Despite the best diligence of everyone involved in blood transfusion from "vein to vein," indeed from pre-blood donation to post-transfusion, transfusion is not risk free. Clinicians must exercise judgment to determine that the expected benefits of transfusion outweigh the risks.
Complications, transfusion reactions, and adverse events range from mild to life-threatening. They may involve immune or non-immune mechanisms and occur within minutes to days or weeks after transfusion.
A summary of the left menu items is listed below to assist in navigating through Complications:
Signs and symptoms related to transfusion reactions range from none to many and may involve multiple body organs and systems.
Complications can be grouped in many ways. They are commonly arranged in two large categories according to when signs and symptoms appear (immediate or delayed), as well as a third "catch-all" category of miscellaneous other complications.
The laboratory investigation can range from minimal to extensive and is dictated by the symptoms and severity of the reaction. Immediate steps to take are discussed in this section.
The immediate treatment of the patient is of utmost importance. The physician manages the course of treatment according to the symptoms.
Many complications of transfusion can be prevented by the diligent application of quality management principles and practice guidelines to all aspects of the vein-to-vein process, i.e., from blood collection to transfusion.
Reporting suspected transfusion reactions to the attending physician and the laboratory is one of the first steps to determining the cause and initiating treatment.
As well, there are national reporting requirements for blood suppliers to report serious adverse events of transfusion to Health Canada. Hospital blood transfusion services are encouraged to voluntarily report to their blood supplier, any case in which it is important to remove other components from the same donor(s) from circulation and/or defer the donor to prevent similar reactions in other recipients. The Transfusion Transmitted Injuries Section of Health Canada's Health Care Acquired Infections Division has established a national surveillance system for transfusion-transmitted injuries called the Transfusion Transmitted Injuries Surveillance System (TTISS).
Types of Transfusion Complications
Complications can be organized by consequences, mechanisms, symptoms, time of onset, and other variables. Below they have been arbitrarily grouped as immediate and delayed.
Immediate
Complications have been classed as immediate if they occur during or up to 24 hours after transfusion.
Delayed
Delayed complications may occur days to months post-transfusion.
See a Complications Table that groups transfusion complications by type of blood component according to whether the risk is common but usually not life-threatening versus rare and potentially life-threatening.
Acute Immune Hemolytic Transfusion Reactions
Description
Acute Hemolytic Transfusion Reactions (AHTR) of immune origin are serious, potentially life-threatening reactions, usually caused by transfusion of ABO-incompatible red cells (and rarely ABO-incompatible plasma) following clerical or systems errors that result in incompatibility of the blood unit with the blood recipient. The most common cause of this is misidentification of the blood recipient, which may occur at any of the following steps:
Incidence
The incidence of AHTR varies with location and when data were gathered. A recent estimate of the risk of AHTR in Canada is approximately 1:12,500 units of red cells with over 90% occurring as a result of ABO errors (See Kleiman S in Further Reading).The typical AHTR ensues when patient anti-A or anti-B react with A and/or B antigens on the transfused donor red cells triggering the binding of complement with subsequent activation of the complement cascade resulting in Intravascular Hemolysis (IVH).
Preventing hemolytic transfusion reactions depends on proper patient identification and labelling of samples and blood components in each and every step, from sample collection to blood administration.NOTE: Less frequently, so-called minor ABO incompatibilities (donor ABO antibodies reacting with A and/or B antigens on the patient's red cells), may cause acute hemolysis. Reactions due to donor antibodies are usually considered low risk for hemolytic reactions due to the small volume of donor plasma in most blood components (except for plasma and apheresis platelets), which would be diluted by the patient's blood volume; as well, soluble A and B antigens in patient plasma help to neutralize the donor antibodies.However, severe life-threatening hemolytic transfusion reactions and death have been reported when a donor has a very high titre of anti-A or anti-B. These reactions are often associated with Single-Donor apheresis platelets (SDPs), which may contain 200 to 400 mL of plasma (see Larsson et al. in Further Reading).
An atypical form of Acute Hemolytic Transfusion Reaction has been reported in patients with Sickle Cell Disease (SCD) following transfusion of compatible RBC that may or may not have an immune mechanism. The pathophysiology is not well-understood; hypotheses include a bystander hemolysis mechanism, suppression of erythropoiesis, or hyperactive macrophages (see Further Reading).
Clinical Presentation - Acute Hemolytic Transfusion Reactions (immune)
Signs and symptoms usually appear within minutes after the transfusion is started but can occur anytime during the transfusion. They may include (but are not limited to):
- fever (temperature increase of more than 1oC)
- chills
- rigors
- nausea and vomiting
- anxiety
- malaise
- hypotension
- tachycardia
- burning along site of infusion
- skin flushing
- chest pain
- dyspnea, wheezing
- severe low back pain
- hemoglobinemia
- hemoglobinuria
- oliguria/anuria
- uncontrolled bleeding
In the anesthetized patient, the only signs may be unexplained bleeding due to disseminated intravascular coagulation (DIC), falling blood pressure, and/or fever.
The more severe transfusion reactions are characterized by shock, chills, fever, dyspnea, chest pain, back pain, headache and/or abnormal bleeding; these reactions may result in death. Hemoglobinemia, hemoglobinuria and subsequent hyperbilirubinemia are often detectable. Potentially life-threatening complications include:
- hypotension and shock
- disseminated intravascular coagulation
- renal failure
Mechanisms
The mechanisms involved in AHTR are complex and not fully understood. Following transfusion of ABO-incompatible red cells, the recipient's ABO antibodies bind to antigens on the transfused red cells triggering complement activation. IgM and IgG anti-A, anti-B, and anti-A,B are all excellent complement binders. As the classical complement pathway progresses, anaphylatoxins C3a and C5a are released into the recipient's plasma. Once C9 is bound, the recipient's cells are destroyed by IVH. Cytokines, such as interleukin-1, tumor necrosis factor, interleukin-6, and interleukin-8, are believed to play key roles in the immune hemolysis and its serious sequelae.
In brief, activation of the complement cascade may lead to:
- intravascular hemolysis with hemoglobinemia and hemoglobinuria
- release of vasoactive complement components resulting in hypotension and shock
- thrombin and platelet activation culminating in DIC
- renal failure due to glomerular deposition of immune complexes, DIC, and reduced renal blood flow due to hypotension
Investigation of Acute Hemolytic Transfusion Reactions (immune)
IMPORTANT: When beginning an investigation, because similar symptoms may occur in several types of complications, all possibilities must be investigated. As patient history, clinical presentation and laboratory results accrue, a differential diagnosis is carefully assessed from which the ultimate diagnosis emerges.
Transfusion services should have clear policies describing the required investigation for transfusion complications. Below is an example of a protocol suitable for laboratory investigation of an adverse event such as an immediate/acute hemolytic transfusion reaction. Individuals should always adhere to the policies developed by their institutions.
- Immediate actions
- Laboratory investigation
Laboratory Investigation
Policies and procedures for investigating suspected hemolytic transfusion reactions will vary among transfusion services. As a minimum, the following should be done in accordance with laboratory policies and procedures:
- Check for clerical errors by:
- reviewing patient identity on the compatibility label (tag)
- Confirming that patient and donor have compatible blood types
- Ensuring that the correct tag is attached to the correct blood product container
- Retrieving the patient's pre-transfusion specimen and request form/worksheet and checking that the information on both is identical and that they match the compatibility tag
- Inspect the patient's post-transfusion specimen for visible hemolysis
- Perform a Direct Antiglobulin Test (DAT) on the patient's post-transfusion specimen
- Depending on results, investigate further and report as appropriate
Further Serological Investigation
Depending on the results of the initial investigation, the transfusion service will perform follow-up serologic testing according to its own policies and procedures. Some examples are outlined under further testing.
Further Investigation of AHTR (Immune)
For an immune-mediated AHTR, the expected results are a misidentification error resulting in transfusion of ABO-incompatible RBC.
Clerical or Systems Error
If a clerical or systems error is found that indicates the patient has received a blood product that was not intended for the patient (such as an ABO-incompatible blood product):
- Immediately notify the
- Patient's physician
- transfusion service
- MD responsible for the blood bank (or designate)
- Search records to determine if misidentification or incorrect issue of other blood components has put other patients at risk
- Document and report findings according to laboratory policies
Visible Hemolysis
If visible hemolysis is present in the patient's post-transfusion blood sample:
- Compare with pre-transfusion blood specimen
- Investigate if the blood collection was a difficult draw that may have produced hemolysis and, if so, recollect
- Document and report findings according to laboratory policies
NOTE: The presence of methemalbumin can result in plasma having a brownish colour. When intravascular hemolysis occurs, methemalbumin is formed after the haptoglobin-binding capacity for free hemoglobin is exceeded and the free hemoglobin binds to albumin. If the post-transfusion specimen was drawn hours after the suspected reaction began, hemoglobin degradation products, such as bilirubin, may be in the bloodstream and cause icteric plasma (yellow discoloration).
Positive Direct Antiglobulin Test (DAT)
To be valid, a DAT should be performed on an EDTA specimen. An EDTA specimen will prevent complement from binding in vitro due to a harmless cold autoantibody such as autoanti-I, which many people have. If the DAT done on the patient's post-transfusion EDTA blood sample is positive:
- Perform a DAT on the pre-transfusion blood sample for comparison (unless already done). If the DAT on the pre-transfusion specimen is also positive, the positive DAT on the post-transfusion specimen is not suggestive of an immune-mediated hemolytic transfusion reaction.
- If the DAT on the pre-transfusion specimen is negative, a more complete investigation may be done, an example of which follows.
NOTE: The DAT on the patient's post-transfusion specimen may be negative -- even though a hemolytic transfusion reaction has occurred – if at the time of testing most or all transfused donor red cells have been removed by rapid intravascular hemolysis (IVH).
If none of the initial tests are positive, but evidence of hemolysis is present post-transfusion, suspect a non-immune cause such as transfusing a hemolysed unit or drug-blood incompatibilities.
Evidence of Hemolysis
Several laboratory tests performed outside the transfusion service in other sections of the clinical laboratory can confirm or suggest that hemolysis is occurring.
Test results most associated with IVH include hemoglobinemia, hemoglobinuria, and increased Lactate Dehydrogenase (LD) levels. Test results occurring with both IVH and EVH include unexplained decreased hemoglobin and hematocrit levels, decreased serum haptoglobin, and hyperbilirubinemia.
These laboratory tests can indicate that red cells are being destroyed but do not reveal why.
Additional Serologic Tests
If any of the initial observations and/or test results are positive, further investigation is warranted. Examples of follow-up tests that may be done include:
ABO and Rh(D) typing of patient's pre and post-transfusion specimens and implicated donor units.
Antibody screen on patient's pre and post-transfusion specimens and implicated donor units (if plasma is available).
NOTE: The antibody screen may be falsely negative if at the time of testing most of the patient's antibody has adsorbed to transfused donor cells. In such cases the DAT will be positive and the antibody can be identified in an eluate prepared from the patient's post-transfusion red cells.
Antibody identification. If a new or unexpected antibody is found in the antibody screen, it should be identified with subsequent antigen phenotyping of patient's pre-transfusion red cells and donor red cells (if available). If the antibody appeared post-transfusion, suspect a delayed hemolytic transfusion reaction due to an anamnestic antibody response following transfusion of antigen-positive red cells. If the patient was transfused with a product, such as Intravenous Immune Globulin (IVIG) or a large dose of Rh immune globulin (RhIG), e.g., to treat immune thrombocytopenia purpura, suspect passive antibodies.
Monospecific DATs. If the post-transfusion DAT is positive with polyspecific antiglobulin serum, the DAT can be repeated with monospecific anti-IgG and anti-C3b/-d to determine the substances sensitizing the patient's red cells. The major purpose is to assess if an elution should be performed to identify antibodies that may be sensitizing the patient's cells.
Elution. If IgG is sensitizing the patient's red cells, an eluate may be prepared from the DAT-positive red cells and tested with a panel to identify the antibodies involved.
Treatment of Acute Hemolytic Transfusion Reactions (immune)
Treatment varies with the clinical condition of each patient and focuses on providing cardiovascular support with IV fluids and vasopressors.
Note, however, that care should be taken to avoid fluid overload in patients with impaired cardiac or renal function.
If present, disseminated Intravascular hemolysis (DIC) and hypotension must be treated early to limit renal damage.
If possible, further transfusions should not be given until the transfusion service has completed its serologic investigation and determined the cause of the reaction.
Reporting - Acute Immune Hemolytic Transfusion Reaction
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Prevention of Acute Hemolytic Transfusion Reactions (Immune)
Prevention of acute intravascular hemolytic transfusion reactions is only possible:
- with careful, comprehensive identification of the patient at the bedside at the time of collection of the blood samples for pretransfusion testing and
- with careful comprehensive identification of the patient and the donor unit immediately prior to initiating the transfusion.
- Polices and procedures that prevent misidentification of the patient and/or donor unit must be in place in the hospital nursing manual and must be strictly adhered to.
Likewise policies and procedures that prevent misidentification of the patient's sample during blood grouping must be in place in the hospital transfusion service and must be strictly adhered to.
Acute Hemolytic Transfusion Reactions (immune) - Further Reading
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Beauregard P, Blajchman MA. Hemolytic and pseudo-hemolytic transfusion reactions: an overview of the hemolytic transfusion reactions and the clinical conditions that mimic them. Transfus Med Rev 1994 Jul;8(3):184-99.
- Callum, JL, Kaplan, HS, Merkley, L L, Pinkerton, PH, Rabin Fastman, B, Romans, RA. Reporting of near-miss events for transfusion medicine: improving transfusion safety. Transfusion 2001; 41: 1204-11. [ Full text ] [ Medline ]
- Capon SM, Goldfinger D. Acute hemolytic transfusion reaction, a paradigm of the systemic inflammatory response: new insights into pathophysiology and treatment. Transfusion 1995;35(6):513-20.
- Davenport RD. Hemolytic transfusion reactions. In: Popovsky MA, ed. Transfusion reactions, 2nd ed. Bethesda, MD: AABB Press;2001. p.2-36.
- Davenport RD. The role of cytokines in haemolytic transfusion reactions. Immunol Invest. 1995 Jan-Feb;24 (1-2): 319-31. [Medline]
- Fitzpatrick T, Fitzpatrick L. Nursing management of transfusion reactions. In: Popovsky M, editor. Transfusion reactions, 2nd ed. Arlington, VA: AABB Press;2001. p.417-48.
- Kaplan H. Lessons learned (editorial). Transfusion 2001;41(5): 575-6. [ Full text ]
- Kleinman S, Chan P, Robillard P. Risks associated with transfusion of cellular blood components in Canada. Transfus Med Rev 2003; 17(2):120-162.
- Larsson LG, Welsh VJ, Ladd DJ. Acute intravascular hemolysis secondary to out-of-group platelet transfusion. Transfusion 2000 Aug;40(8): 902 -6. [Full text ] [ Medline ]
- Linden JV, Wagner K, Voytovich AE, Sheehan J. Transfusion errors in New York State: an analysis of 10 years' experience. Transfusion 2000;40(10):1207-13. [ Full text ] [ Medline ]
- Park TS, Kim KU, Jeong WJ, Kim HH, Chang CL, Chung JS, Cho GJ, Lee EY, Son HC. Acute haemolytic transfusion reactions due to multiple alloantibodies including anti-E, anti-c and anti Jkb. J Korean Med Sci. 2003 Dec; 18(6): 894-6. [Medline]
- Robillard P, Nawef KL, Jochem K. The Quebec hemovigilance system: description and results from the first years. Transfus Apheresis Sci. 2004 Oct; 31(2): 111-22. [Medline]
- Sazama K, JD, DeChristopher PJ,Dodd R, Harrison CR, Shulman IA, Cooper ES, et al. Practice parameter for the recognition, management, and prevention of adverse consequences of blood transfusion. Arch Pathol Lab Med 2000 ;124(1): 61–70.
