Transfusion medicine

Transfusion reactions & complications

Delayed hemolytic

Editorial Board Member: Patricia Tsang, M.D., M.B.A.
Matthew S. Karafin, M.D.

Last author update: 20 July 2020
Last staff update: 17 June 2021

Copyright: 2002-2023,, Inc.

PubMed Search: Delayed hemolytic transfusion reaction [title]

Matthew S. Karafin, M.D.
Page views in 2022: 1,620
Page views in 2023 to date: 417
Cite this page: Karafin MS. Delayed hemolytic. website. Accessed May 30th, 2023.
Definition / general
  • A delayed hemolytic transfusion reaction is a potentially significant adverse event caused by antibody mediated removal of recently transfused red cells due to an amnestic immune response from antibodies against an incompatible minor red blood cell antigen
Essential features
  • This transfusion reaction can cause an unexpected drop in hemoglobin 3 - 28 days after a transfusion and can cause clinically observed symptoms, including fever
  • Caused by an amnestic immune response, where red cell alloantibodies increase in titer and trigger removal of incompatible red cells via splenic macrophages
  • Diagnosis is supported by a new positive direct antiglobulin test (+IgG or +IgG and C3) and the detection of an alloantibody by antibody screen / panel or elution
  • Future transfusions should involve red cells that are antigen negative for the detected alloantibody
  • Prior red cell exposure through pregnancy, transfusion or transplantation → sensitization to minor red blood cell antigens → primary immune response → alloantibody formation
  • Commonly implicated minor antigens: Rh (D, C, c, E, e), Kidd (Jka, Jkb), Duffy (Fya, Fyb), Kell (K, k), MNS (M, N, S, s); antibodies are usually IgG reactive at 37°C and may or may not fix complement
  • Commonly implicated minor antigens: Kidd antibodies (Jk) are most common and most severe
  • Alloantibody titer decreases over time with no reexposure (transfusion / pregnancy) → pretransfusion testing becomes negative (Blood 2019;133:1821)
  • Reexposure to antigens by offending transfusion / pregnancy → amnestic response → production of IgG → extravascular hemolysis
  • Removal of sensitized donor red cells by splenic macrophages leads to typical laboratory or clinical findings
  • Reaction severity depends on the thermal range (a wider thermal range can be more severe than a narrow thermal range), antibody specificity (antibodies to some antigens, such as anti-Jk or anti-K, tend to more commonly result in hemolysis than others), and IgG subclass (the subclasses that bind well to complement and Fc receptors on phagocytic cells, such as IgG3 and IgG1, can result in more severe reactions)
  • Note: this reaction can rarely be due to a primary (nonamnestic) immune response (Immunohematology 2004;20:184)
Clinical features
  • Clinical symptoms and laboratory findings (see below) typically occur 3 - 10 days (up to 28 days) after a transfusion of red blood cells that originally appeared compatible by testing
  • Patients have an unexpected drop in hemoglobin or less than expected rise in hemoglobin post transfusion
  • Delayed hemolytic transfusion reaction (DHTR) is typically mild but may necessitate additional transfusions
  • When amnestic antibody production does NOT cause detectable hemolysis = delayed serologic transfusion reaction (DSTR)
  • In the U.S., DHTR incidence ranges approximately from 1:1,200 - 7,000 transfused patients (Transfusion 2010;50:1444, Transfusion 2017;57:2903)
    • In one single institution study, DHTR incidence has fallen between 1999 and 2007, and was associated with a transition from polyethylene glycol (PEG) to gel technology
    • DSTR is twice as likely as DHTRs (Transfusion 1995;35:26)
  • Incidence of DHTR is significantly increased in sickle cell patients
    • One French study found the incidence to be 4.2% per transfusion episode and 6.8% per patient (Am J Hematol 2017;92:1340)
    • DHTR can mimic vasoocclusive crisis (VOC) in patients with sickle cell disease and new alloantibodies are not always detectable, hindering recognition of this reaction in these patients (Transfusion 2002;42:37)
  • Patients with sickle cell disease and DHTR can also develop hyperhemolysis: hemolysis of bystander red blood cells in addition to the transfused red cells (Pediatrics 2003;111:e661)
Signs and symptoms
Case reports
  • Specific intervention usually not indicated but symptomatic or supportive management can safely be used (i.e. antipyretics for fever)
  • Close communication between transfusion medicine physician and clinical team is critical to explain current and future risks
  • If patient requires red blood cells before the transfusion reaction workup is completed, then benefit of transfusion must be weighed against risk of additional hemolysis
    • Hydration and close monitoring are key for such cases
  • After workup is completed, if clinically indicated, patient should receive antigen negative, crossmatch compatible, red blood cells that avoid the newly detected alloantibody
  • Prevention is key:
    • Accurate transfusion histories are critical to avoid delayed hemolytic transfusion reactions; contact other hospitals or transfusion medicine services for records
    • Once a clinically significant alloantibody is identified, patient will receive red blood cell units that lack that antigen regardless of whether the antibody is detectable
      • Both AABB and College of American Pathology standards mandate permanent preservation of all records of potentially clinically significant alloantibodies, as well as a review of previous records prior to red blood cell transfusion
    • Patients receiving chronic therapeutic red cell transfusions should have a red blood cell phenotype completed (molecular methods are now preferred) for at least Rh, Kell, Duffy, Kidd and MNS antigens before initiation of transfusion therapy
    • Patients with sickle cell disease or thalassemia should prophylactically receive red blood cells matched for C, E and K at a minimum (Blood Adv 2020;4:327)
Sample assessment & plan
  • Assessment:
    • This patient is a 55 year old woman with a recent history of acute gastrointestinal bleeding who received a single red cell transfusion on X/XX/20XX due to symptomatic anemia (hemoglobin: 6.2 g/dL). The transfusion workup at that time revealed no unexpected alloantibodies, a negative direct antiglobulin test and the unit prepared for transfusion was crossmatch compatible. Her hemoglobin responded appropriately to the transfusion and no adverse events were noted. On X/XX/20XX, the patient developed a fever up to 101.3°F. This was accompanied by an unexpected drop in hemoglobin (6.4 g/dL), a rise in bilirubin and a new positive direct antiglobulin test (+IgG). A new anti-K was detected by antibody screen and red cell elution. Evidence for infection or a new GI bleed has been negative to date. The red cell unit provided on X/XX/20XX was tested positive for the K antigen.
  • Diagnosis:
    • Delayed hemolytic transfusion reaction due to anti-K
  • Plan:
    • All future red cell transfusions should be negative for the K-antigen. Please be aware that increased time may be needed to procure antigen matched blood and such red cell units may not be available quickly in an emergency. Symptoms associated with a delayed reaction, such as fever, will be self limited, and can be managed symptomatically. Please contact the medical director on service if you have additional questions about this case.
Differential diagnosis
  • Warm autoimmune hemolytic anemia:
    • Can present with similar signs and symptoms as a DHTR
    • Antibody screen and panel results will most often show panreactivity rather than antigen specificity
    • Elution from a positive direct antiglobulin test will also most often show panreactivity rather than antigen specificity
  • Vaso-occlusive pain crisis:
    • In patients with sickle cell disease, DHTR can mimic pain crises
    • Antibody screen and panel results will show no new alloantibody
    • Direct antiglobulin test will likely be negative (or at least not newly positive)
  • Passenger lymphocyte syndrome:
    • Patient will have had a recent minor ABO incompatible organ transplant (i.e. group O liver into a group A patient)
    • Anti-A or B or A, B will be found on red cells
  • Malaria or Babesia infected red blood cell product:
    • Patient will have symptoms typical of malaria or Babesia
    • Organism will be identified within infected red cells
    • Antibody screen and panel results will show no new alloantibody
    • Direct antiglobulin test will be negative (or at least not newly positive)
Board review style question #1
    A 50 year old woman received a single red cell transfusion 1 week ago due to postsurgery anemia. A second red cell transfusion is now requested from the blood bank for this patient as her anemia has returned to pretransfusion levels. She has no prior transfusion history but has had 4 previous pregnancies. Her blood bank workup 1 week ago was negative. Today, the pretransfusion blood sample is positive for a newly identified anti-C and anti-Fya. The patient's direct antiglobulin test is 3+ positive for IgG and negative for C3d. The elution demonstrates the presence of anti-C and anti-Fya. The patient's phenotype, using a sample from one week ago, is C negative and Fya negative. The unit provided a week ago is now 3+ crossmatch incompatible against the patient’s current blood sample. What is the best explanation for these findings?

