INTRODUCTION — Red blood cell (RBC) transfusion can be lifesaving for patients with severe anemia and/or bleeding and generally is safe. However, transfused blood is a foreign substance that has the potential to elicit an immune response, which can lead to destruction of the transfused RBCs (immune hemolysis).
Transfused RBCs are also susceptible to lysis from mechanical perturbations and other stresses including temperature extremes, osmotic pressure, and chemical injury (non-immune hemolysis).
Other transfusion reactions can sometimes be mistaken for transfusion-associated hemolysis, and other forms of hemolysis associated with underlying disease can sometimes be mistakenly attributed to a transfusion.
Determining whether hemolysis is present and transfusion-associated, and determining the cause of hemolysis associated with a blood transfusion, are critical for the management of the immediate event and for reducing the risk of future transfusion-associated immune hemolysis.
This topic focuses on the causes, evaluation, differential diagnosis, and management of immune hemolysis associated with blood transfusion, especially ABO-incompatible blood transfusion. Our approach is consistent with a 2016 Clinical Practice Guideline from the Association for the Advancement of Blood & Biotherapies (AABB) [1].
Other transfusion reactions, and the approach to the patient when the cause of a transfusion reaction is unknown, are discussed in separate UpToDate topic reviews:
●Transfusion reaction of unknown cause – (See "Approach to the patient with a suspected acute transfusion reaction".)
●Febrile nonhemolytic transfusion reaction (FNHTR) – (See "Immunologic transfusion reactions", section on 'Febrile nonhemolytic transfusion reactions'.)
●Immunologic reactions other than hemolysis – (See "Immunologic transfusion reactions".)
●Transfusion-related acute lung injury (TRALI) – (See "Transfusion-related acute lung injury (TRALI)".)
●Transfusion-associated circulatory overload (TACO) – (See "Transfusion-associated circulatory overload (TACO)".)
●Sepsis – (See "Transfusion-transmitted bacterial infection".)
Important aspects of pretransfusion testing to reduce the likelihood of a hemolytic transfusion reaction are discussed separately. (See "Pretransfusion testing for red blood cell transfusion".)
Other causes of hemolysis unrelated to transfusion are also presented separately. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)
PATHOPHYSIOLOGY — Hemolytic transfusion reactions (HTRs) occur when there is immunologic incompatibility between a transfusion recipient and the red blood cells (RBCs) from the blood donor [1-5]. HTRs can range in severity from instantaneous, massive, intravascular hemolysis that may cause disseminated intravascular coagulation, shock, kidney failure, and death, to mild, clinically inapparent hemolysis weeks after the transfusion or an isolated serologic change. The main determinants of severity and timing are the specific RBC antigens targeted and the nature of the alloantibodies (IgG versus IgM, sub-class of IgG, ability of the antibody to bind complement) as well as their strength (titer).
Mechanism of RBC destruction — Acute HTRs (AHTRs) are classically due to ABO incompatibility, most often the result of clerical or procedural error [6-11]. Pathologically, HTRs are associated with accelerated destruction of RBCs. In the most common situation, transfusion of RBCs leads to hemolysis of the transfused cells by the recipient's immune response against an allogeneic RBC antigen that is foreign to the recipient.
Less commonly, transfusion of plasma-containing antibodies directed against a recipient's RBC antigen leads to hemolysis of the recipient's RBCs. This is less common primarily because the incompatible donor plasma is instantly diluted upon transfusion, reducing the titer of the transfused antibodies.
The first event in a typical AHTR involves binding of recipient antibodies to antigens on the transfused RBCs (figure 1). This requires that the recipient has previously been exposed to the implicated antigen (or a cross-reacting antigen) and has generated antibodies capable of opsonizing the RBCs.
●Type O, A, and B individuals undergo constant stimulation to produce antibodies that react with the antigens that they lack (A and B antigens on type A, B, or AB cells), due to exposure to intestinal microorganisms that are similar enough to A and B to elicit molecular mimicry. These naturally occurring anti-A and anti-B antibodies in type O recipients are typically of the IgM class, but they also can include IgG. In the case of ABO incompatibility, these IgM antibodies can rapidly fix complement and can cause massive, immediate, intravascular hemolysis. (See "Red blood cell antigens and antibodies", section on 'ABO blood group system' and 'Site of RBC destruction (intravascular or extravascular)' below.)
On occasion, an AHTR may occur when an individual with blood group A, B, or AB is transfused with a blood product (eg, plasma, apheresis platelets) containing a high titer of ABO alloantibodies (high titer anti-A given to an A or AB recipient, or high titer anti-B given to a B or AB recipient) [12-14].
●Antibodies to most other RBC antigens such as Kidd, Kelly, or Duffy are elicited by prior transfusion or other forms of exposure to allogeneic RBCs such as pregnancy or sharing of intravenous needles. Only a small amount of exposure (<1 mL of blood) is required to elicit an antibody response, although this can be variable.
•These antibodies may persist in the circulation at high enough levels to cause immediate hemolysis when they encounter the antigen, leading to an AHTR. (See 'Acute hemolytic transfusion reactions' below.)
•In some cases, the titer of antibodies may decline to undetectable levels, and re-exposure to the antigen will cause an anamnestic response over the ensuing several days, leading to a delayed HTR (DHTR). (See 'Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions' below.)
●The abundance of the antigen on the RBC surface also influences the severity of the reaction. Antigen density varies significantly for different RBC antigens. As an example, ABO antigens are present at approximately 200,000 to 800,000 per cell, while Kell antigens are present at approximately 3000 to 6000 per cell, a 100-fold difference [2,15-17]. RBC antigens and their capacity for eliciting HTRs are discussed in more detail separately. (See "Red blood cell antigens and antibodies".)
