Transfusion medicine
Transfusion reactions
Acute hemolytic transfusion reaction (AHTR)


Topic Completed: 1 July 2017

Minor changes: 17 November 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

PubMed Search: Acute hemolytic transfusion reaction[TI]

Faisal Mukhtar, M.D.
J. Peter R. Pelletier, M.D.
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Cite this page: Mukhtar F, Pelletier JPR. Acute hemolytic transfusion reaction (AHTR). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/transfusionmedacutehemolytic.html. Accessed November 23rd, 2020.
Definition / general
  • Acute hemolysis due to incompatible RBC transfusion
  • Most commonly ABO incompatible but other frequency incited antibodies are anti-Kell, anti-Kidd and anti-Duffy
  • All of these antibodies strongly bind complement and cause intravascular hemolysis
Essential features
  • Must occur within 24 hours of blood component administration and often during transfusion itself
  • Mostly due to transfusion of incompatible RBC but may also result from incompatible plasma containing components such as FFP or platelets
  • Usually due to mistransfusion of ABO incompatible RBC
    • Transfusion service error
      • Typing
      • Labeling
      • Crossmatching
    • Clinical service error
      • Wrong patient sample
      • Wrong unit transfused at the bedside to a patient
      • Transfusion of incompatible RBCs (could be ABO incompatible to patient antibodies)
Terminology
  • RBC: red blood cells
  • FFP: fresh frozen plasma
  • DAT: direct antiglobulin test
  • AHTR: acute hemolytic transfusion reaction
  • CBC: complete blood count
  • LDH: lactate dehydrogenase
  • PT: prothrombin time
  • APTT: activated partial thromboplastin time
  • DIC: disseminated intravascular coagulation
  • IVH: intravascular hemolysis
  • EVH: extravascular hemolysis
  • TRALI: transfusion related acute lung injury
Pathophysiology
  • Intravascular hemolysis:
    • ABO incompatible: pre-existing natural occurring anti A or anti B antibodies of IgM type → fixation of complement → formation of membrane attack complex → red cell lysis
    • Some IgG antibodies can also fix complement → mild to fatal AHTR
    • Usually occurs when mistransfusion of antigens in Kell, Duffy and Kidd systems
  • DIC, shock and renal failure:
    • Free hemoglobin from hemolysis → binds to nitric oxide (NO) → vasoconstriction
    • RBC stroma → activates platelets and coagulation cascade → DIC
    • RBC stroma → damages to renal tubules → renal failure
Clinical features
  • Fever (important): early sign of AHTR – need to monitor vital signs frequently during the initial minutes of transfusion
  • Anxiety, sense of doom
  • Nausea, vomiting
  • Pain at infusion site
  • Diffuse bleeding
  • Oozing from IV site
  • Flank and back pain
  • Hyper or hypotension
  • Hemoglobinuria
Transmission / incidence
  • It is estimated that ABO incompatible transfusions occur in about 1 in 40,000 transfusions
  • AHTR incidence estimated at about 1 in 76,000 transfusions (AABB: Technical Manual of the American Assoc of Blood Banks, 18th Edition, 2014)
  • Up to 47% of cases of ABO incompatible mistransfusion had no adverse effect
  • Less than 10% of ABO incompatible transfusions cause death
  • Risk of death from ABO incompatible transfusion is estimated to be 1:1.8 million and correlates with the amount of incompatible blood transfused (Blood 2009;113:3406)
  • Causes 10 - 30 deaths in US each year
Laboratory
  • Check for clerical error (i.e. patient identity and the patient identity on RBC unit)
  • Return implicated blood bag, tags and attached administration set to blood bank
  • Contact the transfusion service immediately
  • Centrifuge postreaction blood sample and examine serum / plasma for hemolysis; if noted, compare with prereaction specimen
  • Perform DAT; if positive, compare with prereaction specimen DAT
  • Repeat ABO type of the donor unit, pre- and posttransfusion patient sample
