Hemolytic anemia

Hereditary (inherited) hemolytic anemia can be due to :

• Defects of red blood cell membrane production (as in hereditary spherocytosis and hereditary elliptocytosis).[2]
• Defects in hemoglobin production (as in thalassemia, sickle-cell disease and congenital dyserythropoietic anemia).[2]
• Defective red cell metabolism (as in glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency).[11][12]
• Wilson's disease may infrequently present with hemolytic anemia without due to excessive inorganic copper in blood circulation, which destroys red blood cells (though the mechanism of hemolysis is still unclear).[13]

Acquired hemolytic anemia may be caused by immune-mediated causes, drugs, and other miscellaneous causes.[2]

• Immune-mediated causes could include transient factors as in Mycoplasma pneumoniae infection (cold agglutinin disease)[14] or permanent factors as in autoimmune diseases like autoimmune hemolytic anemia[15] (itself more common in diseases such as systemic lupus erythematosus, rheumatoid arthritis, Hodgkin's lymphoma, and chronic lymphocytic leukemia).[2]
• Spur cell hemolytic anemia[16]
• Any of the causes of hypersplenism (increased activity of the spleen), such as portal hypertension.[17]
• Acquired hemolytic anemia is also encountered in burns and as a result of certain infections (e.g. malaria).[15][18]
• Paroxysmal nocturnal hemoglobinuria (PNH), sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterized by complement-induced intravascular hemolytic anemia.[19]
• Lead poisoning resulting from the environment causes non-immune hemolytic anemia.[20]
• Similarly, poisoning by arsine or stibine also causes hemolytic anemia.[21]
• Runners can develop hemolytic anemia due to "footstrike hemolysis", owing to the destruction of red blood cells in feet at foot impact.[22][23]
• Low-grade hemolytic anemia occurs in 70% of prosthetic heart valve recipients, and severe hemolytic anemia occurs in 3%.[24]

Intravascular hemolysis describes hemolysis that happens mainly inside the vasculature.[26] As a result, the contents of the red blood cell are released into the general circulation, leading to hemoglobinemia[27] and increasing the risk of ensuing hyperbilirubinemia.[28]

Intravascular hemolysis may occur when red blood cells are targeted by autoantibodies, leading to complement fixation, or by damage by parasites such as Babesia.[29]

Extravascular hemolysis refers to hemolysis taking place in the liver, spleen, bone marrow, and lymph nodes.[26] In this case little hemoglobin escapes into blood plasma.[28] The macrophages of the reticuloendothelial system in these organs engulf and destroy structurally-defective red blood cells, or those with antibodies attached, and release unconjugated bilirubin into the blood plasma circulation.[30][31] Typically, the spleen destroys mildly abnormal red blood cells or those coated with IgG-type antibodies,[32][33] while severely abnormal red blood cells or those coated with IgM-type antibodies are destroyed in the circulation or in the liver.[32]

If extravascular hemolysis is extensive, hemosiderin can be deposited in the spleen, bone marrow, kidney, liver, and other organs, resulting in hemosiderosis.[28]

In a healthy person, a red blood cell survives 90 to 120 days in the circulation, so about 1% of human red blood cells break down each day.[34] The spleen (part of the reticulo-endothelial system) is the main organ that removes old and damaged RBCs from the circulation.[2] In healthy individuals, the breakdown and removal of RBCs from the circulation is matched by the production of new RBCs in the bone marrow.[2]

In conditions where the rate of RBC breakdown is increased, the body initially compensates by producing more RBCs; however, breakdown of RBCs can exceed the rate that the body can make RBCs, and so anemia can develop.[34] Bilirubin, a breakdown product of hemoglobin, can accumulate in the blood, causing jaundice.[29]

In general, hemolytic anemia occurs as a modification of the RBC life cycle.[35] That is, instead of being collected at the end of its useful life and disposed of normally, the RBC disintegrates in a manner allowing free iron-containing molecules to reach the blood.[35] With their complete lack of mitochondria, RBCs rely on pentose phosphate pathway (PPP) for the materials needed to reduce oxidative damage. Any limitations of PPP can result in more susceptibility to oxidative damage and a short or abnormal lifecycle.[36] If the cell is unable to signal to the reticuloendothelial phagocytes by externalizing phosphatidylserine, it is likely to lyse through uncontrolled means.[37][38][39]

The distinguishing feature of intravascular hemolysis is the release of RBC contents into the blood stream. The metabolism and elimination of these products, largely iron-containing compounds capable of doing damage through Fenton reactions, is an important part of the condition. Several reference texts exist on the elimination pathways, for example.[40][41][42] Free hemoglobin can bind to haptoglobin, and the complex is cleared from the circulation; thus, a decrease in haptoglobin can support a diagnosis of hemolytic anemia. Alternatively, hemoglobin may oxidize and release the heme group that is able to bind to either albumin or hemopexin. The heme is ultimately converted to bilirubin and removed in stool and urine.[40] Hemoglobin may be cleared directly by the kidneys resulting in fast clearance of free hemoglobin but causing the continued loss of hemosiderin loaded renal tubular cells for many days.

Additional effects of free hemoglobin seem to be due to specific reactions with NO.[43]