Hemolytic Transfusion Reaction

Etiology

Transfusion of blood components is among the most common procedures for inpatients and outpatients. In the US, an estimated 12.5% of inpatient encounters involve transfusion of blood products. This breakdown results in the transfusion of RBCs in about 11% of encounters and the transfusion of platelets or plasma in about 3%; the total sum is >12.5% because some patients had both.[6]

The incidence of transfusion reactions varies significantly by institution due to differing reporting requirements but is estimated to occur in approximately 0.1% to 3% of all transfusion encounters.[6][7][8] The most common types of transfusion reactions include fever and non-severe allergic reactions, with manifestations such as rash, urticaria, and pruritus. These reactions collectively account for approximately 70% to 80% of all transfusion-related adverse events.[6][8] About 7% of all reactions can be classified as severe, with symptoms such as respiratory distress, hypotension, decreased consciousness, or hemoglobinuria.[8]

The median time for severe reactions was 20 minutes, while the median time for non-severe reactions was significantly longer at 100 minutes. This data suggests that monitoring patients closely for 2 hours after transfusions will likely detect most transfusion reactions;  patients should be monitored for at least one hour for severe reactions.[8]

Hemolytic reactions are uncommon, with the incidence reported as 1% to 3% of total transfusion reactions.[6][8] The causes of HTRs can be preventable (human or systemic error) or unavoidable, such as unidentified immune incompatibility. HTRs are classified as immune-mediated or non–immune-mediated. Immune reactions are further divided into acute and delayed reactions. In addition, hemolysis is classified into intravascular and extravascular.[9][10]

Patients with a history of prior transfusion reactions or multiple past transfusions are at a higher risk of experiencing more severe transfusion reactions, possibly due to alloimmunization. The use of preventative measures and washed blood products may be warranted in these patients.[8]

Epidemiology

The prevalence of acute HTRs has been estimated at approximately 1 in 70,000 blood products transfused. The incidence of delayed HTRs remains uncertain due to underreporting, as most patients are asymptomatic. Estimates for this type of reaction vary, ranging from 1 in 800 transfusions to 1 in 11,000 transfusions. The incidence of non–immune hemolytic reactions is also unknown; however, it is also thought to be very rare. Many systems have been implemented to reduce the incidence of HTRs due to human and systemic errors.[11]

Pathophysiology

The different types of hemolytic reactions depend on the etiology. Intravascular hemolysis occurs when an antibody causing complement activation binds an RBC antigen. Extravascular hemolysis occurs when an antibody targeting an RBC antigen opsonizes the RBC, which leads to sequestration and phagocytosis by macrophages, dendritic cells, and neutrophils of the reticuloendothelial system, with primary involvement in the liver, spleen, and bone marrow. Macrophage activation also increases the production of proinflammatory cytokines that induce a systemic response, resulting in symptoms such as fever, chills, abdominal flank pain, and back pain.

For acute hemolytic reactions, the usual incompatibility is blood group system ABO. However, there can also be reactions with other "minor" antigens such as Duffy and Kell. Acute HTRs are most common with transfusion of RBCs but can occur with any blood product. Individuals tend to produce antibodies against antigens absent on their RBC surfaces. This phenomenon is a fundamental principle in blood bank cross-matching procedures. For example, patients with blood group O make antibodies to A and B, while patients with blood type A make antibodies to B and vice versa. Historically, type O blood has been considered a "universal donor" type; however, recent studies have demonstrated the presence of anti-A and anti-B antibodies even without known prior donor exposure. These antibodies are exceptionally high in blood donations from females younger than 40, raising the possibility of additional testing for these donors.

A potential mechanism for ABO incompatibility involves exposure to intestinal microorganisms that possess structures resembling the A and B antigens. This exposure can trigger the production of cross-reactive antibodies with the genuine A and B antigens when encountered. This phenomenon is referred to as molecular mimicry. In the case of other antigens, patients typically need prior exposure to the antigen, which can occur during pregnancy, blood transfusion, or needlestick injuries.

