Critical Care Medicine

Transfusion reactions

Transfusion Reactions

Also known as

AHTR (acute hemolytic transfusion reaction)

DHTR (delayed hemolytic transfusion reaction)

FNHTR (febrile non-hemolytic transfusion reaction)

TRALI (transfusion-related acute lung injury)

TACO (transfusion-associated circulatory overload)

TA-GVHD (transfusion-associated graft-vs-host disease)

1. Description of the problem

What every clinician needs to know

  • Transfusion reactions (TRs) are defined as any unexpected patient sign or symptom during or following the transfusion of a blood product.

  • TRs may be acute (within 24 hours of transfusion) or delayed (days/weeks); immune or non-immune mediated.

  • TRs may be clinically insignificant (febrile non-hemolytic TR), mild (allergic TR), or potentially fatal (acute hemolytic TR, transfusion-related acute lung injury, septic TR, anaphylactic TR).

  • The type of TR is related to the type of blood component administered.

  • The key to proper patient management is recognition of a possible TR, immediate discontinuation of transfusion, stabilizing/monitoring the patient, and following hospital protocol for laboratory work-up/confirmation.

Clinical features

A TR should be suspected whenever a transfused patient experiences:

  • Significant change in baseline blood pressure or heart rate during or within hours following a transfusion

  • New onset of fever or temperature rise >2 degrees Fahrenheit

  • Chills with or without rigors

  • Chest, flank, abdominal, or back pain

  • Hives, rash, flushing, pruritus

  • Respiratory distress, including wheezing, coughing

  • New or increased oxygen requirement

  • Nausea and/or vomiting

  • Pain at infusion site

  • Oliguria or anuria

  • Hemoglobinemia and/or hemoglobinuria

Signs/symptoms depend on type of TR

  • Acute TR (within 24 hours of transfusion)

    • RBCs mismatched for ABO blood group system may lead to acute hemolysis characterized by one, a few, or all of the symptoms listed above (acute hemolytic TR).

    • Contaminating WBCs in RBC and platelet units may release cytokines and result in an isolated elevation in temperature (febrile non-hemolytic TR).

    • Allergy to donor plasma proteins in RBC, platelet, or FFP units can lead to skin manifestations and anaphylaxis (allergic or anaphylactic TR).

    • Donor antibodies to patient WBCs can lead to transfusion-related acute lung injury (TRALI) characterized by respiratory failure, hypoxemia, hypotension, fever, and bilateral pulmonary edema.

    • Bacterial contamination of blood products can cause fever, chills, hypotension, and shock (transfusion-associated sepsis).

    • Circulatory fluid overload can lead to dyspnea, cough, tachycardia, and hypertension (transfusion-associated circulatory overload).

    • Massive transfusion of citrate anticoagulated blood products can lead to hypocalcemia characterized by paresthesias, tetany, and arrhythmias and subsequent metabolic alkalosis from citrate metabolism.

  • Delayed TR (>24 hours post-transfusion)

    • RBCs mismatched for non-ABO minor antigens may lead to new alloimmunization or anamnestic immune response characterized by low-grade fever, gradually decreasing hemoglobin, and mild jaundice (delayed hemolytic TR).

    • Viable donor lymphocytes in RBC or platelet products can engraft in susceptible patients and cause fever, erythroderma, maculopapular rash, anorexia, nausea/vomiting, diarrhea, hepatitis, and pancytopenia (transfusion-associated graft-vs-host disease).

Key management points

  • Management of all acute TRs includes stopping the transfusion and treating patient symptoms.

  • Initial patient evaluation should focus on vital signs and breath sounds, examination of skin for evidence of urticaria, and urinalysis for hemoglobinuria to determine the likelihood of a potentially serious transfusion reaction versus a mild allergic reaction or simple febrile reaction.

  • A reaction determined to be a mild allergic reaction is the only scenario in which continuation of transfusion is permitted, provided symptoms have resolved following treatment and the blood administration set has NOT been disconnected from patient or from blood product.

  • Any acute reaction other than a mild allergic reaction should follow emergency management approach below.

2. Emergency Management

If medical evaluation of the patient indicates that there is a reasonable likelihood that the patient is experiencing a TR, the following steps must be taken:

  • Stop the transfusion and maintain IV access to facilitate fluid support if necessary. Do not allow remaining blood in the microaggregate filter and tubing to be infused.