In some cases, binding of the alloantibodies to the RBCs is accompanied by binding of complement components such as C3b, with resulting activation of the complement cascade. Antibodies and complement proteins can both act as opsonins and can both facilitate phagocytosis and destruction of the foreign cells by macrophages. (See "IgG subclasses: Physical properties, genetics, and biologic functions" and "Complement pathways".)
In addition to promoting phagocytosis, macrophage activation also leads to production of proinflammatory cytokines that can elicit a systemic response, including fever, chills, abdominal or flank pain, and other nonspecific symptoms (figure 1) [2]. (See 'Clinical presentation of AHTR' below and 'Clinical presentation of DHTRs and DSTRs' below.)
Site of RBC destruction (intravascular or extravascular) — Lysis of RBCs can occur intravascularly (within the circulation) or extravascularly (within the reticuloendothelial system). The principal determinants of the site of RBC destruction are the antibody concentration on the RBC surface and whether the antibody (especially if IgG) is able to fix complement, leading to formation of the membrane attack complex (MAC), which causes the RBCs to lyse osmotically in the circulation (figure 2). The abundance of splenic/hepatic macrophages and their state of activation may also play a role.
●Intravascular hemolysis – Intravascular hemolysis occurs when the antibody against the RBC antigen is capable of binding and activating complement. The terminal, lytic phase of complement activation, involving components C5 to C9 (the MAC), creates multiple holes in the RBC membrane that lead to lysis. The lysis occurs in the circulation, leading to release of free hemoglobin, which in turn can contribute to shock with hypotension, nephrotoxicity with oliguric kidney failure, and disseminated intravascular coagulation (DIC) with bleeding and/or thrombosis. Intravascular hemolysis is more acute, severe, and potentially life-threatening than extravascular hemolysis.
●Extravascular hemolysis – Extravascular hemolysis occurs when the antibody against the RBC antigen opsonizes the RBCs, which leads to their sequestration and phagocytosis by macrophages and other phagocytes of the reticuloendothelial system, highly concentrated in the liver and spleen. The complete destruction of the antibody-coated RBC may take several passes through the macrophage system, with bits of membrane being removed with each pass and the annealing of the remaining membrane resulting in its becoming an osmotically fragile spherocyte or microspherocyte prior to its removal from circulation. Hemoglobin is released intracellularly into the macrophages, bound to ferritin, and stored. Clinical manifestations of extravascular hemolysis are generally milder, often marked only by low grade fever and hyperbilirubinemia, though there is the potential for severe hemolysis and/or kidney failure.
In many cases, the RBC lysis is not purely intravascular or extravascular, especially when the formation of the MAC is partially inhibited and/or when the reticuloendothelial system becomes overwhelmed. Additional information about the different complement pathways and associated proteins is presented separately. (See "Complement pathways".)
There are major clinical implications of the site (or principal site) of RBC lysis. Both lead to a drop in hemoglobin (or lack of the expected rise with transfusion) and laboratory markers of hemolysis such as increased lactate dehydrogenase (LDH), increased indirect bilirubin, and decreased haptoglobin. Intravascular lysis can also lead to diffuse pain, acute kidney failure, and DIC. (See 'Clinical presentation of AHTR' below.)
Assessment of the site of RBC destruction and key features of management of intravascular hemolysis related to transfusion are discussed below. (See 'Evaluation and immediate management of AHTR' below.)
Timing of hemolysis (acute or delayed) — As with other transfusion reactions, HTRs can be classified as acute or delayed based on how soon after transfusion they occur. Acute reactions are those that occur during the transfusion or within 24 hours after the transfusion has been administered. Delayed reactions are those that occur more than one day following completion of the transfusion. DHTRs typically occur one to two weeks following transfusion.
●AHTR – AHTRs typically occur early during the transfusion, after administration of as little as a few mL of incompatible blood due to ABO incompatibility. In AHTRs, the temporal relationship to the transfusion is clear, but it may initially be challenging to determine what type of reaction is occurring (febrile non-hemolytic transfusion reaction, septic transfusion reaction) since there is substantial overlap in presentations.
●DHTR – DHTRs can occur one to two weeks, and as many as four weeks following transfusion. For hospitalized patients, this is often after the patient has left the hospital and is no longer having frequent laboratory monitoring. In DHTRs that are apparent, anemia and hemolysis are often obvious, but it may be challenging to determine whether or not the transfusion is responsible.
●Delayed Serologic Transfusion Reaction (DSTR) – DSTRs occur with the same timing as DHTRs. However, individuals with a DSTR are completely asymptomatic and lack laboratory evidence of hemolysis. A DSTR is not diagnosed until an alloantibody is identified serologically on a subsequent type and screen sample [18,19].
EPIDEMIOLOGY — The prevalence of acute HTRs (AHTRs) has been estimated at approximately 1 in 70,000 per blood product transfused [3]. Overall, the rate of AHTRs and DHTRs have been decreasing.
●In a report of transfusion-associated deaths in the United States from 1976 to 1985, acute hemolysis was the most common cause of death [6]. There were 158 fatalities from AHTRs, 26 fatalities from delayed HTRs (DHTRs), and 6 fatalities from non-immune hemolysis. Of the AHTRs, 131 (83 percent) were due to ABO incompatibility errors, mostly involving a group O recipient who received non-group O blood.
●In a 2019 review of deaths related to transfusion during the years 2013 to 2017, hemolysis accounted for 32 of 185 deaths (17 percent), which was less common than other transfusion reactions such as transfusion-associated circulatory overload (TACO; 32 percent) and transfusion-related acute lung injury (TRALI; 30 percent) [8]. Of the deaths due to hemolysis, roughly one-third (6 percent of the total) were due to ABO incompatibility and the remaining two-thirds (11 percent of the total) to non-ABO reactions.
