Transfusion Transmitted Injuries Section

Noninfectious Adverse Events of Transfusion

• Acute Hemolytic
• Transfusion Reaction (AHTR)
• Febrile Nonhemolytic Transfusion Reaction (FNHTR)
• Urticarial Reaction
• Anaphylactic Reaction
• Transfusion-Related Acute Lung Injury (TRALI)
• Transfusion-Associated Circulatory Overload (TACO)
• Metabolic Reaction
• Transfusion Associated Air Embolism
• Delayed Hemolytic Transfusion Reaction (DHTR)
• Posttransfusion Purpura (PTP)
• Transfusion Associated Graft-Versus-Host Disease (TA-GVHD)
• Iron Overload

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Acute Hemolytic Transfusion Reaction (AHTR)

The acute hemolytic transfusion reaction (AHTR) refers to an accelerated destruction of red blood cells in a transfused recipient occurring during or within 24 hours after a blood transfusion. The destruction of red blood cells results from an interaction between existing antibodies in the recipient and antigens in transfused red cells^1-2. AHTR is characterized by a sudden onset of fever, chills, facial flushing, chest pain or low back pain, hypotension, and dyspnea and may result in severe complications such as renal failure and disseminated intravascular coagulation (DIC)¹.

AHTR is the leading cause of death associated with transfusion.  It has been estimated that AHTR occurs approximately 1 in 12,000 to 1 in 33,000 red cell units transfused³. Fatal AHTR, on the other hand, occurs 1 in 600,000 to 1 in 800,000 units transfused⁴.

The majority of AHTR occurs as a result of erroneous administration of ABO-incompatible red cells to recipients who have corresponding preformed antibodies⁴. Commonly reported errors include improper specimen identification and improper patient identification.  Measures aimed to detect and prevent these errors are essential to reduce the occurrence of ABO-incompatible transfusion and its associated AHTR.  Early diagnosis and treatment are also important in reducing AHTR-related fatalities.    

Febrile Nonhemolytic Transfusion Reaction (FNHTR)

Febrile nonhemolytic transfusion reaction (FNHTR) is the most common, non life-threatening transfusion reaction associated with a transfusion of red cells and platelets⁵. FNHTR is characterized by an isolated temperature increase, of at least one degree Celsius within 24 hours after completion of transfusion, which is not explained by the patient's clinical condition. The fever is usually accompanied by chills, rigors, and discomfort⁶.

Transfusion of platelets is associated with a higher risk of FNHTR than transfusion of red blood cells.  It has been estimated that the risk of red cell associated FNHTR is about 1% of all transfusions, with a range of 0.5% to 6.8%^3,6-7; however, the risk of platelet associated FNHTR occurs in 4% to 37.5% of transfusions^7-8.  Recipients who have had a history of blood transfusion and pregnancy are at increased risk of red blood cell associated FNHTR, however, no specific profiles of recipients have been identified as being associated with an increased risk of platelet associated FNHTR^7-8.

Red cell associated FNHTR is caused by the reaction between leukocyte antibodies present in the plasma of a recipient and leukocytes present in transfused red cells⁶. However, platelet associated FNHTR seems to be related to the presence of pyrogenic cytokines released from leukocytes during the platelet storage.  Leukoreduction of the cellular blood components may effectively reduce the occurrence of FNHTR⁵.

Urticarial Reaction

Urticarial (or allergic) reaction is a common and usually non life-threatening adverse reaction associated with transfusion of plasma, platelets, or red cells⁸.  In general, urticarial reactions manifest mild symptoms such as localized erythema, hives, and pruritus and are usually not accompanied by fever or any other severe symptoms⁹.  The definitive etiology of urticarial reactions remains unknown; however, it may result from the presence of soluble allergen in donors' plasma⁹.

Approximately 1% to 3% of all transfusions result in urticarial reactions^3,10.  Although no specific profiles of  recipients at risk have been identified, a history of allergic predisposition may be associated with increased  risk⁸.

Anaphylactic Reaction

Anaphylactic reaction is a rare but severe complication following a blood transfusion.   Signs and symptoms associated with anaphylactic reactions usually begin within 1 to 45 minutes after the start of a transfusion when only a few millimetres of blood has been transfused¹⁰.  This reaction can be characterized by a severe allergic hypersensitivity in the absence of fever. Patients often present with mild symptoms such as cough and bronchospasm at the beginning, which then progress rapidly and may result in severe consequences such as shock, loss of consciousness, and death³.