  • Provide supportive care to patient while initiating a TR workup. Such workups should follow hospital policy and will generally include:

    • Performing a clerical check across patient, blood component(s), paperwork, etc. to identify potential patient identification error as the cause of the TR

    • Contacting the hospital transfusion service for proper procedure for returning remaining untransfused blood product with associated tubing set, documentation of event, and post-transfusion blood samples required for blood bank laboratory analysis

    • Collecting additional patient specimens depending on the type of suspected TR and sending to the appropriate clinical laboratories for analyses. This will generally include a freshly voided urine sample to assess for hemoglobinuria.

3. Diagnosis

Diagnostic criteria and tests

In addition to evaluating patient signs and symptoms in the context of the particular type of blood component transfused, workup by the blood bank/transfusion service and other clinical laboratories may help rule in or rule out the transfusion as the cause of the patient’s signs/symptoms.

Upon receipt of the remaining untransfused blood product and post-transfusion blood sample, the blood bank/transfusion service will carry out some or all of the following:

  • Examining blood component bag, labels, and paperwork to rule out clerical error by either the transfusionist or laboratory

  • Repeating ABO testing of the post-transfusion blood sample and comparison with pre-transfusion sample to rule out ABO blood group mismatch

  • Centrifuging post-transfusion sample and examining plasma by eye for evidence of hemolysis/icterus and comparison with pre-transfusion sample (sensitive enough to detect the lysis of as little as 2.5 ml of RBCs)

  • Performing a direct antiglobulin test (DAT or direct Coombs test) to detect presence of IgG or complement C3d fragment on RBCs in post-transfusion blood sample. If positive, DAT would be performed on pre-transfusion sample for comparison and if negative, diagnosis of hemolytic TR supported.

  • Performing additional serologic tests, if indicated, including repeat patient antibody screen and repeat antigen typing of donor units and crossmatching (if RBC transfusion) with post-transfusion sample

Additional findings that may aid in the diagnosis of a suspected TR include:

  • Elevated serum unconjugated bilirubin, elevated serum LDH, and/or hemoglobinuria (consistent with hemolytic TR)

  • Positive gram stain or positive bacterial culture of sample of remaining untransfused blood product (transfusion-associated sepsis)

  • Abnormally low ionized calcium (citrate toxicity from massive transfusion)

  • Chest X-ray showing new bilateral pulmonary edema (TRALI)

  • Elevated brain natriuretic peptide (BNP) to aid in distinguishing pulmonary edema secondary to CHF from that due to TRALI (controversial practice due to overlap of “normal” and elevated levels)

It should be appreciated that as often as 50% of the time, the onset of symptoms during a transfusion (e.g., fever, dyspnea, unstable vital signs, pain) is due to the patient’s underlying disease and coincidental to the transfusion. However, the transfusionist should not hesitate to terminate a transfusion and initiate a TR workup if there is any concern that the patient’s symptoms may be related to the transfusion.

Confirmatory tests

In addition to tests performed in the immediate setting of a suspected TR, subsequent follow-up testing may help confirm the diagnosis and be used to prevent future TRs:

  • For suspected non-ABO immune hemolysis: Can repeat serologic testing to search for patient antibodies to low-frequency antigens not initially picked up by routine serum antibody screening. RBCs with such phenotypes can be avoided in the future.

  • For suspected transfusion-related anaphylactic reaction: Can test patient for IgA deficiency and presence of preformed IgE anti-IgA antibodies so that future blood products will represent only those collected from IgA-deficient donors

  • For suspected transfusion-transmitted sepsis: If gram stain of remaining untransfused blood product is negative, await results of blood product culture and blood culture of patient. If positive, blood supplier will be alerted in order to recall other blood components derived from same donor collection.

  • For suspected TRALI: Can report implicated blood units to blood supplier to test donors for anti-HLA antibodies. If positive, determine patient’s HLA type and see if matches antibody specificity(ies). Implicated donors will be deferred from future donation.

  • For suspected TA-GVHD: Skin biopsy, HLA typing of donor/patient, and molecular analysis for chimerism

4. Specific Treatment and Follow-up for Major TRs

See Table I. Therapy and management of transfusion reactions

Table I.

