A possible case of a haemolytic transfusion reaction caused by anti-Le(a) antibody.

Dear Sir, We read with interest the recent case study by Hoglund et al.1 detailing a case of severe haemolytic transfusion reaction caused by anti-Lewisa antibody [anti-Lea] at 37 °C. We too recently observed a possible acute haemolytic transfusion reaction caused by high thermal amplitude anti-Lea. The patient is a 26-year old gravida 8 para 3317 female with sickle cell trait at 38 weeks of gestation, admitted with pyelonephritis and urosepsis. On day 2 she developed fever up to 39.4 °C, persistent hypotension requiring vasopressor support and multiple fluid boluses, and tachypnoea with normal saturations on room air. She was then transferred to the intensive care unit. By the morning of day 3, the patient was off oxygen and vasopressor support and had been transferred back to the medical floor. Concurrent with early second stage labour in the afternoon of day 3, a red blood cell transfusion was begun. After receiving less than a quarter of the unit, she experienced an episode of significant dyspnoea with oxygen saturations to 80% on room air and hypotension, with a blood pressure as low as 88/40 mmHg. Urine collected from her Foley catheter turned red. She did not have either fever or other significant signs or symptoms. The transfusion was stopped immediately and the patient was supported with oxygen and intravenous fluids until delivery and then transferred to the intensive care unit. The patient’s acute dyspnoea suggested transfusion-related acute lung injury. However, her post-transfusion chest x-ray did not show significant oedema or infiltrates. Serological work-up on the post-transfusion specimen was performed according to our institution’s standard operating procedures. Pre-transfusion work-up showed that the patient’s blood type is B positive. She had no previous transfusion history at our hospital. Her initial antibody screen showed a pan-reactive cold-reacting antibody. After separately pre-warming reagents and the patient’s plasma, anti-Lea was identified via a gel indirect antiglobulin test. Other alloantibodies were ruled out after the anti-Lea was neutralised with the addition of Lewis substance and the patient was issued cross-match-compatible red cell units using pre-warmed plasma neutralised with Lewis substance. Regarding the transfusion reaction work-up, a clerical check revealed no irregularities. A visual check was positive for haemoglobinaemia, initially thought to be due to mechanical haemolysis from a traumatic blood draw. However, a blood sample drawn approximately 2 hours after the transfusion continued to show haemoglobinaemia, making mechanical haemolysis less likely. Direct antiglobulin tests of both pre- and post-transfusion samples were negative. Additionally, analysis of the patient’s urine showed the presence of both red blood cells and haemoglobin, which could also have been due to haematuria from urosepsis. Elevation of other markers of haemolysis, such as indirect bilirubin and lactate dehydrogenase, supported post-transfusion haemolysis. Her laboratory values also indicated acute kidney injury and mild disseminated intravascular coagulopathy; however, her recent obstetric and renal issues could have contributed to these as well (Table I). Nonetheless, acute haemolytic transfusion reaction could not be ruled out at this point. Table I Laboratory values before transfusion, 4 hours after the transfusion reaction, and 33 hours after the transfusion reaction. A repeat antibody screen performed on the patient’s post-transfusion specimen showed only the cold-reacting antibody and anti-Lea, ruling out an acute haemolytic transfusion reaction due to an evanescent antibody. A negative direct antiglobulin test, as seen in our case, usually argues against immune-mediated haemolysis; however, it is possible that all the transfused cells had been haemolysed. Furthermore, the patient typed Lea negative and a retrospective cross-match between the transfused cells and the patient’s plasma that had not been neutralised by Lewis substances demonstrated incompatibility (Table II). Table II Serological data before and after the transfusion. Taking into account the preponderance of evidence supporting an acute haemolytic transfusion reaction, including the patient’s signs and symptoms, the laboratory evidence of haemolysis, its temporal proximity to the transfusion, and the serological incompatibility between the patient’s serum and the transfused unit, it is likely that this case represents an acute haemolytic transfusion reaction due to anti-Lea reactive at 37 °C. The patient’s symptoms resolved quickly following her initial reaction, and she was normotensive, afebrile and had improved respiratory status soon after arrival at the intensive care unit. By 33 hours following the transfusion, the patient’s bilirubin had normalised and her lactate dehydrogenase and creatinine levels were decreasing (Table I). Anti-Lewis antibodies are generally considered clinically insignificant and most institutions routinely issue cross-match-compatible red blood cells with untested Lewis antigen to their patients with anti-Lewis antibodies4. However, despite the relatively common occurrence of antibodies with Lewis specificity, reports of haemolytic transfusion reactions caused by anti-Lewis are uncommon1–3. Several factors may contribute to this rarity. First, anti-Lewis antibodies are unlikely to be reactive at 37 °C, and are generally considered to be largely of the IgM class2. However, some IgM antibodies can have high thermal amplitude and react at 37 °C, and some anti-Lewis antibodies may also be of the IgG class2–4. We did not specifically investigate whether this warm-reacting antibody was due to IgM or IgG. In our case, anti-Lea still reacted at the anti-human globulin phase after pre-warming, indicating that it was a warm-reacting antibody and potentially capable of causing an acute haemolytic transfusion reaction. Second, transfusion reactions may be under-reported, particularly when comorbidities are prominent and could confound the diagnosis. Unlike the case described by Hoglund et al.1, the haemolysis in our case was relatively mild, and the patient’s clinical situation complicated the diagnostic picture. It is possible that with improved haemovigilence, less severe (but potentially clinically significant) transfusion reactions due to anti-Lewis antibodies might be identified more frequently. In cases in which the anti-Lewis antibody reactivity persists into the anti-human globulin phase, our standard operating procedure had been to issue extended cross-match-compatible red cell units using plasma neutralised with Lewis substance. However, given the potential haemolysis caused by anti-Lea, as demonstrated in this case, our standard operating procedure was changed to issue cross-match-compatible (with non-Lewis-neutralised plasma) units in cases in which anti-Lewis antibodies are reactive at the anti-human globulin phase. We urge caution in cases of high thermal amplitude anti-Lewis antibodies because of the possibility of clinically significant reactivity. We agree with Hoglund et al.1 that: (i) it is important to report rare cases where normally harmless antibodies cause clinically significant haemolysis, and (ii) that a high index of suspicion for these types of rare reactions should be maintained in transfusion reaction investigations.