  1. Best explanation cannot be determined because the patient has no history of prior transfusions
  2. Patient experienced a delayed hemolytic transfusion reaction
  3. Patient has a clinically significant cold agglutinin disease
  4. Patient has a new diagnosis of a warm autoimmune hemolytic anemia
  5. Patient has evidence of osmotic hemolysis secondary to G6PD deficiency
Board review style answer #1
B. Patient experienced a delayed hemolytic transfusion reaction

Comment Here

Reference: Delayed hemolytic transfusion reaction (DHTR)
Board review style question #2
    A 75 year old man received a crossmatch compatible red cell transfusion 3 days ago. The patient had no detectible alloantibodies and received a crossmatch compatible, ABO compatible unit. The transfusion service was contacted to evaluate this patient for a possible transfusion reaction as the patient has now developed an unexpected fever, hyperbilirubinemia and jaundice 72 hours after the transfusion event. The patient's phenotype on file reveals that patient is positive for the following antigens: D, C, e, K, k, Jkb, Fya, S, M and N. If the patient’s direct antiglobulin test is now positive for IgG, which of the following alloantibodies would we most likely find in this patient's plasma?

  1. Anti-c
  2. Anti-E
  3. Anti-Fyb
  4. Anti-Jka
  5. Anti-s
Board review style answer #2
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