In this large multicentre observational study, we have demonstrated that neither the ABO blood group nor the RhD status is associated with mortality or morbidity in a mixed critically ill patient population. In sensitivity analyses, the ABO blood group and the RhD status did not add predictive value to the SAPS 3, and in five different subgroup analyses there were no differences in mortality between non-O blood groups and blood group O or between the RhD status. Furthermore, we could not demonstrate any differences in the number of transfused patients between the ABO blood groups or between the RhD status.
Based on previous findings, the ABO blood group is likely to affect homeostasis through several mechanisms [1–3]. However, our results imply that this effect is subtle, if not irrelevant, in a large mixed cohort of critically ill patients. It is possible that the ABO blood group may influence outcomes in certain clinical populations suffering from specific diseases; nevertheless, in contrast to a number of previous reports, we did not observe a mortality effect in any of the subgroups (sepsis, septic shock, ARDS, Covid-19, cardiac arrest and trauma). However, it should be noted that in the subgroups septic shock and cardiac arrest, blood group AB was associated with a longer length-of-stay as compared to blood group O. In the ARDS-subgroup, blood group A was associated with increased ventilator time as measured with DAF ventilation.
In contrast to the absence of associations between the ABO blood group and outcomes in the present study of mixed critically ill patients, Slade et al. found that blood group AB conferred a 90-day mortality benefit compared to other ABO blood groups in a similar but smaller patient cohort in the United Kingdom [21]. However, it should be noted that only 3% of patients had blood group AB, and although baseline data were similar for the different ABO blood groups, the mortality analyses were unadjusted, which may at least in part explain the differences compared to our results.
Recent studies have largely focused on Covid-19, where meta-analytic data indicate that blood group O might be protective against Covid-19, whereas blood group A is associated with an increased risk of infection [7]. Apart from the lower thrombotic risk associated with blood group O, anti-A has also been reported to block virus entry into cells through interaction with the receptor angiotensin-converting enzyme-2 [8]. Unfortunately, the number of patients in the Covid-19 subgroup, n=338, in the present study was deemed too small to analyse.
The influence of ABO-blood groups has also been investigated in critically ill patients with non-Covid-19 disease, such as sepsis and ARDS. In two separate studies, Reilly et al. demonstrated that blood group A is associated with increased risk for ARDS in sepsis (and trauma), possibly due to dysfunction of endothelium and microvasculature, as indicated by altered levels of biomarkers (e.g., soluble thrombomodulin and selectins) [14, 15]. These findings are supported by results from a large study of critically ill sepsis patients evaluating ABO blood groups and biomarkers of endothelial damage, which demonstrated moderately decreased mortality for blood group B [12]. In the present study, the potential effect of the ABO-blood group did not influence morbidity and mortality outcomes for any of the sepsis (n=3 016), septic shock (n=1 366) or ARDS (n=5 642) subgroups.
The increased risk of bleeding for patients with blood group O is mainly mediated by lower vWF levels (and associated lower factor VIII levels) [5]. This was not reflected in increased transfusion requirements in the present study. Blood group O has been associated with worse outcomes in severe trauma and increased transfusion volume in severe abdominal trauma, which could be due to the proposed haemostatic effects [17, 18]. As mentioned above, Reilly et al. found a connection between blood group A and the risk of ARDS in trauma patients [14, 15]. Here, congruent with findings from two previous studies, we did not observe worse outcomes for blood group O in the trauma subgroup [9, 10].
The Rh blood group antigen RhD is routinely analysed together with the ABO blood group. RhD blood group is less studied than the ABO system for its association with diseases, including critical illness. We found no effect of RhD status on mortality or morbidity in the general critically ill population or in any specific subgroup. The RhD antigen is only expressed on red blood cells and is primarily of clinical interest in the context of haemolytic reactions (of the newborn and in case of blood transfusion). Individuals who are RhD-negative may have some protection against Covid-19 infection, but the pathophysiological basis is unclear [8].
Although an individual cannot change ABO blood group or RhD status, except in the rare case of stem cell transplantation, the results of the present study expand important knowledge regarding associations between ABO groups, RhD status, mortality and morbidity. In addition to epidemiological studies, such as the present work, studies investigating pathophysiological alterations associated with blood groups, e.g., changes in vWF levels, blockage of virus-receptors and endotheliopathy, should be given high priority since detailed mechanistic insights may potentially guide development of future personalised therapies.
Limitations and strengths
We recognise the limitations in the present study given its retrospective nature, including the absence of a published study protocol. Secondly, data on ethnicity is missing. Thirdly, the division into subgroups in the second set of sensitivity analyses was performed based on diagnoses coded by the treating physician. Hence it cannot be ruled out that some diagnoses were missed. Fourthly, the Covid-19 cohort was deemed too small for robust analyses of independent risk factors. Strengths of the study include a larger sample size compared to previous similar studies, comprehensive datasets and the multicentre design.