The incidence of anaphylactic reactions has been estimated to be 1 in 20,000 to 1 in 47,000 units of blood transfused⁹.

Many anaphylactic reactions result primarily from a reaction between donors' IgA and anti-IgA antibodies produced by IgA-deficient recipients, even though other possible antigens have been reported in the literature⁹. To prevent anaphylactic reactions, it is recommended that IgA-deficient patients with evidence of anti-IgA antibodies in their serum receive IgA-deficient blood components⁹.

Transfusion-Related Acute Lung Injury (TRALI)

Transfusion-related acute lung injury (TRALI) is a rare and life-threatening complication associated with transfusion of blood components containing plasma such as red cells, platelets, granulocytes, and cryoprecipitates¹¹. TRALI usually occurs within 1 to 2 hours after the start of a transfusion and is characterized by acute respiratory distress.  The symptoms of TRALI include severe bilateral pulmonary edema, severe hypoxemia, tachycardia, cyanosis, hypotension, and fever¹².

The incidence of TRALI has varied considerably among different studies, with a range of 1 in 5,000 to 1 in 10,000 units transfused, or 4 to 16 per 10,000 recipients¹¹.  Although no specific profiles are available to identify recipients who may be at increased risk of TRALI, clinical conditions among recipients such as active infection or massive transfusion may be associated with increased risk⁷.  TRALI has been reported to be the third leading cause of death associated with transfusion, with a case fatality rate ranging from 5% to 14%¹².   

The precise mechanism of TRALI is unknown, but increasing evidence has indicated that it is an immune mediated event initiated by pathological antibodies from donors^11-13.  The presence of human leukocyte antigen (HLA)-specific antibodies in the plasma of donors has been strongly associated with the occurrence of TRALI¹². 

To reduce the occurrence of TRALI, some investigators have recommended that donors who have been previously implicated in TRALI in a recipient be permanently deferred and that multiparous donors be screened for HLA antibodies¹³.  On the other hand, prevention of TRALI-related fatalities involves careful bedside observation during and after transfusion for any respiratory distress and provision of respiratory support as early as possible.

Transfusion-Associated Circulatory Overload (TACO)

Transfusion Associated Circulatory Overload (TACO) is a common reaction resulting from a rapid or massive transfusion of blood¹².  TACO usually occurs within several hours after the start of a transfusion and is manifest in signs and symptoms that include dyspnea, orthopnea, peripheral edema, and rapid increase of blood pressure.  

The incidence of TACO is difficult to determine because of underreporting.  It has been estimated that TACO occurs approximately 1 in 100 to 1 in 10,000 transfusions³.  Certain groups of patients are at increased risk for TACO.  These include infants, elderly patients over 60 years of age, patients with cardiac, pulmonary or renal failure, and patients with chronic anemia^9,12.

Identification of patients who may be at risk of TACO and administration of small volumes of required blood components at a well-controlled rate may effectively prevent TACO⁹.

Metabolic Reaction

Transfusion-associated metabolic reactions are associated with massive or rapid transfusion and include citrate toxicity, hypothermia and hyperkalemia.

Citrate toxicity

Sodium citrate is the substance used to prevent blood coagulation during blood collection. The liver, under normal conditions, can rapidly metabolize sodium citrate; however, the metabolic capacity of the liver can be exceeded when large volumes of blood are transfused.  This may result in an increased level of citrate and may induce hypocalcemia and hypomagnesemia with clinical symptoms such as paresthesia, tetany, and arrhytmia³.  In addition, metabolic alkalosis may result from the accumulation of bicarbonate -- the metabolic derivative of citrate¹⁴. 

The incidence of citrate toxicity is unknown.  Patients who are undertaking prolonged apheresis procedures and infants who have already suffered underlying diseases may be at increased risk¹⁴.

Hypothermia

Hypothermia is also associated with rapid transfusion of large amounts of cold blood, which may result in cardiac arrhythmias³.  Hypothermia can be prevented by careful control of the transfusion rate or by the use of ultra-efficient blood warmers to rapidly warm large volumes of blood before transfusion⁹.

Hyperkalemia

Although the potassium level in the plasma increases during blood storage, this rarely causes hyperkalemia among recipients because potassium can be rapidly diluted, redistributed and excreted after the transfusion.   However, a massive or rapid transfusion in a short period of time may cause hyperkalemia, particularly among premature infants and acidotic patients, and result in significant morbidities and even death^15-16. 

