Immunologic transfusion reactions

INTRODUCTION — Transfusions can be lifesaving for patients with severe anemia, thrombocytopenia, or deficiency of plasma components. In general, transfusions are safe. However, allogenic blood cells and plasma proteins are foreign substances that can elicit an immune response in the recipient, and plasma contains antibodies and other immune mediators that can react with recipient cells. As a result, transfusion carries risks of immunologic reactions.

This topic review discusses common immunologic transfusion reactions. Other types of transfusion reactions, and the approach to the patient with a suspected transfusion reaction for which the cause is unknown, are discussed in separate topic reviews.

●Transfusion reaction of unknown cause – (See "Approach to the patient with a suspected acute transfusion reaction".)

●Hemolytic transfusion reactions (HTR) – (See "Hemolytic 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".)

DISTINGUISHING AMONG IMMUNOLOGIC REACTIONS — Many of the acute immunologic reactions discussed below can present with fever and/or respiratory symptoms, making it challenging to distinguish them from each other in the initial stages.

●Distinguishing findings are listed in the table (table 1).

●An overview of our approach to the evaluation and immediate interventions is presented in the algorithm (algorithm 1); these include stopping the transfusion, maintaining a patent intravenous line, and confirming the correct product for the patient.

●Specific testing based on the initial patient symptoms is presented in detail separately. (See "Approach to the patient with a suspected acute transfusion reaction".)

FEBRILE NONHEMOLYTIC TRANSFUSION REACTIONS

Definition of FNHTR — The United States Centers for Disease Control and Prevention (CDC) Biovigilance Network revised the criteria for febrile nonhemolytic transfusion reaction (FNHTR) in 2023 with the following definition [1]:

Definitive FNHTR is a reaction that occurs within four hours of transfusion termination and for which no other conditions could explain the signs or symptoms of either:

●A fever of >38°C with an accompanying temperature increase of >1°C

or-

●Chills/rigors

Prevalence of FNHTR — FNHTRs are among the most common of all transfusion reactions. Approximately 1 percent of all transfusions are associated with an otherwise unexplained rise in temperature of at least 1°C, with or without chills and rigors [2-4].

FNHTRs are not serious, as the fever responds to antipyretics and the rigors to meperidine. However, these reactions are discomforting for the patient and ultimately quite expensive, since they require that an infectious etiology be excluded and, in many cases, that an additional unit of blood be crossmatched and transfused. In some patients (eg, asplenia due to sickle cell disease), development of fever may necessitate hospitalization and empiric antibiotic therapy until an infectious etiology is eliminated [2,3,5].

The following factors affect the likelihood of an FNHTR:

●Patient age – FNHTRs are more frequent in children than adults. In a 2015 study involving over 100,000 transfusions, the rate of FNHTR was 0.2 percent per transfusion in children and 0.05 percent in adults [6].

●Blood product – FNHTRs can occur with any product; overall, they are equally likely from platelets and red blood cells (RBCs), and more likely with either of these cellular products than with plasma products (table 1). They are most likely with platelets prepared from platelet-rich plasma (ie, whole blood-derived platelets, as opposed to apheresis platelets), since these platelet products have the highest concentration of leukocytes (white blood cells [WBCs]) [7,8].

●Leukoreduction – FNHTRs are much less likely if the product has undergone prestorage leukoreduction (removal of WBCs). Bedside leukoreduction may slightly decrease the risk, but pre-storage leukoreduction is more effective [9].

A re-analysis of data from the original article about FNHTRs in 1962 indicated that 40 percent of patients experiencing an FNHTR will experience a subsequent FNHTR, with 24 percent having a recurrent FNHTR on the very next transfusion [10,11].

Mechanism of FNHTR — FNHTRs appear to be mediated both by donor leukocytes (WBCs) and by generation and accumulation of cytokines that occur during the storage of blood components and after transfusion [12-18]. It has been proposed that an interaction between donor leukocytes and recipient antibodies leads to interleukin (IL)-1 release from donor leukocytes or recipient monocytes. IL-1 produces fever by stimulating prostaglandin E2 (PGE2) production in the hypothalamus. Other implicated cytokines include IL-6, IL-8, and tumor necrosis factor-alpha (TNFα).

Cytokine accumulation during storage may play a primary role. The risk of a transfusion reaction has been demonstrated to increase with the age of the unit transfused [13]. Removal of plasma is more effective than post-storage leukoreduction in preventing reactions, especially severe reactions to platelets [19,20].

The role of leukocytes in the stored product as a potential source of cytokines was illustrated in the Trial to Reduce Alloimmunization to Platelets (TRAP), in which FNHTRs were significantly associated with products containing more than 5 x 10⁶ leukocytes per transfusion and with components stored for more than 48 hours [21].

