Before we had a common system for the administration of blood transfusions, including the obligatory compatibility checks prior to any blood transfer, the idea of blood transfusions as a medical solution was seen as a fantasy with a tinge of the macabre. The general public remained unconvinced that blood could be explanted from one individual (or animal) to another without some sort of moral/spiritual/sickness spillover. 

Nevertheless, our predecessors in medicine have worked hard, through trial and error, to give us the nearly fail-safe blood transfusion protocol and procedure that we are so accustomed to today. 

Interestingly, the new challenge when it comes to blood transfusions is that they remain available but are not used in instances when they are clearly indicated. This is demonstrated via a case study presented by De Bruyne and colleagues in Clinical Chemistry and Laboratory Medicine (CCLM). They reported on a patient who required blood transfusions for warm autoimmune hemolytic anemia but did not receive them efficiently due to poor clinical communication and decision-making. 

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A Significant Delay

The case study as described details a 67-year-old man admitted to the emergency department around 3 weeks after receiving his third dose of the Pfizer-BioNTech mRNA COVID-19 vaccine. He reported experiencing fever, fatigue, general weakness, jaundice, and passing dark urine for the last 5 days. In addition, he experienced diarrhea and had clinically significant anorexia. 

Read more about cold agglutinin disease etiology

Physical examinations were unremarkable except for his anemic and icteric appearance. His only past medical history was a case of mild thrombocytopenia documented to have occurred since 2019; no further explanations were provided. 

Laboratory results revealed the following: 

  • Low hemoglobin (75g/L, normal: 135-170g/L)
  • Reticulocytopenia (24.1×109/L, normal: 30–93×109/L)
  • Undetectable haptoglobin (<0.10 g/L, normal: 0.3–2.0 g/L)
  • High lactate dehydrogenase (1100 U/L, normal: 105–250 U/L)

In addition, the patient also had a low platelet count, absolute neutrophilia, and increased total bilirubin. Glucose-6-phosphate dehydrogenase activity was normal. 

A peripheral blood smear and a COVID-19 PCR test were negative. A thoracic computed tomography (CT) scan showed a left lower lobe infiltrate, which was treated with broad-spectrum antibiotics. A full positron emission tomography(PET)/CT scan and cytomorphological and flow cytometric assessment of a bone marrow aspirate were normal. 

The direct antiglobulin test was perhaps the most illuminating of the tests carried out, as it was positive for anti-IgG and anti-C3d. When differentiation by monospecific testing was carried out, it revealed a distinctive positive reaction for anti-IgG and a weak one for anti-C3d/C3d. The scientists involved prepared an eluate from his red blood cells, which showed a strong panreactivity against all test cells. 

“These results indicated the presence of IgG auto-antibodies without specificity and with additional complement activation,” De Bruyne and colleagues explained. “The panreactive autoantibodies also interfered with standard pretransfusion tests (i.e. the indirect antiglobulin test and crossmatching).” 

For patients with warm autoimmune hemolytic anemia who require blood transfusions, two specialized procedures are carried out: genotyping of the red blood cell antigens for extended phenotype-matched units, as well as adsorption tests to identify alloantibodies. 

Read more about cold agglutinin disease treatment 

When a diagnosis of warm autoimmune hemolytic anemia was made, immunosuppressive therapy, such as methylprednisolone 1mg/kg, was initiated. The next day, the patient showed signs of confusion; further investigations revealed a critically low hemoglobin level of 35 g/L. 

“Nevertheless, transfusion was not immediately started due to the incompatible pretransfusion test results and the order was made for an urgent allogeneic adsorption test to exclude the presence of [red blood cell] alloantibodies, but none were detected,” the authors of the study wrote. “These circumstances significantly delayed (overall 8 h) the administration of the first units of compatible packed [red blood cells].” 

The patient’s methylprednisolone dose was increased to 1g/day on day 3 due to inadequate response. His physicians initiated daily plasma exchange on day 5 and weekly rituximab infusions (1g) on day 12. On day 5, the patient’s LDH levels and transfusion needs began to decline and he was eventually discharged on day 21, showing stable hemoglobin levels at 70 g/L.

An Immediate Difference 

This lengthy case presentation highlights the importance of transfusions being carried out without unnecessary delay in patients with life-threatening warm autoimmune hemolytic anemia and incompatible pretransfusion tests, despite some advising against it. This is because this procedure can make a huge immediate difference in the condition of the patient. 

As in this case study, unique caution associated with blood transfusions in warm autoimmune hemolytic anemia could cause more harm than useful delay. To overcome this problem, patients’ individual transfusion needs should be adequately assessed prior to any decision-making. 

In the case of cold agglutinin disease, another form of autoimmune hemolytic anemia, it is imperative that blood transfusions are warmed to the patient’s body temperature before they are administered. This is to avoid a scenario in which cold agglutinin antibodies do not attack the newly administered red blood cells.

“Transfusion is frequently indicated for symptomatic or fast-progressing anemia, which can be life-threatening, especially in cases of associated reticulocytopenia, and should not be withheld just because of fear of theoretical complications,” Voulgaridou and Kalfa wrote in the Journal of Clinical Medicine. “Prompt initiation of steroid treatment on presentation and close monitoring during transfusion is recommended to minimize the risk of transfusion reactions.”


De Bruyne S, Van Landeghem S, Schauwvlieghe A, Noens L. Life-threatening autoimmune hemolytic anemia following mRNA COVID-19 vaccination: don’t be too prudent with the red goldClin Chem Lab Med. 2022;60(6):e125-e128. doi:10.1515/cclm-2022-0118

Voulgaridou A, Kalfa TA. Autoimmune hemolytic anemia in the pediatric settingJ Clin Med. 2021;10(2):216. doi:10.3390/jcm10020216