- Stroncek D, Procter JL, Johnson J. Drug-induced hemolysis: cefotetan-dependent haemolytic anemia mimic an acute intravascular immune transfusion reaction. Am J Hematol. 2000 May; 64(1): 67-70. [Medline]
- Telen M.J. Principles and problems of transfusion in sickle cell disease. Semin Hematol. 2001;38:315-23. [ Medline ].
- Whitsett, CF, Robichaux, MG. Assessment of blood administration procedures:problems identified by direct observationand administrative incident reporting. Transfusion 2001; 41: 581-6. [ Full text ] [ Medline ]
- Williamson LM, Lowe S, Love EM, Cohen H, Soldan K, McClelland DB, et al. Serious hazards of transfusion (SHOT) initiative: analysis of the first two annual reports. Br Med J 1999; 319:16-9.
- Win N, Doughty H, Telfer P, Wild BJ, Pearson TC. Hyperhemolytic transfusion reaction in sickle cell disease. Transfusion 2001 Mar; 41(3)323-8. [ Full text ] [Medline]
Acute Non-Immune Hemolytic Transfusion Reactions
Description
Acute non-immune Hemolytic Transfusion Reactions (non-immune HTR) occur when hemolysed red cells that are serologically compatible are transfused. Hemolysis can be caused by physical or chemical destruction of red blood cells including:
- freezing (e.g., transporting blood at improper temperatures or placing RBC beside a freezer pack/ice with no insulation between the frozen pack/ice and the blood)
- heating (e.g., transfusing RBC using a blood warmer with too high a temperature)
- hemolytic drug or solution added to blood (e.g., if mixed with RBC, 5% dextrose, 50% dextrose, and hypotonic sodium solutions, this can cause red cells to hemolyse)
- mechanical trauma from intraoperative blood collection devices or cardiopulmonary pump-oxygenators
- older RBCs infused under pressure through a small bore needle
- inadequate deglycerolization of frozen RBC
- transfusion of outdated blood
- red cell fragility due to hemoglobinopathies or enzyme deficiencies in the donor, e.g., glucose-6-phosphate dehydrogenase deficiency
NOTE: An atypical form of acute hemolytic transfusion reaction has been reported in patients with Sickle Cell Disease (SCD) following transfusion of compatible RBC. The pathophysiology is not well understood; hypotheses include a bystander hemolysis mechanism, suppression of erythropoiesis, or hyperactive macrophages (see Further Reading).
Incidence
The incidence of non-immune Hemolytic Transfusion Reactions is unknown but they occur only rarely.
Preventing non-immune Hemolytic Transfusion Reactions depends on proper handling, storage, and administration of blood components
Clinical Presentation - Acute Non-Immune Hemolytic Transfusion Reactions
Signs and symptoms usually appear during the transfusion or within 24 hours of transfusion. Transfusing hemolysed red cells may result in hemoglobinemia and hemoglobinuria but usually not the other symptoms associated with immune-mediated AHTR.
However, there are rare reports of life-threatening reactions with hypotension and renal failure occurring.
Mechanism
Transfusion of hemolysed red cells results in hemoglobinuria. Lysed red cells may also lead to release of vasoactive or thrombogenic substances.
Investigation - Acute Non-Immune Hemolytic Transfusion Reactions
For an acute non-immune HTR the investigation does not reveal serologic abnormalities or misidentification errors but rather, in most cases, a handling, storage, or transfusion error or malfunction that results in physical or chemical destruction of red cells.
Non-immune hemolytic transfusion reactions should be suspected in the presence of unexplained hemoglobinuria that is temporally related to red cell transfusion but not associated with other signs and symptoms of an acute hemolytic transfusion reaction.
Transfusion services should have clear policies describing the required investigations for transfusion complications. An example of an immediate investigation shows steps that could be used to investigate any immediate transfusion reaction.
Treatment - Acute Non-Immune Hemolytic Transfusion Reactions
With non-immune hemolysis treatment may be unnecessary, but the patient must be monitored for significant hemolysis.
If hypotension or renal failure occurs, treatment is similar to that for acute immune-mediated hemolytic reactions. i.e., it varies with the clinical condition of each patient and focuses on treating and managing the serious sequelae of intravascular hemolysis with IV fluids, vasopressors, and diuretics.
If possible, further transfusions should not be given until the transfusion service has completed its serologic investigation and determined the cause of the reaction.
Reporting - Acute Non-Immune Hemolytic Transfusion Reactions
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Prevention - Acute Non-Immune Hemolytic Transfusion Reactions
Non-immune hemolytic transfusion reactions are usually due to errors involving handling, storage, and administration of blood components.
The best prevention involves education of all staff involved in administration of blood components to correctly follow protocols for the handling, storage and administration of blood components.
Support personnel involved in prevention of this type of transfusion reaction include:
- Messengers transporting components from the hospital transfusion service to the patient location. An education program should be developed to ensure they are aware of the handling requirements for blood components in transit.
- Transportation personnel handling blood components between the donor centre and the hospital transfusion service.
- Ambulance personnel handling blood components that are transported with patients between facilities.
See these resources:
Acute Non-Immune Hemolytic Transfusion Reactions: Further Reading
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Beauregard P, Blajchman MA. Hemolytic and pseudo-hemolytic transfusion reactions: an overview of the hemolytic transfusion reactions and the clinical conditions that mimic them. Transfus Med Rev 1994 Jul;8(3):184-99.
- Davenport RD. Hemolytic transfusion reactions. In: Popovsky MA, ed. Transfusion reactions, 2nd ed. Bethesda, MD: AABB Press; 2001. p.1-44.
- Win N, Doughty H, Telfer P, Wild BJ, Pearson TC. Hyperhemolytic transfusion reaction in sickle cell disease. Transfusion 2001 Mar.; 41(3)323-8. [ Full text ] [ Medline ]
- Telen MJ. Principles and problems of transfusion in sickle cell disease. Semin Hematol 2001; Oct.; 38(4): 315-23. [ Medline ]
Febrile Non-Hemolytic Transfusion Reactions
Description
Febrile Non-Hemolytic Transfusion Reactions (FNHTR) are one of the most common complications of transfusion. As defined by the TTISS (Transfusion Transmitted Injuries Surveillance System) this would be suspected if the recipient experienced one or more of the following:
- fever (>/= 38 degrees Celsius (use symbols) and a change of >/= 1 degree Celsius from pretransfusion value),
- chills
- sensation of cold or
- rigors
(these symptoms may be accompanied by headache and nausea).
during the transfusion or within four hours of its completion without any other causes such as hemolytic transfusion reaction, bacterial contamination or underlying condition.
Because fever may occur in immediate (acute) and delayed hemolytic transfusion reactions, and transfusion of a bacterially contaminated blood component, an investigation is required to eliminate these serious complications.
NOTE: Because patients are often pretreated with antipyretic drugs, FNHTRs are not always associated with fever.
The most likely cause of FNHTR due to red blood cell (RBC) transfusion is antibodies in the recipient's plasma directed against leukocytes in the red cell component. Patients are often multi-transfused or multiparous. In contrast, most FNHTR due to platelets are probably caused by cytokines that accumulate in the product during storage. Prestorage leukoreduction has reduced the frequency, but has not entirely eliminated these reactions (see Mechanism under Clinical Presentation).
Incidence
The incidence of FNHTR varies with the patient population and type of component, its preparation method, and its storage age. As well, reported incidence rates vary according to diagnostic criteria and the level of surveillance.
There is a pronounced difference in frequency for reactions to red cells versus platelets. The reported incidence of FNHTRs to red cells is about one per cent in the general hospital population and higher in patients with hematologic malignancy, thalassemia, or sickle cell anemia.
The incidence of FNHTR with prestorage leukoreduced platelets has been reported to be approximately six to eight per cent. Severe reactions characterized by chills and rigors occurred in only one to two per cent of transfusions with WBC-reduced platelets. (Further Reading: Heddle et al., Transfusion, May 2002).
Although usually self-limited and not associated with lasting sequelae, FNHTR can cause significant distress to patients.
Clinical Presentation - Febrile Non-Hemolytic Transfusion Reactions
Signs and symptoms of a Febrile Non-Hemolytic Transfusion Reaction (FNHTR) can appear during the transfusion or within four hours of its completion. They may include:
- fever (>/= 38 degrees C and a change of >/= 1 degree C from pretransfusion value)
- chills
- sensation of cold or
- rigors
- headache
- nausea
Mechanisms
FNHTR Mediated by Antibodies
The proposed mechanism for FNHTR to RBC is an antigen-antibody reaction between recipient antibodies to antigens on donor leukocytes in which cytokines are released by donor leukocytes. The cytokines released include interleukin 1 b (IL-1 b), interleukin 6 (IL-6), and tumor necrosis factor (TNF).
Another theory is that the recipient-donor WBC antigen-antibody reaction may activate complement, thus stimulating the recipient's macrophages to produce and release cytokines.
FNHTR Mediated by Accumulation of Cytokines During Storage
According to one proposed mechanism for FNHTR associated with transfusion of platelets, cytokines (IL-1 b,, IL-6, TNF), and possibly other biological response mediators, accumulate in the plasma in which platelets are stored and, when infused, cause the symptoms typical of these reactions. However, prestorage leukoreduction has not entirely eliminated the reactions, as would be expected if leukocyte-derived cytokines were solely responsible.
Because many other biologic response modifiers, including platelet-derived cytokines, chemokines, complement fragments, histamine, and lipids, also accumulate in platelets during storage, and it is possible that these may play a role in the residual reactions. The possibly multifactorial mechanisms of the residual reactions require further investigation.
Investigation - Febrile Non-Hemolytic Transfusion Reactions
Transfusion services should have clear policies indicating the investigations required for suspected FNHTR and whether or not transfusions can be restarted. Because of the risk of hemolytic reactions with RBC and bacterial contamination of platelets, (and particularly since the introduction of universal prestorage leukoreduction and the resulting decrease in the frequency of FNHTR), extreme caution should be used if restarting transfusion.
In all cases, restarting transfusion should be
- exceptional rather than routine
- only with specific MD orders
- accompanied by close patient surveillance for the remainder of transfusion
An example of an immediate investigation shows steps that could be used to investigate any immediate transfusion reaction.
Because fever may occur in immediate and delayed hemolytic transfusion reactions and transfusion of a bacterially contaminated blood component, these complications must be excluded.
Clinical judgement should also be exercised based on all of the patient's symptoms, clinical condition, and prior history of transfusion reactions. For further discussion, see "Controversies in Transfusion Medicine: Should a Febrile Transfusion Response occasion the return of the blood component to the blood bank?" (pro and con by Widmann and Oberman, respectively) in Further Reading.
Suspected FNHTR to RBC Components
Since FNHTRs are diagnosed by exclusion, some laboratories tentatively diagnose reactions to RBC components as FNHTR if the symptoms are limited to those typical of mild to moderately severe FNHTR (fever, chills, discomfort, etc.) and there is no serologic or clerical evidence of a hemolytic transfusion reaction.
In the presence of universal prestorage leukoreduction, others prefer that donor RBC implicated in suspected FNHTR be cultured to rule out bacterial sepsis.
Suspected FNHTR to Platelet Components
Some laboratories follow the above policy with the addition, in the presence of more severe symptoms, that the platelets are returned to the laboratory for Gram stain and culture.
Because platelet components are stored at room temperature for up to five days, they have a higher incidence of septic transfusion reactions.
Treatment - Febrile Non-Hemolytic Transfusion Reactions
Treatment of FNHTR consists of treating the symptom of fever with an antipyretic such as acetominophen.
Demerol (meperidine) in small doses has also been used to treat severe shivering (rigors) that may occur in FNHTR.
Another strategy used by some clinicians is to premedicate patients who have experienced two suspected FNHTR with acetaminophen and diphenhydramine, although its efficacy has not been well studied.
If possible, further transfusions should not be given until the transfusion service has completed its serologic investigation and determined the cause of the reaction.
Reporting - Febrile Non-Hemolytic Transfusion Reactions
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Prevention - Febrile Non-Hemolytic Transfusion Reactions
Canadian Blood Services (CBS) has adopted universal prestorage leukoreduction, in which leukocytes are removed from RBC and platelet components as part of the preparation process prior to storage.
- Prestorage leukoreduction to a threshold of 5 X 106 per component can prevent most FNHTR associated with RBC and platelet component transfusions.
Another strategy is to pre-medicate patients who have experienced two suspected FNHTR with acetaminophen and diphenhydramine, although its efficacy has not been well-studied.
Because prestorage leukoreduction cannot prevent the accumulation of some biological response mediators in platelet components such as IL-8, C3a, and C4a, an additional approach to preventing FNHTR associated with platelet components may be to remove the plasma just prior to transfusion. Currently this strategy is not routinely used, although it has been shown to be effective in preventing severe reactions to platelets. (See Further Reading: Heddle et al., Transfusion 2002.) .
Febrile Non-Hemolytic Transfusion Reactions: Further Reading
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Couban S, Carruthers J, Andreou P, Klama LN, Barr R, Kelton JG, Heddle NM. Platelet transfusions in children: results of a randomized, prospective, crossover trial of plasma removal and a prospective audit of WBC reduction. Transfusion. 2002 Jun.;42(6):753-8. [ Full text ] [ Medline ]
- Enright H, Davis K, Gernsheimer T, McCullough JJ, Woodson R, Slichter SJ. Factors influencing moderate to severe reactions to PLT transfusions: experience of the TRAP multicenter clinical trial. Transfusion. 2003 Nov; 43(11):1545-52. [Medline]
- Kleinman S, Chan P, Robillard P. Risks associated with transfusion of cellular blood components in Canada. Transfus Med Rev 2003; 17(2):120-162.
- Heddle NM, Blajchman MA, Meyer RM, Lipton JH, Walker IR, Sher GD, et al. A randomized controlled trial comparing the frequency of acute reactions to plasma-removed platelets and prestorage WBC-reduced platelets. Transfusion. 2002 May;42(5):556-66. [ Full text ] [ Medline ]
- Heddle NM, Kelton JG. Febrile nonhemolytic transfusion reactions. In: Popovsky M, editor. Transfusion reactions, 2nd ed. Arlington, VA: AABB Press; 2001. p. 45-82.
- Heddle NM, Klama L, Meyer R, Walker I, Boshkov L, Roberts R, et al. A randomized controlled trial comparing plasma removal with white cell reduction to prevent reactions to platelets. Transfusion 1999 Mar.;39(3):231-8. [ Medline ]
- Heddle NM. Pathophysiology of febrile nonhemolytic transfusion reactions. Curr Opin Hematol 1999 Nov.;6(6):420-6. [ Medline ]
- Kelley DL, Mangini J, Lopez-Plaza I, Triulzi DJ. The utility of < or =3-day-old whole-blood platelets in reducing the incidence of febrile nonhemolytic transfusion reactions. Transfusion 2000 Apr.;40(4):439-42. [ Full text ] [ Medline ]
- Oberman HA. Controversies in transfusion medicine: should a febrile transfusion response occasion the return of the blood component to the blood bank? Con. Transfusion 1994 Apr.;34(4):353-5.
