Complications of Blood Transfusion - COLA

COLAFAST FACTS 301 of 3COMPLICATIONS OF BLOOD TRANSFUSION:DISCUSSION AND INVESTIGATIONIt is assumed the reader has a working knowledge of immunohematology. Requirements for COLA’sLaboratory Accreditation and Community Hospital Laboratory Accreditation programs are underlined foryour information.Every medical procedure bears potential benefits to thepatient as well as potential risks. These must be evaluatedwhenever transfusion of blood or blood components is considered.This COLA Fast Facts discusses various adverse effects ofblood transfusion, and suggest a protocol to be followedwhen a transfusion reaction occurs. However, eachimmunohematology laboratory should have its own policiesand procedures to investigate a transfusion reaction.The information in this publication is from generally recognizedauthorities, but does not constitute a comprehensivepractice of immunohematology and transfusion services.Immune-Mediated Transfusion ReactionsAcute HemolyticThe most severe reactions occur when transfused red bloodcells (RBCs) combine with recipient antibodies and lead toincreased RBC destruction. Most of these cases result fromtransfusion of ABO-incompatible red cells, and can be lifethreatening.Other RBC antibodies commonly identified ascausing acute hemolytic transfusion reactions are anti-Kell,anti-Kidd (anti-Jka), and anti-Duffy (anti-Fy a ). Symptoms ofacute hemolytic transfusion reaction may begin mildly,after infusion of as little as 10-15 mL of incompatible blood.The following reactions may occur in an acute hemolyticimmune-mediated transfusion reaction:• When incompatible RBCs bind with patient antibody,the immune complex on the cell surface can activateDefinitionsAnamnestic: An increased antibody responsefollowing a secondary exposure to the antigen.Transfusion Reaction: A transfusion reactionmay be defined as any unfavorable transfusion-relatedevent occurring in a patient duringor after transfusion of blood components.Acute Transfusion Reaction: This unfavorableevent may occur within minutes or hours ofbeginning the transfusion.Delayed Transfusion Reaction: When a transfusionreaction manifests itself a few daysafter the transfusion.Immune-Mediated Transfusion Reaction:Occurs when the reaction is the result of arecipient’s immune response to the transfusedcomponents.Non-Immune-Mediated Transfusion Reaction:When the reaction is the result of mechanismsother than an immune response at work in therecipient.Platelet Refractoriness: When the plateletcount fails to increase after a transfusion of anappropriate dose of platelets.WWW.COLA.ORGFor information about COLA services or for technical inquiries, call our Information Resource Center at (800) 981-9883.©COLA 5/06

2 of 8complement which leads to cell lysis and the releaseof anaphylatoxins C3 a and C3 b .• Hemolysis that occurs intravascularly releaseshemoglobin, RBC stroma, and intracellular enzymesinto the plasma which result in the manifestation ofsymptoms.• Renal failure can result from the presence of cellfragments and microthrombi in the renal vasculature.Complement activation may lead to disseminatedintravascular coagulopathy (DIC) characterizedby the formation of microthrombi within thevasculature, depletion of fibrinogen, production offibrin degradation products, and a general outcomeof uncontrollable bleeding.Table 1 provides a broad categorization of immune-mediatedtransfusion reactions.Table 1Immune-Mediated Transfusion ReactionsAcuteHemolyticFebrile, NonhemolyticTransfusion-relatedlung injury (TRALI)UrticarialAnaphylacticDelayedAlloimmuneHemolyticGraft-vs-HostDiseasePlatelet-refractoryFebrile Non-Hemolytic Transfusion ReactionsFebrile non-hemolytic transfusion reactions occur inabout 1% of transfusions. Along with allergic reactions,febrile reactions are the most commonly encounteredtype of transfusion reaction. The commonly accepteddefinition of a febrile transfusion reaction is an increasein temperature of 1°C or 2°F or more associated withtransfusion and without any other medical explanation.These reactions may be caused by antileukocyte antibodiespresent in the recipient’s plasma directed againstantigens present on transfused monocytes, granulocytes,and lymphocytes.A patient may be sensitized during pregnancy, previoustransfusion, or tissue transplantation. Some reactionsare thought to be due to the infusion of cytokines producedby leukocytes during component storage. Since afebrile condition may be a symptom of a more serioushemolytic transfusion reaction, febrile situations shouldalways be promptly evaluated. Bedside filters thatremove leukocytes, as well as leukocyte-poor blood components,washed RBCs, or deglycerolized RBCs, may beused to prevent a febrile transfusion reaction.Transfusion-Related Acute Lung Injury (TRALI)Whenever a transfusion recipient experiences acute respiratorydifficulties or x-ray findings demonstrate pulmonaryedema without evidence of cardiac involvement,transfusion-related