Practical Transfusion Medicine 4th Ed.

6. Investigation of acute transfusion reactions

Kathryn E. Webert1 & Nancy M. Heddle2

1Department of Medicine and Department of Pathology and Molecular Medicine, McMaster University and Canadian Blood Services, Hamilton, Ontario, Canada

2Department of Medicine, McMaster University and Canadian Blood Services, Hamilton, Canada

The investigation of suspected acute reactions to blood components and plasma derivatives cannot be summarized in a single simple algorithm for several reasons:

·        signs and symptoms are not specific for one type of reaction;

·        the frequency and type of reactions vary with different blood components, e.g. leucocyte-reduced or not;

·        risks are variable with different patient populations;

·        the severity and risk of reactions must be taken into account to ensure a balance between the safety, availability and costs due to wastage.

In this chapter, an algorithmic approach is provided for the clinical management and laboratory investigation of transfusion reactions.

Understanding the clinical presentation and differential diagnosis

Acute reactions are defined as adverse events occurring during or within four to six hours of transfusion. They can usually be placed into the following categories [1,2]:

·        acute haemolysis (AHTR);

·        allergic;

·        anaphylactic;

·        transfusion-related acute lung injury (TRALI);

·        febrile nonhaemolytic reactions (FNHTR);

·        bacterial sepsis;

·        hypotension;

·        transfusion-associated circulatory overload (TACO);

·        acute pain reaction

·        metabolic complications (hyperkalemia, hypo-kalemia, hypocalcemia, hypothermia).

There are other types of reactions that can occur following the acute period including delayed haemolytic reactions, transfusion-associated graft-versus-host disease, posttransfusion purpura, alloimmune thrombocytopenia and alloimmune neutropenia. These reactions are discussed in other chapters.

The diagnosis of an acute transfusion reaction can be challenging as signs and symptoms are not specific for each type of reaction, all possible signs and symptoms do not present with every reaction and different types of reactions can occur simultaneously. In Table 6.1, signs and symptoms have been grouped into nine categories. The information summarized in this table illustrates how similar signs and symptoms can occur in different reactions (e.g. bacterial sepsis, allergic and analyphylactic reactions can all present with cutaneous symptoms).

Table 6.1 Summary of the signs/symptoms typically observed with different types of acute transfusion reactions.


To ensure management strategies and investigations that minimize risks to patients, healthcare professionals need to understand the aetiology and pathophysiology of each type of acute reaction (Table 6.2). It is also essential to understand the typical clinical presentation for each type of reaction so that a differential diagnosis can be formulated as part of the investigative process. Some considerations to assist in the decision-making process and investigation are summarized below [3,4].

Table 6.2 Summary of acute transfusion reactions [3,4].






Patient history

·        The reason for the patient's admission and current diagnosis may give some indication as to the type of reaction. For example, if the patient is being transfused because of anaemia but is also in congestive heart failure, TACO could be the cause of the reaction.

·        Consider whether the patient has been previously transfused or pregnant as this can lead to alloimmunization to red cell and leucocyte antigens, which are known to be associated with certain types of reactions (acute haemolytic, FNHTR).

·        What blood components have been transfused and what is the transfusion timeline? If plasma-containing products have been recently transfused, consider whether the reaction could be caused by passive infusion of antibody or soluble allergens that may now be reacting with the product being transfused.

·        Has the patient had a history of reactions when blood components are transfused? Some patients are prone to developing recurrent FNHTR and/or allergic reactions when transfused.

·        Is the patient known to be IgA deficient? Some patients with IgA deficiency develop anti-IgA antibodies, which may cause anaphylactic transfusion reactions when an IgA-containing blood component is transfused.


·        Determine what medications the patient is receiving or has received in the time period leading up to the transfusion. Considerations should include:

·        the use of premedications given to prevent acute reactions such as allergic (antihistamines) or FNHTR (antipyretics);

·        antimicrobial medication;

·        pyrogenic agents that are known to cause fever such as amphotericin or monoclonal antibodies;

·        ACE inhibitors, which have been associated with hypotensive reactions; and

·        pruritogenic agents such as vancomycin, narcotics, etc.

Type of blood component being transfused

·        Does the component contain significant volumes of plasma? Infusion of plasma is associated with a variety of reactions including allergic, anaphylactic, TRALI and acute haemolysis caused by passive antibody incompatibility with the patient's red cells [3,4].

·        Does the component contain a significant number of red cells? If greater than 50 mL of red cells are present in the component, acute haemolysis needs to be considered as a possible cause of the adverse reaction.

·        Was the component stored at room temperature or in a refrigerator? Platelets have a higher risk of bacterial contamination as they are stored at room temperature. However, products stored at colder temperatures can also be contaminated with bacteria, especially those strains that are known to grow at cold temperatures [3].

·        Is the component leucocyte-reduced and if so was leucocyte reduction performed pre- or post-storage? Non-leucocyte-reduced blood components (especially platelets) are associated with a higher frequency of FNHTR. Post-storage leucocyte reduction also has limited effectiveness in preventing FNHTR to platelets whereas pre-storage leucocyte reduction is highly effective. In contrast, both post- and pre-storage leucocyte reduction are effective in preventing most FNHTR to red cells [5].