- Pruss A, Kalus U, Radtke H, Koscielny J, Baumann-Baretti B, Balzer D, Dorner T, Salama A, Kiesewetter H. Universal leukodepletion of blood components results in a significant reduction of febrile non-hemolytic but not allergic transfusion reactions. Transfus Apheresis Sci. 2004 Feb; 30(1): 41-6. [Medline]
- Widmann FK. Controversies in transfusion medicine: should a febrile transfusion response occasion the return of the blood component to the blood bank? Pro. Transfusion 1994 Apr.;34(4):356-8.
- Yazer MH, Podlosky L, Clarke G, Nahirniak SM. The effect of prestorage WBC reduction on the rates of febrile nonhemolytic transfusion reactions to platelet concentrates and RBC. Transfusion. 2004 Jan; 44(1):10-5. [Medline]
Mild Allergic (Urticarial) Transfusion Reactions
Description
Urticarial transfusion reactions are generally mild allergic reactions thought to be caused by pre-existing recipient IgE antibody to proteins in the plasma of the transfused blood component
Other possible causes include:
- donor plasma contains IgE antibody to an allergen in the recipient plasma
- coincidental reaction in atopic recipients
- coincidental reaction to drugs or food to which the recipient has been exposed before or during the transfusion
Usually a specific allergen or definitive cause is not identified and reactions characterized by hives and itching are designated as "allergic" even though their precise origin is unknown.
Allergic transfusion reactions occur on a continuum of severity. When bronchospasm and laryngeal edema are present, the allergic reactions are often called anaphylactoid. When severe hypotension and shock occur, the reaction is designated as anaphylactic. These more severe types of allergic reactions are discussed in the anaphylactic section.
Incidence
Mild allergic (urticarial) transfusion reactions are the most common type of transfusion reactions, occurring in about 1-3% of transfusions of plasma-containing components.
Clinical Presentation - Mild Allergic (Urticarial) Transfusion Reactions
Mild allergic reactions may occur anytime during the transfusion or shortly thereafter. The typical symptoms are local or generalized urticaria, pruritus, erythema (flushing), and wheezing.
Mechanism
IgE-mediated reactions are type I immediate hypersensitivity reactions. IgE has the ability to bind to mast cells and tissue basophils through Fc receptors on their cell membranes. Mast cells (armed with a surface coating of IgE) are triggered when the patient next becomes exposed to the antigen (allergen) recognized by the IgE. This leads to cross-linking of the bound IgE antibody, producing mast cell degranulation with release of preformed and new mediators of the allergic reaction.
Histamine is the most important preformed mediator. It causes vasodilation, increased vascular permeability, increased mucous secretion by nasal and bronchial glands, and smooth muscle contraction. Other granule compounds that mediate the reaction include heparin, enzymes, leukotrienes, cytokines, and activating factors such as the eosinophil and neutrophil chemotactic factors and platelet activating factor.
Investigation - Mild Allergic (Urticarial) Transfusion Reactions
Transfusion services should have clear policies as to what investigations are required for transfusion complications. An example immediate investigation shows steps that could be used to investigate any immediate transfusion reaction.
IMPORTANT: When beginning an investigation, because similar symptoms may occur in several types of complications, all possibilities must be investigated. As patient history, clinical presentation and laboratory results accrue, a differential diagnosis is carefully assessed from which the ultimate diagnosis emerges.
In the case of isolated urticaria and/or pruritis (i.e., no other signs or symptoms present) if the identification of the patient and donor do not reveal any discrepancies, a laboratory investigation is not usually indicated. The transfusion can usually be restarted after antihistamine is administered provided the patient is monitored and if in accord with an institution's policies and protocols.
Treatment - Mild Allergic (Urticarial) Transfusion Reactions
If the sole symptoms are hives and/or itching, the transfusion may be temporarily interrupted and the patient given an antihistamine, if directed by a physician.
When the reaction subsides, the transfusion may be continued at a slow rate of infusion. In patients known to experience such reactions, antihistamines may be prescribed prior to transfusion.
Reporting - Mild Allergic (Urticarial) Transfusion Reactions
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Prevention - Mild Allergic (Urticarial) Transfusion Reactions
The physician treating a patient who has experienced repeated mild allergic reactions may prescribe antihistamines prophylactically.
Mild Allergic (Urticarial) Transfusion Reactions: Further Reading
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Couban S, Carruthers J, Andreou P, Klama LN, Barr R, Kelton JG, Heddle NM. Platelet transfusions in children: results of a randomized, prospective, crossover trial of plasma removal and a prospective audit of WBC reduction. Transfusion. 2002 Jun.; 42(6):753-8. [Full text ] [ Medline ]
- Heddle NM, Blajchman MA, Meyer RM, Lipton JH, Walker IR, Sher GD, et al. A randomized controlled trial comparing the frequency of acute reactions to plasma-removed platelets and prestorage WBC-reduced platelets. Transfusion. 2002 May; 42(5): 556-66. [Full Text] [Medline]
- Vamvakas EC, Pineda AA. Allergic and anaphylactic reactions. In: Popovsky M, editor. Transfusion reactions, 2nd ed. Arlington, VA: AABB Press; 2001. p. 83-128.
Anaphylactic Transfusion Reactions
Description
Allergic transfusion reactions occur on a continuum of severity ranging from mild (urticarial) to moderate (anaphylactoid) to severe (anaphylactic). Anaphylactic transfusion reactions are severe allergic reactions characterized by profound hypotension and shock. Proposed causes include:
- recipient IgE or IgG antibodies to IgA in patients who have complete or partial (i.e., lack an isotopic or allotypic) IgA determinant
- recipient IgE or IgG antibodies to polymorphic forms of other serum proteins (IgG, haptoglobin, C4, etc.) in transfused donor blood
- recipient sensitization to various compounds, including drugs in donor blood, chemicals used to produce or sterilize IV tubing and plastic bags, and foodstuffs
- coincidental reaction to drugs or food taken prior to transfusion
Incidence
The incidence of anaphylactic transfusion reactions is very rare and unknown. There is no systematic collection of data. Reported incidences from individual studies vary widely.
Recent studies suggest that the risk of severe allergic reactions (anaphylactoid and anaphylaxis) in Canada is approximately 1/25,000 units for red cell transfusions and 1/1600 platelet pools. (See Kleinman S in Further Reading).
Clinical Presentation - Anaphylactic Transfusion Reactions
A severe allergic reaction may begin after infusion of only a few mL with symptoms that may be mild at first but can rapidly progress to loss of consciousness, shock, and, in rare cases, death. Reactions usually occur within 1 to 45 minutes of the start of transfusion, although the less severe anaphylactoid reactions may begin up to 2-3 hours after the transfusion was initiated.
Symptoms are categories by body system in the following table:
|
Cutaneous
- pruritis
- urticaria
- erythema
- flushing
- angioedema
|
Pulmonary
- hoarseness
- wheezing
- dyspnea
- cyanosis
- tightness in chest
- substernal pain
|
|
Gastrointestinal
- nausea
- cramps
- vomiting
- diarrhea
|
Cardiovascular
- headache
- tachycardia
- cardiac arrhythmias
- cardiac arrest
- hypotension
- shock
|
Miscellaneous
- apprehension
- sense of impending doom
|
Mechanism
IgE-mediated reactions are type I immediate hypersensitivity reactions. IgE has the ability to bind to mast cells and tissue basophils through Fc receptors on their cell membranes. Mast cells (armed with a surface coating of IgE) are triggered when the patient next becomes exposed to the antigen (allergen) recognized by the IgE. This leads to cross-linking of the bound IgE antibody, producing mast cell degranulation with release of preformed and new mediators of the allergic reaction.
Histamine is the most important preformed mediator. It causes vasodilation, increased vascular permeability, increased mucous secretion by nasal and bronchial glands, and smooth muscle contraction. Other granule compounds that mediate the reaction include heparin, enzymes, leukotrienes, cytokines, and activating factors such as the eosinophil and neutrophil chemotactic factors and platelet activating factor.
In the case of class-specific antibodies to IgA, IgA deficiency has a frequency of about 1 in 700 in persons of European descent, defined as less than 0.0005 g/L of IgA. Some of these individuals will have immune or naturally occurring (no history of prior exposure to blood or blood products via pregnancy or transfusion) anti-IgA that is capable of causing anaphylactic reactions.
Investigation - Anaphylactic Transfusion Reactions
If a patient develops an anaphylactic or severe anaphylactoid transfusion reaction the patient’s pretransfusion serum must be screened for the presence of anti-IgA. Screening tests for IgA deficiency are available in many hospital laboratories. Anti-IgA usually occurs only in the presence of IgA deficiency. However it may also occur in the presence of a sub-class deficiency.
Patients without detectable IgA in screening tests (or if the test is unavailable), or patients who have experienced more than one anaphylactoid reaction should have specimens referred to Canadian Blood Services.
- If IgA antibodies are present, the patient is a candidate for IgA-deficient blood components
- If anti-IgA antibodies are absent, the patient should also be tested for haptoglobin deficiency, since anaphylactoid reactions due to this deficiency have also been described. Otherwise, no further laboratory testing is usually done.
It is important to differentiate anaphylactic/anaphylactoid transfusion reactions from other transfusion reactions such as immediate hemolytic transfusion reactions, circulatory overload, bacterial sepsis and TRALI, which may present similar signs and symptoms. It is also important to consider than an anaphylactic/anaphylactoid reaction may result from medical treatment other than blood transfusions.
Instructions for sending samples for IgA/anti-IgA testing:
- Collect at least 2 mL of serum or plasma.
- Forward sample and patient information to local CBS site.
- Patient information includes:
- Full name
- Date of birth
- Sample collection date
- Originating lab contact information
- Identification number
- Pertinent transfusion history
- Reason for request
Treatment - Anaphylactic Transfusion Reactions
The transfusion must be immediately stopped and under no circumstances should it be restarted. The attending physician must be notified STAT.
The reaction is managed in the same way as a severe allergic reaction to other allergens (fluids, epinephrine, antihistimines, bronchodilators, vasopressors as appropriate).
Patients experiencing these symptoms should be closely monitored for at least six hours after onset of symptoms.
If possible, further transfusions should not be given until the transfusion service has completed its serologic investigation and determined the cause of the reaction.
Reporting - Anaphylactic Transfusion Reactions
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Prevention - Anaphylactic Transfusion Reactions
Strategies for preventing anaphylactic/anaphylactoid transfusion reactions can be considered in three categories:
1. No IgA deficiency and no detectable anti-IgA
If the patient is not IgA deficient and no anti-IgA has been detected, and has experienced only a single anaphylactic or anaphylactoid reaction, a trial transfusion of unwashed blood components may be performed. The transfusion should be given under controlled clinical conditions, and close medical supervision as described below:
- obtain informed consent from the patient
- transfuse RBC, platelets, or plasma as indicated from unselected donors
- transfuse under close medical supervision (direct nursing supervision and physician immediately available)
- premedicate to reduce the severity, with emergency therapy readily available
- resume transfusion of standard blood components if no anaphylactic and anaphylactoid transfusion reaction occurs
- if anaphylactic or apaphylactoid reaction occurs, transfuse with washed blood components
2. Detectable anti-IgA (or anti-IgA levels pending)
For patients with anti-IgA or anti-IgA levels pending, transfuse with IgA deficient blood components. (See following table)
|
Transfusion Management of Patients with IgA Antibodies |
| RBCs |
- Give RBCs from unselected donors after washing in 3 L of 0.9 per cent NaCl
- If reaction recurs, give frozen-thawed-deglycerolized RBCs
- Alternatives (where available/appropriate)
- autologous RBCs or RBCs from IgA deficient donors
|
| Platelets |
- Use Platelets, Apheresis collected from IgA deficient donors
- Alternatively, give platelets from unselected donors after washing with 0.9% NaCI (infusible)
|
| Fresh Frozen Plasma, Frozen Plasma and Cryoprecipitate |
- Use components collected from IgA-deficient donors
|
| Plasma Derivatives (IVIg, Albumin, Rh Immune Globulin) |
- Check package inserts for instructions, cautions/ contraindications for transfusion of these products
|
3. IgA deficiency without detectable anti-IgA
Patients with IgA deficiency but without detectable anti-IgA who have experienced an anaphylactic or anaphylactoid transfusion reaction, should be treated as in (2) above. However it is possible that their transfusion reaction was unrelated to the IgA deficiency. For patients with IgA deficiency but without detectable anti-IgA who have never experienced an anaphylactic or anaphylactoid transfusion reaction, periodic repeat testing for anti-IgA may be considered before commencing subsequent elective transfusion. However, it is not necessary to routinely administer IgA deficient products to these patients.
Anaphylactic Transfusion Reactions: Further Reading
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Kleinman S, Chan P, Robillard P. Risks associated with transfusion of cellular blood components in Canada. Transfus Med Rev 2003 Apr.17(2):120-62.
- Koda Y, Watanabe Y, Soejima M, et al. Simple PCR detection of haptoglobin gene deletion in anhaptoglobulinemic patient with antihaptoglobin antibody that causes anaphylactic transfusion reactions. Blood 2000; 95(4): 1138-43 [ Medline ] [ Full Text ]
- Koskinen S, Tolo H, Hirvonen M, Koistinen J. Long-term follow-up of anti-IgA antibodies in healthy IgA-deficient adults. J Clin Immunol 1995 Jul, 15(4):194-8. [ Medline ]
- Nishiki S, Hino M, Kumura T, Hashimoto S, Ohta K, Yamane T, Takubo T, Tatsumi N, Kitagawa S, Kamitani T, Watanabe Y, Shimda E, Juji T, Iida S. Effectiveness of washed platelet concentrate and red cell transfusions for a patient with anhaptoglobinemia with antihaptoglobin antibody. Transfus Med. 2002 Feb; 12(1): 71-3. [Medline]
- Salama A, Temmesfeld B, Hippenstiel S, Kalus U, Suttorp N, Kiesewetter H. A new strategy for the prevention of IgA anaphylactic transfusion reactions. Transfusion. 2004 Apr; 44(4): 509-11. [Medline]
- Sandler SG, Eckrich R, Malamut D, Mallory D. Hemagglutination assays for the diagnosis and prevention of IgA anaphylactic transfusion reactions. Blood 1994 Sep. 15; 84(6):2031-5. [ Medline ]
- Sandler SG, Mallory D, Malamut D, Eckrich R. IgA anaphylactic transfusion reactions-Review of reported cases. Transf Med Rev 1995; 9(1):1-8.
- Vamvakas EC, Pineda AA. Allergic and anaphylactic reactions. In: Popovsky M, editor. Transfusion reactions, 2nd ed. Arlington, VA: AABB Press; 2001. p. 83-128.
Bacterial Sepsis
Description
Transfusion-associated bacterial sepsis is an infrequent but potentially fatal transfusion complication.
Bacterial contamination of donor blood may be present due to:
- inadequate aseptic technique during collection
- coring of the skin with the venipuncture needle
- transient asymptomatic donor bacteremia
- chronic low grade donor infection
- improper refrigeration of Red Blood Cells (RBCs) during storage or transportation
- contamination during the processing of pooled products
- contamination by infected water baths during thawing of frozen components
- defects in blood bags
The presence of toxins from gram-negative bacilli can cause severe endotoxin reactions, including shock, and deaths have been reported. Such reactions have been reported following transfusion of RBCs stored at 1- 6°C for several weeks, platelets stored at 20-24°C for up to five days, and frozen/thawed blood components whose ports may have been contaminated in a water bath.