acute lung injury should be considered.The severity of respiratory distress is usually proportionalto the volume of blood product transfused. It isthought that transfused antileukocyte antibodies reactwith recipient granulocytes to initiate a sequence ofevents that result in pulmonary capillary damage, andeventually an accumulation of fluid in alveolar spaces.Decreased efficiency in the exchange of gases leads tohypoxia and respiratory symptoms. Patients shouldreceive appropriate respiratory support, and generallyregain adequate pulmonary function in a day or two.Allergic (Urticarial) Transfusion ReactionsAllergic reactions to blood transfusion complicate about1% of transfusions. The majority of symptoms are mildand include local redness, itching and hives. Fever andother symptoms usually are not present. It is thoughtthis reaction is the result of either foreign allergens inthe donor plasma with which recipient antibodies react,or transfused donor antibodies which combine withrecipient allergens.Some physicians will interrupt the transfusion whenallergic symptoms begin, treat the patient with antihistaminetherapy, then, when symptoms have subsided,resume the transfusion with the remainder of the componentunit. Allergic reactions to transfusion can not becompletely prevented, but patients with a history of thistype of reaction may be premedicated with antihistaminesbefore the transfusion is initiated.Since some allergic reactions are severe, the transfusionistand the laboratory should follow the established protocolsfor transfusion reactions and continue to observethe patient for severe reaction symptoms.Anaphylactic Transfusion ReactionsAnaphylactic transfusion reactions are the result of animmediate hypersensitivity type of immune response.Symptoms may begin after infusion of only a few millilitersof blood. Anaphylaxis may begin rather mildly withskin flushing, hives, and itching, but can progress to lossof consciousness, shock, and death. Any organ systemcan be involved, and symptoms may include coughing,dyspnea, abdominal cramps, nausea, vomiting, diarrhea,chest pain, hypotension, and syncope.Patients with this type of reaction are usually determinedto have a congenital deficiency in IgA and have producedanti-IgA which then reacts with donor IgA in transfusedplasma. IgA deficiency is the most common congenitalimmune deficiency, but anaphylactic transfusion reactionsremain quite rare.©COLA 5/06

4 of 8Non-Immune Mediated Transfusion ReactionsMany of the clinical symptoms of these transfusion reactionsare nonspecific, but include facial numbness,chills, numbness, muscle twitching, cardiac arrhythmias,nausea, vomiting, altered respirations, and anxiety.Laboratory tests for investigation and diagnosis of theseconditions include electrolyte levels, calcium, pH, glucose,urinalysis, hemoglobin, hematocrit, platelet count,prothrombin time, and activated partial thromboplastintime.HemolyticRed blood cells can undergo in-vitro hemolysis due tophysical or chemical factors not associated with theimmune response. Units of blood that are exposed toimproper temperatures during shipping or storage orunits that are mishandled at the time of administrationare candidates for a mechanically induced transfusionreaction.Additionally, RBCs can undergo temperature-relateddamage from the use of microwave ovens or hot waterbathsto warm the units, malfunctioning blood warmers,or from damage caused by freezing in the absence of acryopreservative. The use of pressure infusion pumps,pressure cuffs, roller pumps and needles with an improperbore may also cause physical damage. Hypertonic orhypotonic solutions may damage cell membranes.EmbolicAir embolism is a concern if blood is infused in an opensystem, or if air enters the system when containers ortubings are changed. Proper use of pumps, apheresisequipment, and tubing connectors is essential. Patientsymptoms may include cough, dyspnea, chest pain, andshock.MetabolicDuring massive transfusions, depletion of platelets andcoagulation factors may occur if the patient is not supportedwith transfusion of these components.Hypothermia may occur when large volumes of cold fluidsare infused.Citrate toxicity may result from apheresis procedures andwhen large volumes of fresh frozen plasma (FFP), wholeblood, or platelets are transfused. The citrate will bindthe recipient’s free calcium ions and produce hypocalcemia.This is also a concern when exchange transfusionis performed on infants who are already ill. RBCs loseintracellular potassium during storage and may be thecause of transfusion-induced hypokalemia when washedRBCs are administered.Circulatory OverloadWhereas TRALI is associated with transfusions of bloodvolumes that do not produce hypervolemia, circulatoryoverload may be caused when blood volume is rapidlyincreased.Transfusion that proceeds at too fast a rate may lead tocongestive heart failure and pulmonary edema. Theadministration of 25% albumin may also be