Therapy and management of transfusion reactions
Type of TR Therapy FutureManagement
Acute Hemolytic Promote urine output > 1 ml/kg/hr with fluids and IV diureticsAnalgesics for painPressors for hypertensionDIC management, if necessary Bedside labeling of blood specimens for type and screenProper patient ID by transfusionists and laboratory personnel
Febrile Non-Hemolytic Antipyretic Antipyretic as premedication, though may mask symptoms of potentially serious hemolytic TRsExclusive use of pre-storage leukoreduced RBCs and platelets or use of bedside leukoreduction filters
Allergic Antihistamines (e.g., 25-50 mg IV diphenhydramine)May restart transfusion if symptoms resolveAddition of 50 mg oral prednisone for more severe reactions Usually idiosyncratic, but patients with recurrent reactions can be premedicated with diphenhydramine and 300 mg ranitidine, though use of premedications can mask symptoms of potentially serious hemolytic TRs
Anaphylactic Trendelenburg positioning, fluids, epinephrine (adult dose: 0.2-0.5 ml 1:1000 SC or IM; or 1:10,000 IV, initial rate 1 μg/min if severe); antihistamines, corticosteroids, β2 agonists If follow-up testing shows patient to be IgA deficient with anti-IgA antibodies, then use blood products collected from IgA-deficient donors
Transfusion-Related Acute Lung Injury (TRALI) Supportive care until recovery Identify implicated blood donors and defer from future donation
Transfusion-Associated Sepsis Broad-spectrum antibiotics until sensitivity testing completed Better methods for eliminating/detecting bacteria in banked blood components
Transfusion-Associated Circulatory Overload (TACO) Upright posture, O2; IV diuretic (furosemide) Judicious use of transfusion in particularly susceptible patients (e.g., those with CHF)Transfuse slowly
Citrate Toxicity (massive transfusion) IV calcium gluconate/chloride while following ionized Ca2+
Transfusion-Associated GVHD Corticosteroids; cytotoxic agents γ-irradiation of all cellular blood products administered to at-risk immunocompromised patients

Pathophysiology

Except for TRs that are not specific to the transfused product, such as hypocalcemia from the infusion of citrate or circulatory overload from the infusion of too much fluid too rapidly, TRs are generally caused by cellular and/or humoral interactions between the transfused product and the recipient.

In some cases, the reaction is initiated by antibodies derived from the patient (ABO blood group antibodies directed against transfused RBCs; WBC antibodies directed against contaminating donor WBCs; IgE antibodies directed against donor plasma proteins), by antibodies derived from the donor ("leukoagglutinins" directed against recipient granulocytes; ABO blood group antibodies directed against recipient RBCs), or by viable donor lymphocytes that engraft in recipient and lead to GVHD.

Acute hemolytic transfusion reaction (AHTR)

  • Nearly always the result of an ABO blood group mismatch due to clerical/patient identification error

  • Naturally occurring IgM anti-A, anti-B (or both) antibodies present in the serum of blood group B, A, or O patients bind to mismatched A, B, or AB red cells, activating complement and causing brisk intravascular hemolysis, hemoglobinemia, and hemoglobinuria.

  • Complement activation also produces anaphylatoxin C5a, which, along with C3a, promotes release of histamine and serotonin from mast cells. This can lead to vasodilation and smooth muscle contraction in bronchus and intestines.

  • Anaphylatoxins also stimulate release of cytokines (TNF-α, IL-1), leukotrienes, free radicals, and nitric oxide from monocytes, macrophages, endothelial cells, platelets, and smooth muscle. This can lead to wheezing, flushing, chest pain/tightness, and GI symptoms.

  • Antigen/antibody complexes can also cause release of bradykinin, norepinephrine, and activation of intrinsic pathway of coagulation resulting in activation of Factor XII (Hageman factor). Hageman factor can also lead to bradykinin production, which can increase vascular permeability and cause vasodilation.

  • Activated complement, TNF-α, and IL-1 can increase expression of tissue factor, leading to activation of extrinsic coagulation pathway and DIC.

  • Shock may result from hypotension caused by release of vasoactive amines and kinins and produce a compensatory vasoconstrictive response damaging tissues.

  • Renal failure can result from free hemoglobin as well as compromised renal cortical supply, antibody/antigen complex deposition, vasoconstriction, and thrombus formation.

  • Non-ABO blood group cases of acute HTRs with intravascular hemolysis are usually associated with brisk anamnestic immune responses to the Kidd blood group antigen resulting in the formation of complement-fixing IgG.

Febrile non-hemolytic transfusion reaction (FNHTR)

  • Associated with the transfusion of blood products that contain leukocytes such as platelets and less frequently RBCs

  • Isolated rise in patient temperature results from release of cytokines (IL-2, IL-6, IL-8, and TNF-α) from (mostly) apoptotic WBCs.

  • Cytokine release may be enhanced when recipient has anti-leukocyte antibodies most commonly found in multiparous female and multiply transfused patients.

  • Incidence of these reactions has been greatly reduced through the use of either pre-storage leukoreduction at the time of collection by blood collection centers or bedside leukoreduction filters at the time of transfusion. Pre-storage leukoreduction is preferable as it can eliminate the build-up and subsequent infusion of cytokines liberated from WBCs during storage.