The relative importance of cytokines rather than the leukocytes themselves was illustrated in a study in which 64 platelet concentrates were separated into cellular and plasma components, and then these were transfused into 12 volunteers in random order [22]. There were 20 reactions to the plasma supernatant, six reactions to the cells, and eight reactions to both products. There was a strong correlation between FNHTRs and the concentrations of IL-1 and IL-6 in the plasma. Cytokines can be released from leukocytes that were not removed prior to storage of the blood product (ie, products that did not undergo pre-storage leukoreduction), which explains the greater benefit of pre-storage leukoreduction in reducing the risk of FNHTR compared with bedside leukoreduction. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction'.)

The importance of the duration of product storage in cytokine accumulation has been demonstrated in several studies. As an example, in a series that evaluated reactions to 117 red blood cell transfusions and 65 platelet transfusions, the dominant factors determining the risk of a reaction were a longer duration of product storage and a higher number of leukocytes in the product [13]. In another report, the mean IL-8 concentration increased 100-fold between days 2 and 5 of storage and rose further with continued storage [14].

Alternative mechanisms for FNHTR reactions have been proposed:

●FNHTRs have been associated with antibodies directed against class I HLA antigens present on leukocytes in red cell concentrates, or, less commonly, antibodies to platelet or granulocyte antigens [12,23].

●FNHTRs accompanying platelet transfusions have also been associated with release of platelet-derived CD154 (CD40 ligand), which is capable of inducing production of proinflammatory cytokines from fibroblasts, epithelial cells, and endothelial cells [24-27].

Clinical presentation and diagnosis of FNHTR — Clinical manifestations of FNHTR occur within one to six hours after initiation of a transfusion and within four hours of transfusion termination [1]. These include fever, often a chill, occasionally severe rigors (most often seen with, though not restricted to, granulocyte transfusions), and sometimes mild dyspnea (table 1)

FNHTRs are diagnosed clinically by excluding other causes of fever in a patient receiving a transfusion (algorithm 1). There is no laboratory or other testing that can confirm or exclude the presence of a FNHTR. The extent of the evaluation for other causes depends on the severity of the temperature increase and the presence or absence of other symptoms. It is important that febrile reactions always be reported to the transfusion medicine service or blood bank, since it is almost impossible to distinguish more severe reactions without transfusion service laboratory evaluation.

Other transfusion reactions associated with fever in the differential diagnosis of FNHTR include acute hemolytic transfusion reaction (AHTR), transfusion-related acute lung injury (TRALI), and sepsis.

●AHTR – Unlike FNHTRs, individuals with an AHTR are often acutely ill and have free hemoglobin in blood and urine or red or dark colored serum and urine.

●TRALI – Unlike FNHTRs, individuals with TRALI have prominent dyspnea, with evidence of pulmonary edema on physical examination and chest radiography, In FNHTRs, dyspnea is generally mild or absent, and there is no evidence of pulmonary edema.

●Sepsis – Unlike FNHTRs, individuals with sepsis are often acutely ill with positive blood cultures. In contrast, individuals with FNHTRs are generally not that ill and do not have these other abnormal findings. Both acute hemolysis and sepsis can also be associated with disseminated intravascular coagulation, which is not seen with FNHTRs.

Management of FNHTR — FNHTRs are benign, causing no lasting sequelae, but they are uncomfortable and sometimes frightening to the patient. Furthermore, since fever may be the sign of an acute hemolytic transfusion reaction or infection, FNHTRs require action on the part of the clinical team. This typically involves the following:

●Stop the transfusion.

●Administer antipyretics if the fever is bothersome to the patient.

●Evaluate for other causes of fever, which include more serious (and potentially life-threatening) transfusion reactions as well as non-transfusion-related infection or fever, which may be due to the patient's underlying disorder.

●Admit to the hospital (if the transfusion is administered in an out-patient setting) for presumptive treatment of infection, if this is considered to have high enough likelihood (eg, in a patient receiving immunosuppressive therapy or with functional asplenia from sickle cell disease).

●Administer other medications if needed, such as meperidine (25 to 50 mg) for severe chills or rigors.

Prevention of FNHTR — Regardless of the etiology, FNHTRs can be minimized by reducing the number of leukocytes (WBCs) transfused [28]. Each unit of whole blood or unmodified RBCs contains approximately 2 to 5 x 10⁹ leukocytes. FNHTRs can be largely eliminated if the total leukocyte count is reduced by one to two logs (90 to 99 percent), to <5 x 10⁸ [15].

Use of high quality leukocyte reduction filters is the most common method to achieve effective leukoreduction. Other methods to achieve sufficient leukocyte reduction include saline washing, freezing and deglycerolizing, buffy coat removal, and microaggregate ("second-generation") filters. The most effective leukocyte reduction filters ("third-generation") can achieve a three- to four-log (99.9 to 99.99 percent) reduction in leukocytes, leaving residual leukocyte counts <5 x 10⁶ and generally <1 x 10⁶ [16,17].

The US Food and Drug Administration (FDA) regulations for the quality of "leukocytes reduced" blood products require that components contain <5 x 10⁶ WBCs per unit [29]. The European Community standard has been set at <1 x 10⁶ WBCs per unit [17]. In a multicenter study of the effectiveness of leukoreduction techniques, more than 99 percent of leukoreduced units met the United States standards and more than 91 percent of leukoreduced units met the European Community standard [17].

