Red-blood-cell alloimmunisation in relation to antigens' exposure and their immunogenicity: a cohort study

doi:10.1016/S2352-3026(16)30019-9

The Lancet Haematology

Volume 3, Issue 6, June 2016, Pages e284-e292

https://doi.org/10.1016/S2352-3026(16)30019-9 Get rights and content

Summary

Background

Matching donor red blood cells based on recipient antigens prevents alloimmunisation. Knowledge about the immunogenicity of red-blood-cell antigens can help optimise risk-adapted matching strategies. We set out to assess the immunogenicity of red-blood-cell antigens.

Methods

In an incident new-user cohort of previously non-transfused, non-alloimmunised white patients receiving non-extended matched red-blood-cell transfusions in six Dutch hospitals between 2006 and 2013, we determined the cumulative number of mismatched red-blood-cell units per patient. We used multiple imputation to address missing antigen data. Using Kaplan-Meier analysis, we estimated cumulative alloimmunisation incidences per mismatched antigen dose as a measure of immunogenicity.

Findings

Of 54 347 patients assessed, 21 512 were included in our study. Alloantibodies occurred in 474 (2·2%) of all transfused patients, with cumulative alloimmunisation incidences increasing up to 7·7% (95% CI 4·9–11·2) after 40 units received. The antigens C, c, E, K, and Jk^a were responsible for 78% of all alloimmunisations in our cohort. K, E, and C^w were the most immunogenic antigens (cumulative immunisation incidences after 2 mismatched units of 2·3% [95% CI 1·0–4·8] for K, 1·5% [0·6–3·0] for E, and 1·2% [0·0–10·8] for C^w). These antigens were 8·7 times (for K), 5·4 times (for E), and 4·6 times (for C^w) as immunogenic as Fy^a. The next most immunogenic antigens were, in order, e (1·9 times as immunogenic as Fy^a), Jk^a (1·9 times), and c (1·6 times).

Interpretation

Red-blood-cell antigens vary in their potency to evoke a humoral immune response. Our findings highlight that donor-recipient red-blood-cell matching strategies will be most efficient when primarily focusing on prevention of C, c, E, K, and Jk^a alloimmunisation. Matching for Fy^a is of lower clinical relevance. Variations of antigen frequencies determined by ethnic background prevent extrapolating these conclusions to non-white populations.

Funding

None.

Introduction

Exposure to foreign red-blood-cell antigens can induce alloimmunisation. Notwithstanding current ABO/RhD-matching and stringent antibody screening policies, life-threatening haemolytic reactions resulting from boosting of previously induced alloantibodies still complicate red-blood-cell transfusions.1, 2 Moreover, previous alloimmunisations demand extensive laboratory efforts and can result in delays in finding compatible donor blood.

A complete antigenic phenotype match between donor and recipient would theoretically eliminate all transfusion-induced alloimmunisations, but achieving this entails countless logistical and financial challenges. The next best alternative is to select donor units matched at least on the most immunogenic antigens for patients at high risk. In line with this principle, patients with myelodysplastic syndrome, and autoimmunised or alloimmunised patients in the Netherlands are advised to receive blood matched on the CcEe and K antigens, whereas patients with haemoglobinopathy additionally receive blood matched on Fy^a and preferentially Jk^b and Ss antigens as well.³ Since alloimmunisation can severely complicate subsequent pregnancies, women under 45 years of age receive blood matched on c, E, and K antigens.³ These matching strategies are based on broad expert consensus on the antigens' immunogenicity—ie, their intrinsic potency to stimulate humoral immune responses. RhD is without doubt the most immunogenic antigen and is followed by K.¹ However, data for the relative immunogenicity of several other antigens are conflicting,4, 5, 6, 7 requiring additional observational evidence.

We set out to quantify antigen-specific alloimmunisation incidences in relation to the cumulative number of mismatched transfusions per patient as a measure of the intrinsic immunogenicity of red-cell antigens. This knowledge will enable an evidence-based optimisation of matching strategies, balancing benefits against costs and logistic aspects.

Section snippets

Study design and setting

We performed an incident new-user cohort study in patients consecutively transfused in three university hospitals and three non-university hospitals in the Netherlands. We included all previously non-transfused and non-alloimmunised patients who received at least one red-blood-cell transfusion during the study period, provided the availability of at least one pre-transfusion and post-transfusion antibody screen.

Research in context

Evidence before this study

We searched PubMed for studies

Results

The study period varied per hospital according to the electronic availability of necessary data: from Jan 1, 2005, to Dec 31, 2010, at Leiden University Medical Center (Leiden); from Sept 6, 2006, to Dec 31, 2013, at University Medical Center Utrecht (Utrecht); from Nov 19, 2011, to Dec 31, 2013, at VU University Medical Center (Amsterdam); from May 1, 2007, to April 30, 2013, at Catharina Hospital (Eindhoven); from July 1, 2005, to Dec 31, 2013, at Jeroen Bosch Hospital (‘s-Hertogenbosch); and

Discussion

In this study involving 21 512 newly transfused patients, we established estimates of dose-specific red-cell alloimmunisation risks. In agreement with previous reports, K is most potent in stimulating humoral alloimmune responses. E demonstrates the second highest immunogenicity, followed by C^w, e, Jk^a, and c.

The alloimmunisation rate we observed here of 0·9% after one K-positive unit is five times lower than historically assumed.⁴ Moreover, since previous studies did not take into account the

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^†: These authors contributed equally to this work

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ArticlesRed-blood-cell alloimmunisation in relation to antigens' exposure and their immunogenicity: a cohort study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and setting

Results

Discussion

Blood

Clin Immunol

J Clin Epidemiol

Blood

Transfus Clin Biol

TRIP Hemovigilance report

SHOT report

CBO blood transfusion guideline

A critique of the theoretical hazard of inter vs. intra-racial transfusion

Transfusion

Red blood cell alloantibodies after transfusion: factors influencing incidence and specificity

Transfusion

RBC alloantibody specificity and antigen potency in Olmsted County, Minnesota

Transfusion

Dutch transfusion register for irregular antibodies

Comparing alloimmunization in preterm infants after transfusion of fresh unmodified versus stored leukocyte-reduced red blood cells

J Pediatr Hematol Oncol

The blood group antigen factsbook

Probability of anti-D development in D- patients receiving D+ RBCs

Transfusion

Primary immunization of Rh-negative volunteers

Br Med J

Articles
Red-blood-cell alloimmunisation in relation to antigens' exposure and their immunogenicity: a cohort study