  • The vast majority of febrile non-hemolytic transfusion reactions are benign, although patients may experience significant discomfort and possibly hemodynamic/respiratory effects.

Allergic and anaphylactic reactions

  • Associated with patient antibodies (IgE) directed against soluble donor plasma proteins introduced by a plasma-containing blood product (RBC, platelet, FFP).

  • Actual protein antigen that causes the reaction is generally never identified and this type of reaction is often idiosyncratic and specific to a particular donor/recipient pair who are unlikely to cross paths again. Notable exception is pre-sensitized IgA-deficient patient who received plasma commonly containing IgA antibodies.

  • Most IgA-deficient hosts are not completely deficient in IgA and thus not at risk for anaphylaxis.

  • Blood products for sensitized IgA-deficient patients are those collected from IgA-deficient donors, though RBC products can be extensively washed in the blood bank. Washing IgA-positive platelet products is also possible but platelet loss and dysfunction can occur.

Transfusion-related acute lung injury (TRALI)

  • Associated with the passive transfusion of anti-granulocyte antibodies (HLA antibodies in particular), interleukins, biologically active lipids, or other “biological response modifiers” (BRMs).

  • Interaction of these substances with recipient granulocytes results in cellular activation, damage to pulmonary basement membrane, and leakage of protein-rich fluid into the alveolar space (a.k.a. non-cardiogenic pulmonary edema).

  • HLA Class I/Class II antibodies and human neutrophil-specific antibodies are often implicated. Purported BRMs may accumulate in transfusion products during blood bank storage and enhance PMN oxidative burst.

  • Best available evidence supports “two-hit” model: Predisposed patient (septic, post-surgical, post massive transfusion) endogenously produces biologically active compounds that activate pulmonary vascular endothelial cells priming neutrophils, which sequester in pulmonary microvasculature. Subsequent infusion of anti-granulocyte antibodies or BRMs provides second “hit” leading to pulmonary endothelial damage, capillary leakage, and pulmonary edema.

  • Approximately 80% of affected patients improve within 48 to 96 hours. Nearly 100% require O2 support and ~70% require mechanical ventilation. Remaining 20% will have protracted course or fatal outcome.

  • TRALI is not the result of an error, but the result of “bad luck” -- i.e., anti-HLA antibodies present in particular donor plasma match HLA type of patient.

  • Most effective strategy to date to reduce the incidence of TRALI has been the use of only male donors for the production of FFP as the incidence of HLA antibodies in female plasma is 11%, 23%, and 28% with 1, 2, and >= 3 pregnancies, respectively (in contrast to 0.9%, 1.2%, and 1.5% in nontransfused males, transfused males, and females who have never been pregnant, respectively). Currently, nearly all blood collection centers in the U.S. prepare FFP only from male donors and use female donors for plasma fractionation (e.g., albumin preparation). In some cases, female plasma is still used for the preparation of AB plasma as it is the rarest type of plasma (4% of donors) yet most needed (universal plasma donor type since no anti-A or anti-B isohemagglutinins).

Transfusion-associated septic reactions

  • Associated with bacterial contamination of blood products introduced at the time of blood collection from skin plugs or from transient bacteremia in donor.

  • Platelet products most often implicated because they are stored at room temperature vs. RBCs, which are stored refrigerated, and FFP, which is stored frozen.

  • Gram-positive bacteria are the most common cause of septic transfusion reactions, but products contaminated with gram-negative bacteria can cause the most serious reactions in part due to endotoxin.

  • Rarely are RBC products a cause of sepsis, but when they are, bacteria that grow well in the cold, such as Yersinia entercolitica, are the cause.

  • Incidence of fatal transfusion reactions due to bacterial contamination of blood products has decreased markedly due to the recent implementation of bacterial culturing of apheresis platelet products and the requirement that pooled whole blood-derived platelet products are tested for the presence of bacteria immediately prior to release from blood bank. In addition, current blood collection bags include a skin plug "diversion pouch" into which the first few mls of blood are diverted before donor blood enters main collection bag.

Transfusion-associated graft-vs-host disease (TA-GVHD)

  • Results from the engraftment of viable residual donor-derived passenger lymphocytes in a host whose immune system is unable to eliminate the lymphocytes

  • Typically begins 8 to 10 days after transfusion (range: 3 to 30 days)

  • Patients at risk include those with leukemia or lymphoma, patients receiving immunosuppressive drugs for transplant or myeloablative chemotherapy, patients with congenital immunodeficiency disorders, and the neonatal state.