Randomized trials of leukocyte reduction for prevention of FNHTR are scarce [18,30].

Three large retrospective cohort studies compared the frequency of acute reactions to RBCs and platelets before and after universal leukoreduction (ie, 100 percent of a particular blood component [eg, RBC units] undergo leukoreduction) had been implemented [9,29,31,32].

●The frequency of FNHTRs to RBCs was 0.33 to 0.37 percent prior to leukoreduction and was reduced to 0.15 to 0.19 percent following universal leukoreduction.

●The frequency of FNHTRs to platelets was 0.45 to 2.18 percent prior to leukoreduction and was reduced to 0.11 to 0.15 percent following universal leukoreduction.

There is no evidence that pathogen inactivation (or pathogen reduction technology [PRT]) has any impact on the incidence of FNHTRs, despite its profound effect on WBC function, as neutrophils subjected to PRT can still leak cytokines during storage. (See "Pathogen inactivation of blood products".)

We do not use premedications (diphenhydramine or acetaminophen) to decrease the incidence of FNHTRs, as these medications are ineffective in preventing reactions and may cause adverse events on their own such as cardiovascular symptoms and central nervous system alterations. This lack of benefit was highlighted in a 2019 meta-analysis that evaluated the rates of FNHTR with premedication versus placebo or no treatment; no benefit was seen with premedication [33]. All blood products used in the trials in the meta-analysis were leukoreduced. Individuals who received premedication had a slightly higher rate of FNHTRs and a slightly lower rate of minor allergic reactions, neither of which reached statistical significance. An earlier review came to similar conclusions regarding the lack of efficacy of premedication [34].

ALLERGIC REACTIONS

Prevalence and mechanisms of allergic reactions — Allergic reactions, characterized by itching and hives, are one of the most common transfusion reactions, although the true prevalence is unknown because these are likely to be underreported [35]. They are seen in as many as 1 to 3 percent of recipients of platelet and plasma components and 0.1 to 0.3 percent of recipients of red blood cell (RBC) components [4,34,36-38].

Allergic transfusion reactions are a type 1 hypersensitivity reaction that occurs when a soluble substance in the plasma of the donated blood product (or the recipient) reacts with preexisting IgE antibodies in the recipient (or the product), respectively. Allergic reactions are thought to be due to mast cell or basophil release of histamine, although other mechanisms may be involved. (See "New-onset urticaria".)

Allergic reactions are multifactorial and often involve donor, product, and recipient factors.

●Plasma proteins are a common etiology. Recipients may be predisposed to a specific allergen with high IgE levels and react to the blood product that contains that allergen [39]. Alternatively, there have also been case reports of a donor with a peanut allergy and high levels of IgE to peanuts triggering an allergic reaction after receiving a transfusion from a recipient who had ingested peanuts [40-43].

●Non-antibody mechanisms are also important [38]. As an example, a study compared inflammatory mediators in 20 apheresis platelet products associated with allergic transfusion reactions versus apheresis platelet products that did not cause allergic reactions [44]. The platelet products associated with allergic transfusion reactions had higher levels of the direct allergic agonists than the control platelet products (C5a, 17 percent higher; brain-derived neurotrophic factor [BDNF], 42 percent higher; CCL5 [RANTES], 14 percent higher) [44].

●In addition to donor and product factors, recipient factors play a critical role. This was illustrated in a study of different recipients who received a transfusion from the same donor and did not have the same reaction. Generally, two or three apheresis platelet units are produced from the same donor during one collection (split apheresis platelet products). In a study of 1616 allergic reactions among 93,737 recipients of split apheresis platelet products in which split apheresis platelet units from the same donor were transfused to at least two different recipients, an allergic reaction in one recipient was not associated with an increased risk of an allergic reaction in the other recipients [45].

The major difference between allergic reactions and anaphylactic reactions is of degree; allergic reactions are mild, whereas anaphylactic reactions are associated with massive release of histamine and other mediators. It is unknown whether certain mediators are specific for anaphylaxis. (See 'Anaphylactic transfusion reactions' below.)

Clinical presentation and diagnosis of allergic reactions — Allergic reactions present with pruritus, hives or urticaria, or localized angioedema, which can occur during, at the end, or shortly after a transfusion. No other allergic findings are present (there is no wheezing or systemic angioedema). This timing slightly differs from anaphylactic reactions, which typically occur within minutes of starting a transfusion. (See 'Clinical presentation and diagnosis of anaphylactic reactions' below.)

Criteria from the United States Centers for Disease Control and Prevention (CDC) Biovigilance Network define allergic transfusion reactions as definitive if the patient has at least two symptoms within four hours after the completion of the transfusion [1].

Minor allergic reactions are diagnosed clinically when a patient develops itching, hives, localized erythema or edema, or a maculopapular rash without progression to more severe symptoms that suggest an anaphylactic reaction. (See 'Clinical presentation and diagnosis of anaphylactic reactions' below.)