Transfusion Associated Air Embolism

Air embolism is a rare complication of blood transfusion. It may result from  transfusion of blood under pressure using an open system.  Small amounts of air may enter into the circulation during transfusion and result in clinical symptoms such as cough, dyspnea, chest pain and shock, and occasionally deaths^3,9. The incidence of transfusion associated air embolism is unknown.  Intraoperatively or postoperatively recovered blood has been associated with the occurrence of air embolism if it is not properly performed¹⁷.

Delayed Hemolytic Transfusion Reaction (DHTR)

Delayed hemolytic transfusion reaction (DHTR) is an accelerated destruction of transfused red blood cells that usually occurs days to weeks (usually within 2 weeks) after a transfusion^2,18.  Unlike AHTR, most patients with DHTR are either asymptomatic or present with mild symptoms such as low-grade fever, decreased hemoglobin level, and jaundice. Occasionally, patients may present with hemoglobinemia and hemglobinuria¹.

The estimated risk of DHTR ranges from 1 in 5,000 to 1 in 11,000 transfusions^19-21. The majority of DHTR cases result from a secondary immune response in patients previously sensitized by a transfusion or pregnancy.  Thus, patients who have a history of transfusions and pregnancy are at increased risk of DHTR.  To prevent DHTR, it has been recommended that red cells that do not carry the associated antigens be provided to patients who have a history of DHTR¹.

Posttransfusion Purpura (PTP)

Posttransfusion purpura (PTP) is a rare complication associated with transfusion of blood components that contain platelets antigens such as whole blood, packed red blood cells, plasma, and platelet concentrates²².  PTP can be characterized by a sudden diminution of the platelet count to less than 10,000/µL, which usually occurs 5 to 10 days after a blood transfusion.  Clinical signs and symptoms associated with PTP include wet purpura with mucous membrane hemorrhage, epistaxis, gastrointestinal bleeding, and bleeding from the urinary tract^3,8,22.

The incidence of PTP is unknown, but it has been estimated to be 1 in 200,000 transfusions⁷.  The most severe complication following PTP is intracranial hemorrhage.  The case fatality rate of PTP ranges from 0% to 13%²².  Individuals who have a history of transfusion or pregnancy are at increased risk of PTP.  Thus women, in particular middle aged or elderly women, are at the risk⁷.

To prevent PTP, it is recommended that patients who have a documented history of PTP receive antigen-negative blood components²².

Transfusion Associated Graft-Versus-Host Disease (TA-GVHD)

Transfusion associated graft-versus-host disease (TA-GVHD) is a rare but often fatal complication following a blood transfusion.  TA-GVHD is an acute syndrome that occurs usually 2 to 30 days after a transfusion and can be characterized by fever, liver dysfunction, skin rash, diarrhea, and severe pancytopenia⁸. 

The incidence of TA-GVHD is currently unknown; however, some patients have been identified as being at increased risk: patients with congenital immunodeficiency syndromes, Hodgkin's disease, chronic lymphocytic leukemia, and recipients of blood donated by relatives²³.  It has been estimated that TA-GVHD occurs at a rate of approximately 0.1% to 1% among these high-risk patients.  About 90% of patients with TA-GVHD eventually die as a result of the reaction⁸.

TA-GVHD occurs when donors' lymphocytes are not recognized as foreigners by recipients' lymphocytes and therefore are not destroyed.  Consequently, donor lymphocytes multiply and initiate an immune attack against the recipient's cells, resulting in TA-GVHD^24-25.

There is no effective treatment once TA-GVHD has occurred.  Prevention of its occurrence  among high-risk patients is critical to reducing TA-GVHD related fatalities.  Gamma-irradiated blood components are highly recommended for use among high-risk recipients²⁴.

Iron Overload

Iron overload is a transfusion-induced reaction that can damage organs and result in dysfunction of the liver, heart, and kidneys.  Iron overload occurs primarily among patients who receive repeated red blood cell transfusions over a long period and, therefore, accumulate a high level of iron that the body cannot physiologically excrete⁷.

The incidence of iron overload is currently unknown³. However, certain individuals such as patients with thalassemia, sickle cell anemia, and myelodysplasia have been identified as being at increased risk of iron overload⁷.  Prevention involves several approaches, including minimization of red cell transfusions, the use of pharmacological therapy or iron-chelating agents to reduce the need for red cell transfusions, and the use of red blood cell exchange procedures⁹.  