Incidence
The reported rates of transfusion-associated bacterial sepsis vary widely depending on the surveillance system used. The true incidence is unknown and is likely under-reported. Platelets, which are stored at room temperature, present a greater risk than RBCs.
Estimated rates of bacterial contamination of RBCs and platelets resulting in bacterial infections in transfusion recipients are shown below:
| |
RBCs
|
Whole Blood Derived Platelets
|
| Bacterial Contamination |
1/10,000 unit
|
1/2,000 units
|
| Bacterial Infection |
1/100,000 units
|
1/10,000 transfusions (platelet pool)
|
| Fatal Bacterial Infection |
1/500,000 units
|
1/50,000 transfusions (platelet pool)
|
Implicated Organisms
Both gram-negative and gram-positive organisms have been implicated. There are many reports of gram-positive bacteria from normal skin flora and gram-negative bacteria from transient bacteremia. Gram-negative organisms are found more frequently in contaminated RBCs and are generally associated with more severe infections. Implicated organisms include but are not limited to:
|
Gram-positive
- Bacillus species
- Corynebacterium species
- Micrococcus species
- Staphylococcus aureus
- Staphylococcus epidermidis
- Streptococcus pneumoniae
- Streptococcus viridans
|
Gram-negative
- Escherichia coli
- Enterobacter aerogenes
- Pseudomonas fluorescens
- Salmonella species
- Yersinia enterocolitica (will grow at 4°C)
- Serratia Marsescens
|
Clinical Presentation - Bacterial Sepsis
Some symptoms are similar to immune-mediated immediate hemolytic transfusion reactions and transfusion-related acute lung injury (TRALI). Milder reactions may be indistinguishable from febrile non-hemolytic transfusion reactions. The degree of severity relates to many factors, including the virulence of the organism, bacterial load infused, and host factors such as coincidental antibiotic therapy and level of immunosuppression.
Symptoms generally appear during or immediately after transfusion and may include:
- fever
- rigors
- nausea
- vomiting
- diarrhea
- dyspnea
- tachycardia
- lumbar pain
- rise or drop in systolic pressure
- shock
- circulatory collapse
- oliguria
- uncontrolled bleeding due to Disseminated Intravascular Coagulation (DIC)
Mechanism
Bacterial endotoxins stimulate macrophages, which in turn secrete cytokines such as tumour necrosis factor (TNF- , interleukin-1, IL-6, IL-8, etc. Cytokine release causes the signs and symptoms and may lead to acute septic shock.
Investigation - Bacterial Sepsis
Transfusion services should have clear policies describing the required investigations for transfusion complications. An example of an immediate investigation shows steps that could be used to investigate any immediate transfusion reaction.
Bacterial sepsis needs to be differentiated from complications that share some similar symptoms such as immediate hemolytic transfusion reactions, TRALI, and febrile non-hemolytic transfusion reactions. The immediate management of the patient as well as recommendations for reporting the reaction and the management of future transfusions are different for each of these complications.
CSA Standard Z902-04, Blood and Blood Components pertaining to investigating bacterial sepsis should be followed. Patient survival depends on
- early recognition
- stopping the transfusion
- rapidly beginning appropriate treatment
Below is an example of a protocol suitable for laboratory investigation of a case of suspected bacterial sepsis. Individuals should always adhere to the policies developed in their institutions.
Laboratory Investigation
In bacterial sepsis hemoglobinemia and hemoglobinuria may be present. Visible examination of the RBC unit may show discolouration (darkening) of the red cell unit, bubbles, hemolysis, or clots.
To diagnose transfusion-related bacterial sepsis, promptly perform a Gram's stain on the remaining donor unit and aerobic and anaerobic cultures on the
- recipient
- implicated donor unit or units (bag, not segments)
- IV solutions (if applicable)
If little of the transfused component remains, culture media may be injected directly into the blood bag. Blood samples from the recipient, the blood container(s) and the transfusion set filter should be collected in a manner to avoid external contamination. The blood container should be refrigerated, and both the blood container and the bacterial isolates should be saved until an investigation can be completed.
A diagnosis of transfusion-related bacterial sepsis is proven by the isolation of the same organism in the donor unit and recipient.
Treatment - Bacterial Sepsis
Transfusion-associated bacterial sepsis is treated like any septic shock.
Septic and toxic reactions may be life-threatening, and treatment must be aggressive. Treatment should be initiated immediately after the collection of recipient blood samples for culturing. Treatment should include:
- broad-spectrum antimicrobials
- vasopressors to maintain blood pressure and urinary flow
- intravenous fluid therapy to maintain fluid and electrolyte balance
Other severe sequelae such as Disseminated Intravascular Coagulation (DIC) require prompt attention.
If possible, further transfusions should not be given until the transfusion service has completed its serologic investigation and determined the cause of the reaction.
Reporting - Bacterial Sepsis
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Prevention - Bacterial Sepsis
Strategies for preventing bacterial sepsis vary according to potential cause. They are described in further detail below and include:
- Blood Donor Screening
- Blood Collection
- Component Storage and Transportation
- Visual Inspection of components
- Thawing and Pooling Blood Components
- Further possibilities.
- See Further Reading for more details about existing and proposed strategies being investigated
Blood Donor Screening
Strategies include deferral of potential donors for the following conditions:
- elevated temperature
- recent dental work
- not feeling well
- cold, flu, infection, or sore throat
- on antibiotics.
Blood Collection
Most bacteria found in platelets are normal skin flora, emphasizing the importance of aseptic blood collection techniques with careful skin sterilization.
Despite precautions, it may be almost impossible to decontaminate human skin. As well, needle coring may result in a small core of patient skin entering the needle at the time of blood collection and viable bacteria may be associated with deeper layers of skin, despite adequate surface disinfection. CBS has recently introduced whole blood collection bags with a sample diversion pouch for removal of an initial aliquot of 30-40 mL of donor blood. This approach reduces, but does not entirely eliminate, the rate of contamination by skin flora. However it does not decrease the rate of bacterial contamination due to other potentially more serious causes, in particular asymptomatic donor bacteremia.
Blood Component Storage and Transportation
Proper pretransfusion storage and transportation are critical to preventing bacterial growth in blood components that may be contaminated.
Policies must be in place to monitor and document the temperature of blood components, blood product storage equipment (e.g., refrigerators, freezers, platelet incubators), and transportation containers and take corrective action when necessary.
Visual Inspection
All blood components should be visually inspected upon labelling and entry into blood centre inventory, issue from the blood center, and prior to release for transfusion from the transfusion service. See an example of visual inspection criteria suitable for use in a transfusion service.
Individual hospital transfusion services may employ slightly different criteria as authorized by the medical director of the transfusion service.
Thawing & Pooling Blood Components
Several criteria relate to preventing bacterial contamination when transfusing, pooling, and thawing components. For example:
- When platelets are pooled immediately prior to transfusion, the product must be issued for transfusion within four hours.
- If RBC units are opened they must be transfused within 24 hours with appropriate storage in a controlled refrigerator until transfusion.
- Once transfusion is begun, a blood component should be transfused within four hours.
- Water baths used to thaw plasma and cryoprecipitate should be emptied and disinfected regularly. Donor units can be further protected from possible contamination by thawing components in plastic over-wraps.
NOTE: Frozen products must be thawed in the transfusion service according to standard operating procedures and specialized equipment and must NOT be thawed on hospital wards, unless the procedure is properly controlled and plasma thawing equipment is used.
Further Possibilities
Research on further ways to reduce transfusion-related transmission of bacteria and other organisms includes bacterial detection systems and pathogen inactivation.
Several methods for bacterial detection have been investigated, including visual inspection, culture, Gram's staining or acridine orange staining, PCR, chemiluminescence-linked rRNA hybridization, and urine reagent strips (to measure pH and glucose consumption). The American Association of Blood Banks (AABB) has recently published an Association Bulletin advising its membership on the use of those techniques. (See further reading)
Several pathogen inactivation methods are under investigation. These methods involve the exposure of blood components to reagents such as psoralen, riboflavin, dimethylmethylene blue and inactine in order to inactivate a variety of pathogens including viruses, bacteria, protozoa and fungi.
Bacterial Sepsis: Further Reading
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- American Association of Blood Banks. Requirement for the implementation of bacterial detection methods. AABB Bulletin March 3, 2004.
- America's Blood Centers. Bacterial contamination of blood components. (pdf file) Blood Bulletin Jul 2000;3(2).
- Blajchman MA, Goldman M. Bacterial contamination of platelet concentrates: incidence, significance, and prevention. Semin Hematol 2001 Oct; 38(4 Suppl 11): 20-6. [ Medline ]
- Blajchman MA, Goldman M, Baeza F. Improving the bacteriological safety of platelet transfusions. Transfus Med Rev. 2004 Jan;18(1):11-24. [ Full Text ] [ Medline ]
- Brecher ME, Holland PV, Pineda AA, Tegtmeier GE, Yomtovian R. Growth of bacteria in inoculated platelets: implications for bacteria detection and the extension of platelet storage. Transfusion. 2000 Nov;40(11):1308-12. [ Full text ] [ Medline ]
- CDC. Assessment of the frequency of blood component bacterial contamination associated transfusion reaction. (slide show outlining the BaCon Study Adverse Reaction in USA from 1997-2000) Also see recipient adverse reaction forms.
- Chang AH, Kirsch CM, Mobashery N, Johnson N, Levitt LJ. Streptococcus bovis septic shock due to contaminated transfused platelets. Am J Hematol. 2004 Nov; 77(3): 282-6. [Medline]
- Goldman M, Blajchman MA. Bacterial contamination. In: Popovsky MA, ed. Transfusion reactions, 2nd ed. Bethesda, MD: AABB Press;2001. p.129-54.
- Golubic-Cepulic B, Budimir A, Plecko V, Plenkovic F, Mrsic M, Sarlija D, Vuk T, Skrlin J, Kalenic S, Labar B. Morganella morganii causing fatal sepsis in a platelet recipient and also isolated from a donor’s stool. Transfus Med. 2004 Jun; 14(3): 237-40. [Medline]
- Hillyer CD, Josephson CD, Blajchman MA, Vostal JG, Epstein JS, Goodman JL. Bacterial contamination of blood components: risks, strategies, and regulation: Joint ASH and AABB Educational Session in Transfusion Medicine. Hematology (Am Soc Hematol Educ Program). 2003;:575-89. [ Medline ]
- Jafari MJ, Forsberg J, Gilcher RO, Smith JW, Crutcher JM, McDermott M, Brown BR, George JN. Salmonella sepsis caused by a platelet transfusion from a donor with a pet snake. NEJM Oct 3, 2002: 14 Vol 347: 1075-1078.
- Kim DM, Brecher ME, Bland LA, Estes TJ, Carmen RA, Nelson EJ. Visual identification of bacterially contaminated red cells. Transfusion 1992 Mar-Apr;32(3):221-5. [ Medline ]
- Kopko PM, Holland PV. Mechanisms of severe transfusion reactions. Transfus Clin Biol 2001 Jun;8(3):278-81. [ Medline ]
- Kuehnert MJ, Roth VR, Haley NR, Gregory KR, Elder KV, Schreiber GB, et al. Transfusion-transmitted bacterial infection in the United States, 1998 through 2000. Transfusion 2001 Dec; 41(12): 1493-9. [ Full text ] [ Medline ]
- Lee, JH. Workshop on Bacterial Contamination of Platelets. CBER, FDA September 24, 1999.(June 1, 2000).
- Reading FC, Brecher ME. Transfusion-related bacterial sepsis. Curr Opin Hematol. Nov. 2001;8(6)380-6. [ Medline ]
- Roth VR, Kuehnert MJ, Haley NR, Gregory KR, Schreiber GB, Arduino MJ, et al. Evaluation of a reporting system for bacterial contamination of blood components in the United States. Transfusion 2001 Dec; 41(12): 1486-92. [ Full text ] [ Medline ]
- Wagner SJ. Transfusion-transmitted bacterial infection: risks, sources and interventions. Vox Sang. 2004 Apr; 86(3): 157-63.
Transfusion-Related Acute Lung Injury (TRALI)
By Tanya Petraszko, MD FRCPC and Heather Hume, MD FRCPC
Description and Incidence
Transfusion-Related Acute Lung Injury (TRALI) is a syndrome characterized by acute respiratory distress following transfusion. All plasma-containing blood products have been implicated including rare reports of IVIG and cryoprecipitate. It is a rare complication of allogeneic blood transfusion but the incidence has not been well established due to difficulty in defining the syndrome and to variable reporting mechanisms worldwide. Various studies have estimated the overall frequency of TRALI to be between 1/1,120 and 1/57,810 units transfused. However, there is wide discrepancy in the literature with the reported frequency is as low as 1/557,000 RBC units and as high as 1/432 platelet units.
TRALI is associated with a high morbidity with the majority of patients requiring ventilatory support. However, the lung injury is generally transient with PO2 levels returning to pretransfusion levels within 48 -96 hours and CXR returning to normal within 96 hours. TRALI is associated with a significant mortality rate, often approximated at 5 to 10%. Given the gains in safety made within the blood component production industry, particularly with respect to transmission of infectious diseases, TRALI is now among the three leading causes of transfusion related fatalities along with ABO incompatibility and bacterial contamination.
Clinical Presentation - Transfusion-Related Acute Lung Injury (TRALI)
By Tanya Petraszko, MD FRCPC and Heather Hume, MD FRCPC
Symptoms of TRALI typically develop during, or within 6 hours of a transfusion. Patients present with the rapid onset of dyspnea and tachypnea. There may be associated fever, cyanosis, and hypotension. Clinical exam reveals respiratory distress and pulmonary crackles may be present with no signs of congestive heart failure or volume overload. CXR shows evidence of bilateral pulmonary edema unassociated with heart failure (non-cardiogenic pulmonary edema), with bilateral patchy infiltrates, which may rapidly progress to complete "white out" indistinguishable from Acute Respiratory Distress Syndrome (ARDS).
Treatment and Clinical Course - Transfusion-Related Acute Lung Injury (TRALI)
By Tanya Petraszko, MD FRCPC and Heather Hume, MD FRCPC
Treatment of TRALI is supportive. Mild forms of TRALI may respond to supplemental oxygen therapy. Severe forms may require mechanical ventilation and ICU support. As with ARDS there is no role for diuretics or corticosteroids. The majority of patients recover within 72 to 96 hours and subsequently recover to their baseline pulmonary function without apparent sequelae. However, some patients are slower to recover and may remain hypoxic with persistent pulmonary infiltrates up to seven days. As stated above, approximately 5 to 10% of cases are fatal in spite of aggressive supportive care.
Differential Diagnosis
The differential diagnosis of acute lung injury after transfusion includes transfusion-associated circulatory overload (TACO), cardiogenic edema, allergic and anaphylactic transfusion reactions, and bacteremia/sepsis due to transfusion of bacterially contaminated blood products.
TRALI may be distinguished from TACO and cardiogenic pulmonary edema by the absence of signs of circulatory overload such as a normal central venous pressure (CVP) and normal pulmonary capillary wedge pressure (PCWP). Clinical response to diuretics also suggests a diagnosis of TACO rather than TRALI. Allergic and anaphylactic transfusion reactions may be manifest as hypotension and respiratory distress but are marked by laryngeal edema or bronchospasm with wheezing and a normal CXR. Transfusion transmitted bacteremia my present with fever, hypotension, and culminate in severe sepsis with associated acute lung injury which may be difficult to distinguish from TRALI. The presence of positive blood cultures is a useful delineating finding.
