INTRODUCTION — Transfusions can be lifesaving for patients with severe anemia, thrombocytopenia, or deficiency of plasma components. However, allogenic blood cells and plasma proteins are foreign substances that can elicit an immune response in transfusion recipients, 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)".)

●Febrile nonhemolytic transfusion reactions (FNHTR) – (See "Leukoreduction to prevent complications of blood transfusion".)

●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 REACTIONS

Prevalence of FNHTR — Febrile nonhemolytic transfusion reactions (FNHTRs) are the most common of all transfusion reactions. They occur in approximately 0.1 to 1 percent of transfusions.

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 in children and 0.05 percent in adults [1].

●Blood product – FNHTRs can occur with any product; overall, they are equally likely from platelets and red blood cells, 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 white blood cells (WBCs) [2,3].

●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.

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 [4,5]. However, there is no evidence to support the use of prophylactic acetaminophen or antihistamines to prevent these reactions. (See 'Prevention of FNHTR' below.)

Prevention of FNHTRs and the benefits of leukoreduction in reducing the risk of FNHTR are discussed below and separately. (See 'Prevention of FNHTR' below and "Leukoreduction to prevent complications of blood transfusion".)

Mechanism of FNHTR — FNHTRs are commonly caused by cytokines that are generated and accumulate during the storage of blood components [6-9]. Implicated cytokines include interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor-alpha (TNFα).

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 [10].

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 [11]. 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 [6]. In another report, the mean IL-8 concentration increased 100-fold between days 2 and 5 of storage and rose further with continued storage [8].

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 [12,13]; however, such antibodies are not always found.

●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 [14-17].

Clinical presentation and diagnosis of FNHTR — Clinical manifestations of FNHTR occur within one to six hours after initiation of a transfusion; 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). The temperature increase is typically in the range of 1 to 2°C. A temperature increase of <1°C is not considered clinically significant, while an increase of >2°C is more suggestive of an acute hemolytic or septic transfusion reaction, providing that a non-transfusion-related infection can be excluded.

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. As an example, a patient with fever, hypotension, and back pain should have a full evaluation for hemolytic transfusion reaction and possibly sepsis, whereas an individual with isolated mild fever may have a physical examination, clerical check of the transfusion, and visual inspection of the blood product.

●Other transfusion reactions associated with fever include acute hemolytic reactions and sepsis. Unlike FNHTRs, individuals with acute hemolysis are acutely ill and have free hemoglobin in blood and urine or red or dark colored serum and urine. Unlike FNHTRs, individuals with sepsis are 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.

●Other transfusion reactions associated with dyspnea include transfusion-associated circulatory overload (TACO), transfusion-related acute lung injury (TRALI) and anaphylactic reactions. Dyspnea is a major finding in these reactions, whereas it is generally mild or absent in a FNHTR. Unlike FNHTRs, individuals with TACO and TRALI have evidence of pulmonary edema on physical examination and chest radiography (table 2), and individuals with anaphylactic reactions have wheezing and sometimes other findings such as hypotension or angioedema.

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:

●Stopping of the transfusion.

●Administration of antipyretics if the fever is bothersome to the patient.

●Evaluation for other causes of fever, which include more serious (and potentially life-threatening) transfusion reactions as well as non-transfusion-related infection or fever.

●Hospital admission (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 with functional asplenia from sickle cell disease).

●Administration of other medications, if needed, such as meperidine (25 to 50 mg) for severe chills or rigors, which may characterize any FNHTR but are most often precipitated by a granulocyte transfusion.

Prevention of FNHTR — The major means of preventing FNHTRs is pre-storage leukoreduction of the product (removing most of the white blood cells by passing the cellular blood products through a filter shortly after the collection, or using an apheresis collection technology with effective leukoreduction), as discussed in detail separately. (See "Leukoreduction to prevent complications of blood transfusion".)

We do not use premedications (eg, diphenhydramine, acetaminophen) to decrease the incidence of FNHTRs, as they are ineffective and may cause adverse events on their own such as cardiovascular symptoms and central nervous system alterations. The lack of benefit was highlighted in a 2019 meta-analysis that evaluated the rates of FNHTR with premedication versus placebo or no treatment; this analysis found no benefit from premedication in preventing these reactions [18]. The meta-analysis identified three randomized trials that included 4444 transfused units (approximately half red blood cells and half platelets) in 517 individuals (most of whom received more than one transfusion). The largest trial included 315 hematology-oncology patients [19].

All blood products used in the trials in the meta-analysis were leukoreduced [18]. Nonhemolytic reactions occurring within 4 hours of transfusion were seen in approximately one-fifth of patients (approximately 2.5 percent of transfusions), regardless of whether the patient received premedication with diphenhydramine and acetaminophen. 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. Patients with a history of a nonhemolytic transfusion reaction also did not have a statistically significant reduction with premedication, but numbers were too small to reach firm conclusions in this subpopulation.