Improvement of the allergic symptoms with stopping the transfusion and administration of diphenhydramine is strongly supportive of an allergic rather than an anaphylactic reaction. (See 'Management of allergic reactions' below.)

Rarely, an allergic reaction may be the first sign of a more serious reaction. If there is evidence of hypotension or respiratory distress, the possibility of anaphylaxis should be evaluated urgently. (See 'Clinical presentation and diagnosis of anaphylactic reactions' below.)

For patients who have recurrent allergic reactions, further evaluation for specific substances to which the patient is allergic may be performed (allergy testing). (See "Overview of skin testing for IgE-mediated allergic disease" and "Diagnostic evaluation of IgE-mediated food allergy".)

Management of allergic reactions — Allergic transfusion reactions are one of the few transfusion reactions in which the remainder of the blood product can be administered. However, before this is done, the transfusion should first be stopped, and, if the hives and urticaria are extensive, 25 to 50 mg of diphenhydramine can be given orally or intravenously.

●If the hives/urticaria wane and there is no evidence of dyspnea, hypotension, or anaphylaxis, the transfusion may be resumed.

●If the hives/urticaria persist, additional doses of diphenhydramine (and/or other symptomatic therapies) can be administered.

Data supporting treatments other than diphenhydramine are limited. However, more serve allergic reactions or those refractory to diphenhydramine can be treated with famotidine (20 mg intravenously), hydroxyzine (50 mg orally), or solumedrol (125 mg intravenously).

Prevention of allergic reactions — Several studies have demonstrated that product manipulation to decrease the amount of plasma can reduce allergic transfusion reactions.

●Studies have demonstrated that transfusing platelets stored in platelet additive solution rather than plasma decreased minor allergic reactions by 46 percent and was cost-effective for patients with recurrent allergic reactions [46,47].

●Additional small studies suggested that allergic reactions to platelets could be decreased by platelet washing (pooled whole blood-derived and apheresis platelets) [48,49].

●A retrospective cohort study of 179 individuals who first received unmanipulated platelets and subsequently received platelets from which plasma had been removed found a decline in allergic transfusion reactions from 5.5 percent for unmanipulated platelets to 1.7 percent for concentrated platelets and 0.5 percent for washed platelets [50].

Concentrating or washing should only be used for patients who experience severe or repeated allergic reactions that cannot otherwise be prevented.

It is appropriate to try concentrating the blood component (either RBCs or platelets) first and only washing the cells if plasma removal by concentration does not prevent the allergic reactions. Concentrating and washing platelet products decreases the number of viable platelets in the transfusion and may necessitate additional transfusions in some cases [51].

Among individuals who receive washed RBCs for recurrent allergic reactions without anaphylaxis for >12 months, the washed RBC protocol can often be safely removed without return of the recurrent allergic reactions [52].

Similar to FNHTR, we do not recommend the use of premedications (diphenhydramine and/or acetaminophen) to decrease the incidence of allergic reactions, as they are ineffective and may cause adverse events such as drowsiness. A systematic review of three randomized control trials demonstrated there is no clinical benefit of antihistamine premedication [34,53-56]. (See 'Prevention of FNHTR' above.)

ANAPHYLACTIC TRANSFUSION REACTIONS

Prevalence and mechanisms of anaphylactic reactions — Anaphylactic transfusion reactions are a severe form of allergic reactions and are rare, with an estimated incidence of 1 in 20,000 to 1 in 50,000 per unit transfused [4,57,58].

Anaphylaxis results from sudden (typically massive) systemic release of mediators such as histamine and tryptase by mast cells and basophils, typically in response to an IgE-mediated (or IgG-mediated) immune reaction. (See "Pathophysiology of anaphylaxis".)

Anaphylaxis can occur with transfusion of red blood cells (RBCs), platelets, granulocytes, or plasma products (eg, Fresh Frozen Plasma [FFP], Cryoprecipitate, or intravenous immune globulin [IVIG]). These reactions are not seen with plasma derivatives (albumin, purified clotting factors). Typically, the reaction occurs because the transfused product contains a substance to which the recipient is allergic; the converse has also been reported (ie, the reaction occurs because the transfused product contains IgE that reacts with a substance in the recipient).

Several specific mechanisms and the clinical settings in which they occur have been described:

●A well-characterized mechanism is class-specific IgG anti-IgA antibodies in patients who are IgA deficient. Selective IgA deficiency is common, occurring in approximately 1 in 300 to 500 people. However, few IgA-deficient patients develop anti-IgA antibodies (eg, 1 in 1200 to 1600 IgA-deficient patients have anti-IgA antibodies). (See "Selective IgA deficiency: Management and prognosis", section on 'Reactions to blood products'.)

●Anaphylaxis has been described after blood product transfusion in patients with anhaptoglobinemia (ie, congenital deficiency of haptoglobin) who develop anti-haptoglobin antibodies; this disorder primarily occurs in individuals from East Asia [59,60].

