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Delayed Hemolytic Transfusion Reaction

Delayed hemolytic transfusion reactions (DHTR) occur in patients who have undetectable levels of antibody when pretransfusion testing is performed, so that seemingly compatible units of red blood cells are transfused. Exposure to antigen positive red blood cells provokes an anamnestic response and increased synthesis of the corresponding antibody.  After several days, the antibody titer becomes high enough to hemolyze transfused red cells. The frequency of delayted hemolytic transfusion reactions is estimated to be approximately 1 case per 5400 red cell units transfused.

Approximately 3 months is required for a patient to produce detectable levels of antibody after first exposure to a foreign red blood cell antigen through transfusion or pregnancy. If no additional red cell antigen stimulus occurs, the antibody can become undetectable in 50% of patients within 5 years. Following renewed exposure to the same red cell antigen, a more rapid antibody response can occur from 3 to 21 days later. Peak antibody production usually occurs between 7 and 10 days after exposure. Transfused red cells containing the antigen undergo extravascular hemolysis by the reticuloendothelial system of the spleen and liver over a period of several hours to days.

In most cases, delayed hemolytic reactions are asymptomatic and the only noticeable sign is a more rapid fall in the post-transfusion hemoglobin level than is clinically expected. Occasionally a patient experiences a flu-like illness. Fever is the most common symptom, followed by jaundice. In rare instances, hemolysis may be brisk (especially when Kidd antibodies are implicated) resulting in fever, hemoglobinemia and hemoglobinuria.

The National Healthcare Safety Network (NHSN) hemovigilance protocol defines DHTR as a positive direct antiglobulin test (DAT) that develops between 24 hours and 28 days after cessation of transfusion AND EITHER a positive elution test with alloantibody present on the transfused red blood cells OR newly identified red blood cell alloantibody in recipient serum AND EITHER inadequate rise of post-transfusion hemoglobin level or rapid fall in hemoglobin back to pre-transfusion level OR otherwise unexplained appearance of spherocytes.

Delayed hemolytic transfusion reactions are most often detected by the blood bank in retrospect when laboratory tests reveal a positive direct antiglobulin test and/or an indirect antiglobulin test. Other lab findings include decreasing hemoglobin or hematocrit, increasing indirect bilirubin, elevated LDH and positive antibody screen posttransfusion. Conjugated bilirubin is excreted in urine and bile and seldom exceeds 6 mg/dL.

 Generally, delayed hemolytic reactions do not result in serious adverse sequelae. Occasionally, the decrease in a patient’s hemoglobin associated with a delayed hemolytic transfusion reaction may be misdiagnosed as internal bleeding. Treatment is rarely necessary. Urine output and renal function should be monitored. Transfusion of antigen negative blood may be necessary for treatment of anemia.

 The responsible antibody should be identified and all additional units should be negative for the corresponding antigen. When RBC antibodies are identified, patients should be informed and advised to provide this information when they are hospitalized elsewhere. Carrying a transfusion alert card is recommended. Physicians whose patients tell them about previously identified antibodies should immediately notify the Transfusion Service.

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