatitis B virus is 1:137,000 transfusions; hepatitis C virus, 1:1,1000,000 transfusions; and HIV, 1:1,900,000 transfusions.