●Severe laryngeal edema or bronchospasm can occur in recipients of plasma exchange, occurring in 1 in every 500 to 1000 plasma exchanges in some studies [61,62]. Some of these reactions may be due to hypersensitivity to ethylene oxide or other substances used to sterilize components of the apheresis kit [63]. Anaphylaxis to methylene blue, used as a pathogen inactivation agent, has also been reported, although this is not likely to be a common cause of anaphylaxis [36].

●A blood donor was found whose transfused blood components (platelets) were implicated in two cases of anaphylactic transfusion reaction in 2002. The donor plasma showed mast cell degranulation activity due to the presence of high molecular weight (dimeric and trimeric) IgEs that likely directly activated the recipient's mast cells by crosslinking the immunoglobulin FC-epsilon receptor 1 [64]. The donor was ultimately diagnosed as having IgE kappa multiple myeloma.

●Case reports have described anaphylactic reactions due to passive transfer of a peanut allergen ingested by the blood donor and transfused into a child with a prior anaphylactic reaction to peanuts [65,66].

Clinical presentation and diagnosis of anaphylactic reactions — Anaphylactic transfusion reactions are of rapid onset (as are all anaphylactic reactions), typically occurring within a few seconds to a few minutes following initiation of a transfusion. The patient may experience shock, hypotension, angioedema, respiratory distress, and/or wheezing. These may or may not be preceded or accompanied by symptoms commonly described in allergic transfusion reactions including pruritus, urticaria, and flushing. (See 'Clinical presentation and diagnosis of allergic reactions' above.)

The diagnosis of an anaphylactic transfusion reaction is made clinically based on the timing of the reaction, rapid progression to potentially life-threatening symptomatology, and rapid response to therapy.

The differential diagnosis of an anaphylactic transfusion reaction includes other causes of dyspnea and hypotension during a transfusion (eg, transfusion-related acute lung injury [TRALI], transfusion-associated circulatory overload [TACO], sepsis), as well as other, non-transfusion-related allergic conditions (eg, asthma, drug allergy). Unlike anaphylactic reactions, these other reactions (TRALI, TACO, and sepsis) are generally not associated with wheezing and angioedema, and they do not resolve rapidly with epinephrine.

The evaluation should not delay prompt/emergency treatment. (See 'Treatment of anaphylactic reactions' below.)

The typical evaluation of a patient with a moderate to severe anaphylactic reaction, almost always performed after the acute situation has been treated and symptoms resolved, involves quantitative measuring of IgA levels as well as anti-IgA (if indicated), preferably on a pre-transfusion sample. Mast cell tryptase can be measured if the test is available with a reasonable turnaround time, but the results generally do not alter diagnosis or management when the clinical diagnosis appears obvious. Chest imaging may help distinguish between pulmonary edema and bronchospasm if these cannot be differentiated clinically.

Treatment of anaphylactic reactions — Anaphylactic reactions are frightening and potentially life-threatening. The initial assessment and emergency management of anaphylaxis is presented in the tables for adults (table 2) and children (table 3). Additional details of treatment are discussed separately. (See "Anaphylaxis: Emergency treatment".)

Major interventions include the following:

●Immediately stop the transfusion.

●Give intramuscular epinephrine, preferably to the mid-outer thigh, 0.01 mg/kg (maximum 0.5 mg) which requires use of a 1 mg/mL solution. The dose may be repeated every 5 to 15 minutes (or more frequently) if needed. In some countries other than the United States, 1 mg/mL solution may be labeled as 1:1000.

In many settings use of an autoinjector may be preferred; dosing is as follows:

•Patients >25 kg – 0.3 mg

•Infants and children 10 to 25 kg – 0.15 mg

Epinephrine should not be withheld due to concerns with bleeding due to a bleeding disorder or thrombocytopenia; the potential lifesaving benefit outweighs the small potential risk of intramuscular bleeding [67].

In severe cases such as impending cardiovascular collapse refractory to intramuscular and volume resuscitation, a slow intravenous bolus of epinephrine is indicated, ideally with hemodynamic monitoring while an epinephrine infusion is prepared. In adults, the intravenous epinephrine dose is 0.05 to 0.1 mg, which requires 0.5 to 1 mL of a 0.1 mg/mL solution; this preparation is typically stocked on resuscitation carts as a syringe (1 mg epinephrine in 10 mL). In some countries other than the United States, the 0.1 mg/mL solution may be labeled as 1:10,000.

●For hypotension, use intravenous fluid resuscitation usually with normal saline. Some patients may require a second vasopressor (in addition to epinephrine infusion). All vasopressors should be given by infusion pump, with the doses titrated continuously according to blood pressure and cardiac rate/function and oxygenation monitored by pulse oximetry.

●Maintain the airway and provide oxygen if needed.

●For severe bronchospasm, inhaled bronchodilators, continuous positive airway pressure (CPAP), and/or an H2-antihistamine such as famotidine may be appropriate.

●For pruritus or angioedema, an H1-antihistamine (loratadine or cetirizine, 10 mg orally, or diphenhydramine, 25 or 50 mg orally or intravenously) may also be administered. The diphenhydramine dose is at the discretion of the clinician treating the reaction and depends on the size of the individual and severity of the reaction. A repeat dose can be given 15 or 30 minutes after the first dose if needed for persistent itching or hives. The maximum dose of diphenhydramine is 100 mg in a one-hour period.

