Eleven years of alloimmunization in 6496 patients with sickle cell disease in France who received transfusion

Abstract

Red blood cell (RBC) transfusion is a major therapy for sickle cell disease (SCD). Patients are at risk of forming antibodies to RBC antigens, which can result in the impossibility to find compatible units and can cause hemolytic transfusion reactions. This retrospective study investigates the evolution of RBC consumption and the frequencies, specificities, and chronology of the appearance of antibodies in a population of patients consistently receiving RH (C, D, E, c, e) and K-matched RBC units (RBCus) from a predominantly European donor population. Over the 11-year period in the Paris area, 6496 patients received transfusion at least once for a total of 239 944 units. Antibodies were made by 1742 patients. The first antibodies of a patient were predictive of subsequent immunization. By the 17th RBCu transfused (by the 20th, excluding warm autoantibodies), 75% of the patients who would make antibodies had made their first. By the 16th, 90% who would make antibodies to a high frequency antigen had made their first antibody to these antigens. Females made their first antibodies slightly earlier than males. Patients who received multiple transfusions (>50 units) had a higher immunization prevalence than those who rarely received transfusion (<12 units) but fewer clinically significant antibodies. Patients with SCD and prophylactic RH-K matching not immunized by the 20th RBCu are likely to have a low alloimmunization risk (to antigens other than RH-K), that is, be low responders, especially relative to the most clinically significant antibodies. This number of 20 units is a point before which close monitoring of patients is most important but remains open to future adjustment.

Graphical abstract

Figure 1.

Study flowchart and overview of analysis performed.

Figure 2.

RBC transfusions for N = 6496 pSCDs in the Paris area. (A) Number of patients receiving transfusion and number of RBCus transfused each year: 2008-2018 study period and recent 2019-2021 evolution (data added during revision). (B) Sum of all RBCus transfused per year based on the age at transfusion (curve) and comparison between year 2008 and year 2018 (histogram). (C) Mean number of RBCus per patient per year based on the age at transfusion (curve), and comparison between year 2008 and year 2018 (histogram). (D) Overlay histogram of the distribution of the number of RBCus transfused per patient, comparing the proportion of immunized and nonimmunized patients for each number of RBCus received. Data shown as percentages (of immunized or nonimmunized patients, respectively), rather than the number of patients, to facilitate visual comparison. The first bar shows that 3.8% of immunized patients and 10.5% of nonimmunized patients only received 1 unit. Data are truncated at 100 units received for clarity, but the distribution goes on with similar profile until the largest number of units received in the cohort (1372).

Figure 3.

Antibodies (historical or newly developed) reported in n = 1742 pSCDs who received transfusion. (A) Distribution of antibodies per antibody specificity and (B) distribution of antibodies per patient; there were 498 different combinations of antibodies. Antibodies or combinations reported in <5 patients are not shown. Antibodies to HFAs included anti-Fy3 (n = 58), anti-Fy5 (n = 17), anti-Js^b (n = 5), anti-U (n = 9), anti-Co^a (n = 3), (n = 1), and anti-Hy, anti-Jo^a, and anti-En^a (n = 1 each). n = 31 antibodies to HFAs were not identified at the first occurrence. HTLA, high titer-low affinity; NI-LFA, nonidentified low-frequency antigen; US, unspecified specificity (which could be a previously identified antibody that was not characterized to save resources or for lack of appropriate panel cells, or an emerging antibody).

Figure 4.

Influence of age and sex on immunization. (A) Comparison based on sex and for ages 18 to 50 years (pregnancy data were not available, and some pregnancies might have occurred earlier or later than these ages). (B) Comparison between patients whose first transfusion occurred before or after the age of 5 years. Crosses show censored data, that is, each time a patient made an antibody or the last known transfusion for the patient if they made no antibodies.

Figure 5.

Risk of second antibody formation, depending on the antibody formed at first immunization in n = 643 patients for whom chronological analysis of immunization could be performed. Relative risk (RR) compared with that for all immunized patients, with 95% confidence interval (CI). When the first immunization included a WAA or NOA (RR and CI < 1), the risk was reduced compared with that in other patients; when the first immunization included an antibody to RH-K, AEP, or antibody to a HFA, the risk was higher (RR and CI > 1); the risk of second immunization after a first immunization including an AUS or antibody to a LFA was not significantly altered. The RR was highest when the first immunization included an antibody to an HFA. Those included anti-Fy3 (n = 8), anti-Fy5 (n = 4), anti-U (n = 4), anti-Co^a, anti-Js^b, and anti-Jo^a, (n = 1 each), and n = 8 not identified at first detection.

Figure 6.

Kaplan-Meier curve for the number of RBC units received before the first positive antibody screen in n = 643 patients for whom no antibodies had been reported before the study period or before their first transfusion. The first positive antibody screen for each patient is counted as an event. Curves are shown for all antibodies and for subgroups: WAAs, AUS, antibodies to RH antigens (D, C, E, c, and e) or Kell (RH-K), to AEP, and to HFA. (A) The full cohort. (B) Zoom-in focusing on 0 to 50 RBCus, with a vertical bar representing 20 RBCus, after which 90% of patients who will make antibodies to HFA have made their first such antibody, and >75% of patients who will make antibodies to RH-K antigens, AEPs, WAAs, and AUSs will have made their first such antibody. The figure was generated with software SAS 9.4 and R.