●A review by the US Food and Drug Administration (FDA) that evaluated ABO-incompatible RBC fatalities reported between 2000 and 2019 documented a significant decline [20]. Between 2000 and 2009, there were an average of six cases/year, which decreased to two cases/year. The FDA estimated the fatality rate decreased from 1 per 2 million RBC units transfused to 1 per 7.14 million RBC units between 2010 and 2019.
The prevalence of DHTRs and DSTRs are likely to be underestimated since symptoms are usually mild or absent; frequency estimates range from approximately 1:800 to 1:11,000. The large range exists because some studies reporting DHTRs also include DSTRs. Overall, the rates of DHTRs and DSTRs have been decreasing as more sensitive RBC antibody screening assays have become available and have prevented exposure to allogeneic RBC antigens [21]. (See 'Differential diagnosis of DHTR or DSTR' below.)
HTRs occur most often after transfusion of RBCs, but they can also occur after transfusion of other products (eg, Fresh Frozen Plasma, platelets, granulocytes), because RBCs or anti-RBC antibodies may be present in these products [22]. (See 'Mechanism of RBC destruction' above.)
ACUTE HEMOLYTIC TRANSFUSION REACTIONS — Acute HTR (AHTR) refers to transfusion-associated hemolysis that occurs during the transfusion or within the first 24 hours after transfusion. AHTR is a medical emergency that requires immediate cessation of the transfusion, as well as immediate evaluation and interventions to reduce the risks of serious organ damage to the patient and other potentially affected patients. (See "Approach to the patient with a suspected acute transfusion reaction", section on 'Immediate actions (all patients)'.)
Clinical presentation of AHTR — The presentation of AHTR depends on the type of incompatibility, blood product, and volume transfused; together these determine the degree of hemolysis. The most common etiology is a sample collection error (wrong blood in tube) or an administrative error (wrong unit transfused to the wrong patient).
Criteria from the Centers for Disease Control and Prevention (CDC) Biovigilance Network in the United States were revised in 2021 [23]. For a definitive AHTR, symptoms must occur during or within 24 hours of completing the transfusion. There also must be laboratory evidence of hemolysis.
●Symptoms – Symptoms and clinical findings may include:
•Back or flank pain
•Fever, chills, or rigors
•Hypotension
•Evidence of disseminated intravascular coagulation (DIC) such as epistaxis or oozing from intravenous sites
•Hematuria
•Oliguria, anuria, or acute kidney failure
●Laboratory – At least two laboratory findings must be present, such as:
•Decreased fibrinogen
•Decreased haptoglobin
•Elevated bilirubin
•Elevated lactate dehydrogenase (LDH)
•Hemoglobinemia
•Hemoglobinuria
•Plasma discoloration from free hemoglobin, or
•Spherocytes on the peripheral blood smear.
●Mechanistic confirmation – Documentation of either immune-mediated or non-immune mediated hemolysis requires:
•Immune – Positive direct antiglobulin test (DAT) for anti-IgG and/or anti-C3 and positive elution test with alloantibody present on the transfused red blood cells (RBCs)
or
•Non-immune – Serologic testing is negative, and a physical cause is confirmed (thermal, osmotic, mechanical, or chemical).
The most common presentation of AHTR is after RBC transfusion, and the most commonly implicated RBC antigens are those of the ABO blood group, due to clerical error (labelling the wrong tube of blood) or the wrong blood given to the wrong patient (see 'Epidemiology' above). A very small proportion are caused by other antigens, including those in the Kell, Duffy, and Jk blood groups [3]. The blood group antigens are described separately. (See "Red blood cell antigens and antibodies".)
Rarely, a recipient of a plasma-containing product (Plasma Frozen Within 24 Hours After Phlebotomy [PF24], Thawed Plasma, Fresh Frozen Plasma [FFP]; platelets) or a recipient of intravenous immune globulin (IVIG) or anti-D immune globulin may develop an AHTR due to antibodies in the plasma or immunoglobulin product that react with the recipient's RBCs. (See "Clinical use of plasma components", section on 'Risks' and "Intravenous immune globulin: Adverse effects", section on 'Hemolysis'.)
ABO-associated AHTRs often occur during the early minutes of the transfusion, although they may not be immediately appreciated, especially if the patient is under anesthesia. An ABO-associated AHTR may be suspected when a patient develops chills, fever, hypotension, hemoglobinuria, kidney failure, back pain, or signs of DIC. The serum or urine may be pink due to the presence of free hemoglobin. In a patient under anesthesia or in a coma, oozing from venipuncture sites due to DIC or change in the urine color to red or brown due to hemoglobinuria may be the only finding.
Hemoglobinemia (red or dark plasma), hemoglobinuria (red or dark urine), DIC, shock, and acute kidney failure due to acute tubular necrosis are indicative of intravascular hemolysis. (See 'Site of RBC destruction (intravascular or extravascular)' above and "Clinical features and diagnosis of heme pigment-induced acute kidney injury".)
However, it is important to note that the classic presenting triad of fever, flank pain, and red or brown urine is rarely seen as a triad; patients may present with isolated fever and chills, sometimes accompanied by pain along the infusion vein and a feeling of anxiety.
In addition to laboratory findings of immune hemolysis, the patient may have spherocytes or microspherocytes on the peripheral blood smear, and urinary hemosiderin on urine analysis (although these are much more common in delayed HTRs [DHTRs] than in AHTRs).
Recipients of allogeneic hematopoietic stem cells (eg, with hematopoietic cell transplantation [HCT]) may also develop AHTRs as their blood type changes. This subject is discussed separately. (See "Pretransfusion testing for red blood cell transfusion", section on 'Hematopoietic cell transplant recipient' and "Donor selection for hematopoietic cell transplantation", section on 'ABO and Rh status'.)