Pathophysiology
The hallmark of acute lung injury (ALI) is that of increased pulmonary microvascular permeability with increased protein in the edema fluid. This is true regardless of the cause of the ALI.
It is hypothesized that TRALI may be precipitated by the infusion of donor antibodies directed against recipient leukocytes. The infusion of donor anti-HLA (human leukocyte antigens) or anti-HNA (human neutrophil antigens) antibodies is thought to directly cause complement activation, resulting in the influx of neutrophils into the lung, followed by neutrophil activation and release of cytotoxic agents, with subsequent endothelial damage and capillary leak. Donor derived antibodies to HLA class I antigens and neutrophils have been demonstrated in up to 89% of TRALI cases examined in the literature.
An alternate hypothesis argues that TRALI is the result of at least two independent clinical events: the first is related to the clinical condition of the patient (infection, cytokine administration, recent surgery, or massive transfusion) that causes activation of the pulmonary endothelium. This then leads to the sequestration of primed neutrophils to the activated pulmonary endothelium. The second event is the infusion of donor derived anti-HLA or anti-HNA antibodies directed against antigens on the neutrophil surface and/or biological response modifiers (e.g., lipids) in the stored blood component that activate these adherent, functionally hyperactive neutrophils, causing neutrophil-mediated endothelial damage and capillary leak. Many studies in the literature support this hypothesis which may explain how some TRALI reactions occur in the absence of donor HLA/HNA antibodies, or why TRALI reactions do not occur in all recipients of blood components from donors who are known to have these antibodies.
Yet a third hypothesis suggests that high levels of donor derived vascular endothelial growth factor (VEGF) or antibodies to class II HLA antigens residing on pulmonary vascular endothelium may directly cause endothelial shape change and fenestration. This theory purports to explain the syndrome in neutropenic patients.
Identification and Definition - Transfusion-Related Acute Lung Injury (TRALI)
By Tanya Petraszko, MD FRCPC and Heather Hume, MD FRCPC
Identifying TRALI
It is imperative that medical personnel and hospitals identify suspected cases of TRALI and report them to Canadian Blood Services. The reporting of TRALI allows us to better understand the true incidence of this reaction, in addition to its clinical course and associated mortality. Further, by identifying cases of TRALI , CBS can take steps to prevent further cases of TRALI by removing companion components of units that may have caused the reaction and by investigating donors involved in these cases and deferring them from further donations if they are found to be implicated as outlined below.
Definition
Canadian Blood Services has adopted the definition put forth by the Canadian Consensus Conference Panel on TRALI as outlined below. This definition is applied consistently to all cases of TRALI reported to CBS and is used to determine whether reported cases will be investigated.
|
Table 1: Canadian Consensus Conference Panel TRALI definitions
|
| Term |
Definition |
| TRALI |
Acute lung injury (defined below) occurring within 6 hours of completion of transfusion of blood component.
No pre-existing acute lung injury.
No other temporally associated risk factors for acute lung injury (see below). |
| Possible TRALI |
Acute lung injury (defined below) occurring within 6 hours of completion of transfusion of blood components. No pre-existing acute lung injury. One of more temporally associate risk factors for acute lung injury. |
|
Table 2: Definition of Acute Lung Injury (ALI)
|
| Term |
Definition |
| Acute Lung Injury |
New onset
Hypoxemia SpO2 <90% or Pa02/Fi02 < 300 mm Hg on room air, or other clinical evidence of hypoxemia
Bilateral infiltrates on frontal chest X-ray |
|
Table 3: Risk Factors for Acute Lung Injury
|
| Direct Lung Injury |
Indirect Lung Injury |
Aspiration
Pnuemonia
Toxic inhalation
Lung contusion
Near drowning |
Severe sepsis
Shock
Multiple trauma
Burn injury
Acute pancreatitis
Cardiopulmonary bypass
Drug overdose |
Because the diagnosis of Acute Lung Injury (ALI) can be difficult, it is important for the transfusion service medical director and the patient’s physician to communicate to determine, in particular, whether a patient has evidence of volume overload. Although ALI and hydrostatic pulmonary edema may coexist, the latter is a more common complication of transfusion and must be excluded in order for a diagnosis of TRALI or possible TRALI to be made.
Prevention - Transfusion-Related Acute Lung Injury (TRALI)
By Tanya Petraszko, MD FRCPC and Heather Hume, MD FRCPC
Hospitals
It is unlikely that TRALI can ever be entirely prevented, but its frequency may be reduced by the judicious use of blood components only for indications that are justified based on sound medical evidence. Hospitals should have procedures in place (e.g. blood utilization guidelines, blood conservation programs) which minimize unnecessary transfusions. In addition, hospital medical staff must continue to have a high index of suspicion in order to diagnose TRALI appropriately. All cases of TRALI or possible TRALI should be reported to Canadian Blood Services (in addition to the Provincial/Territorial Surveillance office as part of the TTISS program) who in turn is required to report all possible TRALI or possible TRALI cases to Health Canada.
Reporting
Cases of suspected TRALI should be reported to CBS using standard procedure for reporting Adverse Reactions. In order to correctly and consistently diagnose TRALI, the following information must be included in the report:
- Timing of transfusion with respect to symptom onset
- Presence of other risk factors for acute lung injury (see Table 3)
- CXR findings
- Evidence of hypoxia: PaO2 or SaO2
- Clinical indicators of volume status such as clinical evaluation, response to diuretics (if given), or where available JVP, PCWP, CVP, echocardiogram report etc.
In addition to the standard procedure for reporting adverse event, and in order to fully investigate and identify TRALI cases; patient samples must be sent for further testing. Complete the TRALI Patient Data form and forward the original as instructed to the local CBS site and photocopy of the form with samples to the named testing laboratory. TRALI Patient Data Form
Blood Supplier
Recognizing that donor derived antibodies may be one of the causes of TRALI, CBS has adopted a standardized, national donor management strategy in an attempt to improve the safety of the blood supply for Canadians by reducing the risk of TRALI.
Secondary Prevention
Secondary prevention refers to the management of donors whose donations have been temporally associated with a TRALI or possible TRALI reaction. In order to evaluate such donors and their continued eligibility to donate, the following definitions apply:
|
Table 4: Definition of Donors Temporally linked with TRALI or possible TRALI
|
| Term |
Definition |
| Implicated Donor |
A donor is implicated in TRALI if they have demonstrated antibodies to an HLA Class I or II antigen or HNA; the antibody must have specificity for an antigen present on the recipient’s WBCs or there must be a positive reaction noted between donor serum and recipient WBCs, a positive crossmatch. |
| Associated Donor |
A donor is associated with a TRALI reaction if a blood component was transfused during the six hours preceding the first clinical manifestation of TRALI. |
The disposition of donors associated with or implicated in a TRALI reaction is provided in the following table:
|
Table 5: Disposition of Donors Involved in a Reported TRALI
|
| Donor |
Test Results |
Disposition |
| Implicated donor |
Positive as per definition |
Defer |
| Associated donor |
Negative |
Washed RBC
Plasma for fractionation |
 |
Positive for HLA antibodies but recipient crossmatch not available |
Washed RBC
Plasma for fractionation |
|
Positive for HNA antibodies |
Defer |
Note CBS is currently implementing more sensitive testing methods which will allow donors who test negative to be redefined as not-implicated. Donors who are not implicated following a TRALI investigation will be able to continue to donate without restriction.
Primary Prevention
Primary prevention refers to measures taken to reduce TRALI that are unassociated with a particular TRALI event. In the fall of 2007, the AABB published the recommendation that “...blood collecting facilities should implement interventions to minimize the preparation of high plasma-volume components from donors known to be leukocyte-alloimmunized (i.e. donors with antibodies to leukocytes) or who are at increased risk of leukocyte alloimmunization”.
In an effort to reduce the incidence of TRALI, Canadian Blood Services has implemented several measures to institute the use of predominantly male plasma for preparation of high-volume plasma components and to reduce the use of plasma from donors at high risk for HLA immunization, particularly previously pregnant females.
TRALI reduction measures began with the use of predominantly male plasma for production of Frozen Plasma, Fresh Frozen Plasma, cryosupernatant plasma and plasma for resuspension of platelet pools in October 2007.
In March 2008 these measures were expanded to include predominately male apheresis plasma donations.
On July 20, 2009 CBS began collecting apheresis platelets from males and females without a history of pregnancy.
The majority of plasma made from female whole blood donors is sent to the fractionator to be processed into plasma protein products such as intravenous immunoglobulin (IVIG) and albumin.
CBS no longer issues plasma or platelets made from female directed donors unless there is a clear medical indication for their use and after consultation and approval of the site Medical Director. Red cells may be issued from female directed donors as well as red cells, platelets and plasma, as required, from male directed donors.
Despite the move towards predominantly male plasma for transfusion, female plasma from female donors continues to be critically important to support the blood product needs of Canadian patients and may still be issued to meet group or component specific urgent shortfalls eg, Group group AB FFP, HLA or HPA matched platelets, IgA deficient donors.
The CBS TRALI Review Group
The TRALI Medical Review Group (TMRG) was established at Canadian Blood Services in 2006 as a national resource team to assist physicians at CBS in the management of reported TRALI cases. The TMRG is available to CBS physicians to review the results of TRALI investigations, to determine donor management in cases where the results are not straightforward, to assist CBS physicians in applying the definition of TRALI consistently and investigating/managing donors when the diagnosis is not immediately apparent. In addition, the TMRG is responsible for developing national policies with respect to the investigation of TRALI within CBS, for developing educational strategies for hospitals, community physicians and other health care providers and health authorities with respect to TRALI identification and reporting.
Members of the TMRG include Dr B. Hannach (Toronto), Dr T. Petraszko (Vancouver), Dr K. Webert (Hamilton), Dr Y Lin (Toronto), Dr C Saw (Winnipeg), Dr M Goldman (Ottawa) , Dr. J. Hannon (Edmonton) and Dr. D. Towns (Calgary).
Further Reading - Transfusion-Related Acute Lung Injury (TRALI)
This is a comprehensive list of pertinent TRALI related articles where the reader may find further information.
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
Recent Reviews
-
Marik PE, Corwin, HL. Acute lung injury following blood transfusion: Expanding the definition. Crit Care Med 2008; 36 (11): 3080- 84.
-
Triulzi, DJ. Transfusion Related Acute lung injury: current concepts for the clinician. Anesthesia and analgesia. 2009;108 (3): 770-76
- Chapman CE, Stainsby D, Jones H, Love E, Massey E, Win N, Navarrete C, Lucas G, Soni N, Morgan C, Choo L, Cohen H, Williamson LM. Ten years of hemovigilance reports of transfusion-related acute lung injury in the United Kingdom and the impact of preferential use of male donor plasma. Transfusion. 2008 Oct 28. [Epub ahead of print]
- Silliman CC, McLaughlin NJ.Transfusion-related acute lung injury. Blood Reviews 2006; 20(3):139-59.
- Silliman CC, Ambruso DR, Boshkov LK. Transfusion-related acute lung injury. Blood 2005; 105(6):2266-73.
- Bux J.Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sanguinis 2005; 89(1):1-10.
- Shander A, Popovsky MA. Understanding the consequences of transfusion-related acute lung injury. Chest.2005; 128(5 Suppl 2):598S-604S.
Definition/Consensus articles
- Toy P, Popovsky MA, Abraham E, Ambruso DR, Holness LG, Kopko PM, McFarland JG, Nathens AB, Silliman CC, Stroncek D; National Heart, Lung and Blood Institute Working Group on TRALI. Crit Care Med. 2005;33(4):721-6.
- Kleinman S, Caulfield T, Chan P, Davenport R, McFarland J, McPhedran S, Meade M, Morrison D, Pinsent T, Robillard P, Slinger P. Toward an understanding of transfusion-related acute lung injury: statement of a consensus panel. Transfusion. 2004;44(12): 1774-89.
- Skeate RC, Eastlund T. Distinguishing between transfusion related acute lung injury and transfusion associated circulatory overload. Current Opinion in Hematology. Nov 2007; 14(6):682-687.
- Gajic O, Gropper MA, Hubmayr RD. Pulmonary edema after transfusion: How to differentiate transfusion-associated circulatory overload from transfusion-related acute lung injury. Crit Care Med. 2006;34(5) Suppl:S109-S113.
Pathogenesis
- Jacobi KE, Wanke C, Jacobi A, Weisbach V, Hemmerling TM. Determination of Eicosaniod and cytokine production in salvaged blood, stored red blood cell concentrates, and whole blood. J Clin Anesth 12: 94-99, 2000.
- Kopko PM, Paglieroni TG, Popovsky et al. TRALI: correlation of antigen-antibody and monocyte activation in donor-recipient pairs. Transfusion 2003;43:177-184.
- Densmore, TL, Goodnough, LT, Ali S, Dynis M, Chaplin H. Prevalence of HLA sensitization in female apheresis donors. Transfusion 1999; 39:103-6.
Pathophysiology of TRALI
- Silliman CC, Curtis BR, Kopko PM, et al. Donor antibodies to HNA-3a implicated in TRALI reactions prime neutrophils and cause PMN-mediated damage to human pulmonary microvascular endothelial cells in a two-event in vitro model. Blood. 2007;109(4): 1752-1755.
- Curtis BR, McFarland JG. Mechanisms of transfusion-related acute lung injury (TRALI): anti-leukocyte antibodies. Critical Care Medicine. 2006; 34(5 Suppl):S118-23.
- Silliman CC.The two-event model of transfusion-related acute lung injury. Critical Care Medicine. 2006; 34(5 Suppl):S124-31.
- Toy P, Hollis-Perry KM, Jun J, Nakagawa M. Recipients of blood from a donor with multiple HLA antibodies: a lookback study of transfusion-related acute lung injury. Transfusion. 2004 Dec; 44(12): 1683-8.
- Kopko PM. Leukocyte antibodies and biologically active mediators in the pathogenesis of transfusion-related acute lung injury. Curr Hematol Rep. 2004 Nov;3(6): 456-61.
- Silliman CC, Bjornsen AJ, Wyman TH, Kelher M, Allard J, Bieber S, Voelkel NF. Plasma and lipids from stored platelets cause acute lung injury in an animal model. Transfusion. 2003 May; 43(5): 633-40.
- Silliman CC, Boshkov LK, Mehdizadehkashi Z, Elzi DJ, Dickey WO, Podlosky L, Clarke G, Ambruso DR. Transfusion-related acute lung injury: epidemiology and a prospective analysis of etiologic factors. Blood. 2003; 101(2): 454-62
Prevention/Donor Management
-
Triulzi DJ, Kleinman S, Kakaiya RM et al. The effect of previous pregnancy and transfusion on HLA alloimmunization in blood donors: implications for a transfusion related acute lung injury risk reduction strategy. Transfusion 2009; 49(9):1825-35.
- Engelfriet CP, REesink HW, Wendel S et al. Measures to prevent TRALI. Vox Sang 2007; 92 (3): 258-77.
- AABB association bulletin #05-09
- AABB association bulletin #06-07
For Nurses
- Knippen MA. Transfusion-related acute lung injury. Am J Nursing. 2006;106(6):61-4.
