Effect of Change in Haemoglobin Mass on Physiology in Anaemic and Non-Anaemic Subjects: An Umbrella Review

Introduction

Globally, the prevalence of anaemia is estimated to be 23.2% and of erythrocytosis 0.8 - 3.4%. Apart from the cause, the haemoglobin concentration(Hb) too has a substantial effect on a person's quality of life. For instance, impaired oxygen transport due to anaemia may cause symptoms of fatigue and decreased physical and cognitive function. On the other hand, erythrocytosis may result in hyperviscosity, which may cause, amongst other symptoms, shortness of breath, and physical and cognitive deterioration.

When suffering from an abnormal Hb-level, various treatments may be of benefit: Erytropoiesis Stimulating Agents (ESAs), iron supplementation, transfusion or in case of symptoms of hyperviscosity: cytoreduction and phlebotomy. Moreover, athletes may try to enhance their exercise capacity by increasing their Hb to supraphysiologic levels. All in all, uncertainty remains about optimal Hb-levels, transfusion thresholds, and treatment targets due to a lack of tools that effectively evaluate Hb-related outcomes. We therefore aim to summarize reviews that assess the effects of Hb changes on the human physiology at various baseline Hb-levels (anaemic, non-anaemic and polycythaemic), and identify gaps in existing evidence.

Methods

An umbrella review was conducted, based on the Joanna Briggs Institute methodology (PROSPERO protocol: CRD42022299392). PubMed, MEDLINE, Embase, Web of Science, Cochrane Library and Emcare were searched from inception to April 2022 for studies that report on physiological, and patient reported outcomes (PROMs) affected by interventions that change the Hb. Included interventions are transfusion, phlebotomy, altitude training, ESA, iron supplementation and cytoreduction. Included outcomes are VO2max, tissue oxygenation, heart rate, exercise capacity, fatigue, quality of life and haematological outcomes. Methodological quality was assessed in duplicate using the AMSTAR-2 tool. GRADE was utilized to score the quality of evidence. A narrative synthesis of accumulated evidence, meta-analyses and narrative systematic reviews, is presented. Quantitative data were summarized in a forest plot. Meta-biases were evaluated with a funnel-plot and sensitivity analyses were conducted.

Results

After screening of 1,719 records and 93 full-text eligibility assessments, 34 reviews (18 meta-analyses) were included, of which 25 were of critically low quality. Figure 1 depicts the overall findings: many outcomes have not yet been properly evaluated, especially with regard to transfusion and phlebotomy; 61% (11/18) of meta-analyses evaluated ESAs. Quality of evidence was predominantly graded low to very low. The reported data generally show that an increase in Hb leads to improvement of PROMs and physical outcomes in anaemic and non-anaemic subjects. At lower baseline Hb-levels, the effect of a Hb-increase on PROMs appears more pronounced (fig. 2.). Moreover, at lower Hb-levels, the interventions also lead to a higher mean increase in Hb. Physiological effect sizes were not correlated to the magnitude of Hb-increase, while PROMs did correlate possitively to the magnitude of the Hb-increase (P<.001). PROMs appeared subject to publication bias (Eggers: P<.0001). Other than the often critically low quality of reporting, physiological outcomes showed no indication of (meta-)biases. Selecting only high quality reviews did not affect our results.

Discussion

The key finding is that we lack high quality data to objectively compare the effect of Hb-changes on human physiology. Drawing conclusions on the magnitude of these effects on different baseline Hb-levels is complicated due to 1) heterogeneous designs, 2) incomplete reporting of data, 3) larger ΔHb in groups with a low baseline Hb, 4) High risk of bias and publication bias and 5) small sample sizes. PROM data appear heavily affected by publication bias and are prone to information bias. While important to include patient experience, more objective parameters such as exercise capacity, heart rate and VO₂max may result in novel insights on the relation between patient specific outcomes and Hb levels. Future research should, besides interventions as ESAs and iron, also focus on transfusion and phlebotomy. We hypothesize that standardized but dynamic physiological outcomes attained via remote monitoring devices, will replace fixed Hb-thresholds and targets for personalized transfusion regimens.

Zwaginga:Sanofi: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; SOBI: Membership on an entity's Board of Directors or advisory committees.