●Prepare for possible administration of an intravenous epinephrine drip if needed (table 4).

Additional information is presented separately. (See "Anaphylaxis: Emergency treatment".)

Prevention of anaphylactic reactions — Prevention of anaphylactic transfusion reactions consists of establishing the diagnosis after the fact and avoiding future exposures.

In general, it is best to avoid plasma transfusion in individuals with a previous anaphylactic transfusion reaction. If plasma is required and the patient is not IgA-deficient, allergic reactions may be less with solvent/detergent treated plasma (S/D plasma) [68]. Washing RBCs and platelet products also reduces the likelihood of allergic transfusion reactions [50].

If the previous anaphylactic transfusion reaction is proven to be due to anti-IgA antibodies, blood products from IgA-deficient donors may be used [69-71]. IgA-deficient blood products can be obtained through large regional blood centers. Immune globulin products such as intravenous immune globulin (IVIG) with low IgA levels are also available. (See "Selective IgA deficiency: Management and prognosis", section on 'Safe administration of blood products'.)

HEMOLYTIC TRANSFUSION REACTIONS — Hemolytic transfusion reactions (HTRs) are characterized by immune-mediated red blood cell (RBC) destruction (hemolysis). They can be acute (during or within 24 hours after a transfusion) or delayed (days to weeks after a transfusion); and the hemolysis can be intravascular (releasing free hemoglobin into the circulation) or extravascular (resulting in removal of RBCs by the reticuloendothelial system) (figure 1).

These reactions are reviewed briefly here and discussed in much greater detail separately. (See "Hemolytic transfusion reactions".)

●AHTR – Acute HTRs (AHTRs) are hemolytic reactions that occur during the transfusion or within 24 hours of completing the transfusion [1,72]. AHTRs are typically associated with rapid intravascular hemolysis, which can lead to acute kidney injury (AKI), disseminated intravascular coagulation (DIC), and hemodynamic collapse. The classic AHTR is a medical emergency requiring immediate intervention. Typical symptoms and findings include fever, chills, back or chest pain, and pink/red serum, plasma or urine, although the full "classic triad" of fever, flank pain, and red urine is rarely seen [1,73]. In a patient under anesthesia or in a coma, evidence of DIC (oozing from intravenous catheter sites) or hematuria may be the only findings. Additional laboratory evaluation will show evidence of hemolysis.

AHTRs are most commonly seen in the setting of ABO blood group incompatibility due to a clerical or procedural error (transfusion of the wrong product); this will become apparent upon clerical check and laboratory testing. 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.

Additional details of the pathophysiology, evaluation, and management of AHTR is presented separately. (See "Hemolytic transfusion reactions", section on 'Acute hemolytic transfusion reactions'.)

●DHTR and DSTR – Delayed HTRs (DHTRs) are hemolytic reactions that occur more than 24 hours after completing the transfusion [1,74]. DHTRs are typically gradual and less severe. Laboratory findings may include a mild increase in anemia (or failure of the hemoglobin to increase as expected after transfusion) and evidence of extravascular hemolysis, which may include spherocytes on the peripheral blood smear. DHTRs almost always result from an anamnestic response following re-exposure to a foreign RBC antigen such as one from the Kidd or Rh system. Previous exposure may have occurred through transfusion or pregnancy. The Centers for Disease Control and Prevention (CDC) Biovigilance Network in the United States criteria for a DHTR require a positive DAT between 24 hours and 28 days after the transfusion, identification of the RBC antibody in the serum or eluate, and symptoms [1]. DHTRs generally do not require any treatment except for future avoidance of transfusions containing the implicated RBC antigen. If a DHTR is accompanied by more brisk hemolysis, more aggressive treatment may be required, similar to an AHTR.

Delayed serologic transfusion reactions (DSTRs) are identical to DHTRs except that 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 [1].

DHTRs and DSTRs are discussed in more detail separately. (See "Hemolytic transfusion reactions", section on 'Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions'.)

TRANSFUSION-RELATED ACUTE LUNG INJURY — Transfusion-related acute lung injury (TRALI) is a life-threatening form of acute lung injury that occurs when recipient neutrophils are activated by the transfused product (often due to either antibodies directed against HLA or neutrophils) in an appropriately primed pulmonary vasculature. Presenting findings include fever, chills, and respiratory distress. Therapy is largely supportive and may include intubation and mechanical ventilation. A subsequent evaluation is directed at identifying an implicated donor so that individual does not continue to donate due to the possible risk of TRALI in other recipients. (See "Transfusion-related acute lung injury (TRALI)".)

An individual with previous TRALI can receive blood products from other donors without restrictions but should not receive any remaining untransfused portion of the implicated product or any other products from the implicated donor. No other transfusion recipients should receive split blood products from the implicated donor until TRALI has been excluded.