  • Repeat antibody screen on the pre- and posttransfusion sample
  • Repeat crossmatch with the pre- and posttransfusion sample
  • If there is evidence of a hemolytic transfusion reaction, additional testing should be performed as needed:
    • Send clinical tests for evidence of red cell hemolysis (i.e. hemoglobin, hematocrit, haptoglobin, LDH, CBC, bilirubin at 5 - 12 hours, urinalysis for hemoglobinuria) (Eur J Clin Invest 2006;36:202)
    • Perform coagulation tests for DIC: PT, APTT, fibrinogen, platelet count
Transfusion of significant incompatible plasma
  • Occurs less frequently
  • Due to minor ABO mismatch - transferring of donor anti A, anti B or anti A,B in plasma containing products (platelets, FFP) → hemolysis of patient's own ABO incompatible RBCs
  • Most often due to transfusion of out of group platelet (most commonly group O platelets to group A patient, Arch Pathol Lab Med 2007;131:909); also donor with high titer of anti A (> 1,000), transfusion of large volume of plasma into a smaller patients (such as neonate, infants or children)
  • Clinical symptoms are identical to transfusion of incompatible pRBCs
Case reports
Treatment
  • Stop the transfusion
  • Provide good supportive care
  • Maintain good urine output (> 1ml/kg per hour), can use diuretics (furosemide)
  • Treat shock and support cardiac and respiratory function
  • Administer low dose dopamine for hypotension (1 - 5 µg/kg per min)
  • Manage DIC and hemorrhage as clinically indicated
Prevention
  • Strictly adhere to the protocol to prevent mislabeled and miscollected samples
  • Always perform bedside check before administering blood products
  • Other innovations include barcoding of blood components and patient ID
  • Educate physicians and nurses regarding transfusion practice
Sample assessment & plan
  • Monitor patient carefully during transfusion
  • Stop the transfusion at first sign or symptom of an adverse reaction
  • Recheck the identification of the patient and donor unit; verify that the unit is correct
  • Notify the patient physician and the transfusion service
  • Maintain IV fluids and urinary output; monitor and maintain vital signs
  • Collect posttransfusion blood and urine samples
  • Complete the transfusion investigation request, documenting patient symptoms, vital signs and the amount of blood transfused
  • Send to the transfusion service:
    • Postreaction blood and urine samples from the patient
    • Transfusion reaction investigation request
    • Blood bag with the attached administration set and IV solutions
Differential diagnosis
  • Septic transfusion reaction:
    • Contaminated blood product; bacteria (e.g. Pseudomonas, Escherichia coli, Yersinia enterocolitica) produce endotoxin
    • Chills, fever, hypotension
    • Broad spectrum antibiotics and resuscitative therapy
  • TRALI:
    • Typically donor antibody versus recipient HLA or WBC antigens
    • Fever, chills, shortness of breath, respiratory failure, hypotension or non cardiogenic pulmonary edema
    • Supportive care, administer oxygen, intubate (mechanical ventilation) if necessary
  • Febrile nonhemolytic reaction:
    • Recipient antibody to donor WBC leads to IL-1 production; accumulation of cytokines (IL-1) from donor WBC in blood product; underlying condition
    • Temperature increase ≥ 1.8° F (1°C) with or without chills
    • Premedicate with antipyretics; use leukoreduced products for future transfusions
Board review style question #1
    15 minutes after starting a transfusion of a group A Rh negative pRBC, a patient typed as group A Rh positive has a new onset fever, back pain, abdominal cramping, rigors and dyspnea. Hypotension is also noted. Red urine is evident in the Foley catheter bag, but urine output decreases in the next hour. The pretransfusion antibody screen was negative. What is the most likely cause of this patient's symptoms?