Evaluation and immediate management of AHTR
Rapid evaluation — AHTR is a medical emergency. The initial steps are similar to those for any suspected acute transfusion reaction, and include immediately stopping the transfusion, providing hemodynamic support, and contacting the transfusion service (or following the institutional protocol) to help with the evaluation (algorithm 1). Many of the initial interventions such as vigorous hydration and hemodynamic support are made immediately, without waiting for the results of laboratory testing. The evaluation occurs at the bedside and in the transfusion service laboratory or blood bank.
Every hospital has a protocol for evaluating transfusion reactions that should be followed rigorously. The goal is to determine if hemolysis has occurred, to distinguish among possible causes, and to stabilize the patient. (See "Approach to the patient with a suspected acute transfusion reaction", section on 'Immediate actions (all patients)'.)
The initial clerical check and notification of the transfusion service is critical for the evaluation of the index patient as well as other potentially affected patients (if the bag was mislabeled or if two products for two recipients were switched accidentally). Although less likely, obvious causes of non-immune hemolysis should also be evaluated, including a check of the transfusion setup to confirm that the blood was not co-administered with a hypotonic fluid, leading to osmotic lysis. If a blood warmer was used, a temperature check should be performed to make sure the blood was not heated to a temperature that could cause thermal lysis. (See 'Non-immune hemolysis' below.)
Laboratory testing for an AHTR, done in consultation with the transfusion service, should be performed on blood drawn from the patient’s opposite arm (not the one used for the transfusion), or, if this cannot be done, from a separate site on the same arm. The following should be included:
●Repeat ABO compatibility testing on both a pretransfusion and posttransfusion sample.
●Additional antibody studies (antibody screen and identification) if ABO incompatibility is excluded.
●Repeat crossmatch with pre- and post-transfusion specimens using an indirect antiglobulin test (IAT; indirect Coombs). IAT is likely to be positive in an AHTR that is not caused by ABO incompatibility.
●Direct antiglobulin (Coombs) testing (DAT), which may be positive in AHTR but may be negative in ABO incompatibility or if hemolysis is so severe that all RBCs with antibody on the surface have been lysed.
●Visual inspection of the serum and urine for pink or dark brown color. The serum should be analyzed for free hemoglobin, and a urine sample should be saved in case analysis of the urine for free hemoglobin is required. Pink or dark brown serum and/or urine and a positive test for free hemoglobin will be present in severe intravascular hemolysis but not in extravascular hemolysis.
●Testing for hemolysis with serum haptoglobin, lactate dehydrogenase (LDH), and unconjugated (indirect) bilirubin. In hemolysis, haptoglobin will be low and LDH and bilirubin will be increased, although the increase in unconjugated bilirubin may be delayed and is more likely to be helpful in evaluating the patient for a DHTR than for an AHTR. (See "Overview of hemolytic anemias in children", section on 'Serum LDH, haptoglobin, and plasma free hemoglobin' and "Diagnosis of hemolytic anemia in adults", section on 'Post-diagnostic testing to determine the cause'.)
●Testing for DIC if the patient has obvious signs of intravascular hemolysis (pink serum or urine, hypotension), oozing from intravenous sites, or increased bleeding. DIC is a sign of severe intravascular hemolysis. Tests include prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen level, D-dimer, and platelet count. (See "Disseminated intravascular coagulation in infants and children" and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)
●Electrolyte testing and cardiac monitoring if the patient has obvious signs of intravascular hemolysis, since lysis of RBCs releases potassium into the circulation and may cause severe hyperkalemia.
●Serial hemoglobin levels, because hemoglobin may decline to the point that additional transfusions are needed. If another transfusion is needed, pretransfusion testing should be repeated to avoid transfusing RBCs that express the implicated antigen.
Findings suggestive of intravascular hemolysis include evidence from the clerical check that ABO-incompatible blood was administered (or other clinically significant antigen mismatch), or findings of hypotension, pink or dark brown urine or serum, DIC, a positive DAT, and mixed-field agglutination.
Findings suggestive of extravascular hemolysis include a positive DAT without pink or dark brown serum or urine, as well as laboratory evidence of hemolysis. Later testing of the urine may show urine hemosiderin. If the patient has evidence of extravascular hemolysis in the midst of a transfusion that was temporarily stopped, the transfusion should not be resumed.
Hemodynamic support — If the initial bedside evaluation (or subsequent testing) is consistent with intravascular hemolysis, normal saline should be infused immediately to reduce the risks of hypotension and renal injury. An infusion rate of 100 to 200 mL/hour is typically used to support a urine output above 1 mL/kg/hour or 100 to 200 mL/hour to reduce the likelihood of acute oliguric renal failure [20]. The beneficial effect of urinary alkalinization in patients with marked hemoglobinuria is uncertain. Vasopressors may be required to treat hypotension. A nephrologist may be consulted for advice on prophylactic measures to prevent or reduce renal damage and in some cases to treat severe hyperkalemia; a hematologist may be consulted if the patient has evidence of DIC. (See "Clinical features and diagnosis of heme pigment-induced acute kidney injury" and "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)".)
Ringer's lactate solution should be avoided in the tubing used for the transfusion because it contains calcium, which may initiate clotting of any blood remaining in the intravenous line. Dextrose-containing solutions should be avoided because the dextrose may promote hemolysis any of the remaining RBCs in the intravenous tubing. Normal saline administration to induce diuresis should not be significantly delayed while awaiting the results of additional laboratory testing. A diuretic may be used in some patients, such as those at risk for transfusion-associated circulatory overload, as long as the blood pressure remains adequate. (See "Transfusion-associated circulatory overload (TACO)".)