POST-TRANSFUSION PURPURA

Prevalence and mechanisms of post-transfusion purpura — Post-transfusion purpura (PTP) is an extremely rare transfusion reaction. Data are limited, but the incidence has been estimated to be approximately 1 in every 50,000 to 100,000 transfusions [75]. The United Kingdom Serious Hazards of Transfusion (SHOT) data document approximately one to three cases reported per year; this is a reduction from 9 to 11 cases per year prior to the implementation of universal leukoreduction [76].

PTP occurs primarily in individuals sensitized to platelet antigens by exposure during pregnancy or transfusion; the female-to-male ratio is approximately 26:1 [77,78]. Red blood cells (RBCs) are most commonly implicated, but PTP can be seen with transfusion of any platelet-containing product, including RBCs, platelets, fresh (but not frozen) plasma, or granulocytes [75,78].

PTP can be thought of as a delayed transfusion reaction involving platelets, in which an anamnestic response to a previously encountered foreign platelet antigen leads to an increase in production of anti-platelet antibodies by the recipient. The antigen most commonly implicated is the platelet antigen PlA1, now known as human platelet antigen 1a, (HPA-1a) [79]. Unlike a delayed hemolytic reaction, however, these antibodies cause destruction of both the PlA1-positive transfused platelets as well as bystander destruction of the patient's own PlA1-negative platelets, leading to thrombocytopenia. The mechanism by which the antibodies destroy the recipient's own platelets lacking the antigen is not well understood. Possibilities include adsorption of immune complexes onto the patient's own platelets, which are then destroyed, passive acquisition of the antigen from donor plasma, or elaboration of a new autoantibody to another platelet antigen.

Approximately 97 to 99 percent of individuals are PlA1 positive [80]. An individual lacking the antigen can be sensitized during pregnancy (ie, upon exposure to the antigen on fetal platelets) or by prior transfusion. Of note, PlA1 is also the antigen system most commonly implicated in neonatal alloimmune thrombocytopenia. (See "Neonatal immune-mediated thrombocytopenia", section on 'Neonatal alloimmune thrombocytopenia'.)

An alternative and even rarer syndrome leading to post-transfusion thrombocytopenia has been reported, in which the recipient of a plasma-containing blood product such as Fresh Frozen Plasma (FFP) develops severe thrombocytopenia, which may be accompanied by bleeding and an acute transfusion reaction, caused by the passive transfer of anti-platelet antibodies (eg, anti-HPA-1a/PlA1) from a previously immunized donor [81]. The time-course is much more rapid than PTP; thrombocytopenia due to passive antibody transfer occurs in hours rather than days, and recovery typically occurs within five days. Implicated donors are females with a history of pregnancy; these donors should be deferred from subsequent donations.

Clinical presentation and diagnosis of post-transfusion purpura — Patients with PTP can present with severe thrombocytopenia (with platelet counts ≤20,000/microL), which is sufficient to cause purpura, petechiae, and clinically significant bleeding. For PTP caused by an alloantigen on the transfused platelets, the onset is approximately 5 to 12 days following transfusion, and the thrombocytopenia often lasts for days to weeks [1]. For thrombocytopenia caused by passive transfer of an antiplatelet antibody, the onset is within hours, and recovery is within several days [81].

If a patient with unexplained thrombocytopenia has received a transfusion in the previous one to two weeks, efforts should be made to confirm or exclude the diagnosis of PTP. The diagnosis is confirmed by demonstrating a circulating alloantibody to a common platelet antigen, most often HPA-1a/PlA1, and lack of this antigen on the patient's own platelets [82]. However, specific tests to determine the platelet antigenic composition and/or the presence of anti-platelet antibodies may not be readily available, and it may be necessary to contact a specialty laboratory (such as Versiti) to obtain this testing [83].

The differential diagnosis of PTP includes other immunologically mediated forms of thrombocytopenia, including immune thrombocytopenia (ITP), acquired autoimmune thrombotic thrombocytopenic purpura (TTP), and drug-induced thrombocytopenia. Like PTP, these conditions are associated with hallmarks of immune platelet destruction such as severe thrombocytopenia, occasional large platelets on the blood smear, and increased megakaryocytes in the bone marrow (if tested). Unlike PTP, these other thrombocytopenias rarely have a temporal relationship to a transfusion. (See "Immune thrombocytopenia (ITP) in adults: Clinical manifestations and diagnosis" and "Drug-induced immune thrombocytopenia".)

Treatment and prevention of PTP — The preferred therapy for PTP is intravenous immune globulin (IVIG) in high doses (400 to 500 mg/kg per day), usually for five days; alternatively, 1 g/kg per day for two days can be given for severe thrombocytopenia [84-86]. It usually takes approximately four days for the platelet count to exceed 100,000/microL [84,85].

High-dose glucocorticoids have been useful in some patients with PTP, as has exchange transfusion; however, both of these treatments take two or more weeks to act and have side effects (eg, alterations in blood glucose, infectious risk); therefore, these are not our preferred therapies.

HPA-1a/PlA1-negative patients diagnosed with PTP who require subsequent transfusion should receive blood products from an HPA-1a/PlA1-negative donor or RBCs that are washed to remove contaminating HPA-1a/PlA1-positive platelets [87].

