https://orcid.org/0000-0003-4147-8388
Abstract
Chronic hemolytic anemia and intermittent acute pain episodes are the 2 hallmark characteristics of sickle cell disease (SCD). Anemia in SCD not only signals a reduction of red cell mass and oxygen delivery, but also ongoing red cell breakdown and release of cell-free hemoglobin, which together contribute to a number of pathophysiological responses and play a key role in the pathogenesis of cumulative multiorgan damage. However, although anemia is clearly associated with many detrimental outcomes, it may also have an advantage in SCD in lowering risks of potential viscosity-related complications. Until recently, clinical drug development for SCD has predominantly targeted a reduction in the frequency of vaso-occlusive crises as an endpoint, but increasingly, more attention is being directed toward addressing the contribution of chronic anemia to poor outcomes in SCD. This article aims to explore the complex pathophysiology and mechanisms of anemia in SCD, as well as the need to balance the benefits of raising hemoglobin levels with the potential risks of increasing blood viscosity, in the context of the current therapeutic landscape for anemia in SCD.
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Antenatal anemia is associated with maternal and fetal complications including stillbirth and intra-uterine growth restriction in the general population.1 Mechanistic and clinical evidence suggest anemia may also negatively affect SCD pregnancies. The angiogenic signaling molecules that are associated with abnormal placenta formation and maturation are over-expressed in chronic anemia in SCD.2 Clinically, a low first trimester hemoglobin is identified as a predictor for adverse maternal events in SCD pregnancy.3 We do not yet know whether people with chronic anemia from SCD, who have endothelial dysfunction, increased cardiac output, and decreased systemic vascular resistance at baseline, have the cardiovascular reserve to adapt to the additional strain of pregnancy.
Evidence suggests a modest benefit of prophylactic transfusions in pregnancy.3 However, indications for initiation of this therapy are indiscriminate and do not consider anemia risks.4 This may be partly explained by the near-universal presence of anemia in SCD pregnancy and the lack of a transfusion threshold below which maternal or fetal morbidity would be expected.
Besides transfusion, no SCD treatments are established in pregnancy. Hydroxyurea is a chemotherapeutic agent and its discontinuation at conception is recommended, although the lack of alternatives to transfusions leads to occasional use during pregnancy. Neither voxelotor nor crizanlizumab had promising pregnancy safety profiles in animal studies, and there is no data on L-glutamine.5
Reproductive organs are the less often considered end-organs in SCD. However, patients around the globe are surviving into their reproductive years. Continued research on the effects of anemia in SCD on all reproductive end-organs, including the placenta and fetus, is imperative.
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