Was fever present?

·        Fever is a common finding in most types of reactions. However, it does not occur in allergic transfusion reactions or with anaphylaxis. Therefore, fever can be useful to help differentiate between severe hypotension caused by bacterial contamination, acute haemolysis or TRALI (fever may be present) versus hypotension caused by anaphylactic shock (fever is absent).

·        Was the rise in temperature ≥2°C? Significant temperature increases are typically seen with bacterial contamination, especially if the patient has not been premedicated with an antipyretic or is not receiving antibiotic therapy. Increases in temperature greater than 2°C are not usually seen with other types of reactions [6].

Volume of component transfused

The volume of the component transfused can also be an important consideration for a differential diagnosis.

·        Some types of reactions are dose-dependent; hence, they tend to occur towards the end of the transfusion after most of the component has been given. Such reactions include allergic reactions, FNHTR and TRALI. This observation becomes less useful when symptoms occur during the transfusion of multiple blood components. In this situation, it is difficult to determine if the reaction is caused by the first unit transfused or the current unit that is being administered.

·        Anaphylactic reactions can present after a small amount of component is transfused (1–10 mL) [7].

·        Acute haemolytic reactions usually require at least 50–100 mL of red cells to be transfused before symptoms appear.

Other considerations

·        Always remember that the patient's clinical comorbidities and therapies could also be causing many of the symptoms typical of acute transfusion reactions. Hence, these always need to be considered as part of the differential diagnosis.

·        Although most reactions are relatively infrequent, it is possible for a patient to have more than one type of reaction concurrently. This possibility should always be considered when the patient presents with atypical findings.

·        For many reaction types, there is a spectrum of severity, ranging from mild to severe, depending on such factors as characteristics of the patient and blood component, and amount of blood transfused. For example, bacterial contamination of a blood component may result in an acute septic reaction with high fever and hypotension. Alternately, such a component may cause no or only mild symptoms.

·        Consider how well you know the patient and their previous response to blood component transfusions. Less concern may be appropriate for a patient who develops hives every time they are transfused, whereas action would be appropriate for the sudden development of moderate respiratory symptoms in the multitransfused patient who has previously had no adverse events.

General approach for investigation and treatment of acute transfusion reactions

Using all of the information noted above, the clinician must make a decision whether to stop the administration of the blood component temporarily or discontinue the transfusion and must decide the extent of the investigations to be performed. Stopping and investigating every transfusion reaction is often assumed to provide the highest level of safety for the patient, but in reality may contribute to other morbidities such as bleeding or respiratory/cardiovascular morbidity if an essential transfusion is delayed. Hence, some clinical judgement is required to ensure a balance between risk and benefit. The following approach should be used if there is any concern about patient safety and an investigation is required.

Action to be taken on the clinical unit

·        Stop the transfusion immediately. The severity of some reactions is dose-dependent. For example, the risk of severe morbidity and mortality with acute haemolysis is generally proportional to the volume of component transfused.

·        Keep the IV line open with saline (or other appropriate IV solution) in the event that a decision is made to continue the transfusion or if the patient requires other IV therapy.

·        Support the patient's clinical symptoms with appropriate medical therapy.

·        Perform a bedside clerical check to ensure that the name on the blood component and requisition matches the patient's armband/identifier.

·        Look carefully at the remaining blood component to determine if there is any evidence of haemolysis or particulate matter. A contaminated unit of red cells may have discoloration either in the primary bag or in the first few segments closest to the blood bag.

·        Complete a transfusion reaction form and notify the blood transfusion laboratory that a reaction has occurred. The transfusion laboratory will perform relevant investigations, notify the blood supplier if applicable so appropriate actions can be taken and ensure that relevant reactions are reported to the country's haemovigilance system (see Chapter 18). This reporting provides cumulative statistics about reactions that may be the first clue of a new emerging threat to the blood supply or a problem with component manufacturing.

·        If a decision is made to perform a more extensive investigation to rule out problems with a donor unit (e.g. serological incompatibility causing haemolysis, bacterial contamination, TRALI), the remainder of the blood bag should be returned to the blood transfusion laboratory and/or blood service for further testing. Local policies should be followed for additional patient samples to be collected for specialized testing.

Action to be taken in the laboratory

When a reaction is reported to the blood transfusion laboratory, there should always be a clerical check performed to verify that the paperwork is accurate and that the correct component was issued for transfusion. To rule out haemolysis from the differential diagnosis, the following screening tests should be performed:

·        clerical check as mentioned above;

·        centrifuge a posttransfusion sample of the patient's blood and observe the plasma for visual evidence of haemolysis; and

·        perform a direct antiglobulin test on a posttransfusion EDTA sample taken from the patient.