  • Leukoreduction of RBC and platelet blood products (pre-storage or bedside) is not sufficient to remove enough of the contaminating viable lymphocytes to eliminate risk of TA-GVHD. Only γ-irradiation of cellular blood components can reliably ensure reduction of the number of viable lymphocytes to a level guaranteed to prevent TA-GVHD.

  • Mortality can approach 100% due to the severe pancytopenia that results.

  • TA-GVHD can also occur in immunocompetent patients, such as those in relatively inbred populations where there is an increased prevalence of donors homozygous at an HLA locus at which the recipient is heterozygous but share one allele. A unidirectional HLA mismatch occurs in which the recipient is unable to recognize the donor-derived passenger lymphocytes as foreign, whereas passenger lymphocytes can recognize nonshared HLA allele on recipient’s cells and initiate a graft-vs.-host reaction. This phenomenon is also a very important consideration when contemplating the use of direct donor blood from 1st-degree patient relatives. Such units should be γ-irradiated.

Epidemiology

See Table II. Incidence of transfusion reactions

Table II.

Incidence of transfusion reactions
Type of TR Incidence
Acute Hemolytic ABO/Rh mismatch 1:6,000 - 1:20,000Fatal: 1:100,000 - 1:600,000 of all RBC transfusions
Febrile Non-Hemolytic 0.1% - 1% since advent of pre-storage leukoreduction
Allergic 1% - 3%
Anaphylactic 1:20,000 - 1:50,000
Transfusion-Related Acute Lung Injury (TRALI) 1:5000 - 1:190,0005% - 10% fatality rate
Transfusion-Associated Sepsis RBC transfusion: 1:500,000; fatal 1:10,000,000Platelet transfusion: 1:75,000; fatal 1:500,000 since use of bacterial detection/culture and better blood collection procedures (skin plug diversion pouch)
Transfusion-Associated Circulatory Overload (TACO) <1%
Transfusion-Associated GVHD Rare

Special considerations for nursing and allied health professionals.

Since the majority of transfusions are carried out by nursing staff, it is essential that they be intimately familiar with specific hospital policies regarding the administration of blood products, the proper procedure for performing bedside clerical check of blood products with intended recipients, monitoring of patients during and after transfusion, recognition of possible transfusion reactions, and proper reporting and immediate management of possible reactions to transfusion.

Excellent lines of communication should exist between nursing, clinical staff and the transfusion service physicians and blood bank medical technologists.

What's the evidence?

Mazzei, C, Popovsky, M, Kopko, P, Roback, JD, Rae Combs, M, Grossman, BJ, Hillyer, CD. Technical Manual. American Association of Blood Banks. pp. 715-50.

(Provides a comprehensive description of the noninfectious complications of transfusion. It provides the incidence, mechanism, and treatment for these reactions.)

http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/TransfusionDonationFatalities/ucm204763.htm.

(This link on the FDA website provides a recent accounting and analysis of transfusion-associated fatalities broken down by type of FDA-reportable transfusion reaction.)

Davenport, RD. Semin Hematol. vol. 42. 2005. pp. 165-8.

(Reviews the pathophysiology of transfusion reactions.)

Alter, HJ, Klein, HG. Blood. vol. 112. 2008. pp. 2617-26.

(Reviews both infectious and non-infectious complications of blood transfusion with an historical perspective.)

Markiewski, MM, Nilsson, B, Ekdahl, KN, Mollnes, TE, Lambris, JD. Trends Immunol. vol. 28. 2007. pp. 184-92.

(Reviews the intersection between the complement pathway and coagulation pathway. Provides the mechanistic basis for understanding why complement fixation of RBCs leads to a massive reaction that includes activation of coagulation pathways, which eventually leads to DIC and bleeding.)

Gajic, O, Rana, R, Winters, JL, Yilmaz, M, Mendez, JL. Am J Respir Crit Care Med. vol. 176. 2007. pp. 886-91.

(Provides evidence for multiple risk factors for TRALI in addition to the presence of anti-HLA antibodies.)

Li, G, Daniels, CE, Kojicic, M, Krpata, T, Wilson, GA. Transfusion. vol. 49. 2009. pp. 13-20.

(Study that demonstrates that BNP levels are only slightly higher in patients with fluid overload vs. TRALI, limiting the utility of BNP.)

Vamvakas, EC, Blajchman, MA. Blood. vol. 113. 2009. pp. 3406-17.

(Summarizes the mortality associated from allogeneic blood transfusion using data collected by the FDA and the hemovigilance system in France and the U.K.)

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