Older Reviews
- Kopko PM. Review: transfusion-related acute lung injury: pathophysiology, laboratory investigation, and donor management. Immunohematol. 2004; 20(2): 103-11.
- Looney MR, Gropper MA, Matthay M. Transfusion-related acute lung injury: a review. Chest. 2004 Jul; 126(1): 249-58.
- Webert KE, Blajchman MA. Transfusion-related acute lung injury. Transfus Med Rev. 2003 Oct; 17(4): 252-62.
- Toy P, Gajic O. Transfusion-related acute lung injury. Anesth Analg. 2004 Dec; 99(6): 1623-4.
Massive Transfusion
Description
Massive transfusion is generally defined as the rapid administration of large volumes of blood (in an adult, >5 L, ≥10 units RBC's, or >1 blood volume) in a 24-hour period. This may result in several adverse effects which must be monitored and corrected in order to minimize patient mortality and morbidity.
Clinical Presentation
Complications of massive transfusion are dependent on the number of units transfused, the rate of transfusion, and factors intrinsic to the patient. They can be discussed in three categories:
- Hypothermia
- Metabolic
- Hemostatic
Massive Transfusion Policies
Many hospitals have policies that allow for:
- Abbreviated crossmatch methods when the amount equivalent to blood volume has been given within 24 hours (this is usually 10-12 red blood cell units for an adult).
- Switching to another compatible ABO blood type when group specific blood components are unavailable.
- Switching Rh negative patients to Rh positive blood components when Rh negative blood components are unavailable or in short supply.
Complications and management of massive transfusion in a table format
|
Complication
|
Mechanisms
|
Management
|
|
Coagulopathy
|
- Dilution
- Depletion
- Disseminated Intravascular Coagulation (DIC)
|
Monitor patient coagulation parameters
- If INR/aPTT is ≥ 1.5-2.0 consider transfusing FFP
- If fibrinogen is < 1.0 g/L consider transfusing cryoprecipitate
|
|
Thrombocytopenia
|
- Dilution
- Depletion
- Disseminated Intravascular Coagulation (DIC)
|
Monitor patient platelet counts
- If platelet count falls below 50 X 10/L consider transfusing platelets
|
|
Hypothermia
|
- Infusion of cold IV fluids and blood products
|
Monitor patient temperature
- Consider warming the patient and/or blood components
|
|
Hypocalcemia
|
- Calcium chelation by citrate
|
Monitor the patient for arrhythmias and calcium levels
- Initiate intravenous calcium therapy if indicated
|
|
Hyperkalemia
|
- Rapid transfusion of older cells (potassium concentration increases in RBC units with storage time and after irradiation; neonates may be more susceptible)
|
Monitor patient electrolytes and ECG; consider treatment to lower serum potassium |
|
Metabolic Acidosis
|
- Shock
- Acid pH of blood components
|
Monitor patient pH, and correct imbalance if indicated |
Adapted with permission from the Transfusion Manual for Nursing Units from St. Michaels Hospital, Toronto Ontario. Canada.
Hemostatic Abnormalities in Massive Transfusion
Description
Clinically significant haemostatic abnormalities complicating massive transfusion can occur due to dilution and depletion of coagulation proteins and platelets.
Decreased platelet counts may complicate massive transfusion of components which do not contain platelets. Thrombocytopenia is usually not as severe as predicted by simple hemodilution. With red blood cell replacement for loss of up to one blood volume, clotting factor levels may be reduced to 25% of normal and PT INR measurements may be slightly prolonged without clinical coagulopathy.
50% of massively transfused patients develop an INR >2.0 and about 33% have thrombocytopenia with a platelet count <50 x 109/L. Disseminated intravascular coagulation (DIC) occurs in 5-30% of massively transfused trauma patients.
Further Reading
Clinical Presentation -Hemostatic Abnormalities in Massive Transfusion
The number of RBCs transfused does not accurately predict the need for platelet and coagulation factor transfusion.
Patient condition (including ongoing bleeding) as well as laboratory investigation should help determine the need for component therapy.
Further Reading
Investigation - Hemostatic Abnormalities in Massive Transfusion
Patient condition and the likelihood of ongoing bleeding will help to interpret the laboratory results and aid determination of transfusion therapy. Laboratory investigation can include haemoglobin, hematocrit, platelet count, INR, aPTT, fibringogen, and D-dimer.
Further Reading
Treatment - Hemostatic Abnormalities in Massive Transfusion
If the patient is actively bleeding, transfuse to keep the platelet count >50 x 109/L, INR ≤ 1.5-2.0 and fibrinogen >1.0g/L. (Head injury patients should have a platelet count >100 x 109/L). Component therapy (RBC, platelets, FFP, and cryo) should not be administered in a fixed ratio to the number of red cells transfused. It should be noted that a normothermic, normovolemic patient with a hematocrit >0.35 is more likely to maintain optimal haemostasis.
Further Reading
Reporting - Hemostatic Abnormalities in Massive Transfusion
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Further Reading
Prevention - Hemostatic Abnormalities in Massive Transfusion
There is no specific measure to prevent the hemostatic complications of massive transfusion. Factors causing ongoing bleeding should be addressed. Normothermia, normovolemia, and an optimal hematocrit should be maintained. Platelets and coagulation factors should be replaced as indicated.
Further Reading
Metabolic Complications of Massive Transfusion
Description
Potential metabolic abnormalities secondary to massive transfusion include hypocalcemia, hypomagnesemia, metabolic alkalosis, hyperkalemia or hypokalemia.
Citrate Toxicity: hypocalcemia, hypomagnesemia, metabolic alkalosis
Blood components are anticoagulated with sodium citrate. It is rapidly metabolized by the liver, and a normothermic adult can tolerate the citrate in a unit of plasma or several units of red blood cells given every five minutes. When transfused, citrate may bind with circulating ionic calcium and magnesium. During massive transfusion, the capacity of the liver to metabolize citrate may be overwhelmed, and potentiated by hypothermia or hypotension, particularly in the presence of underlying liver disease, leading to hypocalcemia and/or hypomagnesemia. Metabolic alkalosis may also develop secondary to the accumulation of bicarbonate, the metabolic by-product of citrate.
Metabolic acidosis
Metabolic acidosis is rare. It may be caused from the acid pH of blood products, and aggravated by lactic acidosis seen in patients with tissue hypoxia.
Hyperkalemia or Hypokalemia
Potassium release from red cells increases during storage, and after irradiation. Levels of up to 80 mmol/L may be reached in a unit of red blood cells. Massive transfusion may lead to hyperkalemia, which can cause cardiac arrhythmias or myocardial depression. Young infants are the most susceptible patients, particularly if stored blood is transfused rapidly into a central line.
Paradoxically, hypokalemia has also been described with massive transfusion. Possible causes include metabolic alkalosis secondary to citrate metabolism and re-accumulation of potassium in transfused potassium-depleted RBCs.
Further Reading
Clinical Presentation - Metabolic Complications of Massive Transfusion
Metabolic complications of massive transfusion may cause multi-system, non-specific abnormalities in cardiac function, muscular function, and tissue oxygenation. Diagnosis is made by ongoing laboratory monitoring.
Blood components are anticoagulated with sodium citrate. It is rapidly metabolized by the liver, and a normothermic adult can tolerate the citrate in a unit of plasma or several units of red blood cells given every five minutes. When transfused, citrate may bind with circulating ionic calcium and magnesium. During massive transfusion and particularly in the presence of diffuse liver disease and/or hypothermia and hypotension, the capacity of the liver to metabolize citrate may be overwhelmed. Citrate toxicity may lead to a functional hypocalcemia and hypomagnesemia. Metabolic alkalosis may develop secondary to the accumulation of bicarbonate, the metabolic by-product of citrate.
Potassium release from red cells increases during storage, and after irradiation. Levels of up to 80 mEq/L may be reached in a unit of red blood cells. Massive transfusion may lead to hyperkalemia, which can cause cardiac arrhythmias or myocardial depression. Hypokalemia, possibly due to alkalosis, catecholamine effects, and intracellular influx, may also complicate massive transfusion.
Metabolic acidosis is rare. It may be caused from the acid pH of blood components and aggravated by lactic acidosis seen in patients with tissue hypoxia.
Clinical symptoms of electrolyte abnormalities include hypotension, decreased ventricular function, decreased pulse pressure, i.e., the difference between the systolic BP and the diastolic BP, increased pulmonary artery pressure, neuroexcitability, tetany (muscular irritability or spasms), paresthesia (abnormal sensation), and arrhythmias.
Further Reading
Investigation - Metabolic Complications of Massive Transfusion
Ongoing monitoring of serum electrolytes, and acid-base status should take place in patients undergoing massive transfusion, including serum potassium, calcium, and magnesium. Myocardial function should be monitored, including ECG, blood pressure, central venous pressure, and pulmonary artery pressure.
Further Reading
Treatment - Metabolic Complications of Massive Transfusion
If hypocalcemia develops, or the patient develops signs or symptoms of hypocalcemia, administer one gram of calcium chloride IV. Measures to normalize serum potassium, magnesium, and acid base should be undertaken according to laboratory values. As always, normothermia should be maintained.
Further Reading
Reporting - Metabolic Complications of Massive Transfusion
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Further Reading
Prevention - Metabolic Complications of Massive Transfusion
The abnormalities described in the Clinical Presentation of metabolic complications of massive transfusion should be anticipated, and ongoing monitoring and correction of the patient's electrolytes and acid base status should be undertaken before extreme abnormalities occur.
Further Reading
Hypothermia due to Massive Transfusion
Red blood cells are stored at 2 - 6 °C. Blood does not require warming for most routine transfusions. However, rapid, massive transfusion may result in clinically significant hypothermia (body temperature <35 °C.), particularly in paediatric patients. In addition, cardiac arrhythmias are reported to be increased in anaesthetized patients receiving massive transfusions of cold blood.
The incidence of transfusion-induced hypothermia associated with massive transfusion is unknown.
Further Reading
Clinical Presentation - Hypothermia due to Massive Transfusion
Hypothermic patients experience increased morbidity and mortality. Hypothermia (body temperature < 35 °C) may reduce platelet and coagulation function, decrease citrate metabolism, increase hemoglobin-oxygen affinity, decrease myocardial function, (hypotension; decreased cardiac output) and predispose to cardiac arrhythmias and ECG changes.
Further Reading
Investigation - Hypothermia due to Massive Transfusion
Core body temperature should be constantly measured during massive transfusion. Awareness of the clinical consequences of hypothermia (body temperature < 35° C) requires ongoing monitoring of: BP, ECG, and coagulation function.
Further Reading
Treatment - Hypothermia due to Massive Transfusion
Treatment of hypothermia focuses on raising the patient's core body temperature. A variety of warming devices are available for clinical use. Clinicians should familiarize themselves with available equipment in their institution.
Other sequelae of massive transfusion (cardiac, metabolic, and haemostatic) must also be assessed and treated.
Further Reading
Reporting - Hypothermia due to Massive Transfusion
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Further Reading
Prevention - Hypothermia Related to Massive Transfusion
An approved blood warmer should be used if massive transfusion is likely. Other measures to keep the patient warm should also be employed. If blood is warmed by any method, there must be careful attention to prevent excessive warming beyond 38 °C, which can cause hemolysis of red blood cells. Any warming device should be subject to regular checks of temperature control.
Further Reading
Massive Transfusion: Further Reading
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Popovsky, MA, ed., Transfusion Reactions, Second Edition, Bethesda MD, AABB Press, 2001, Ch 13: Complications of Massive Transfusion pp 339-357.
- Brecher, ME, ed., AABB Technical Manual, 14th ed., Bethesda MD, AABB Press, 2002, Ch 21: Blood Transfusion practice pp 476-478.
- Gutierrez G, Reines HD, Wulf-Gutierrez ME. Clinical review: hemorrhagic shock. Crit Care. 2004 Oct;8(5): 373-81. [Medline]
- Mintz, PD, ed., Transfusion Therapy, Clinical Principles and Practice, Bethesda MD, AABB Press, 2001; Ch 9 Transfusion in Surgery and Trauma pp 183-190.
- Hardy J-F et al. Massive transfusion and coagulopathy: pathophysiology and implications for clinical management. Can J Anesth 2004; 51:4 ; 293-310.
Adverse Interactions with Medications and Solutions
Description
Several medications and IV solutions, if mixed with red cells in a confined space such as a unit of blood or infusion tubing, may result in adverse effects. No medications or solutions may be routinely added to or infused through the same tubing with blood or blood components, except 0.9% Sodium Chloride Injection (USP). ABO-compatible plasma or 5% Albumin may be used with the approval of the patient’s physician.
The following solutions have known adverse effects on blood components:
- hypotonic solutions (e.g., 5% dextrose) may cause red cells to Iyse
- calcium (e.g., Ringer's Lactate) may cause red cells and plasma to clot
Other solutions intended for intravenous use may be used in an administration set or added to blood or components only under either of the following conditions:
- they have been approved for this use by Health Canada, or
- there is documentation available to show that addition to the component involved is safe and efficacious.
Hypotonic solutions, in particular D5W, or electrolyte solutions containing calcium, such as Lactated Ringer’s Injection (USP), should never be added to or administered concurrently with blood or blood components collected in an anticoagulant containing citrate.
Incidence
The incidence of interactions of blood components with medications and solutions is unknown because of lack of reporting mechanisms to detect incidence or lack of recognition of the interaction as a cause of the adverse effect.
Treatment - Adverse Interactions with Medications and Solutions
Treatment of medication/solution interaction with a blood component is usually similar to treatment of non-immune hemolytic transfusion reactions.
Reporting - Adverse Interactions with Medications and Solutions
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Air Embolism
Description
Air embolism occurs when a bubble of air is introduced into the vascular system and obstructs a blood vessel. As little as 100 mL of air introduced rapidly into a vein, may be fatal. The air circulates via the venous system to the right atrium, and right ventricle. This leads to outflow obstruction from the ventricle into the pulmonary system, causing circulatory collapse.
In patients who have any degree of right to left shunting within the heart, (up to 10 per cent of patients in some settings) air can be pumped directly from the venous system (right heart) to the arterial system (left heart). Extremely small amounts of air can cause a stroke if subsequently circulated into the cerebral arterial system.
Air embolism may occur when air is introduced into a blood bag, particularly if it is being transfused under pressure. However, most reported cases associated with blood transfusion occur in association with cell salvage devices, usually because of failure to follow manufacturer's instructions.
The incidence of air embolism associated with conventional transfusion is unknown, but rare. One study showed that the frequency of fatal air embolism after re-administration of recovered blood was approximately 1:30,000-1:38,000 patients transfused.
Clinical Presentation - Air Embolism
Patients with clinically significant air embolism may experience complete circulatory collapse. Cyanosis and petechiae may be observed. Dramatic falls in arterial blood pressure, elevation of central venous pressure (CVP), arrhythmias, and ECG changes may indicate the presence of severe pulmonary air embolism. A characteristic cog wheel or mill wheel murmur may be heard over the precordium.
A patient at risk for air embolism who experiences the above signs and symptoms should be investigated and treated rapidly.
Investigation - Air Embolism
The urgency of the situation may allow little time for investigation. Auscultatory findings by esophageal stethoscope, or Doppler examination, if immediately available, may aid the diagnosis. Arterial and central venous pressures, and end-tidal CO2 levels, as well as clinical suspicion in a setting at high risk for this complication will aid the diagnosis.
