Causative Genetic Mutations and Phenotypic Expressions<unk>  is caused by a variety of molecular defects in the genes that code for the red blood cell proteins spectrin (alpha and beta), ankyrin, band 3 protein, protein 4.2, and other red blood cell membrane proteins:<unk>  Type Genotypic Etiology Phenotypic Expression OMIM* Gene Locus Erythrocyte Membrane Protein Affected<unk> -1 ANK1 8p11.2 Ankyrin<unk> -2 SPTB 14q22-q23 Spectrin (Beta)*<unk> -3 SPTA 1q21 Spectrin (Alpha-1)*<unk> -4 SLC4A1 17q21-q22 Band-3 Protein<unk> -5 EPB42 15q15 Protein-4.2 Online Mendelian Inheritance in Man (OMIM). The Alpha-1 refers the Alpha-1 Subunit of the Spectrin protein. The Beta refers the Beta Subunit of the Spectrin protein. These genetic mutations are acted upon and executed by erythrocyte progenitor cells within the bone marrow, where red blood cells are normally produced in the non-pathological state (see Extramedullary Hematopoiesis for pathological production outside of the bone marrow). Pathophysiology of Mutated Erythrocytic Membrane Proteins These proteins are necessary to maintain the normal shape of a red blood cell, which is a biconcave disk. The integrating protein that is most commonly defective is spectrin which is responsible for incorporation and binding of spectrin to the greater actin cytoskeleton. This dysfunction of cytoskeletal instabilities ensue, and leave the plasma membrane of the cell less supported and/or weakened. + Erythrocyte Membrane Protein Protein Function Compromised Process Effect Pathogenesis of<unk>  Likelihood Mechanical Effect (In Order) Spectrin (Alpha-1) Alpha-1 subunit Actin Association Failure in plasma membrane tethering to actin cytoskeleton. Caption: The deficiency of Alpha-1 subunits in Spectrin protein network (top). The resulting failed or weakened tethering of Spectrin interior to the plasma membrane to the greater actin cytoskeleton (bottom).Caption: The deficiency of Alpha-1 subunits in Spectrin protein network (top). The resulting failed or weakened tethering of Spectrin interior to the plasma membrane to the greater actin cytoskeleton (bottom). Most Common # Erythrocytic plasma membrane loss. # Formation of spherocytes. # Decreased surface area. # Decreased plasma membrane compliance. # Fragility # Hemolysis Micrograph of a spherocyte (center). Spectrin (Beta) Hydrophobic interactions and electrostatic attraction to ankyrin and actin Failure in plasma membrane tethering to actin cytoskeleton. Caption: The deficiency of Beta subunits in Spectrin protein network (top). The resulting failed or weakened tethering of Spectrin interior to the plasma membrane to the greater actin cytoskeleton (bottom).Caption: The deficiency of Beta subunits in Spectrin protein network (top). The resulting failed or weakened tethering of Spectrin interior to the plasma membrane to the greater actin cytoskeleton (bottom). Ankyrin Hydrophobic interactions and electrostatic attraction to Beta subunit Failure to mediate anchorage of integral plasma membrane proteins to spectrin. Caption: The deficiency of Ankyrin that normally associates with plasma membrane proteins (top). The resulting failed or weakened anchorage of Spectin to interior plasma membrane, and subsequently weakened association between the greater actin cytoskeleton and the plasma membrane (bottom).Caption: The deficiency of Ankyrin that normally associates with plasma membrane proteins (top). The resulting failed or weakened anchorage of Spectin to interior plasma membrane, and subsequently weakened association between the greater actin cytoskeleton and the plasma membrane (bottom). Common Band-3 Failure to mediate the exchange of chloride (Cl−) with bicarbonate (HCO3−) across plasma membranes. Deficiency causes reduced lipid-stabilization at the plasma membrane. Caption: The deficiency of Band-3 Protein (top). The resulting destabilized plasma membrane without integral Band-3 Protein for association with Protein-4.2 and subsequently Ankyrin (bottom).Caption: The deficiency of Band-3 Protein (top). The resulting destabilized plasma membrane without integral Band-3 Protein for association with Protein-4.2 and subsequently Ankyrin (bottom). Less Common Protein-4.2 Failure of ATP binding that regulates the association of Band-3 with Ankyrin. Reduced density of plasma cell membrane skeleton, destabilizing the plasma lipid bilayer, thus releasing Band-3 