Delayed Hemolytic Transfusion Reaction: Clinical Presentation and Characteristics
A delayed hemolytic transfusion reaction (DHTR) presents as a significant drop in hemoglobin within 21 days post-transfusion, often accompanied by hemoglobinuria, jaundice, fever, bone pain, and symptoms that can mimic a vaso-occlusive crisis in sickle cell disease patients. 1
Timing and Onset
- DHTR typically occurs 3-21 days after transfusion, with the median time to diagnosis being approximately 6 days post-transfusion. 2
- In rare cases involving primary immune responses, symptoms may appear as late as 4 weeks after transfusion. 3
Clinical Manifestations
Hemolytic Features
- Hemoglobinuria (dark, tea-colored urine from red blood cell breakdown) is a hallmark finding. 1, 4
- Jaundice and pallor develop from accelerated hemolysis and hyperbilirubinemia. 2
- Profound anemia, often with hemoglobin dropping below the pre-transfusion level in severe cases (hyperhemolysis syndrome). 1, 4
Systemic Symptoms
- Severe generalized bone pain occurs in the majority of patients, present in all cases in one pediatric series. 2
- High-grade fever is common, occurring in nearly all patients. 2
- Generalized body ache, exertional dyspnea, headache, and easy fatigability are frequently reported. 5
- Symptoms can mimic acute chest syndrome or severe vaso-occlusive crisis, particularly in sickle cell disease patients. 2
Laboratory Findings
Diagnostic Markers
- New red cell alloantibody detection (though notably, in 5 of 8 cases in one series, no new antibody was identified, highlighting diagnostic complexity). 2
- Positive direct antiglobulin test (Coombs test) indicating antibody coating of red blood cells. 5
- Accelerated HbS% increase with concomitant fall in HbA in sickle cell patients post-transfusion. 1
- Significant LDH rise from baseline reflecting red cell destruction. 1
Hematologic Changes
- Relative reticulocytopenia or paradoxical reticulocytosis from baseline values. 1
- In severe cases, reticulocyte count may fall below 150×10⁹/L despite ongoing hemolysis. 2
- Hemoglobin levels can drop to life-threatening levels (4-5 g/dL or lower). 5, 2
Hyperhemolysis Syndrome
The most severe form of DHTR is hyperhemolysis syndrome, where hemoglobin rapidly declines below the pre-transfusion level, indicating destruction of both transfused and the patient's own red blood cells. 1
- This represents destruction of red cells that do not even carry the targeted antigen. 4
- While typically seen in sickle cell disease, it can occur in patients without hemoglobinopathies. 4
- This complication can lead to multiple organ failure and death if not recognized and treated promptly. 5
Diagnostic Complexity
A critical pitfall is that DHTR symptoms closely resemble other complications of the underlying disease, particularly vaso-occlusive crisis in sickle cell patients, which can delay diagnosis. 5, 2
- In many cases, no new antibody is identified despite clear hemolysis, underscoring the complex pathophysiology. 2
- Some patients may have only weakly reactive antibodies that are difficult to detect. 2
- The most commonly implicated antibodies include anti-C, anti-E, anti-Jkb, anti-Fya, and anti-K. 4, 2
Risk Factors
- Previous transfusions or pregnancies increase alloimmunization risk, though DHTR can occur even after a first transfusion. 6
- Sickle cell disease patients are at particularly high risk due to antigen mismatches between predominantly European donor blood and African-descent recipients. 2
- Multiple recent transfusions (such as 6 units over 6 months) significantly increase risk. 5