Treatment - Air Embolism
Mechanical ventilation with 100% oxygen, positive end-expiratory pressure, pharmacologic circulatory support, and external cardiac massage may be required. Positioning the patient in the left lateral decubitus position, as well as attempting to aspirate the air from the central venous system may be tried but are often ineffective.
Reporting - Air Embolism
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Prevention - Air Embolism
Prevention is paramount in this potentially fatal complication. Due care and attention when administering intravenous fluids and blood products, including the setting of intraoperative cell salvage, should completely eliminate air embolism as a risk of transfusion.
Air Embolism: Further Reading
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Popovsky MA, ed., Transfusion Reactions, Second Edition, Bethesda MD, AABB Press, 2001, p351; 285, 286.
- Brecher, ME, ed., AABB Technical Manual, 14th ed., Bethesda MD, AABB Press, 2002, p 588, 601
- Linden JV, Kaplan HS, Murphy MT. Fatal air embolism due to perioperative blood recovery. Anesth Analg 1997, 84: 422-6.
- Breen PH, Hong A. Beware of air in the blood pump. Anesth Analg 2000; 91:1038.
Circulatory Overload
Description
Circulatory overload is characterized by acute respiratory distress and congestive heart failure. It may occur in patients with reduced cardiac capacity or chronic anemia following rapid or massive transfusion, although it may also occur after transfusion of even a small volume, especially in infants. Adults over 60 and infants are particularly susceptible, as are any patients with severe chronic anemia (e.g., sickle cell anemia, thalassemia) in whom low red cell mass is associated with high plasma volume.
Incidence
The incidence of circulatory overload is unknown and varies with patient population, surveillance vigilance, and whether the major sequelae (acute respiratory distress) was differentiated from TRALI.
Reported incidences vary widely and are in the range of 1 in 100 to 1 in 3000 patients transfused.
Clinical Presentation - Circulatory Overload
Circulatory overload begins within hours of transfusion. General symptoms include headache, dry cough, and chest pain. More specific signs and symptoms include:
- coughing
- wheezing
- dyspnea
- cyanosis
- tachycardia
- hypertension
- pedal edema
- pulmonary edema
Mechanism
Very young or very old patients with underlying congestive heart failure or chronic anemia and an expanded blood volume are most at risk. When too much blood is transfused too quickly, these patients cannot handle the increased volume and develop heart failure and acute pulmonary edema.
Investigation - Circulatory Overload
Transfusion services should have clear policies describing the required investigation for transfusion complications. An example of an immediate investigation shows steps that could be used to investigate any immediate transfusion reaction.
This type of complication is rarely reported to the hospital transfusion service and laboratory investigation is therefore rare unless the symptoms are severe.
Circulatory overload needs to be differentiated from other causes of acute respiratory distress such as anaphylaxis and TRALI as the management of future transfusion is very different in these complications. Both anaphylaxis and TRALI are characterized by hypotension (moderate to severe); TRALI symptoms include a fever and pulmonary edema; anaphylaxis includes a rash but not pulmonary edema.
Treatment - Circulatory Overload
Treatment focuses on providing oxygen support and reducing plasma volume with diuretics (and phlebotomy if symptoms persist).
Pulmonary edema should be promptly and aggressively treated, and infusion of colloid preparations, including plasma in cellular components, reduced to a minimum.
Initial treatment includes
- early recognition;
- stopping the transfusion;
- not transfusing further units;
- keeping the IV line open with saline;
- placing the patient in a sitting position
- initiating early treatment based on symptoms under direction of a physician.
Reporting - Circulatory Overload
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Prevention - Circulatory Overload
Prevention consists of transfusing at-risk patients slowly and with blood components in the most concentrated form.
Except for replacement of acute, massive blood loss, infusion rates should ordinarily be no greater than 2 - 4 mL per kg body weight per hour, and for patients at known risk of hypervolemia, a rate no faster than 1 mL/kg/hr is advisable.
Circulatory Overload: Further Reading
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Popovsky MA. Circulatory overload. In: Popovsky MA, ed. Transfusion reactions, 2nd ed. Bethesda, MD: AABB Press;2001. p. 255-60.
- Popovsky MA, Audet Am, Andrzejewski JRC. Transfusion-associated circulatory overload in orthopedic surgery patients: a multi-institutional study. Immunohematol. 1996 Jun; 12(2): 87-9.[Medline]
Isolated Hypotensive
Description
First described in 1996, this type of reaction is characterized by a hypotensive episode where the primary symptom is an immediate and drastic drop in blood pressure.
It has most commonly been reported following platelet transfusions.
In addition, most reported reactions have occurred with the use of negatively charged bedside leukocyte reduction filters and/or in patients on ACE inhibitor therapy. Similar reactions have been described in patients on ACE inhibitors undergoing therapeutic plasma exchange.
Incidence
No known prospective study has determined incidence. Considered rare but may also be under-recognized.
Clinical Presentation - Isolated Hypotensive
Symptoms typically appear within minutes of initiation of transfusion. Hypotension may be the only symptom and rapid response is seen once the transfusion is stopped. Other symptoms, if present, are minor.
Signs and symptoms include:
Primary
- A hypotensive episode is defined as a drop in systolic and/or diastolic blood pressure of greater than 30 mm Hg.
Secondary (±)
- Dyspnea
- Urticaria
- Flushing
- Pruritis
- Diarrhea
- Nausea
Mechanism
Thought to involve the generation of bradykinin and/or the metabolite des-Arg3-BK. Plasma contact with a negatively charged surface activates the contact system of plasma leading to the generation of plasma kallikrein that cleaves high molecular weight kininogen to liberate the nonapeptide bradykinin which is further metabolized. When ACE inhibitor is present the transformation of BK to des-Arg3-BK is inhibited. For reactions that occur in the absence of negatively charged bedside leukoreduction filters and/or ACE inhibitor therapy, unidentified mechanisms not involving BK generation may be responsible.
Investigation - Isolated Hypotensive
Transfusion services should have clear policies describing the required investigation for transfusion complications. An example of an immediate investigation shows steps that could be used to investigate any immediate transfusion reaction.
A hypotensive reaction needs to be differentiated from other types of transfusion reaction that may have hypotension as a symptom. These include but are not limited to bacterial contamination, acute hemolytic, anaphylactic, TRALI and/or allergic reactions.
Fever does not occur with a primary hypotensive reaction. If symptoms do not subside immediately after discontinuing the transfusion, a chest x-ray should be considered to exclude TRALI, and blood cultures to exclude a septic transfusion reaction. Consideration must also be given to whether the hypotensive episode was unrelated to the transfusion or an underlying medical condition. Only after all other reactions and reasons are eliminated should hypotensive transfusion reaction be considered.
Treatment - Isolated Hypotensive
Initial treatment includes:
- early recognition
- stopping the transfusion immediately
- not transfusing further units until the cause is resolved
- keeping the IV line open with saline
- initiating early treatment based on symptoms and as directed by a physician
An Isolated Hypotensive Transfusion Reaction is treated with a bolus of saline to restore blood pressure.
Reporting - Isolated Hypotensive
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Prevention - Isolated Hypotensive
If the implicated transfusion was administered through a negatively charged bedside leukoreduction filter, use of other types of filters or prestorage leukoreduction should be considered.
In therapeutic apheresis procedures, consideration should be given to discontinuing ACE inhibitor therapy for 24 hours to several days depending on the half-life of the ACE inhibitor used.
Isolated Hypotensive: Further Reading
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Arnold DM, Molinaro G, Warkentin TE, DiTomasso J, Webert KE, Davis I, Lesiuk L, Dunn G, Heddle NM, Adam A, Blajchman MA. Hypotensive transfusion reactions can occur with blood products that are leukoreduced before storage. Transfusion. 2004 Sep; 44(9): 1361-6. [Medline]
- Cyr M, Eastlund T, Blais C Jr, Rouleau JL, Adam A. Bradykinin metabolism and hypotensive transfusion reactions. Transfusion. 2001 Jan.41(1):136-50.[ Full text ]
- Cyr M, Hume HA, Champagne M, Sweeney JD, Blais C Jr, Gervais N, Adam A. Anomaly of the des-Arg9-bradykinin metabolism associated with severe hypotensive reactions during blood transfusions: a preliminary study. Transfusion 1999 Oct. 39(10):1084-8. [ Full text ] [ Medline ]
- Hume HA, Adam A. In: Popovsky M, editor. Transfusion reactions, 2nd ed. Arlington, VA: AABB Press; 2001. p. 212-233.
- Hume HA, Popovsky MA, Benson K, Glassman AB, Hines D, Oberman HA, et al. Hypotensive reactions: a previously uncharacterized complication of platelet transfusion? Transfusion. 1996 Oct. 36(10):904-9. [ Medline ]
Delayed Hemolytic Transfusion Reactions
Description
Delayed Hemolytic Transfusion Reactions (DHTR) involve the destruction of transfused red blood cells (RBCs) after an interval of time, usually 3 to 21 days following transfusion, with most occurring about 7 days post-transfusion.
DHTR occur when weak alloantibodies that are undetected in pretransfusion antibody screening tests increase in strength following a secondary (anamnestic) antibody response to transfused donor red cells possessing the corresponding antigen. Such antibodies occur in persons originally sensitized by exposure to RBCs through previous transfusions and/or pregnancies.
Antibodies of several blood group systems may cause DHTR, with antibodies in the Rh (anti-c, -E), Kidd (anti-Jka), Kell (anti-K), and Duffy (anti-Fya) systems most often implicated.
NOTE: Historically, many reactions classed as DHTR did not involve red cell destruction but rather serologic criteria such as antibody production post-transfusion and development of a positive Direct Antiglobulin Test (DAT). The latter events have been termed Delayed Serologic Transfusion Reactions (DSTR).
Incidence
The reported incidences of DHTR vary with types of patients, degree of surveillance, length of time following the transfusion over which data is collected, criteria used to define the reaction, and sensitivity of antibody detection methods.
In studies done since the 1980s, the incidence of DHTR includes rates ranging from 1:5405 to 1:9094 per RBC unit transfused.
Clinical Presentation - Delayed Hemolytic Transfusion Reactions
DHTR may go undetected as the symptoms may be mild and subclinical. Death is a rare event but has been reported. Red cell destruction is usually by extravascular hemolysis (EVH). When present, typical signs and symptoms include:
- fever with or without chills
- unexplained drop in hemoglobin and hematocrit
- transient jaundice due to elevated serum bilirubin
Mechanism
Upon re-stimulation by red cells positive for the corresponding antigen to the patient's weak, undetectable alloantibody, memory B cells differentiate into antibody-producing plasma cells. As new IgG antibody is produced, it sensitizes transfused donor cells with the corresponding antigen. The IgG-sensitized donor cells are removed by EVH mainly in the spleen.
Investigation of a Delayed Hemolytic Transfusion Reaction (DHTR)
Transfusion services should have clear policies describing the required investigation of transfusion complications.
A Delayed Hemolytic Transfusion Reaction is seen days to weeks post-transfusion, and usually detected serologically with the direct antiglobulin test (DAT) showing a positive result.
Depending on the results of the initial investigation, the transfusion service will perform follow-up serologic testing according to its own policies and procedures. Some examples are outlined below.
NOTE: The expected results in a DHTR include the appearance of a"new" antibody and development of a positive DAT, although these may not always be detectable depending on the time of testing.
Positive Direct Antiglobulin Test (DAT)
To be valid, a DAT should be performed on an (EDTA) specimen. An EDTA specimen will prevent complement from binding in vitro due to a harmless cold autoantibody such as autoanti-I, an autoantibody, which many people have. If the DAT done on the patient's post-transfusion EDTA blood sample is positive:
- perform a DAT on the pre-transfusion blood sample for comparison (unless already done). If the DAT on the pre-transfusion specimen is also positive, and of approximately the same strength, the positive DAT on the post-transfusion specimen is not suggestive of a hemolytic transfusion reaction.
If the DAT on the pre-transfusion specimen is negative, a more complete investigation should be done, an example of which follows.
Monospecific DATs
If the post-transfusion DAT is positive with polyspecific antiglobulin serum, the DAT should be repeated with monospecific anti-IgG and anti-C3b/-d to determine the substances sensitizing the patient's red cells. The major purpose is to assess if an elution is worthwhile to identify antibodies that may be sensitizing the patient's cells.
Elution
An elution should be performed if a DAT using a monospecific anti-IgG is positive. The eluate is then tested with a panel to identify the antibodies involved.
Antigen type
If a specific antibody is identified, the patient's pre-transfusion specimen should be phenotyped for the antigen(s) corresponding to the antibody(ies) identified.
Treatment of a Delayed Hemolytic Transfusion Reaction (DHTR)
Treatment of a delayed hemolytic transfusion reaction is usually not required unless anemia is severe enough to require treatment.
Alternatives to transfusion should be explored whenever possible.
Reporting of a Delayed Hemolytic Transfusion Reaction (DHTR)
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Prevention of Delayed Hemolytic Transfusion Reactions (DHTR)
Preventing DHTR may be impossible if the patient's antibody is too weak to be detected by routine antibody detection methods. However there are many standard procedures and protocols that transfusion services can use to minimize this complication. Some examples include:
- Performing a history check to identify patients that have existing antibodies that may have weakened over time.
- Using sensitive antibody detection methods.
- Using antibody screen cells from donors who between them are homozygous for all of the common antigens that are expressed more strongly on homozygous RBCs (i.e., show a "dosage effect"). Such blood groups include Rh (C,E,c,e), Kidd (Jka, Jkb), Duffy (Fya, Fyb), MNSs.
- For patients who have been transfused or pregnant in the last three months, using crossmatch specimens that are no older than three days (where the date of collection is day one).
- For patients who have clinically significant antibodies, antigen phenotyping donors using commercial antisera, followed by serologic crossmatching of antigen-negative donors using an antiglobulin test or equivalent method, even when the antibody (antibodies) are not currently detectable.
- For patients with known clinically significant antibodies, assuring, on each pre-transfusion sample tested, that the evaluation for the presence of additional (new) clinically significant antibodies has been correctly performed (i.e., that appropriately phenotype tested RBCs have been selected to investigate this possibility).
- For patients with clinically significant antibodies, issuing, via the patient's physician, antibody cards that specify the antibodies present. Patients can carry these cards and alert medical staff as appropriate.
Antibody Detection & Crossmatch
The goal of antibody screening is to detect unexpected clinically significant red cell antibodies. In general, clinically significant antibodies are antibodies known to have caused Hemolytic Disease of the Newborn (HDN), hemolytic transfusion reaction, or shortened survival of transfused red blood cells.
There are several ways to detect red cell antibodies. Each hospital or region determines its method of antibody screening and compatibility testing. Regardless of the method or enhancement media used, the method must be capable of detecting clinically significant antibodies, which requires that the antibody screen method include a 37oC incubation with reagent red cells that have not been pooled followed by an Indirect Antiglobulin Test (IAT), or an alternate method that has documented capability to provide comparable sensitivity.
Methods of Antibody Detection & Crossmatch
- Indirect Antiglobulin Test
- LISS
- PEG
- MTS™ GEL Test (Gel-IAT)
- Solid Phase Adherence Assay (SPAA)
Whenever the antibody screen is found to be positive, an antibody investigation must be performed.
Crossmatch Methods
- Immediate Spin Crossmatch
The Immediate Spin (IS) crossmatch is performed only after an antibody screen is done and found to be negative on a current specimen. The patient should have no history of clinically significant antibodies.
