What is a delayed hemolytic transfusion reaction (DHTR)?

Delayed Hemolytic Transfusion Reaction (DHTR)

A delayed hemolytic transfusion reaction is a significant complication occurring within 21 days after blood transfusion, characterized by a drop in hemoglobin associated with hemolysis of both transfused and sometimes the patient's own red blood cells. DHTR is defined as a significant drop in hemoglobin within 21 days post-transfusion associated with one or more of the following: new red cell alloantibody, hemoglobinuria, accelerated HbS% increase with concomitant fall in HbA, relative reticulocytopenia or reticulocytosis, significant LDH rise, and exclusion of alternative causes. 1

Clinical Presentation and Diagnosis

• DHTR typically manifests days to weeks after transfusion, with symptoms including fever, jaundice, and hemoglobinuria 2
• Laboratory findings include:
  • Decreased hemoglobin levels (sometimes below pre-transfusion levels in hyperhemolysis syndrome)
  • Elevated LDH and bilirubin
  • Positive direct antiglobulin test (though can be negative in some cases)
  • Detection of new alloantibodies 1, 2
• Hyperhemolysis syndrome, a severe form of DHTR, is characterized by hemoglobin dropping below pre-transfusion levels, indicating destruction of both transfused and patient's own red cells 2

Pathophysiology

• DHTR results from alloimmunization to red cell antigens following previous exposure through transfusion, pregnancy, or transplantation 2
• Common antibodies implicated include those against Rh system (C, E), Kidd system (Jka, Jkb), Duffy system (Fya), and others 2, 3
• Primary immune responses can cause DHTR with antibodies first detected up to 8 weeks post-transfusion 4
• In hyperhemolysis, bystander hemolysis of the patient's own cells occurs through mechanisms that may involve complement activation 3

High-Risk Populations

• Most commonly seen in patients with sickle cell disease (SCD) due to frequent transfusions and higher rates of alloimmunization 1, 3
• Can occur in other populations including thalassemia patients 5, 6
• Even patients without hemoglobinopathies or history of multiple transfusions can develop DHTR, though this is rare 2

Management

For patients experiencing DHTR with ongoing hyperhemolysis:

• Avoid further transfusions unless life-threatening anemia is present 1, 5
• First-line immunosuppressive therapy includes:
  • IVIg (0.4-1 g/kg/day for 3-5 days, up to total dose of 2 g/kg) 1
  • High-dose steroids (methylprednisolone or prednisone 1-4 mg/kg/day) 1
• Second-line agent is eculizumab for complement inhibition 1, 3
• Rituximab (375 mg/m² repeated after 2 weeks) is primarily indicated for prevention of additional alloantibody formation in patients who may require further transfusion 1
• Supportive care with erythropoietin with or without IV iron 1
• If transfusion is absolutely necessary, extended matched red cells (C/c, E/e, K, Jka/Jkb, Fya/Fyb, S/s) should be considered 1

Prevention in High-Risk Patients

For patients with history of DHTR requiring transfusion:

• The American Society of Hematology suggests immunosuppressive therapy (IVIg, steroids, and/or rituximab) over no immunosuppressive therapy for patients with an acute need for transfusion and at high risk for acute hemolytic transfusion reaction or with history of multiple or life-threatening DHTRs 1
• Preventive immunosuppression should be considered when:
  • Compatible blood cannot be found due to multiple alloantibodies
  • Patient has history of severe DHTR even when compatible blood is available 1
• Extended antigen matching for transfusions can reduce risk of alloimmunization 1

Challenges and Pitfalls

• DHTR is often underdiagnosed, especially in non-SCD populations 2
• Antibodies may not be detectable at the time of hemolysis, requiring sequential testing 4
• Further transfusions during a DHTR episode can exacerbate hemolysis and lead to life-threatening complications 1, 5
• Treatment efficacy varies; some patients continue to experience hemolysis despite immunosuppressive therapy 5
• In refractory cases, splenectomy has been reported as potentially beneficial in select cases 5

Research Needs

• Tools for accurately predicting clinical relevance of alloantibodies in individual patients 1
• Better understanding of mechanisms of hemolytic transfusion reactions with different alloantigen targets 1
• High-quality studies evaluating efficacy of immunomodulatory agents in preventing DHTR 1
• Development of universally available transfusion registries to reduce alloimmunization-related sequelae 1