AHTRs are by definition self-limited, although the course is highly dependent on the volume of blood transfused and whether or not shock, DIC, and/or renal failure develop. The importance of reducing the risk of these complications provides the rationale for the importance of early detection in order to prevent death or long-term complications. Once hemolysis resolves and the patient is clinically stable, no long-term interventions are needed. However, if the patient requires additional transfusions in the future, it is important to alert the transfusion service or blood bank about the history of AHTR so that the implicated antigen can be avoided and all necessary crossmatching steps can be taken. (See 'Prevention' below.)
Reporting requirements — An AHTR is considered a sentinel event, as it is unexpected and can lead to significant morbidity and mortality.
The Medical Director of the Blood Bank or transfusion service is required to report any fatalities due to an AHTR to the Center for Biologics Evaluation and Research (CBER) within the FDA within 24 hours, by either email or telephone. A full written report must then be submitted within seven days.
Sentinel events may also be reported to The Joint Commission.
Differential diagnosis of AHTR — Other possible diagnoses to consider in a patient with a suspected AHTR include other transfusion reactions, other causes of hemolysis of the transfused RBCs, and other causes of hemolysis unrelated to the transfusion (table 1).
Other acute transfusion reactions — Other acute transfusion reactions include anaphylaxis or allergic reactions, transfusion associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), and transfusion-transmitted bacterial infection.
Like AHTR, these reactions may be associated with fever, chills, hypotension, tachycardia, and other systemic manifestations (table 2). Unlike AHTRs, the patient's serum (and urine) will not be pink in these reactions, and the evaluation in these other reactions will not show evidence of RBC incompatibility or hemolysis.
These other acute transfusion reactions are discussed in more detail separately (algorithm 1). (See "Approach to the patient with a suspected acute transfusion reaction".)
Non-immune hemolysis — Although uncommon, RBC lysis by a non-immune mechanism can occur during transfusion, due to thermal, osmotic, chemical, or mechanical injury to the RBCs.
●Thermal injury – Thermal injury, which is extremely rare, occurs when RBCs are exposed to excessive heat or cold. Exposure to high temperatures is typically caused by improper use of a blood warming device. RBCs cannot tolerate temperatures above 40°C (104°F) [24]. Excessive heat can damage the RBC membrane, leading to changes in viscosity, fluidity, deformability, permeability, and osmotic fragility. Heat-damaged RBCs that have not already lysed are rapidly cleared from the circulation by the spleen.
Freezing injury occurs when RBCs are exposed to below-freezing temperatures in the absence of a cryoprotective agent such as glycerol or DMSO. This can lead to dehydration injury if the freezing is slow or ice crystal formation if the freezing is rapid [25]. Inadequately deglycerolized RBCs can undergo intravascular osmotic lysis; one such circumstance was reported to have been the cause of death in a 1000 gram infant [6].
●Osmotic injury – Osmotic injury occurs when RBCs are exposed to a hypotonic solution. This is also extremely rare. It may result from inadvertent mixture with a drug or hypotonic solution (5 percent dextrose, half-normal saline, distilled water). Hypo-osmolar solutions permit free water to enter the RBCs, causing them to swell and lyse.
●Mechanical injury – Mechanical injury occurs when RBCs are exposed to physical trauma. During transfusion, this may result from especially fine gauge needles, kinked or twisted intravenous lines, mechanical pumps, or defective blood administration sets [26].
Like immune hemolysis, these other forms of RBC injury can cause an acute systemic reaction with signs of intravascular hemolysis, including fever, chills, back pain, free hemoglobin in the serum or urine, increased LDH, high bilirubin, and low haptoglobin. Unlike immune hemolysis, in individuals with non-immune hemolysis, there will often be a history of improper use of a blood warmer, diluent fluid, or infusion tubing; and in non-immune RBC injury the direct and indirect antiglobulin (Coombs) tests will be negative.
Proper administration of RBC transfusions is discussed in detail separately. (See "Red blood cell transfusion in infants and children: Administration and complications" and "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion".)
Intrinsic defect in transfused cells — Although uncommon, it is possible that the transfused RBCs come from a donor with a hereditary hemolytic anemia that is undiagnosed or not manifest in the donor but becomes clinically significant in the recipient.
●G6PD deficiency – The most common example is glucose-6-phosphate dehydrogenase (G6PD) deficiency. RBCs with this enzyme deficiency are susceptible to lysis when exposed to oxidant stress, which may include exposure to certain drugs (sulfonamides, phenacetin, vitamin K, primaquine, nitrofurantoin, and others); infections such as viral hepatitis; ingestion of fava beans; or alterations in plasma pH [27]. G6PD-deficient RBCs will survive almost normally in recipients not subjected to oxidant stress, with the exception of premature infants, in whom hemolysis has been reported without oxidant exposure. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)
●Sickle cell trait – RBCs from donors with sickle cell trait, while able to survive normally in most recipients, have been shown to have shortened survival in recipients subjected to hypoxic conditions [28]. Blood from donors with sickle cell trait is less likely to be transfused in the era of universal pre-storage leukoreduction than it was previously, since most blood from donors with sickle cell trait will have problems such as clogging the leukoreduction filter, rendering the unit unsuitable for transfusion. As a result, this clinical situation is rarely encountered.
Like an AHTR, recipients of RBCs that hemolyze when transfused can have evidence of hemolysis on laboratory testing. Unlike AHTR, in these conditions certain findings such as fever, hypotension, or DIC are absent.
Hemolysis unrelated to the transfusion — Certain autoimmune hemolytic anemias (AIHAs) can be exacerbated by transfusion, with increased hemolysis that may be difficult to distinguish from hemolysis of the transfused cells:
●Autoimmune hemolysis – AIHA or compensated autoimmune hemolysis without anemia may be present but undetected, or known and exacerbated by transfusion. In patients with underlying AIHA, lysis of the transfused RBCs by the autoantibody can either mimic or mask alloantibody-induced hemolysis. Like transfusion-associated AHTRs, AIHA is associated with laboratory evidence of immune hemolysis. Unlike an AHTR, in AIHA, the hemolysis was present before the transfusion and often could be detected on pretransfusion testing. AIHA is typically characterized by extravascular hemolysis, and the direct antiglobulin (Coombs) test (DAT) is positive, with no free hemoglobin in the serum or urine.