An earlier review came to similar conclusions regarding the lack of efficacy of premedication [20].

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".)

ANAPHYLACTIC TRANSFUSION REACTIONS

Prevalence and mechanisms of anaphylactic reactions — Anaphylactic transfusion reactions are rare, with an estimated incidence of 1 in 20,000 to 1 in 50,000 [21,22].

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 about 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 [23,24].

●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 [25,26]. Some of these reactions may be due to hypersensitivity to ethylene oxide or other substances used to sterilize components of the apheresis kit [27]. 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 [28].

●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 [29]. 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 [30,31].

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 urticarial transfusion reactions (see 'Urticarial (allergic) reactions' below) including pruritus, urticaria, and flushing.

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, TRALI, 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 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 (see 'Treatment and prevention of anaphylactic reactions' below), 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. Similarly, a chest radiograph could help distinguish between pulmonary edema and bronchospasm if these cannot be differentiated clinically.

Treatment and prevention 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 3) and children (table 4).

Major interventions include the following:

●Immediate cessation of the transfusion

●Epinephrine, 0.3 mL of a 1:1000 solution intramuscularly (adult dose)

●Resuscitation of hypotensive patients with intravenous fluids

●Preparation, for possible administration, of an intravenous epinephrine drip (table 5)

●Airway maintenance, oxygenation

●Vasopressors (eg, dopamine), if necessary

Of note, epinephrine should be administered even if the patient has a known coagulation abnormality or thrombocytopenia, because the benefit of this lifesaving intervention outweighs the small potential risk of intramuscular bleeding [32]. Additional information is presented separately. (See "Anaphylaxis: Emergency treatment".)

Prevention of anaphylactic transfusion reactions consists of establishing the diagnosis after the fact and avoiding future exposures. The blood center that obtained the component should be notified so that appropriate actions can be taken (eg, removal of the donor from the donor pool if indicated, extra washing of RBC or platelet products).

If the reaction is proven to be due to anti-IgA antibodies, IgA-deficient blood products may be used [33-35]. IgA-deficient blood products can be obtained through large, regional blood centers. IVIG products with low IgA levels are also available. (See "Selective IgA deficiency: Management and prognosis", section on 'Safe administration of blood products'.)

URTICARIAL (ALLERGIC) REACTIONS

Prevalence and mechanisms of urticarial reactions — Urticarial (allergic) reactions, characterized by hives without other allergic findings, are one of the most common transfusion reactions, although the true prevalence is unknown because these are likely to be underreported. They are seen in as many as 1 to 3 percent; use of premedications has not appeared to change this incidence [20].

Urticarial transfusion reactions occur when a soluble substance in the plasma of the donated blood product (or the recipient) reacts with pre-existing IgE antibodies in the recipient (or the product), respectively. Urticarial reactions are thought to be due to mast cell or basophil release of histamine, although other mechanisms may be involved. (See "New-onset urticaria".)

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 not known whether certain mediators are specific for anaphylaxis.

A commonly cited example of urticarial reactions is donor peanut allergy, with hives in the recipient triggered by recent peanut ingestion by the recipient [36-38]. The converse (recipient peanut allergy, with peanut antigen in the donated product) has also been described.

Non-antibody mechanisms have also been proposed. As an example, a study compared inflammatory mediators in 20 apheresis products associated with allergic transfusion reactions versus apheresis platelet products that did not cause allergic reactions [39]. The platelet products associated with urticarial transfusion reactions had levels of the direct allergic agonists C5a, brain-derived neurotrophic factor (BDNF), and CCL5 (RANTES) that were 17, 42, and 14 percent higher than the control platelet products [39].

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

Urticarial reactions are diagnosed clinically when a patient develops hives or urticaria without progression to more severe symptoms, such as those that suggest an anaphylactic reaction. (See 'Clinical presentation and diagnosis of anaphylactic reactions' above.)

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

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

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

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

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

Rarely, an urticarial 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 'Anaphylactic transfusion reactions' above.)

Two small studies suggest that urticarial reactions to platelets can be decreased by washing pooled whole blood-derived platelets and apheresis platelets [40,41]. In a retrospective cohort study of 179 individuals who first received unmanipulated platelets, and subsequently received platelets from which plasma had been removed by concentrating or washing them, the incidences of allergic transfusion reactions declined from 5.5 percent for the unmanipulated platelets to 1.7 and 0.5 percent for the concentrated and washed platelets, respectively [42].

These manipulations (removal of plasma, washing) should only be used for patients who experience severe or repeated urticarial reactions that cannot otherwise be prevented. It is appropriate to try concentrating the implicated cells (RBCs or platelets) first (by removing plasma) and only washing the cells if plasma removal does not prevent the urticarial reactions.

