Transfusion Reactions to Blood and Hematopoietic Stem Cell Therapy Products

Pathophysiology

Acute hemolytic reactions are those that occur during or within 24 hours, typically after incompatible RBCs are transfused into a patient with preexisting antibodies. A reaction caused by a naturally occurring antibody against ABO-incompatible RBC is the prototypical example of an acute, intravascular hemolytic transfusion reaction. ABO antibodies are naturally occurring immunoglobulin IgM and less commonly IgG antibodies to foreign A and B blood group antigens. IgM antibodies efficiently fix and activate complement after binding to ABO-incompatible RBCs. The formation of excessive terminal membrane attack complexes consisting of complement components C5 through C9 creates multiple pores in the transfused RBC membranes, resulting in a clinically significant acute intravascular hemolytic transfusion reaction. Such a reaction could occur, for example, after transfusion of A RBCs into an O recipient who has significant amounts of circulating anti-A (see box on Acute Hemolytic Transfusion Reaction ). The excess cell-free hemoglobin that is generated supersaturates the binding capacity of plasma albumin, haptoglobin, and hemopexin and manifests by hemoglobinemia and hemoglobinuria. Free heme induces renal vasoconstriction through nitric oxide scavenging. This may eventually result in acute tubular necrosis and renal failure. In IgM-mediated ABO-incompatible transfusion reactions, activation of the complement cascade generates anaphylatoxins C3a and C5a, leading to capillary leak, hypotension, and phagocyte and mast cell activation. Furthermore, the deposition of C3b on the RBC membrane increases extravascular hemolysis.

In addition to complement components, cytokines also play a role in the clinical syndrome of hemolysis and fever. For example, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α have pyrogenic activity; IL-8 is a neutrophil chemotactic and activating factor. These four cytokines have been generated in various in vitro models of intravascular hemolysis and IgG-mediated RBC incompatibility. TNF-α induces tissue factor expression on endothelium while decreasing thrombomodulin, which contributes to disseminated intravascular coagulation (DIC). TNF-α also promotes endothelin production, promoting renal vasoconstriction. The clinical variability of hemolytic transfusion reactions is explained in part by the relative balance of cytokine production in the transfusion recipient. Factors that increase the circulating levels of proinflammatory cytokines and chemokines often result in more severe reactions. Factors that determine the severity of hemolysis include the antibody titer, antibody avidity, antibody subtype, antigen density on the RBC membrane, and volume and infusion rate of incompatible blood. Patient factors also play an important role. Transfusing as little as 30 mL of incompatible RBC concentrate can be fatal, and there is a direct relationship between increasing volumes of incompatible blood transfused and mortality. Conversely, there may be no reaction at all in an elderly or immune-compromised patient, or in the setting of massive transfusion.

Acute hemolytic reactions can also occur with incompatible plasma transfusion. Because of limited platelet inventories, platelet components with incompatible plasma are frequently transfused, for example, a group O platelet concentrate (with anti-A) transfused to a group A recipient. This plasma incompatibility (i.e., minor incompatibility) can occasionally result in acute ABO-incompatibility hemolytic reactions.

Clinical Manifestations and Laboratory Testing

An acute intravascular hemolytic transfusion reaction is a medical emergency. Initial clinical symptoms can include fever and chills, shortness of breath, chest pain, dizziness, reddish urine, back or flank pain, hypotension, and oliguria. Some patients report feeling anxiety or pain or warmth ascending from the site of infusion. RBC transfusions must be stopped and the patient evaluated clinically and by laboratory testing if fever develops (≥2°C increase in temperature). The transfused incompatible RBCs undergo complement-mediated lysis, producing hemoglobinemia and hemoglobinuria. Cardinal signs of an acute intravascular hemolytic transfusion reaction are the presence of red plasma (hemoglobinemia) and red/dark urine (hemoglobinuria). Acute transfusion reactions can quickly progress to shock and acute renal failure. Many patients, curiously even anephric patients, often complain of lower back pain. It is speculated that this symptom is caused by ischemic muscle pain or vasospasm rather than by kidney pain from developing renal failure.

When an acute hemolytic transfusion is suspected, the transfusion should be stopped immediately and clerical checks performed to check ABO and Rh compatibility and verify that the correct unit is being transfused to the intended recipient. If it is confirmed that the transfusion was ABO-incompatible, it is important to investigate where an error occurred. If there has been a mix-up of samples or units, could a second patient be receiving an incorrect unit? There may be a systemic error that could put other patients at risk.

Laboratory findings confirming hemolysis include hemoglobinuria, hemoglobinemia, and a haptoglobin level that is low to undetectable. During the hemolytic episode, the bilirubin (especially indirect bilirubin) usually increases only modestly (2 to 3 mg/dL) if the patient has normal liver function. Because of the lysis of RBCs, levels of lactate dehydrogenase (LDH) may rise markedly. The direct antiglobulin test (DAT) becomes positive in an immune hemolytic reaction (if tested before all the incompatible RBCs are destroyed). Preparation of an antibody eluate is often necessary to identify the presence of an offending IgG antibody. Elution is a procedure that chemically separates the bound antibody from the RBCs and concentrates it so that it may be identified.

Initial therapy consists of immediately stopping the transfusion, administering intravenous fluids, cardiorespiratory support, and ensuring a brisk diuresis. Increasing renal blood flow is the best way to prevent acute oliguric renal failure. Usually, 0.9% NaCl is infused to maintain a urine output of 100 mL/h for approximately 24 hours. Diuresis can be achieved with loop diuretics or mannitol, but this is not evidence based. The mechanisms responsible for the beneficial effect of increased renal blood flow likely include increased clearance of free hemoglobin and a return of more physiologic control of renal vasodilation. Creatinine and blood urea nitrogen (BUN) should be monitored; dialysis may be necessary for the treatment of oliguric acute renal failure. Support of blood pressure and respiration may require the use of vasopressors, bronchodilators, or intubation. DIC can occur in severe cases. The prothrombin time, activated partial thromboplastin time, and fibrinogen level should be monitored (see box on Workup of an Acute Intravascular Hemolytic Transfusion Reaction ). If the patient shows no signs of cardiovascular instability and if hemostatic and renal function are unchanged at least 24 hours after the incompatible transfusion, the episode can be considered to be over, with serious sequelae unlikely.

Hyperhemolysis

Hyperhemolysis is a specific type of acute intravascular hemolysis of (autologous) bystander RBCs that do not express the antigen to which an immune-mediated hemolysis is directed.

Hyperhemolysis occurs primarily with transfusion in the setting of sickle cell disease and is also reported to occur in acute malarial infection, passenger lymphocyte syndrome, paroxysmal nocturnal hemoglobinuria, and select cases of autoimmune hemolytic anemia. Since hyperhemolysis is frequently associated with sickle cell disease, Petz and colleagues proposed the term sickle cell hemolytic transfusion reaction syndrome to describe the constellation of hemolysis, sickle cell pain crisis, reticulocytopenia, severe anemia, RBC transfusion leading to accelerated hemolysis, and lack of a clear serologic reason for hemolysis. Hyperhemolysis is frequently fatal because transfusion may exacerbate hemolysis and the primary treatment for severe anemia (RBC transfusion) makes anemia worse. Recognition of this syndrome is therefore critical because treatment should shift from transfusion to administering erythropoietin, glucocorticoids, intravenous immunoglobulin (IVIG), and rituximab, which have been used successfully in case series.