●Cold agglutinin disease – Cold agglutinin disease is a form of AIHA in which the autoantibodies cause agglutination of RBCs at cold temperatures. Cold agglutinin disease is rare; it is most often seen in older females and/or in association with infection, especially those involving mycoplasma pneumoniae and Epstein-Barr virus (infectious mononucleosis). In individuals with cold agglutinins, infusion of blood at refrigerator temperatures may exacerbate hemolysis. All intravenous infusions for these patients, including blood, should be warmed using approved blood warming devices. (See "Cold agglutinin disease", section on 'Cold avoidance'.)
●Paroxysmal nocturnal hemoglobinuria (PNH) – PNH is an acquired disorder characterized by clonal expansion of hematopoietic cells that lack glycosylphosphatidylinositol (GPI) anchored proteins, some of which prevent spontaneous complement-mediated lysis (intravascular and extravascular) of RBCs. Because of the increased sensitivity of the recipient's RBCs to complement, any antigen-antibody reaction capable of activating complement (donor RBC-recipient antibody; donor WBC-recipient antibody; recipient RBC-donor antibody) can trigger hemolysis in a recently transfused patient with PNH. Various methods to reduce this effect have been used, including washing RBCs to remove donor plasma and leukoreduction to remove donor WBCs, but none are supported by high quality evidence. Leukoreduction is standard practice and is recommended on general principles, especially if a future hematopoietic stem cell transplant is contemplated. We generally do not advocate washing. (See "Pathogenesis of paroxysmal nocturnal hemoglobinuria" and "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria".)
●Drug-induced hemolysis – A number of drugs can cause hemolysis and mimic an AHTR. Common examples include intravenous immune globulin (IVIG), quinidine, penicillins, and cephalosporins. Like AHTRs, drug-induced hemolysis is characterized by findings of hemolysis. Unlike an AHTR, drug-induced hemolysis has a temporal relationship to drug administration rather than the transfusion and can be treated by eliminating the drug exposure. The transfusion service laboratory should be able to perform or send-out the testing to evaluate for drug-induced hemolysis. A more extensive list of implicated drugs and an approach to the patient evaluation are presented separately. (See "Drug-induced hemolytic anemia".)
Separate topic reviews discuss the importance of searching for underlying alloantibodies in patients with AIHA prior to transfusion (see "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Initial management'), and other causes of hemolytic anemia that may be exacerbated by transfusion or discovered during a transfusion reaction evaluation. (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)
DELAYED HEMOLYTIC TRANSFUSION REACTIONS AND DELAYED SEROLOGIC TRANSFUSION REACTIONS — Delayed HTRs (DHTRs) are defined as HTRs that occur more than 24 hours following transfusion. Delayed serologic transfusion reactions (DSTRs) are identical to DHTRs except that the patients are asymptomatic and lack evidence of hemolysis. (See 'Timing of hemolysis (acute or delayed)' above.)
Clinical presentation of DHTRs and DSTRs — DHTRs most commonly present one to two weeks after transfusion of RBCs, although the interval can range from 24 hours to 28 days. DSTRs are only diagnosed once a new clinically significant antibody is detected, which may be weeks or months later.
In most cases, DHTRs and DSTRs are not due to clerical errors; the alloantibody is simply too low in titer to be detected by conventional serologic testing prior to transfusion. In most cases, the alloantibody is detected on the transfusion reaction evaluation or on antiglobulin (Coombs) testing.
DHTRs and DSTRs are most commonly due to an anamnestic response to a foreign RBC antigen to which the recipient was previously exposed. Common routes of previous exposure include prior transfusions and pregnancy; less common routes include hematopoietic stem cell or solid organ transplantation, or sharing of intravenous needles [4]. RBC antigens most commonly responsible for DHTRs and DSTRs include those of the Kidd or Rh system.
The Centers for Disease Control and Prevention (CDC) Biovigilance Network in the United States have defined criteria for a DHTR that require [23]:
●A positive direct antiglobulin test (DAT; direct Coombs test) from 24 hours to 28 days after the transfusion
●Identification of the RBC antibody in the serum or eluate
●Laboratory findings such as inappropriate hemoglobin increment, spherocytes on peripheral blood smear, or findings of hemolysis (low grade fever, jaundice, increased lactate dehydrogenase [LDH], increased indirect bilirubin, decreased haptoglobin)
The Biovigilance Network defines a DSTR as absence of clinical signs of hemolysis and detection of a new clinically significant antibody by either a positive DAT or a positive antibody screen on subsequent type and screen sample testing
DHTRs, characterized by extravascular hemolysis (see 'Site of RBC destruction (intravascular or extravascular)' above), are evaluated when there are signs or symptoms of hemolysis. However, the majority of patients who develop an alloantibody do not have any symptoms and are diagnosed with a DSTR. Excluding patients with sickle cell disease (SCD), <10 percent of patients who develop an alloantibody after a transfusion are clinically diagnosed as having a DHTR. Individuals with SCD are more likely to be symptomatic because they may have a component of intravascular hemolysis. Symptomatic patients can present with low-grade fever or jaundice.
Laboratory evaluation of DHTRs generally reveals evidence of hemolysis and a positive DAT or indirect antiglobulin test (IAT). The hemoglobin may be lower than expected given the patient's clinical picture and timing of the transfusion. If the DHTR has been ongoing, the reticulocyte count may be correspondingly increased in patients with a normally functioning bone marrow. In addition to laboratory findings of immune hemolysis, the peripheral blood smear may show spherocytes or microspherocytes, and urinalysis may show urinary hemosiderin.