Delayed transfusion reactions often result from an amnestic response, a secondary immune reaction of the immune system to a foreign RBC antigen previously encountered. This prior exposure can occur through events such as pregnancy or previous blood transfusions. The antibody may be so weak as to escape detection on initial cross-match, but the subsequent exposure to the antigen can trigger new antibody formation. Hemolysis is mostly extravascular, of slower and longer duration, and the symptoms are less pronounced compared to an acute hemolytic reaction. The implicated antigens are usually minor antigens like Rh, Kidd, Duffy, Kell, and the MNS constituents.[11]   

Thermal, osmotic, and mechanical injury are the most common non-immune reactions. Thermal injury is divided into excess heat or freezing. Excessive heat damages the RBC membrane, causing spontaneous RBC lysis, known as intravascular hemolysis. The blood cells that are not lysed are cleared from the circulation by the spleen through extravascular hemolysis. Freezing injury occurs when RBCs are exposed to below-freezing temperatures in the absence of a cryoprotective agent such as glycerol. This can lead to dehydration injury if the freezing is slow or ice crystal formation if the freezing is rapid, resulting in intravascular hemolysis.

In osmotic injury, hypoosmolar solutions, eg, 5% dextrose, permit free water to enter the RBCs, causing them to swell and lyse (intravascular hemolysis). Mechanical injury is an external force on the RBC causing lysis, known as intravascular hemolysis. This occurs during hemodialysis when RBCs are exposed to physical trauma, such as a small gauge intravenous access or excess transmembrane pressure. Of note, there is an obligate amount of mechanical RBC hemolysis in the centrifuge techniques most commonly used to separate the different blood components. RBC lysis and further cell breakdown during storage contribute to the diminished shelf-life of RBCs and the need for precautions in special populations such as neonates, infants, and patients at risk for transfusion reactions.[12]

When recipient antibodies target and attack donor RBCs, this is referred to as "major incompatibility."Conversely, when donor antibodies attack recipient RBCs, it is termed "minor incompatibility" because fewer antibodies are involved. Inter-donor incompatibility is a very rare condition in which antibodies in donor plasma interact with antigens on the erythrocytes of another donor from a prior transfusion.[11]  

Another potential HTR is the sickle cell hemolytic reaction syndrome, characterized by a delayed HTR in patients with sickle cell disease who have developed autoantibodies as a result of previous transfusions. Due to cross-reactivity, there is hemolysis of the donor RBCs, and there can also be hemolysis of the patient's own RBCs.[11] Patients have pain symptoms or dark urine days to weeks after the RBC transfusion; these symptoms can sometimes be misdiagnosed as veno-occlusive disease.[13] 

Passenger lymphocyte syndrome occurs when donor lymphocytes, whether solid organ or bone marrow, are transmitted with the transplant. They produce antibodies, especially those towards minor incompatibility targets on the recipient's erythrocytes, causing hemolysis; this is delayed in onset and presents as anemia and jaundice.[14][15] These findings occur immediately post-transplant and can obscure other transplant issues.   

Histopathology

In HTRs, a peripheral blood smear will often reveal evidence of hemolysis, which may include the presence of keratocytes, helmet cells, bite cells, blister cells, spherocytes, or microspherocytes. These abnormal RBC shapes and forms are indicative of the destruction of RBCs that can occur in such reactions.

History and Physical

Classically, an acute HTR is described as a triad of symptoms: fever, flank pain, and red or brown urine (hemoglobinuria).[16] However, this classic presentation is rarely seen. Symptom onset is within 24 hours of the transfusion, usually within the first hour. Symptoms may include agitation, chills, burning at the infusion site, chest pain or tightness, headache, nausea, vomiting, and dyspnea. Signs, such as fever, flushing or edema of the skin, tachycardia, hypotension, and reddish-colored urine, may be observed. Diffuse bleeding due to disseminated intravascular coagulation (DIC) or decreased urine output due to renal failure are later signs. 

Delayed transfusion reactions can be similar to acute HTRs but more insidious, and presentation is 24 hours to 30 days posttransfusion. Presenting symptoms are most often fever, jaundice, and signs of anemia. Mortality is rare with delayed HTRs, but morbidity increases, and hospital stays can be prolonged. 