implicatedas it causes a shift of large amounts of interstitial fluidinto vascular spaces. The transfusion should be stopped,or at least slowed when completion of the transfusion iscritical.Patient support generally includes administration of oxygen,diuretics, and in severe cases, therapeutic phlebotomyto reduce blood volume.For patients at risk of developing circulatory overload,blood units may be split into aliquots to allow for transfusionover longer time periods, and the use of washedRBCs may help diminish the plasma load administeredto the recipient.Metabolic Iron OverloadA complication of long-term RBC transfusion is an accumulationof iron that may affect heart, liver, andendocrine gland function. Also called hemosiderosis,symptoms of iron overload include muscle weakness,fatigue, weight loss, jaundice, anemia, and cardiac arryhythmias.Laboratory investigation will include iron andferritin levels and possibly tissue stains for iron.Bacterial Contamination ReactionsNo matter how carefully blood is collected andprocessed, bacteria can never be completely eliminated.Bacterial contamination is responsible for one-eighth ofreported transfusion-associated fatalities.It is believed that bacteria in blood products originatewith the donor, either from the venipuncture or frominapparent donor bacteremia. Bacterial multiplication instored blood may occur with the production of endotoxinsthat give rise to symptoms including fever and chills,hypotension, hemoglobinuria, muscle pain, shock, renalfailure, and disseminated intravascular coagulopathy(DIC).Gram negative organisms capable of growing at coldtemperatures include Pseudomonas species, Citrobacterfreundii, Escherichia coli, and Yersinia enterocolitica.Gram positive organisms are more likely to be found inproducts stored at room temperature. Before release tothe transfusionist, examine each unit of blood for visualevidence of contamination. Color change to dark purpleor black, clots in the bag, and hemolysis may suggest©COLA 5/06

5 of 8contamination, but more often the unit appearanceremains unremarkable.Whenever a septic reaction occurs, the transfusionshould be immediately stopped, and the remainingblood product, transfusion tubing, and intravenous fluidsreturned to the laboratory for Gram stain and cultureworkup.Preventive measures are the most effective in reducingthe occurrence of bacterial contamination of blood products.Strict adherence to sterile techniques must beensured during the collection and processing of components.In the laboratory, frozen products (such as FreshFrozen Plasma) must be handled with care to preventdamage to packaging during storage in the freezer. Whenthawed, protect frozen units from contamination withwaterbath liquid by overwrapping, and examine the unitports for trapped fluid.Frequently empty, clean, and decontaminate the waterbathsused in the laboratory. Employ great care andgood technique when pooling platelets to prevent bacterialcontamination.Viral or Parasitic Contamination ReactionsOther delayed effects of blood transfusion may includethe transmission of parasites such as malaria, babesia,and trypanosomes, and viral agents such ascytomegalovirus (CMV), hepatitis B (HBV), hepatitis C(HCV), human immunodeficiency virus (HIV), and humanT cell lymphotropic viruses (HTLV I & II). Good donorscreening is the key to preventing transmission of theseagents, in conjunction with laboratory testing of donorproducts.Symptoms of a Transfusion ReactionTransfusionists must be alert to the symptoms of a transfusionreaction so that the transfusion can be halted andappropriate immediate patient care be given. Retainblood specimens of each donor and patient for at leastseven days after transfusion to facilitate follow-up of allsuspected transfusion reactions. When a transfusionreaction is suspected, promptly investigate the event toprovide an accurate diagnosis and guide appropriatepatient therapy. Signs and symptoms that may indicate atransfusion reaction include:• Fever, defined as at least 1°C or 2°F increase frombaseline temperature, with or without chills.• Shaking chills, with or without fever.• Pain, at infusion site, in chest, abdomen, back, orflank.• Changes in blood pressure, usually acute, eitherhypertension or hypotension.• Respiratory difficulties such as dyspnea, tachypnea,or hypoxemia.• Skin changes, including facial flushing, urticaria(hives), and localized or generalized edema.• Nausea and/or vomiting.• Hemoglobinemia.• Hemoglobinuria.• Generalized bleeding or oozing.• Anemia.• Oliguria or anuria.• Acute onset of sepsis.• Anaphylaxis.