A transfusion is defined as an infusion of whole blood or any one of its components. Transfusions like any other medical intervention have benefits and risks. Hemolytic transfusion reactions are one of the possible complications from transfusions. Hemolysis is described as rupture of red blood cells and leakage of their contents. The site of hemolysis can be intravascular (in circulation) or extravascular (in reticuloendothelial system). Hemolytic transfusion reactions can be immune or non-immune mediated.
Immune hemolytic transfusions reactions occur due to mismatch or incompatibility of the patient with the donor products. Immune hemolytic transfusion reactions are divided into acute versus delayed hemolytic reactions. Acute hemolytic reactions happen within 24 hours of transfusion and delayed hemolytic reactions happen after 24 hours. Delayed reactions usually occur two weeks after but can go up to 30 days post transfusion. The severity of the hemolytic reaction is dependent on the type and quantity of antigens, alloantibodies and ability to bind to complement.
Non-immune hemolysis can be due to thermal, osmotic, mechanical injury to red blood cells or other blood products. Human or machine error cause these forms of hemolysis.
Hemolytic transfusion reactions, in general, occur most often after transfusion of packed red blood cells but they can also occur after transfusion of other blood products.
Transfusion hemolytic reactions are either preventable (human or mechanical error) or unavoidable, for example, immune incompatibility. As described before, hemolytic transfusion reactions have various classifications, and those classifications reflect their etiologies. They can be immune or non-immune mediated. Immune reactions are further divided into acute and delayed reactions. Hemolysis is also classified into intravascular and extravascular hemolysis. We will discuss the mechanisms of these classifications in the pathophysiology section.
The overall incidence of immune hemolytic reactions is not known. The prevalence of acute hemolytic transfusion reactions has been estimated at approximately 1 in 70,000 per blood product transfused. Delayed hemolytic transfusion reaction incidence is unknown because most patients are asymptomatic, so it is under reported. There is a large range from studies with estimates ranging from approximately 1:800 transfusions to 1:11,000 transfusions. The incidence of non-immune hemolytic reactions is also not known; however, it is thought to be very rare. Many systems have been put in place to try to reduce the incidence of hemolytic transfusion reactions due to human and machine error.
As referenced before, the pathophysiology for the different types of hemolytic reactions is dependent on the type. Firstly, we will describe the basic mechanisms for intravascular and extravascular hemolysis. Intravascular hemolysis is hemolysis produced when the antibody to the red blood cell (RBC) antigen binds and causes complement activation. Extravascular hemolysis is hemolysis produced when the antibody to the RBC antigen can opsonize the RBC, which leads to their sequestration and phagocytosis by macrophages and other phagocytes of the reticuloendothelial system (liver and spleen). Macrophage activation also increases 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, you can also have reactions with other antigens such as Duffy and Kell. The usual reactions are found with red blood cell transfusions, but they can also happen with plasma product transfusions. For acute hemolytic reactions, when exposed, the recipient’s antibodies bind to antigens. While the topic of blood bank cross matching is too vast to be described here, in general, people produce antibodies for antigens they lack on their red cell surface. 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. With ABO incompatibility, there is exposure to intestinal microorganisms with structures like the A and B antigens stimulating antibody production which can then cross-react with actual A and B antigens when exposed. This phenomenon is called molecular mimicry. For other antigens, patients would have had to be exposed to the other antigen previously, for example during pregnancy, transfusion, or needle stick.
Delayed transfusion reactions usually are caused by an amnestic response of the immune system to a foreign red blood cell antigen from previous exposure, for example, pregnancy or previous transfusions. Hemolysis is mostly extravascular and less clinically dramatic compared to the acute hemolytic reaction. The implicated antigens are usually minor antigens like Rh.
For non-immune reactions, there is thermal, osmosis, and mechanical injury. Thermal injury is divided into excess heat or freezing. Excessive heat damages the red blood cell membrane, and this can cause spontaneous lysis of the red blood cell (intravascular hemolysis). The blood cells not lysed are cleared from the circulation by the spleen (extravascular hemolysis). Freezing injury occurs when red blood cells 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. For osmotic injury, hypo-osmolar solutions, e.g., 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 red blood cell causing lysis (intravascular hemolysis). Mechanical injury occurs when RBCs are exposed to physical trauma such as small gauge intravenous access.
Classically, acute hemolytic transfusion reaction is described as a triad of symptoms; fever, flank pain, and red or brown urine. However, this classic presentation is not seen often. Other symptoms are chills, hypotension, renal failure, back pain, or signs of disseminated intravascular coagulation. On a peripheral blood smear, signs are consistent with immune hemolysis such as keratocytes, helmet cells, bite cells, blister cells, spherocytes, or microsporocytes. There is urinary hemosiderin on urine analysis. Serum haptoglobin is low, lactate dehydrogenase and unconjugated bilirubin are high.
Delayed transfusion reactions are usually insidious. Patients present late after transfusion, 24 hours to 30 days. The presenting symptom is usually jaundice or low-grade fever. Clinical labs look similar to those described above and are consistent with hemolysis.
Non-immune hemolysis patients present like acute hemolytic transfusion reaction patients.
Whenever a transfusion hemolytic reaction is suspected, immediately stop transfusion. Check labels on the patient, blood components, and paper work to rule our clerical error, since this is the most common cause. Also check signs of machine/mechanical error like intravenous needle gauge size, any other fluids given to patient and temperature of blood to rule out non-immune causes of hemolysis. Repeat ABO testing on the post-transfusion patient sample. Repeat crossmatch with pre-and post-transfusion specimens using an indirect antiglobulin testing and do direct antiglobulin (Coombs) testing. Order a peripheral smear to look for signs of hemolysis. Trend complete blood counts to monitor the severity of hemolysis. Trend other hemolysis labs like bilirubin, haptoglobin, and lactate dehydrogenase. Coagulation studies to monitor for disseminated intravascular coagulation. Urinalysis and microscopy to monitor for hemoglobinuria. Basic metabolic panel to monitor for signs of renal failure. If ABO incompatibility is negative, then test for other antibodies.
Treatment for hemolytic transfusion reactions is mainly supportive care. Reactions can range from mild to severe. As mentioned before, the first step is always to stop the transfusion. If unsure of the diagnosis, then one should send the blood for testing as discussed previously. However, if clinical suspicion is high or symptoms are severe, e.g., hypotension, immediate resuscitation should be started. Ensure the patient has good intravenous access. Aggressive hydration is usually recommended with normal saline to maintain a urine output at least 1 ml/kg/hr. This is to reduce the likelihood of complications of free hemoglobin in the blood stream such as acute kidney injury or disseminated intravascular coagulation. Sometimes diuretics are used to achieve adequate urinary output. If the patient does have disseminated intravascular coagulation (DIC), it will also need to be managed with appropriate blood products.
Though not always, sometimes transfusion hemolytic reactions can be completely preventable. For immune reactions, good documentation and careful cross-checking can minimize the incidence of this complication, secondary to clerical errors. Non-immune reactions are also prevented by checking equipment and appropriate storage and administration of blood products.
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