Acute HTR symptoms often are not specific [1][2] and can include agitation, chills, burning sensation at the infusion site, chest, abdomen, or back pain, headache, nausea, vomiting, tachypnea, and dyspnea. Signs such as fever, skin changes (eg flushing, edema, or paleness), tachycardia, hypotension, or urine color change (transparent reddish color) can be seen. Diffuse bleeding may follow as a sign of DIC or anuria due to renal failure. Especially in an anesthetized patient with missing subjective signs, shock, hemoglobinuria, and systemic hemorrhagic state may be the first symptoms of an acute HTR.

Delayed HTR symptoms may be similar to those of an acute HTR but are often less severe. Malaise, fever of unknown origin, and clinical signs of anemia may be present. An unexplained fall in hemoglobin and mild jaundice about one week after blood transfusion can be symptoms of delayed HTR. Sometimes, hemoglobinuria is seen in a delayed HTR, but renal failure is uncommon. Death caused by a delayed HTR is very rare, but in critically ill patients, delayed HTR may add to other severe conditions. In several cases, however, a delayed HTR after incompatible RBC transfusion shows no clinical symptoms but is only recognized—often by chance—by laboratory investigations like positive antibody tests. In such cases, referring to this as a delayed serological transfusion reaction might be more appropriate, as it involves serological (immune-mediated) mechanisms and occurs after some time following the transfusion.[19][20]

Evaluation

If an acute transfusion reaction is suspected, the transfusion should be stopped, and the blood should be sent back to the blood lab for additional testing. This may also require retesting of the patient receiving the transfusion. The most important tests to look for in immune-mediated hemolysis are direct and indirect Coombs tests, also called direct and indirect antibody tests. Free hemoglobin from the transfusion bag should be measured to evaluate for hemolysis within the transfusion sample, which will cause similar symptoms. Blood cultures from the patient and transfusion sample should be drawn to assess for infection and sepsis. 

In delayed transfusion reactions, antibodies should be retested in the patient sample and compared with the patient's pretransfusion sample to evaluate for new autoantibodies. This is important to avoid future occurrences of acute HTRs. Institutions have different protocols for how long samples are kept, which can affect the pretransfusion sample's availability. 

Other serum lab tests should be performed, including CBC with peripheral smear, indirect bilirubin, haptoglobin, and lactate dehydrogenase. Urine hemoglobin should also be sent. A basic metabolic panel (BMP) to evaluate renal function and coagulation studies to monitor for DIC should also be sent.[11] 

Treatment / Management

HTRs can vary in severity, from mild to severe, and it is crucial to identify and treat them promptly, as they can be life-threatening. The first step is always to stop the transfusion. If clinical suspicion is high or symptoms are severe, such as hypotension, respiratory difficulty, or airway closing, immediate resuscitation and emergency treatment are warranted. Corticosteroids, antihistamines, and epinephrine in the case of airway compromise are usually administered. The patient should be aggressively hydrated unless volume overload is suspected to reduce the complications of free hemoglobin in the bloodstream, such as acute kidney injury or disseminated intravascular coagulation. Exchange transfusion is used as a treatment of last resort.[11]

Differential Diagnosis

The differential diagnosis for acute HTRs is broad and includes non-immune and non-hemolytic reactions to transfusion, including infection from bacteria in the transfusion sample, hemolysis within the transfusion sample, anaphylaxis to components of the transfusion or chemicals used in the separation of blood components, or transfusion of expired blood products. Other underlying pathological states that can have similar symptoms include transfusion-related acute lung injury (TRALI), acute urticaria, drug-induced hemolysis, angioedema, pulmonary edema, cold agglutinin disease, DIC, sepsis, paroxysmal nocturnal hemoglobinuria, hereditary erythrocyte defects (eg, sickle-cell disease, G6PDH deficiency), thrombotic thrombocytopenic purpura, and mechanical hemolysis (eg, from heart valves or dialysis).

Prognosis

Acute HTRs can be life-threatening and require immediate identification. Both acute and delayed HTRs warrant the identification of causative antibodies to avoid severe reactions in the future.[17]

Complications

Transfusion reactions can result in secondary complications, primarily due to the presence of autoantibodies, which raise the risk of future reactions, systemic hypotension-related issues, and the potential development of volume overload leading to cardiopulmonary compromise.[18]