Management of hemolytic transfusion reactions

Abstract

Delayed hemolytic transfusion reactions (DHTRs) in patients with sickle cell disease are underappreciated and potentially fatal. Patients with DHTRs typically have symptoms of pain or dark urine days to weeks following a red blood cell (RBC) transfusion. In instances of DHTRs with hyperhemolysis, the patient's hemoglobin (Hgb) may be significantly lower than it was pretransfusion, and the Hgb A may drop by more than 50%. In most cases, at least 1 RBC alloantibody and sometimes multiple RBC alloantibodies can be identified during the DHTR, with those antibodies presumably having fallen below the level of detection at the time of the implicated transfusion. However, in up to one-third of cases, no new RBC alloantibodies can be identified posttransfusion. Complement is increasingly being appreciated to play a role in DHTRs and hyperhemolysis, not only due to classic pathway activation (with complement fixed antibody bound to RBCs) but also due to alternative pathway activation (resulting in part from plasma free heme). As such, anti-C5 inhibition has recently been reported to be effective at mitigating hemolysis in the setting of some severe DHTRs. Transfusion avoidance during DHTRs is recommended if possible, with long-term transfusion support advice being less clear; for example, a history of a severe DHTR may lead to questions regarding the safety of transfusions prior to curative therapies such as stem cell transplantation or gene therapy. A better understanding of antibody-positive and antibody-negative DHTRs, including patient- or disease-specific risk factors, is necessary to improve transfusion safety.

Graphical abstract

Figure 1.

DSTRs, DHTRs, and DHTRs with hyperhemolysis. In the general population, DSTRs are much more common that DHTRs, although the DSTR to DHTR ratio has not been well studied in patients with SCD. Bystander hemolysis occurs in an unclear percentage of DHTRs in patients with SCD.

Figure 2.

Antibody detection and evanescence considerations. Upon initial RBC exposure (red arrow), 1 or multiple RBC alloantibodies may be generated. Once an antibody concentration gets above a certain level (dotted line), it can be detected by blood bank methods. Over time, that antibody may evanesce and fall below the level of detection (white arrow). If the patient needs a transfusion at a later time point (blue arrow), the antibody may not be detected. Of note, if an antibody screen was not completed within weeks of the initial transfusion, the antibody or antibodies may not have been detected at all. If the patient was seen at a different hospital in the United States at the time point indicated by the blue arrow, that hospital will most likely be unaware of an antibody or antibodies previously detected by the initial hospital. Figure generated with the assistance of R. George Hauser, MD.