If the clerical check does not indicate any problems and the two screening tests are negative, acute haemolysis as the cause of the reaction can usually be eliminated. However, if the patient's symptoms are severe and consistent with a haemolytic reaction, a complete serological work-up may be indicated, including repeating the compatibility test on both the pre- and posttransfusion patient samples and specific tests for haemolysis (i.e. lactate dehydrogenase, haptoglobin, methaemalbumin, etc.).

All blood transfusion laboratories should have specific protocols for the investigation of other types of reactions. The Public Health Agency of Canada has developed guidelines for the investigation of suspected reactions caused by bacterial contamination, which can be accessed from the website ( [8]. Similar documents may be present in other countries. Investigation of TRALI, anaphylaxis and TACO requires specialized testing, which may be available only from a reference centre or specialized laboratory [9–11]. However, each facility should have policies and procedures in place to direct and facilitate these investigations. Results from these specialized tests are not usually available in a timely manner. Hence, treatment and prevention strategies must be made based on clinical findings and test results available on site.


As mentioned previously, some clinical judgement is required when deciding what reactions to investigate more fully and the management strategies required. Aggressive investigation of mild reactions can burden resources within the healthcare setting and may cause unnecessary delays in transfusion therapy for a patient in critical need of blood components. In contrast, patient safety should always be paramount. The algorithm in Figure 6.1 can be used as a guide to develop a safe but logical approach to managing acute transfusion reactions.

Fig 6.1 Flow diagram illustrating a possible approach for the management and investigation of an acute transfusion reaction.


Key points

1. Decisions related to the investigation of acute transfusion reactions require some clinical judgement based on the severity of the reactions (Figure 6.1).

2. Effective management decision making requires that healthcare professionals understand the types of acute transfusion reactions that can occur and their pathophysiology (Tables 6.1 and 6.2).

3. Patient factors to consider when formulating the differential diagnosis include the history of transfusion, pregnancy, medications, previous reactions, types of symptoms and diagnosis and clinical morbidities.

4. Component factors to consider when formulating the differential diagnosis include the type of component, leucocyte reduction status, volume transfused and component age.

5. Each institution must have policies and procedures for the investigation of acute reactions.


1. Braendstrup P, Bjerrum OW, Nielsen OJ, Jensen BA, Clausen NT, Hansen PB et al. Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura. Am J Hematol 2005; 78: 275–280.

2. Hendrickson JE & Hillyer CD. Noninfectious serious hazards of transfusion. Anesth Analg 2009; 108: 759–769.

3. Callum J, Lin Y, Pinkerton PH, Karkouti K, Pendergrast JM, Robitaille N et al. Bloody Easy 3, Blood Transfusions, Blood Alternatives and Transfusion Reactions: A Guide to Transfusion Medicine [Internet], 2011 [cited 16 November 2011]. Available from:

4. Popovsky, M (ed.). Transfusion Reactions. Bethesda, MD: AABB Press; 2007.

5. Heddle N. Febrile nonhemolytic transfusion reactions. In: M Popovsky (ed.), Transfusion Reactions, 3rd edn. Bethesda, MD: AABB Press; 2007, pp. 57–103.

6. Ramirez-Arcos S, Goldman M & Blajchman M. Bacterial contamination. In: M Popovsky (ed.), Transfusion Reactions, 3rd edn. Bethesda, MD: AABB Press; 2007, pp. 163–206.

7. Vamvakas E. Allergic and anaphylactic reactions. In: M Popovsky (ed.), Transfusion Reactions, 3rd edn. Bethesda, MD: AABB Press; 2007, pp. 105–156.

8. Public Health Agency of Canada. Guidelines for the Investigation of Suspected Transfusion Transmitted Bacterial Contamination [Internet], 2007 [updated January 2008; cited 16 November 2011]. Available from: URL:

9. Stroncek DF, Fadeyi E & Adams S. Leukocyte antigen and antibody detection assays: tools for assessing and preventing pulmonary transfusion reactions. Transfus Med Rev 2007; 21: 273–286.

10. Vassallo RR. Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products. Immunohematology 2004; 20: 226–233.

11. Zhou L, Giacherio D, Cooling L & Davenport RD. Use of B-natriuretic peptide as a diagnostic marker in the differential diagnosis of transfusion-associated circulatory overload. Transfusion 2005; 45: 1056–1063.

Further reading

Bakdash S & Yazer MH. What every physician should know about transfusion reactions. Can Med Assoc J 2007; 177: 141–147.

Bux J & Sachs UJH. Pulmonary transfusion reactions. Transf Med Hemotherapy 2008; 35: 337–345.

Eder AF & Benjamin RJ. TRALI risk reduction: donor and component management strategies. J Clin Apher. 2009; 24: 122–129.

Eder AF & Chambers LA. Noninfectious complications of blood transfusion. Arch Pathol Lab Med 2007; 131: 708–718.

Sandler SG. How I manage patients suspected of having had an IgA anaphylactic transfusion reaction. Transfusion 2006; 46: 10–13.

Vamvakas EC & Blajchman MA. Blood still kills: six strategies to further reduce allogeneic blood transfusion-related mortality. Transfus Med Rev 2010; 24: 77–124.