• Disseminated intravascular coagulopathy (DIC).Observe the recipient of a transfusion frequently duringthe infusion for the development of the symptoms notedabove. In anesthetized patients who cannot report symptoms,diffuse bleeding, changes in blood pressure, orhemoglobinuria may be the only warning signs of atransfusion reaction.Transfusion Reaction InvestigationImmediate InvestigationEvery transfusion service must have a procedure manualdetailing the procedures to follow when a transfusionreaction is observed. Promptly investigate all adversetransfusion reactions. Investigations are important fordiagnosis and the determination of appropriate patientcare and prevention of future transfusion reactions.Transfusionists are generally the first to suspect a transfusionreaction and the first to take action. The transfusionshould be immediately stopped, when symptomsare recognized, to limit the volume of blood componentinfused. Maintain the intravenous line with normal salineor other FDA-approved solution compatible for use withblood administration for possible use in patient therapyand support. Recheck all labels, forms, and patient identificationfor clerical errors at the bedside to determine ifthe component transfused was administered to the correctpatient. If it is found that the wrong unit has beenadministered, undertake an immediate search to locatethe correct component and avert putting another patient©COLA 5/06

6 of 8at risk. Immediately notify the recipient’s physician andthe transfusion service when a transfusion reaction issuspected.The medical staff attending to the transfusion recipientshould complete a transfusion reaction form. Documentationon this form should include:• The patient’s vital signs before and aftertransfusion.• The type of reaction and symptoms.• Time of occurrence.• Volume of transfused blood.• Type of component transfused.• The rate of infusion.• Length of time the unit was infused.• Whether components were warmed.• Whether pressure was applied to accelerateinfusion.• The needle size used.• The type of filter used.• Any solutions or drugs given just prior to or at thetime of infusion.To perform a laboratory investigation, carefully collect(avoiding hemolysis) a post-transfusion blood specimenin a plain barrier-free collection tube, an EDTA-anticoagulatedspecimen, and a first-voided post-transfusion reactionurine specimen. Return the blood unit to the laboratory,even if empty, along with the administration set(minus the needle), and solutions infused with theblood.Other post-reaction specimens may be useful in thelaboratory investigation as determined by the initial laboratoryfindings and the guidance of the medical directorof the transfusion service. If the reaction symptoms areclearly limited to urticaria (hives), or symptoms of circulatoryoverload, the post-transfusion blood specimens donot need to be evaluated for other possible types ofreactions.Laboratory InvestigationImmediate Procedures• Clerical checks.• Visual inspection of pre-transfusion and post-transfusionsera and plasma for hemolysis or icterus.• Direct antiglobulin test on post-transfusion EDTAspecimen, and pre-transfusion specimen.In the laboratory, immediately perform clerical checks ofall paperwork, forms, and specimens to detect discrepancies.Perform a visual check of the recipient’s serumfor hemolysis, comparing the pre-transfusion specimento the post-transfusion specimen.If only the post-transfusion specimen displays evidenceof hemolysis, rule out the possibility of a traumaticvenipuncture as a cause. A second post-transfusionspecimen may be warranted. If the post-transfusion samplecollection is delayed, hemoglobin may be convertedto bilirubin in the bloodstream causing the serum toappear bright yellow or brown (icterus). Laboratoriesmust collect a post-transfusion urine specimen to evaluatethe presence of free hemoglobin in suspectedhemolytic transfusion reactions.Perform a direct antiglobulin test (DAT) on the post-reactionblood specimen, preferably using an EDTA anticoagulatedspecimen to diminish the effects of complementthat may be coating the RBCs. A mixed-field appearanceis frequently observed if transfused cells have been coatedwith antibody but not immediately destroyed. If transfusedcells are rapidly destroyed, the DAT may be negative.When a non-immune mechanism, such as thermaldamage, is the cause of hemolysis, the DAT will be negative.If the post-reaction specimen demonstrates a positivetest, perform a DAT on the pre-transfusion specimenfor comparison.If any of the immediate procedures give a positive or suspiciousresult, consider immune hemolysis and conductadditional laboratory procedures at the direction of thephysician or laboratory director. Protocols for extendedinvestigation of transfusion reactions must be includedin the procedure manual.Additional Procedures (as appropriate)• Repeat ABO and Rh testing on pre-transfusion andpost-transfusion specimens, and on blood from thetransfused unit or an attached segment.• Perform antibody screening on pre- and post-transfusionspecimens, and on donor blood.• Identify alloantibodies detected.• Repeat crossmatch procedures with pre- and posttransfusionspecimens and donor blood.• Test first-voided urine after transfusion reaction forfree hemoglobin.• Test post-transfusion blood specimen for bilirubin(5-7 hours post reaction).• Periodically check patient’s hemoglobin and hematocritfor therapeutic rise or unexpected decline.©COLA 5/06