References

1. Knowles S. Hemolytic Transfusion reactions. In: Murphy MF, Pamphilon DH. Practical Transfusion Medicine. Blackwell Science 2001:147-156.

2. Kicklighter EJ, Klein HG. Hemolytic transfusion reactions. In: Linden JV, Bianco C, eds. Blood Safety and Surveillance. New York, Marcel Dekker Inc 2001: 47-70.

3. American Association of Blood Banks, Technical Manual. Non-infectious Complications of blood transfusion, 1999: 577-600.

4. America's Blood Centers. Hemolytic transfusion reactions. Part 1. Biological product deviations (Errors and accidents) Vol 3, Nov 2000: 1-5.

5. Heddle NM. Pathophysiology of febrile non-hemolytic transfusion reactions. Current Opinion in Hematology 1999, 6: 420-426.

6. Heddle NM, Kelton J. Febrile non-hemolytic transfusion reactions. In : Popovsky MA, ed. Tranfusion reactions, Bethesda, MD. AABB Press 2001: 45-82.  

7. Murphy MF. Febrile reactions and tranfusion related acute lung injury. In: Murphy MF, Pamphilon DH. Practical Transfusion Medicine. Blackwell Science 2001: 157-163.

8. Perrotta PL, Snyder EL. Non Infectious Complication of transfusion therapy. Blood Reviews 2001; 15:69-83.

9. Gresens CJ, Holland PV. Other reactions and alloimmunization.In:  Linden JV, Bianco C, eds. Blood Safety and Surveillance. New York, Marcel Dekker Inc 2001: 71-86.

10. Vamvakas EC, Pineda AA. Allergic and Anaphylactic transfusion reactions. In Popovsky MA, ed. Transfusion reactions, Bethesda, AABB Press 2001:83-127.

11. Kopko PM, Popovsky MA, Malcom R et al. HLA class II antibodies in tranfusion-related acute lung injury. Transfusion 2001; 41:1244-48.

12. Popovsky MA. Transfusion and lung Injury. Transfusion Clin Biol 2001; 8:272-7.

13. Popovsky MA. Transfusion-related acute lung injury. In: Linden JV, Bianco C, eds. Blood Safety and Surveillance. New York, Marcel Dekker Inc 2001: 125-38.

14. Uhl L, Kruskall MS. Complications of massive transfusion. In Popovsky MA, ed. Transfusion reactions, Bethesda , MD: AABB Press 2001: 339-57.

15. Hall TL, Barnes A, Miller JR et al. Neonatal mortality following transfusion of red cells with  with high plasma potassium levels. Transfusion 1993; 33: 606-609.

16. Brown KA, Bissonnette B,  MacDonald M et al. Hyperkalemia during massive blood transfusion in paediatric craniofacial surgery. Can J Anaesth 1990; 37: 401-8.

17. Linden JV. Errors in Transfusion Medicine. Scope of the problem. Arch Pathol Lab Med 1999 (123): 563-5.

18. Davenport RD. Hemolytic Transfusion Reactions. In: Popovsky MA ed. Tranfusion reactions, 2^nd Edition, Bethesda, MD: AABB Press 2001:1-44.

19. Heddle NM, Soutar RL, O'Hoski Pl et al. A prospective study to determine  the frequency and clinical significance of alloimmunization posttransfusion. Br J Haematol. 1995 Dec;91(4):1000-5.

20. Ness PM, Shirey RS, Thoman SK, Buck SA. The differentiation of delayed  serologic and delayed hemolytic transfusion reactions: Incidence,long term serologic findings and clinical significance. Transfusion 1990; 30: 688-93.

21. Vamvakas EC, Pineda AA, Reisner R et al. The differentiation  of delayed hemolytic and serologic transfusion reactions: Incidence and predictors of hemolysis. Tranfusion 1995; 35: 26-32.

22. McFarland J.  Post transfusion purpura. AABB Annual Meeting, October 13-17, 2001.

23. Webb IJ, Anderson KC. Graft-Versus-Host Disease. In: Linden JV, Bianco C, eds. Blood Safety and Surveillance. New York, Marcel Dekker Inc. 2001, p. 109-124.

24. Pisciotto TP. Transfusion associated graft-versus-host disease, AABB Annual meeting, October 13-17, 2001.

25. McCullough J.  Complications of Transfusion. Transfusion Medicine. McGraw-Hill 1998, p. 337-359