The immediate spin crossmatch is meant to detect ABO incompatibility. It can also detect cold reactive (clinically insignificant) antibodies that react at room temperature (RT).
If the patient's expected ABO antibodies are not reactive or weak at immediate spin, donor units should be ABO confirmed prior to testing with this method.
- Computer or Electronic Crossmatch
Antibody Detection and Crossmatch Requirements for Neonatal Patients
Initial pretransfusion testing must be performed on a peripheral blood specimen. Cord blood is not acceptable for this purpose. Alternatively maternal blood may be used.
Since neonates and infants under four months of age rarely form antibodies in response to foreign red cell antigens, it is reasonable to omit a crossmatch when providing blood for this group of pediatric patients. However, initial ABO and Rh grouping, an antibody screen and, where appropriate, a test to detect the presence of maternal anti-A and/or anti-B must first be performed on the infant. If unexpected antibodies are present in the infants' blood and after four months of age, adult compatibility testing applies. When a crossmatch is omitted the ABO and Rh type of the donor blood must be verified.
Exceptions
ABO group of donor RBC is unconfirmed. A crossmatch must be performed on donor cells with an unconfirmed ABO group.
When the antibody screen is positive
If the antibody screen demonstrates a clinically significant unexpected red cell antibody, RBC negative for the corresponding antigen must be crossmatched by IAT each time transfusion is required.
Additional testing on neonates
When a non-group O infant is to be transfused with non-group O RBC (e.g., a group A infant is to receive group A RBC), the infant’s serum or plasma must be tested for the presence of maternal anti-A and/or anti-B. Neonatal serum or plasma is tested against donor or reagent A1 and/or B cells (depending upon the neonatal ABO group). If anti-A or anti-B is detected, RBC lacking the corresponding ABO antigen must be issued.
Selecting Units for Transfusion
- CMV safe cellular blood components should be selected to reduce the risk of CMV transmission for all intrauterine transfusions or when the recipient weighs less than 1200 g at birth and either the infant or the mother is CMV antibody-negative or that information is unknown.
- Choice of Product for Small Volume Transfusion
Iatrogenic blood loss is a major cause of anemia in infants and may necessitate transfusion.
• For small volume transfusion, AS-3 or CPDA-1 red cell units may be used.
• Special small packs of red cells (and plasma) may be available on special order for neonates and small children.
Age of Blood
For the majority of small volume transfusions to preterm infants AS-3 blood up to 42 days and CPDA-1 blood up to 35 days from the date of donation may be used without modification. Exceptionally, it may be advisable to remove the supernatant fluid (by washing or centrifugation and resuspension in saline) for transfusions to extremely premature infants with renal insufficiency.
(Consultation with the medical director of the hospital transfusion service should be considered for the transfusion of extremely premature neonates)
- Choice of Product for Large Volume Transfusion (massive transfusion, e.g., two volume exchange transfusion, cardiac bypass surgery and ECMO).
Red blood cells for exchange transfusion should be the freshest available.
If CPDA-1 Red Blood Cells over seven days from the date of donation are to be used, they should be washed to remove excess potassium and resuspended with Albumin or FFP to desired hematocrit. Neonates are frequently polycythemic. CPDA-1 Red Blood Cells have hematocrits >0.70 which may aggravate polycythemia.
If AS-3 Red Blood Cells are to be used, it is recommended that the preservative medium be removed, regardless of the age of cells, and that they be resuspended in FFP.
Irradiated Blood
- Blood for intrauterine transfusion must be irradiated with a minimum of 25 Gy to prevent graft-versus-host disease.
- Blood from relatives should also be irradiated
- May be indicated for use with all low birth weight premature infants (less than 1200 grams) and severely immunocompromised patients who need a transfusion
Delayed Hemolytic Transfusion Reactions: Further Reading
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Davenport RD. Hemolytic transfusion reactions. In: Popovsky MA, ed. Transfusion reactions, 2nd ed. Bethesda, MD: AABB Press; 2001. p.1-44.
- Heddle NM, Soutar RL, O'Hoski PL, Singer J, McBride JA, Ali MA, Kelton JG. A prospective study to determine the frequency and clinical significance of alloimmunization post-transfusion. Br J Haematol 1995 Dec.;91(4):1000-5. [ Medline ]
- Ness PM, Shirey RS, Weinstein MH, King KE. An animal model for delayed hemolytic transfusion reactions. Transfus Med Rev 2001 Oct.;15(4):305-17. [ Medline ]
- Pineda AA, Vamvakas EC, Gorden LD, Winters JL, Moore SB. Trends in the incidence of delayed hemolytic and delayed serologic transfusion reactions. Transfusion 1999 Oct.;39(10):1097-103. [ Full text ] [ Medline ]
- Schonewille, H., Haak, H.L., van Zijl, A.M. Alloimmunization after blood transfusion in patients with hematologic and oncologic diseases. Transfusion 1999 Jul.;39(7):763-71. [ Full text ] [ Medline ]
- Schonewille H, Haak HL, van Zijl AM. RBC antibody persistence. Transfusion 2000 Sep.;40(9):1127-31. [ Full text ] [ Medline ]
- Vamvakas EC, Pineda AA, Reisner R, Santrach PJ, Moore SB. The differentiation of delayed hemolytic and delayed serologic transfusion reactions: incidence and predictors of hemolysis. Transfusion 1995 Jan.;35(1):26-32. [ Medline ]
Post-Transfusion Purpura (PTP)
Description
Post-Transfusion Purpura (PTP) is a rare complication that results in sudden severe thrombocytopenia developing about nine
(range 1-24) days post- transfusion.
The syndrome is associated with recipient antibody to a platelet-specific antigen (usually HPA-1a developing in recipients who are HPA-1a negative). Affected women outnumber men 5:1 probably because of the requirement for pre-exposure to platelet specific antigens through pregnancy or transfusion.
- The thrombocytopenia is self-limiting and usually resolves within two weeks. Implicated blood components include red blood cell, platelet concentrate, and plasma components.
Incidence
The incidence of PTP is rare but unknown
Clinical Presentation - Post-Transfusion Purpura (PTP)
Signs, symptoms, and sequelae include:
- severe thrombocytopenia (< 10 x 109/L in 80% of cases)
- mucous membrane bleeding
- epistaxis
- GI hemorrhage
- urinary tract bleeding
- intracranial hemorrhage
- occasionally accompanied by fever, chills or bronchospasm
Mechanism
The mechanism of post transfusion purpura (PTP) is unclear but seems related to the platelet-specific alloantibody formed from prior transfusion/pregnancy and triggered in some way by the recent transfusion. Of the many hypotheses proposed to explain the syndrome, one is that autoantibody forms in conjunction with the platelet alloantibody and so that both transfused allogeneic and recipient autologous platelets are destroyed.
Investigation - Post-Transfusion Purpura (PTP)
Transfusion services should have clear policies describing the required investigation for transfusion complications.
In Post-Transfusion Purpura (PTP) laboratory tests usually reveal:
- Severe thrombocytopenia
- Normal red cell morphology
- Antibody with specificity for HPA-1a (or other platelet-specific antibody)
- HPA-1a negative phenotype or platelet genotype of HPA-1b/1b (or antigen-negative phenotype/genotype for another platelet specific antigen)
Clinically, PTP needs to be differentiated from Immune Thrombocytopenia Purpura (ITP), Thrombotic Thrombocytopenic Purpura (TTP), drug-induced thrombocytopenia, bacterial sepsis, Disseminated Intravascular Coagulation (DIC), and bone marrow failure. It should also be differentiated from otherwise uncomplicated alloimmunization to platelet specific antigens (See Further Reading- Popoksky MA).
Treatment - Post-Transfusion Purpura (PTP)
Treatment may include:
- corticosteroids
- intravenous immune globulin (IVIG)
- plasma exchange (for patients refractory to IVIG therapy).
Warning: Affected women are at risk of Neonatal Alloimmune Thrombocytopenia (NAIT) in future pregnancies and should be counselled accordingly.
Reporting - Post-Transfusion Purpura (PTP)
Overview
Documenting and reporting complications of blood transfusion involve many aspects and interrelationships. Policies and procedures will vary from site to site. Where applicable, please find examples of the types of reporting that are required.
Responsibilities of Medical and Nursing Staff
Physicians and nurses attending to patients who experience suspected transfusion complications should perform the following documentation and reporting functions:
- Report suspected reactions immediately to the attending physician and transfusion service.
- Document the patient's signs and symptoms and implicated donor units and send them to the transfusion service, as shown in this example from the National TTI Surveillance System (TTISS):
- Canadian Transfusion Adverse Event Reporting Form
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Maintain records of the complication in the patient’s medical record, including the report of the investigation completed by the transfusion service.
Note: Documentation must be maintained for all transfusions, whether or not complications occur.
Responsibilities of the Transfusion Service
The transfusion service is responsible for several aspects of documenting and reporting transfusion reactions and complications. These include documenting and reporting:
- results of transfusion reaction investigations to the attending physician;
- accidents and errors to the hospital transfusion committee;
- significant complications to the manufacturer and/or distributor;
- significant complications to other authorities as specified by provincial or federal regulations.
The types of reactions that should be reported are provided in the Standards for Blood Safety and below (under Canadian Blood Services).
Responsibilities of Canadian Blood Services
Canadian Blood Services, the blood supplier in all Canadian provinces and territories except Quebec, receives reports of serious adverse reactions from transfusion services and reports them to Health Canada.
IMPORTANT: In Canadian Blood Services’ Circular of Information, review a detailed description about the reporting responsibilities and relationships between itself and transfusion services, including transfusion-transmissible diseases: Section A6. Reporting Serious Adverse Reactions.
Prevention - Post-Transfusion Purpura (PTP)
Prevention of initial reaction is not possible.
Although recurrence is rare, patients with a documented history of Post Transfusion Purpura (PTP) should receive, if possible, blood components that are antigen-negative for the platelet antibody.
Warning: Affected women are at risk of Neonatal Alloimmune Thrombocytopenia (NAIT) in future pregnancies and should be counselled accordingly.
Post-Transfusion Purpura (PTP): Further Reading
Note: Canadian Blood Services offers no endorsement of and assumes no liability for the currency, accuracy, or availability of any information on these sites.
- Loren AW, Abrams CS. Efficacy of HPA -1a (P1A1)-negative platelets in a patient with post-transfusion purpura. Am J Hematol. 2004 Jul; 76 (3); 258-62. [Medline]
- McFarland J. Posttransfusion purpura. In: Popovsky MA, ed. Transfusion reactions, 2nd ed. Bethesda, MD: AABB Press; 2001. p. 187-212.
- von Baeyer H. Plasmapheresis in immune hematology: review of clinical outcome data with respect to evidence-based medicine and clinical experience. Ther Apher Dial. 2003 Feb; 7(1): 127-40. Review. [Medline]
Transfusion-Associated Graft-vs- Host Disease (TA-GVHD)
Description
Transfusion-associated graft-versus-host disease (TA-GVHD) is a life-threatening complication that may occur in immunocompromised patient following the transfusion of cellular blood components (red cell concentrates, platelet concentrates, granulocyte concentrates).
In rare circumstances, TA-GVHD may occur in immunocompetent patients who receive HLA-matched blood components or transfusions from first-degree family members (namely, parents, children, siblings) due to shared specificities at the major histocompatibility complex. For example, if the patient is heterozygous at an HLA locus and the donor is homozygous for one of the corresponding loci, the immunocompetent patient will not recognize the donor as foreign.
Incidence
The incidence of TA-GVHD is unknown but rare.
Clinical Presentation - Transfusion-Associated Graft-vs- Host Disease (TA-GVHD)
The clinical syndrome consists of fever, skin rash, diarrhea, hepatic dysfunction, and bone marrow aplasia, typically appearing eight to ten days after transfusion.
The outcome has a high fatality rate, with hemorrhage and infection as the most common causes of death.
Mechanism
TA-GVHD results when transfused T lymphocytes present in cellular blood components engraft, multiply, and react against the tissues of the recipient.
Investigation - Transfusion-Associated Graft-vs- Host Disease (TA-GVHD)
Transfusion services should have clear policies describing the required investigation transfusion complications.
An investigation will only be initiated if the treating physician is aware of this possibility in a susceptible patient with a clinical picture suggestive of Transfusion-Associated Graft vs. Host Disease (TA-GVHD).
The investigation begins with the confirmation of the presence of GVHD. This is a pathologic diagnosis requiring a skin or intestinal biopsy. If GVHD is present, further studies should be performed to confirm the engraftment of donor lymphocytes.
Autologous blood donations are a means for patients to donate their blood many weeks pre-operatively for transfusion to themselves during or post surgery.
The whole blood donation is centrifuged at room temperature to separate red cells from plasma.
Approximately 190-260 mL of donor plasma is expressed through a filter into the first satellite bag to produce platelet-rich plasma (PRP).
The PRP is centrifuged at room temperature using a “hard spin” to concentrate the platelets.
The platelet units rest at room temperature for one to two hours to recover from the preparation manipulations. The platelet units are then 
collections called the Buffy Coat Component Production method. This method offers significant benefits for hospitals: a pooled, bacterially tested, ready-to-transfuse platelet concentrated with a higher yield of platelets, greater availability and a five-day shelf life.
Laboratory Screening Tests
When in doubt, do not transfuse.
Many small laboratories do not have a platelet agitator and/or incubator but occasionally must order platelets for transfusion. In these cases, a Standard Operating Procedure (SOP) that addresses this type of situation should be written. In the SOP, the following items should be included:
Platelet components must be continuously agitated and the platelet components should not be used if agitation has not occurred for more than 24 hours. This means that transportation of these components cannot take longer than 24 hours from the time the product leaves the blood supplier. As well, the platelet components should be shipped between two gel packs that have been maintained at 20 - 24o C.
Compatibility testing consists of the following tests to determine if the patient's plasma or serum is compatible with the donor’s red cells.
Rh testing is done by testing the patient's red cells with anti-D. Unless otherwise indicated by the manufacturer of the anti-D, a control system appropriate to the anti-D reagent must be used to avoid false positive results.
The antihuman globulin test is used in numerous ways in pretransfusion and compatibility testing.
The gel test was developed in Switzerland in the late 1980s as a way to standardize the method of obtaining agglutination and to provide a simple and reliable way to read it. Unlike tube tests in the gel method, agglutination does not take place in a liquid phase but rather in a gel contained in a special microtube.
Each hospital determines the method of antibody identification but usually the same method used for antibody screening and compatibility testing is used for identification.
Because platelet concentrates contain few red blood cells, compatibility tests prior to transfusion are not necessary. The donor plasma in platelets should be ABO-compatible (but not necessarily group-specific) with the recipient’s red blood cells, a requirement that is even more critical when transfusing neonatal recipients with a smaller blood volume.
Compatibility testing prior to transfusion is not necessary for Cryo although some hospitals have policies that require a patient specimen be tested for ABO and Rh upon each new admission to hospital.
Frozen plasma may be thawed in a water-bath or in a microwave specifically designed for this purpose. When using a water-bath, frozen components should be placed in a watertight protective plastic over-wrap and thawed using gentle agitation. Careful examination of the component container is required to look for evidence of container breakage or of thawing during storage. Thawed plasma should be transfused within 24 hours.
Messenger
Some hospital transfusion services transport blood to patient care areas using a pneumatic tube system. Processes must be established and monitored to prevent delay and misdirection of blood components to the intended destination. As well, additional procedures should be established to ensure 
STOP
Incidence and Symptoms