A DHTR may less commonly present with intravascular hemolysis and associated findings, similar in quality but often less severe in degree compared with intravascular hemolysis during an AHTR. This situation is generally indicative of an acquired alloantibody to an antigen in the Kidd (Jk) blood group system, as these antibodies (though IgG) can be capable of binding complement, which is necessary for causing intravascular hemolysis, or, in individuals with SCD, due to bystander hemolysis or hyperhemolysis. (See 'Clinical presentation of AHTR' above.)
Hyperhemolysis (also referred to as hyperhemolytic crisis) is an extremely rare type of DHTR in which hemolysis of transfused RBCs is accompanied by hemolysis of the patient's own RBCs. This phenomenon is often clinically severe and has been seen most often in multiply-transfused patients with SCD, but it has also been reported in patients with thalassemia and in other settings [29]. Treatment with intravenous immune globulin (IVIG) and glucocorticoids has been reported to be successful in some cases, as discussed in more detail separately. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Hyperhemolytic crisis'.)
When a new alloantibody is identified and there is no evidence of hemolysis, the diagnosis of DSTR is often made by the blood bank when more blood is ordered. This provides the rationale for repeating pretransfusion testing in an individual who has recently received a transfusion. (See "Pretransfusion testing for red blood cell transfusion".)
If an asymptomatic, recently transfused patient is found to have either a new positive DAT or antibody screen, a thorough evaluation is indicated to enable the clinician to distinguish between a DHTR and a DSTR. (See 'Differential diagnosis of DHTR or DSTR' below.)
Evaluation of DHTR and DSTR — The initial evaluation of a suspected DHTR involves review of the transfusion history and laboratory testing for hemolysis, including a complete blood count (CBC) with reticulocyte count, indirect bilirubin, antiglobulin (Coombs) testing (both direct and indirect), and antibody identification if indicated. If the hemolysis appears brisk, based on falling hemoglobin and rising indirect bilirubin levels, an LDH or serum haptoglobin may be confirmatory. (See "Overview of hemolytic anemias in children", section on 'Diagnostic approach' and "Diagnosis of hemolytic anemia in adults", section on 'Diagnostic approach'.)
It is important to have an antibody screen performed by the transfusion service or the hospital blood bank, because prevention of future reactions depends on the blood bank identifying and permanently recording the specific RBC antigen to which the patient has become sensitized in the patient's record. It is also helpful for the blood bank or transfusion service to give the patient written or electronic documentation about the implicated antigen in case the patient is seen at a different facility that does not have direct access to the information.
Differential diagnosis of DHTR or DSTR — Other possible diagnoses to consider in a patient with a suspected DHTR include other causes of anemia unrelated to the transfusion, other causes of fever and jaundice, and a RBC alloantibody without hemolysis.
●Anemia – Other causes of anemia are numerous, and include iron deficiency, bleeding, anemia of chronic disease, hemolysis, bone marrow disorders, and inherited anemias. At least one of these is likely to be responsible for the original need for transfusion. Like DHTR, these may be apparent following transfusion; some may be associated with laboratory evidence of hemolysis; and some may be characterized by a positive antiglobulin (Coombs) test. Unlike DHTR, these anemias are not caused by alloantibodies. The evaluation of unexplained anemia is discussed in detail separately. (See "Approach to the child with anemia" and "Diagnostic approach to anemia in adults".)
●Fever/Jaundice – Other causes of fever and jaundice in a patient who has received a transfusion more than 24 hours prior to the onset of these symptoms include infections and other complications. Like DHTR, these reactions may require a high index of suspicion and a more thorough evaluation. Unlike DHTR, these reactions are not associated with alloimmune hemolysis. Possible causes are presented in the table (table 3) and in separate topic reviews. (See "Fever in the surgical patient" and "Classification and causes of jaundice or asymptomatic hyperbilirubinemia".)
Management of DHTR and DSTR — For individuals with a DHTR, the hemoglobin level should be monitored until it is clear that hemolysis has ended. The frequency of monitoring is determined by the severity of hemolysis. DSTRs are only identified in retrospect, so hemoglobin monitoring does not apply.
No specific interventions are required for a DHTR in the absence of brisk hemolysis, as defined by a falling hemoglobin, rising bilirubin, absent serum haptoglobin, and/or the presence of evidence of intravascular hemolysis (hemoglobinuria), although symptomatic treatment may be helpful (eg, with antipyretics) [3]. If there is ongoing hemolysis, it would be prudent to consult the hematology service and consider giving a glucocorticoid, intravenous immune globulin (IVIG), or rituximab. (See 'Evaluation of DHTR and DSTR' above.)
Kidney failure can occur in the setting of brisk hemolysis; thus, prophylactic measures to protect kidney function should be used until it is clear that the hemolysis has ended, as indicated by the stability of the hemoglobin level. These measures include hydration (if not contraindicated) with close monitoring of urinary output.
For both DHTR and DSTR, it is critical to avoid future transfusions containing the implicated RBC antigen. It is therefore important to perform the evaluation, document the alloantibody, and inform the patient and caregivers of the importance of avoiding the antigen in future transfusions. (See 'Evaluation of DHTR and DSTR' above and 'Prevention' below.)
PREVENTION — Some HTRs are preventable, including those due to misidentification of the patient or blood product due to clerical error. Others may be impossible to prevent, such as those due to a low level or weak alloantibody that does not reach the limits of detection on pretransfusion testing. Antibodies to allogeneic RBC antigens may have developed during exposures of which the patient was not aware, such as exposure to a paternal red blood cell (RBC) antigen during pregnancy.
