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Editorials
Figure 1. The complex relationship among aging, inflammation, and anemia. Clonal hematopoiesis and “inflammaging” are increasingly recognized as age-related conditions (see the text). Both are able to induce a mild chronic pro-inflammatory status, and can influence each other in a vicious circle. For example, chronic inflam- mation in the bone marrow can favor the development of somatic mutations in hematopoietic stem cells (dotted arrow). Clonal hematopoiesis and “inflammaging” are plausible explanations for at least a fraction of unexplained anemia in the elderly, likely through mechanisms similar to those involved in the pathophysiology of the classical anemia of overt inflammation. It is worth noting that clonal hematopoiesis is also able to induce anemia because of ineffective erythropoiesis. When cytopenia occurs in association with clonal hematopoiesis, it is termed clonal cytopenia of undetermined significance. Anemia in the elderly is strongly and independ- ently associated with adverse outcomes, but whether or not this relationship is actually causal remains to be demonstrated. CV: cardiovascular; CCUS: clonal cytope- nia of undetermined significance.
tion (e.g. hepcidin-driven iron-restricted erythropoiesis and cytokine-mediated suppression of erythropoiesis) remains to be demonstrated. Of note, clonal hematopoiesis can also cause anemia because of ineffec- tive erythropoiesis, since progenitors carrying certain mutations can have a proliferative advantage over nor- mal hematopoietic stem cells, but are less able to differ- entiate adequately.15 Indeed, clonal hematopoiesis has been identified in a high proportion (64%) of elderly with unexplained cytopenia, for example with anemia not fulfilling all the morphological and cytogenetic crite- ria for the diagnosis of myelodysplastic syndrome.16 In such cases, the term “clonal cytopenia of undetermined significance” has been proposed.9
Finally, a key point to be kept in mind when thinking about anemia in the elderly is that its robust association with mortality, even independently of the many possible
confounders, does not prove a causal link, because of inherent limitations of observational epidemiology.2 The only way to prove causality definitively would be the reduction of mortality and/or other adverse outcomes after successful correction or amelioration of anemia. The increasing number of promising anti-anemic drugs that are entering the clinical arena, including hepcidin antago- nists,17 novel iron formulations,18 activin receptor IIA lig- and trap,19 and hypoxia inducible factor stabilizers,20 may represent an unprecedented opportunity to clarify this crucial point in the near future.
References
1 Mannino RG, Myers DR, Tyburski EA, et al. Smartphone app for non-invasive detection of anemia using only patient-sourced photos. Nat Commun. 2018;9(1):4924.
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haematologica | 2019; 104(2)