The transfusion of HPA-1a/PlA1-negative platelets is generally not effective during the acute episode because most platelets (even antigen-negative platelets) are destroyed [88]. However, for patients who require a transfusion in the acute setting, avoidance of HPA-1a/PlA1-positive components is prudent because it will limit the exposure to immunogenic antigens and may prevent additional allosensitization.

TRANSFUSION-RELATED IMMUNOMODULATION (TRIM) — TRIM refers to the immunosuppressive activity of allogeneic blood, which has been evaluated since studies on kidney allograft survival were published in the 1970s. Increasing attention has been directed towards the impact of the immunosuppressive effect of allogeneic blood (particularly the leukocyte component) on postoperative infection, tumor recurrence, and nosocomial infection in critically ill patients [89,90]. The evidence that postoperative infection is increased in patients receiving allogeneic blood during surgery is compelling, though not absolute [91-99]. The same is true for the data implicating the leukocyte as the "culprit" [98,100,101].

Several meta-analyses have been performed using slightly different approaches and have yielded conflicting results [102-104]. There is insufficient evidence to recommend routine use of leukocyte-reduced blood as a way to decrease the risk of postoperative infections. Other benefits of leukoreduction are presented separately. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Pre-storage leukoreduction'.)

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

●Initial steps – Many acute immunologic transfusion reactions can present with fever and/or respiratory symptoms. The table lists distinguishing findings (table 1); the algorithm depicts initial evaluation and interventions (algorithm 1), including immediately stopping the transfusion and maintaining a patent intravenous line. (See "Approach to the patient with a suspected acute transfusion reaction".)

●FNHTRs – Febrile nonhemolytic transfusion reactions (FNHTRs) are caused by white blood cells or cytokines in the transfused product. FNHTRs typically present with fever and/or chills. The diagnosis is made clinically by excluding other causes of these symptoms. Management is supportive. Pre-storage leukoreduction reduces the risk of an FNHTR. (See 'Febrile nonhemolytic transfusion reactions' above.)

●Allergic reactions – Minor allergic reactions present with hives and/or urticaria without systemic manifestations. These reactions are quite common and are one of the few reactions in which the remainder of the blood product can be administered; this should only be done after the transfusion has been temporarily stopped and the reaction has resolved, with diphenhydramine if necessary. Data do not support the use of diphenhydramine premedication to prevent allergic reactions. (See 'Allergic reactions' above.)

●Anaphylactic reactions – Anaphylactic transfusion reactions are severe allergic reactions caused by sudden massive systemic release of mediators such as histamine and tryptase in response to an IgE (or IgG)-mediated immune response. They often occur within minutes of starting the transfusion and may present with wheezing, angioedema, and hypotension. These reactions are rare but potentially life-threatening and must be treated immediately, with stopping the transfusion, administering epinephrine, and providing hemodynamic and respiratory support, as described for adults (table 2) and children (table 3). (See 'Anaphylactic transfusion reactions' above.)

●Hemolytic reactions – Hemolytic transfusion reactions (HTRs) involve immune-mediated hemolysis. They can be acute (AHTR; during or within 24 hours after transfusion) or delayed (DHTR; days to weeks after a transfusion). AHTRs are usually due to ABO incompatibility following a clerical/procedural error and are associated with intravascular hemolysis, which can be life-threatening. DHTRs are usually due to an anamnestic response to a previously encountered RBC antigen (through prior transfusion or pregnancy) and are often mild. Delayed serologic transfusion reactions (DSTRs) are similar to DHTRs except that the recipient is asymptomatic and the reaction is identified retrospectively during pretransfusion testing in the blood bank. The implicated RBC antigen should be avoided in future transfusions. (See 'Hemolytic transfusion reactions' above.)

●Transfusion-related acute lung injury — Transfusion-related acute lung injury (TRALI) is a life-threatening form of acute lung injury that occurs when recipient neutrophils are activated by the transfused product. Presenting findings include fever, chills, and respiratory distress. Therapy is largely supportive and may include intubation and mechanical ventilation. A subsequent evaluation is directed at identifying an implicated donor so that individual does not continue to donate due to the risk of TRALI in other recipients. (See "Transfusion-related acute lung injury (TRALI)".)

●Post-transfusion purpura – Post-transfusion purpura (PTP) is an extremely rare transfusion reaction in which the recipient has an anamnestic response with increased production of an anti-platelet alloantibody. This is similar to a DHTR, but the thrombocytopenia can be quite severe due to bystander destruction of the patient's own platelets that lack the alloantigen. Therapy involves high dose intravenous immune globulin (IVIG); platelet transfusion may also be required for severe bleeding or severe bleeding risk. (See 'Post-transfusion purpura' above.)

ACKNOWLEDGMENT — We are saddened by the death of Arthur J Silvergleid, MD, who passed away in April 2024. The UpToDate editorial staff gratefully acknowledges the extensive contributions of Dr. Silvergleid to earlier versions of this and many other topic reviews.