7 of 8• Examine the returned unit and administration set forhemolysis, contamination, or physical damage ormalfunction.• Gram stain and culture blood from the unit, if indicated.• Perform serum haptoglobin levels on pre- and posttransfusionspecimens.• If anaphylactic reaction is suspected, test patientserum for presence of IgA.Confirm ABO and Rh reactions on pre-transfusion andpost-transfusion patient specimens and on blood fromthe donor unit or attached segment. If ABO and Rhresults do not agree between the pre- and post-reactionspecimens, an error has been made in patient or specimenidentification, or in testing.If specimen mix-ups in labeling or testing have occurred,other patients may be at risk and a thorough check of allspecimens received and tested in the same time periodshould be conducted. If the blood in the unit is of a differenttype than what is on the label of the unit, an errorhas been made in unit labeling.Perform antibody detection tests on pre- and post-transfusionspecimens to determine if the reaction is due toalloantibody. Identify all detected antibodies. In addition,if a positive DAT is observed, an antibody elutionshould be attempted and the antibody coating the RBCsidentified. When the antibody specificity is determined,test the donor unit and the patient for the presence ofthe corresponding antigen.If antibody is detected in the post-reaction specimen butnot in the pre-reaction specimen, an anamnesticresponse should be considered or, less likely, passivetransfer of antibody from the donor plasma. Antibodydetection procedures performed on donor blood may behelpful in this instance. It is important, as well, to obtaina thorough patient history including previous tranfusions,tissue transplantation, and pregnancies that mayhave given opportunity for alloimmunization.Perform compatibility testing with pre- and post-reactionspecimens and donor blood cells. These proceduresshould be completed through the antiglobulin phase,even if your routine protocol outlines an immediate-spinor computer crossmatch. Incompatibility with the pretransfusionspecimen indicates a technical or clericalerror in the original testing. Incompatibility with thepost-reaction specimen only may indicate an anamnesticresponse to a donor antigen, or the possibility of specimenidentification errors.The first-voided, post-transfusion reaction urine specimenmust be collected and tested for the presence offree hemoglobin. A positive test for hemoglobinuria indicateshemolysis, whereas the presence of intact RBCsindicates bleeding. A urine sediment microscopic examinationwill be helpful to identify intact RBCs in conjunctionwith the use of standard urinalysis reagent strips.Hemoglobin degradation products in the bloodstream,especially bilirubin, will cause a color change in the plasmafrom the normal straw color to a bright yellow orbrown (icterus). This may be detected as early as onehour after the transfusion reaction has occurred, with apeak in five to seven hours. With normal liver function,plasma returns to normal in about 24 hours. Comparisonof pre- and post-reaction sera for the presence of icterusas well as serum bilirubin determinations may indicateon-going hemolysis.Under normal circumstances, administration of one unitof packed RBCs should have a therapeutic effect of elevatinga recipient’s hemoglobin level by 1 g/dL for eachunit received. When this hemoglobin increase is notobserved, or if a decrease in hemoglobin and hematocritare noted in the absence of active bleeding, suspecthemolytic processes.Examination of the returned donor unit and transfusionset may reveal evidence of hemolysis, especially when anon-immune mechanism is suspected. Hemolysis may bepresent only in the administration tubing, or in both thetubing and the unit, depending upon how the damageoccurred. Malfunctioning blood warmers or infusiondevices, hypotonic solutions added to the unit, and othersuch devices may be at fault.Examination of the returned materials may also indicatebacterial contamination when the unit has an abnormalappearance including clots, or discolorations describedas brown and muddy, opaque, or purplish. Perform Gramstain and culture studies when these changes areobserved, or when the patient symptoms indicate sepsis.Comparison of pre-transfusion and post-transfusion haptoglobinlevels may be helpful in diagnosing a hemolyticprocess. A decrease in haptoglobin is observed whenhaptoglobin molecules combine with free hemoglobinand are removed from circulation by the RES.When a patient presents with anaphylactic symptoms,testing for the presence of IgA in the pre-transfusionspecimen is useful. If an IgA deficiency is detected, itmay be worthwhile to test for the presence of anti-IgA inthe recipient.An example of a laboratory transfusion reaction worksheetand record is included at the end of this COLA FastFacts.©COLA 5/06