protein-containing microvesicles. Caption: The deficiency of Protein-4.2 (top). The resulting inability of the greater actin cytoskeleton to associate with the plasma membrane via Spectrin and Ankyrin, and the subsequent loss of Band-3 Protein within microvesicles (bottom).Caption: The deficiency of Protein-4.2 (top). The resulting inability of the greater actin cytoskeleton to associate with the plasma membrane via Spectrin and Ankyrin, and the subsequent loss of Band-3 Protein within microvesicles (bottom). Least Common Cellular Implications A secondary defect in<unk>  is a deficiency of membrane surface area. The decrease in surface area leads to less efficient gas exchange of the erythrocyte at the alveoli of the lungs and throughout circulation. Decreased surface area may be produced by two different mechanisms: # Defects of Spectrin, Ankyrin (most commonly), or Protein 4.2 lead to reduced structural integrity of the plasma membrane, destabilizing the overlying lipid bilayer, and releasing band 3-containing microvesicles. Band-3 is important for gas exchange (as seen above). # Defects of band 3 lead to band 3 deficiency and loss of its lipid-stabilizing effect within the plasma membrane lipid bilayer. This results in the release of band 3-free microvesicles. Both pathways result in compromised plasma membrane integrity, decreased surface area, and formation of spherocytes with decreased mechanical compliance during circulation. Cardiovascular and Organ Sequelae Spherocytes have less plasma membrane compliance and fluidity, and this has implications throughout the entirety of circulation within the body, i.e. arteries, arterioles, capillaries, venules, veins, and organs. The lack of compliance and fluidity lead to a higher viscosity value for blood (thickened blood), which can have implications for both larger and smaller diameter vasculature. However, the most pronounced issues with the lack of compliance and fluidity declare themselves in the failure of the erythrocyte to deform itself when transiting arterioles, capillary beds, and venules. These vessels are smaller, and can become congested or blocked altogether. Studies have demonstrated that<unk>  is related to deep vein thrombosis (DVT) and arterial cardiovascular disease for this reason. The spleen typically acts as a filter for blood, and targets pathogens and other damaged cells within circulation. Removing blood contaminants promotes entire-body homeostasis. The following facts about the spleen's role in normal body functioning are crucial to understanding the implications of<unk>  on the overall health of the individual: * Removal of pathogens includes encapsulated bacteria, which reduces sepsis risk (see Complications below). * Removal of damaged erythrocytes reduces iron burden from heme via hepatosplenic recycling, which reduces sepsis risk (see Complications below). * Removal of damaged erythrocytes continues healthy signaling to bone marrow, where erythropoiesis replaces red blood cells lost to wear and tear. In relation to the three facts above, the spleen misguidedly filters spherocytes - regardless of the age or functional status of the cell. The spleen is not dysfunctional itself when selecting spherocytes for destruction, as this is the regular function of the spleen both at an anatomic structure level, and at the molecular cellular level. At the anatomic level, the passage from the Cords of Billroth into the Sinusoids may be seen as a "bottleneck", where red blood cells need to be flexible in order to pass through. In<unk> , the erythrocytes fail to pass through fenestrations, and this is where resident splenic macrophages sample, or "bite," part of the stuck spherocytes' plasma membranes. The macrophages recognize that the spherocyte is not normal, and the macrophage is "programmed" to destroy irregularities filtered at the spleen from the blood. The resident splenic macrophages therefore phagocytose the spherocytes, causing extravascular hemolysis. This leads to both splenomegaly and anemia. Should this process continue unchecked chronically, inappropriate regulation of erythropoeisis leads to extramedullary hematopoiesis.
Hereditary spherocytosis
Glucose-6-phosphate dehydrogenase deficiency
Paroxysmal nocturnal hemoglobinuria
Paroxysmal cold hemoglobinuria
Hereditary elliptocytosis
Congenital hemolytic anemia
Mixed autoimmune hemolytic anemia
Alpha-thalassemia