  1. Bacterial contamination of the unit
  2. Cytokines elaborated by donor white blood cells
  3. Laboratory errors in compatibility testing
  4. Mislabeling of the pretransfusion sample
  5. Transfusion of Rh negative blood
Board review answer #1
D. The patient is exhibiting acute hemolytic transfusion reaction. The dramatic symptoms and signs presenting early in a transfusion reaction represent an AHTR until proven otherwise. Immediate cessation of the transfusion and prompt evaluation are called for, often while normal saline is being given in an effort to maintain urine flow and prevent severe renal damage. The vast majority of these reactions are caused by incompatibilities involving the ABO system. These are overwhelmingly caused by improper identification of the recipient or through mislabeled samples. Laboratory error in ABO typing has become a rare event through the efforts of laboratory regulatory agencies which require maintenance of staff proficiency and competency as well as quality controls systems for sample processing and reporting results. Antibodies with specificity for the A and B antigen occur naturally and are expected to be present in antigen negative individuals. These antibodies are always IgM class and, although reactive at colder temperatures like most IgM antibodies, making their detection at room temperature possible, they bind to antigen positive red cells at 37°C. This leads to rapid onset of intravascular hemolysis and activation of complement and other inflammatory cascades, releasing vasoactive peptides. The symptoms experienced by this patient may overlap with other adverse reactions that can present early in transfusion but the red urine is a clue that IVH is present. Rh antibodies rarely fix complement and cause chiefly EVH, with paucity of most other symptoms. Besides, Rh negative blood lacks the RhD antigen and can be safely given to Rh positive individuals. Bacterial contamination is commonly associated with platelets products, which must be stored at 22°C, rather than in the refrigerator like red cell units. Storage under refrigerated conditions keeps the incidence of reactions to contaminated red cells extremely low. Although cytokine mediated reactions may present early in transfusion and cause some overlapping symptoms, especially fever and hypotension, they are not associated with hemolysis.

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Reference: Acute hemolytic transfusion reaction (AHTR)
Board review style question #2
    A 35 year old man with group A Rh positive recently underwent a second peripheral blood stem cell transplantation from the same group A Rh positive matched sibling donor for relapsed acute myeloid leukemia and has persistent thrombocytopenia 1 month after transplantation. He is scheduled for platelet transfusion. 15 minutes and 100 ml into the transfusion of a blood group O single donor platelet component, he develops severe back and flank pain associated with hypertension and chest pain; vital signs are otherwise stable. The transfusion is discontinued; a posttransfusion specimen is grossly hemolyzed and a urine specimen is dark brown. The hemoglobin has decreased from 9.7 gm/dL before transfusion to 5.5 gm/dL. The DAT is positive for IgG and complement. Which of the following is the most appropriate next step in the management of this patient's symptoms?

  1. Initiate corticosteroids
  2. Transfuse a unit of pRBC, group A, crossmatch compatible
  3. Transfuse a unit of pRBC, group A, crossmatch incompatible
  4. Transfuse another bag of platelets, group A, washed
  5. Transfuse another bag of platelets, group O, washed
Board review answer #2
B. In routine adult transfusion practice, platelets are transfused without regard to ABO compatibility (ABO incompatible hematopoietic stem cell transplantation recipients are the exception). Platelets are suspended in plasma. Not surprisingly, ABO antibodies in incompatible plasma occasionally cause a hemolytic transfusion reaction (with a positive DAT) after platelet transfusions. The patient is typically group A and the platelet component group O (minor incompatibility). This patient is symptomatic from the anemia so the priority should be to be transfuse RBC that are crossmatch compatible. A positive DAT is seen in autoimmune hemolytic anemia (AIHA), for which crossmatch incompatible units may need to be transfused (answer D) and corticosteroids initiated (answer E); this patient does not have AIHA. Future platelet transfusions should be restricted to ABO identical components; if group A platelets are not available for this patient, group O platelets should be washed (plasma depleted) prior to transfusion.

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Reference: Acute hemolytic transfusion reaction (AHTR)
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