Sickle cell disease (SCD) is one of the best characterized human monogenic disorders. The development of molecular biology allowed the identification of several genomic polymorphisms responsible for its clinical diversity. Research on the first genetic modulators of SCD, such as coinheritance of α-thalassemia and haplotypes in the β-globin gene cluster, have been followed by studies associating single nucleotide polymorphisms (SNPs) with variable risks for stroke, leg ulceration, pulmonary hypertension, priapism and osteonecrosis, with differences in the response to hydroxyurea, and with variability in the management of pain. Furthermore, multigenic analyses based on genome-wide association studies have shed light on the importance of the TGF-β superfamily and oxidative stress to the pathogenesis of complex traits in SCD, and may guide future therapeutic interventions on a genetically oriented basis.

In preclinical and early phase pharmacologic trials in sickle cell disease, the percentage of sickled erythrocytes after deoxygenation, an ex vivo functional sickling assay, has been used as a measure of a patient's disease outcome. We developed a new sickle imaging flow cytometry assay (SIFCA) and investigated its application. To perform the SIFCA, peripheral blood was diluted, deoxygenated (2% oxygen) for 2 hr, fixed, and analyzed using imaging flow cytometry. We developed a software algorithm that correctly classified investigator tagged “sickled” and “normal” erythrocyte morphology with a sensitivity of 100% and a specificity of 99.1%. The percentage of sickled cells as measured by SIFCA correlated strongly with the percentage of sickle cell anemia blood in experimentally admixed samples (R = 0.98,P ≤ 0.001), negatively with fetal hemoglobin (HbF) levels (R = −0.558,P = 0.027), negatively with pH (R = −0.688,P = 0.026), negatively with pretreatment with the antisickling agent, Aes‐103 (5‐hydroxymethyl‐2‐furfural) (R = −0.766,P = 0.002), and positively with the presence of long intracellular fibers as visualized by transmission electron microscopy (R = 0.799,P = 0.002). This study shows proof of principle that the automated, operator‐independent SIFCA is associated with predictable physiologic and clinical parameters and is altered by the putative antisickling agent, Aes‐103. SIFCA is a new method that may be useful in sickle cell drug development. Am. J. Hematol. 89:598–603, 2014.

While iron deficiency remains the most common cause of anemia worldwide, low iron stores are associated with symptoms regardless of the presence of typical microcytic, hypochromic anemia and may be hard to recognize in patients with concurrent inflammation. Diagnosing and treating iron deficiency become more of a challenge because markers of iron status are influenced by low-grade inflammation present in common conditions, such as chronic kidney disease, cirrhosis, or heart failure. Here I present a pragmatic way of interpreting diagnostic lab tests to help clinicians recognize patients who are most likely to benefit from iron supplementation, choose between oral and parenteral administration, and make personalized decisions when patients do not fit usual guidelines.

Aceruloplasminemia is a rare autosomal recessive genetic disease characterized by mild microcytic anemia, diabetes, retinopathy, liver disease, and progressive neurological symptoms due to iron accumulation in pancreas, retina, liver, and brain. The disease is caused by mutations in the Ceruloplasmin (CP) gene that produce a strong reduction or absence of ceruloplasmin ferroxidase activity, leading to an impairment of iron metabolism. Most patients described so far are from Japan. Prompt diagnosis and therapy are crucial to prevent neurological complications since, once established, they are usually irreversible. Here, we describe the largest series of non-Japanese patients with aceruloplasminemia published so far, including 13 individuals from 11 families carrying 13 mutations in the CP gene (7 missense, 3 frameshifts, and 3 splicing mutations), 10 of which are novel. All missense mutations were studied by computational modeling. Clinical manifestations were heterogeneous, but anemia, often but not necessarily microcytic, was frequently the earliest one. This study confirms the clinical and genetic heterogeneity of aceruloplasminemia, a disease expected to be increasingly diagnosed in the Next-Generation Sequencing (NGS) era. Unexplained anemia with low transferrin saturation and high ferritin levels without inflammation should prompt the suspicion of aceruloplasminemia, which can be easily confirmed by low serum ceruloplasmin levels. Collaborative joint efforts are needed to better understand the pathophysiology of this potentially disabling disease.