Congenital Hemolytic Anemias: Is There a Role for the Immune System?

Abstract

Congenital hemolytic anemias (CHAs) are a heterogeneous group of rare hereditary conditions including defects of erythrocyte membrane proteins, red cell enzymes, and disorders due to defective erythropoiesis. They are characterized by variable degree of anemia, chronic extravascular hemolysis, reduced erythrocyte life span, splenomegaly, jaundice, biliary lithiasis, and iron overload. Although few data are reported on the role of the immune system in CHAs, several immune-mediated mechanisms may be involved in the pathogenesis of these rare diseases. We reported in ∼60% of patients with hereditary spherocytosis (HS), the presence of naturally-occurring autoantibodies (NAbs) directed against different membrane proteins (α-and β-spectrin, band 3, and dematin). Positive HS subjects showed a more hemolytic pattern and NAbs were more evident in aged erythrocytes. The latter is in line with the function of NAbs in the opsonization of damaged/senescent erythrocytes and their consequent removal in the spleen. Splenectomy, usually performed to reduce erythrocyte catheresis and improve Hb levels, has different efficacy in various CHAs. Median Hb increase is 3 g/dL in HS, 1.6-1.8 g/dL in pyruvate kinase deficiency (PKD), and 1 g/dL in congenital dyserythropoietic anemias (CDA) type II. Consistently with clinical severity, splenectomy is performed in 20% of HS, 45% of CDAII, and in 60% of PKD patients. Importantly, sepsis and thrombotic events have been registered, particularly in PKD with a frequency of ∼7% for both. Furthermore, we analyzed the role of pro-inflammatory cytokines and found that interleukin 10 and interferon γ, and to a lesser extent interleukin 6, were increased in all CHAs compared with controls. Moreover, CDAII and enzymatic defects showed increased tumor necrosis factor-α and reduced interleukin 17. Finally, we reported that iron overload occurred in 31% of patients with membrane defects, in ∼60% of CDAII cases, and in up to 82% of PKD patients (defined by MRI liver iron concentration >4 mg Fe/gdw). Hepcidin was slightly increased in CHAs compared with controls and positively correlated with ferritin and with the inflammatory cytokines interleukin 6 and interferon γ. Overall the results suggest the existence of a vicious circle between chronic hemolysis, inflammatory response, bone marrow dyserythropoiesis, and iron overload.

Case Report: Resetting the Humoral Immune Response by Targeting Plasma Cells With Daratumumab in Anti-Phospholipid Syndrome

“…At the time of writing of this manuscript, off-label use of daratumumab for autoimmune diseases has increased and some cases have been reported in the literature. In the most recent cases, the authors chose longer cycles with more doses than we proposed for our patient ( 41 ).…”

“…Daratumumab was approved in 2016 in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of multiple myeloma patients as a second line therapy ( 33 ). However, some off-label uses have been reported in the literature for autoimmune hemolytic anemia ( 34 – 37 ), Evans’ Syndrome ( 38 , 39 ), cold agglutinin disease ( 40 , 41 ), pure red cell aplasia ( 42 ), immune thrombocytopenia ( 43 ), systemic lupus erythematosus ( 44 ), and anti-CASPR2 encephalitis ( 45 ).…”

High definition analyses of single cohort, whole genome sequencing data provides a direct route to defining sub-phenotypes and personalising medicine

“…For example, while genetic variants predisposing to pathogenic venous thromboses are usually assumed to encode components and mediators of the coagulation cascade, the current cohort suggested a possible trend with erythrocyte enzyme variants, and there has been some discussion of thrombosis in red cell enzymopathy fields. [47] Opportunities to test current associations will be enhanced if enzymopathy genes are included in gene panels for VTE, and further scientific examination appears warranted. Similarly, the observed enrichment of deleterious erythrocyte membrane gene variants in patients experiencing severe deep-seated infection warrants further study in the setting of the common (daily) bacteremias that can seed abscesses by currently unknown mechanisms.…”

Congenital dyserythropoietic anemia and drug‑induced liver injury present as bland cholestasis: A case report

“…These rare disorders may be caused by any genetic defect affecting RBCs, including Diamond-Blackfan anemia, congenital dyserythropoietic anemias, thalassemia, sickle cell disease, enzyme deficiency and red cell membrane disorders. These disorders are characterized by a variable degree of anemia, chronic extravascular hemolysis, reduced erythrocyte lifespan, splenomegaly, jaundice, biliary lithiasis and iron overload (17). Each type may require contradictory therapeutic approaches (3); therefore, the precise genetic diagnosis is of great importance.…”