Issue Archive

Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disorder arising due to somatic mutations inactivating the PIGA gene, which manifests variably as hemolytic anemia, hemoglobinuria, thrombosis, and bone marrow failure. Two thought leaders in the field, Luzzatto and Nakao, provide their perspective on why the malignant clone waxes and wanes under the influence of autoimmunity and therapy, and the authors seek to explain the mechanisms leading to the pathogenesis and natural history of aplastic anemia associated with PNH.

Hereditary stomatocytosis refers to a group of inherited human hemolytic anemias characterized by increased red cell membrane permeability to sodium and potassium, resulting in abnormal morphology ranging from stomatocytes to xerocytes. With advances in genomics, various mutations in 6 genes are now recognized as causative, and classification is now evolving from 1 based on morphology to a system that reflects genotype-phenotype associations. This is the theme of this review by Andolfo and coauthors, which brings readers up to date with current understanding of pathophysiology, diagnosis, and association with nonhematological manifestations, including hepatic iron overload in some instances.

Priapism is a common complication of sickle cell disease, but high-quality evidence for its prevention is lacking. Idris et al report the results of a phase 2 randomized feasibility trial that compared addition of low-dose tadalafil or placebo to fixed moderate-dose hydroxyurea to prevent priapism in 64 patients, finding that key aspects of such a trial are feasible. While not powered to detect a difference between arms, the data indicate that rates of priapism are lower and quality-of-life indices capturing priapism are higher in both arms compared to an individual patient’s baseline. These results encourage the conduct of fully powered phase 3 trials to identify the most effective prevention strategies.

Multiple myeloma (MM) is a disease characterized by deficiency of adaptive immunity and like most cancers has been considered to occur in the context of failure of immune surveillance. Using multiomic single-cell analyses of serial samples, Shasha and colleagues report that CD8⁺ T cells in patients with newly diagnosed MM do not exhibit transcriptional, phenotypic, or functional hallmarks of terminal exhaustion that are commonly seen in other advanced cancers. This surprising finding helps explain why checkpoint inhibitors are disappointing in this disease and refocuses efforts on discovering how MM eludes our immune system’s defenses.

The risk of death from myelofibrosis varies according to whether the disease is primary or secondary, the presence of disease-causing and disease-modifying mutations, and clinical factors such as age and comorbidities. While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy, a patient’s suitability for undertaking this morbid procedure is often a vexed issue, even when the prognosis of the disease is considered unfavorable. Hernández-Boluda and colleagues describe the development and utility of an improved machine learning–derived model and web-based application to identify whether individual patients have high, intermediate, or low risk of poor outcomes with allo-HSCT. Pending further validation, this tool offers a simple-to-apply approach to resolving whether allo-HSCT is an acceptable option for patients.

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the subunits of the NADPH oxidase complex that reduce the oxidative burst and stop phagocytes from clearing a range of pathogens. Inflammatory bowel disease is common in CGD, and Darbinian and colleagues help explain this by reporting that mucosal immunity varies with CGD genotype in murine models. Exposure to specific microbiomes elevates inflammasome activation within the intestinal barrier, and regulatory T-cell numbers and mucin production diminish, with the clinical outcome reflecting both the type of CGD and the pathogenicity of the intestinal microbiota.

Thrombin cleaves protein C (PC) in the microvasculature with assistance of thrombomodulin and generates activated PC (APC) that inactivates factor Va (FVa). While the clinical significance of this interaction is well established and the biochemistry is largely resolved, key structural understanding has been lacking. This is now provided by Mohammed et al, validating existing hypotheses about interactions and laying the groundwork to answer outstanding mechanistic questions regarding APC-mediated proteolytic inactivation of FVa.