Unlike anaphylactic reactions, urticarial reactions generally are not pursued back to the blood center that obtained the blood component.

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. AHTRs are typically associated with rapid intravascular hemolysis, which can lead to acute renal failure, 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. In a patient under anesthesia or in a coma, evidence of DIC (oozing from intravenous catheter sites) may be the only finding.

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. If a clerical error is identified, it is critical to notify the transfusion service or hospital blood bank as quickly as possible to prevent another transfusion of the wrong product to another patient (if two patients' products were switched). Additional laboratory evaluation will show evidence of hemolysis.

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

●DHTR – Delayed HTRs (DHTRs) are hemolytic reactions that occur more than 24 hours after completing the transfusion. Often, they occur days to weeks later. DHTRs are typically gradual and less severe; sometimes they are clinically silent. 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. 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 (ie, as for AHTR). DHTRs are discussed in more detail separately. (See "Hemolytic transfusion reactions", section on 'Delayed hemolytic transfusion reactions and delayed serologic transfusion reactions'.)

On rare occasions, a DHTR is accompanied by hemolysis of the patient's own RBCs, a condition termed "hyperhemolysis" or hyperhemolytic crisis. This phenomenon has been seen most often in multiply-transfused patients with sickle cell disease, but it has also been reported in patients with thalassemia and in other settings [43]. The mechanism by which such "bystander hemolysis" occurs is not known. This complication and its management are discussed separately. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Hyperhemolytic crisis' and "Hemolytic transfusion reactions", section on 'Management of DHTR and DSTR'.)

POST-TRANSFUSION PURPURA

Prevalence and mechanisms of post-transfusion purpura — Post-transfusion purpura (PTP) is an extremely rare transfusion reaction, with only approximately 250 cases reported. PTP occurs primarily individuals sensitized to platelet antigens by exposure during pregnancy or transfusion; the female-to-male ratio is approximately 26:1 [44,45]. PTP most commonly occurs after exposure to foreign red blood cells (RBCs) but it can be seen with transfusion of any platelet-containing product, including RBCs, platelets, fresh (but not frozen) plasma, or granulocytes [45].

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) [46]. 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 [47]. 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 [48]. 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 10 days following transfusion, and the thrombocytopenia often lasts for days to weeks. For thrombocytopenia caused by passive transfer of an antiplatelet antibody, the onset is within hours, and recovery is within several days [48].

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 [49]. 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 the Blood Center of Wisconsin) to obtain this testing.

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 [50-52]. It usually takes about four days for the platelet count to exceed 100,000/microL [50,51].

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 [53].

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 [54]. 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.

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 of the acute immunologic transfusion reactions can present with fever and/or respiratory symptoms. The table lists distinguishing findings (table 1); the algorithm illustrates features of the immediate evaluation and interventions (algorithm 1), which include immediately stopping the transfusion and maintaining a patent intravenous line. A thorough discussion of our approach is presented separately. (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. FNHTR typically presents with fever and/or chills. The diagnosis is made clinically by excluding other causes of these symptoms, and management is supportive. Pre-storage leukoreduction reduces the risk of FNHTR. We do not use premedications as they are ineffective and may cause adverse events on their own. (See 'Febrile nonhemolytic reactions' above.)

●HTRs – Hemolytic transfusion reactions (HTRs) are characterized by immune-mediated red blood cell (RBC) destruction (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 or clinically silent. The implicated RBC antigen should be avoided in future transfusions. These reactions are discussed in much greater detail separately. (See "Hemolytic transfusion reactions".)

●Anaphylactic reactions – Anaphylactic transfusion reactions are rare 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 transfusion and may present with wheezing, angioedema, and hypotension. These reactions are potentially life-threatening and must be treated with immediate stopping of the transfusion and administration of epinephrine, as well as hemodynamic and respiratory support, as described in the tables for adults (table 3) and children (table 4). (See 'Anaphylactic transfusion reactions' above.)

●Allergic reactions – Allergic reactions characterized by isolated hives and/or urticaria but no systemic manifestations, are quite common, and are due to mild release of mediators. These are one of the few reactions in which the remainder of the blood product can be administered; but this should only be done after the transfusion has been temporarily stopped and the reaction has resolved, with administration of diphenhydramine if necessary. (See 'Urticarial (allergic) reactions' above.)

●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 delayed hemolytic transfusion reaction, but the thrombocytopenia can be quite severe, since there is bystander destruction of the patient's own platelets that lack the alloantigen. Therapy is with intravenous immune globulin (IVIG) in high doses; platelet transfusion may also be required for severe bleeding or severe bleeding risk. (See 'Post-transfusion purpura' above.)