For the 1990 report on deaths due to HTRs, the authors concluded that "wherever errors could be made, errors occurred" and "human errors occur at an irreducibly small rate despite our best efforts (to prevent them)" [6]. A multicenter study evaluating 331 type and screen sample collection errors leading to wrong blood in tube (WBIT) found that 50 percent were due to the wrong label being applied to the type and screen blood draw tube, and 48 percent were due to blood being drawn from the wrong patient [30]. Most WBITs were due to a combination of protocol violations and lapses. WBIT errors dramatically increase the risk of AHTRs due to ABO incompatible transfusion [31].
Systematic procedures to minimize the likelihood of an HTR should be incorporated into standard institutional policies and operating procedures [10,11]. Examples include the following:
●Meticulous record keeping and accurate patient identification are needed to prevent transfusion of a product intended for a different patient. (See "Pretransfusion testing for red blood cell transfusion", section on 'Labeling'.)
●Some hospitals require at least two type and screen samples drawn at separate times (a check sample) be available prior to issuing type specific blood [32]. One of the samples may be a previous sample on historical record.
●As an alternative approach to the two type and screen samples that some hospitals require, an electronic patient identification system can be used to ensure the correct blood sample is being drawn and labeled accurately, and units issued to the patient are the correct ABO type; this is often available as part of the electronic medical record [33-36].
●The type and screen should be repeated within three days prior to transfusion if the patient has any risk factors for alloimmunization such as pregnancy, receipt of a transfusion in the previous three months, or an unclear history regarding these events. (See "Pretransfusion testing for red blood cell transfusion", section on 'Specimen age/collection date'.)
●Extended serologic matching (or molecular [DNA-based] matching) may be used for certain populations at high risk of developing alloantibodies, such as individuals with sickle cell disease. If the recipient is known to have alloantibodies, antigen negative units are required. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'RBC antigen matching'.)
●Proper handling and administration of blood products is essential, including avoiding extremes of temperature and ensuring compatible fluids, as discussed in detail separately. (See "Red blood cell transfusion in infants and children: Administration and complications", section on 'Administration' and "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Administering the transfusion'.)
●Proper notation should be placed in the patient's medical record and blood bank records, and a medical alert card or bracelet can be used for a patient with known RBC alloantibodies. (See "Red blood cell antigens and antibodies".)
Additional details about these measures are discussed in the topic links included above, in the AABB technical manual, and in several excellent review articles [3,5,37].
If a patient has an AHTR caused by transfusion of the incorrect product, it may be possible to prevent a second transfusion reaction by contacting the transfusion service to make sure that a second patient is not about to receive the product intended for the first patient. (See 'Evaluation and immediate management of AHTR' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Transfusion and patient blood management".)
SUMMARY AND RECOMMENDATIONS
●Mechanism – Hemolytic transfusion reactions (HTRs) most often occur when there is immunologic incompatibility between a transfusion recipient and the red blood cells (RBCs) from the blood donor. The main determinants of severity, site of hemolysis (intravascular or extravascular) (figure 2), and timing are the specific RBC antigens and the nature and titer of alloantibodies present at the time of transfusion. (See 'Pathophysiology' above.)
●Prevalence – ABO incompatible acute HTRs (AHTRs) are rare and getting rarer, but fatal reactions continue to happen, on the order of 1 to 2 events per 10 million transfusions. ABO incompatible AHTRs are most often due to clerical error. HTRs are most common with RBC transfusion but can also occur with plasma-containing products. (See 'Epidemiology' above.)
●AHTRs – AHTRs occur during or within 24 hours of completing the transfusion. An AHTR is a medical emergency that requires immediate cessation of the transfusion if still in progress, as well as immediate evaluation and interventions to reduce the risks of serious organ damage to the patient and other potentially affected patients. (See 'Acute hemolytic transfusion reactions' above.)
•Immediate actions – The most common presentation of AHTR is immediately upon RBC transfusion with ABO blood group incompatibility. The initial steps include immediately stopping the transfusion, providing hemodynamic support, and contacting the transfusion service to help with the evaluation (algorithm 1). Immediate goals are to determine if hemolysis has occurred, to distinguish among possible causes, and to stabilize the patient. The untransfused blood and tubing should not be discarded.
•Additional testing – Laboratory testing for AHTR includes repeat ABO compatibility testing and in some cases additional antibody testing; inspection of the serum and urine for pink color due to free hemoglobin; testing for hemolysis (haptoglobin, lactate dehydrogenase [LDH], and bilirubin levels); and direct and indirect antiglobulin (Coombs) testing. Some individuals may require testing for disseminated intravascular coagulation (DIC), hyperkalemia, and renal insufficiency, and nephrologist and/or hematologist consultation.
•Differential diagnosis – The differential diagnosis of AHTR includes other acute transfusion reactions and other causes of hemolysis, either caused by, exacerbated by, or unrelated to the transfusion.
●Delayed hemolytic transfusion reactions (DHTRs) – DHTRs occur >24 hours after the transfusion, typically due to an anamnestic response to a previously encountered foreign RBC antigen (through pregnancy, prior transfusion, solid organ, or hematopoietic cell transplantation), especially those of the Kell or Rh system. DHTR symptoms are often mild. If a DHTR is suspected, it is important to have an evaluation for RBC alloantibodies performed in the blood bank. No specific interventions are required for a DHTR in the absence of brisk hemolysis, but monitoring of the hemoglobin (and occasionally other parameters) may be appropriate. (See 'Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions' above.)
●Delayed serologic transfusion reactions (DSTRs) – DSTRs are identical to DHTRs, but the patients are asymptomatic. DSTRs are diagnosed when the transfusion service laboratory detects a new clinically significant antibody on subsequent sample testing by either a positive DAT or a positive antibody screen.
ACKNOWLEDGMENT — The UpToDate editorial staff gratefully acknowledges the extensive contributions of Arthur J. Silvergleid, MD, to earlier versions of this and many other topic reviews.
