Hemolytic anemia

Hemolysis, defined as shortened red blood cell (RBC) survival, may result from any number of abnormalities, whether intrinsic or extrinsic to the RBCs. Intrinsic abnormalities include membrane defects, abnormal hemoglobin, and enzyme defects. Extrinsic abnormalities include microangiopathy and anti-RBC antibody. Hemolysis is sometimes defined as intravascular or extravascular. Intravascular hemolysis occurs within the bloodstream with release of hemoglobin and phospholipids, and extravascular hemolysis occurs in the marrow, spleen, or liver ( Fig. 7.1 ).

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Hemolysis. LDH, Lactate dehydrogenase; RBC, red blood cell.

Intravascular hemolysis is caused by destruction of circulating RBCs by extreme heat, toxins, infectious agents, complement lysis, or shear forces induced by damaged capillaries or mechanical heart valves. The loss of plasma membrane integrity destabilizes the RBC osmotic gradient, leading to a rapid influx of sodium and water, cell swelling, and physical disintegration. In intravascular hemolysis, circulating haptoglobin -bound hemoglobin and haptoglobin-bound heme are absorbed by hepatosplenic macrophages, where heme is converted to biliverdin by heme oxidase , reduced to bilirubin by bilirubin reductase , and bound to albumin for transport to hepatocytes for conjugation to diglucuronide form, and excetion in bile. Heme iron is transferred to plasma apotransferrin for transport to tissues, most prominently to the bone marrow.

As a thrombogenic material, free RBC membrane phospholipid can initiate disseminated intravascular coagulation (DIC) . Free hemoglobin can be deposited in the kidneys and lead to renal tubular damage. Laboratory abnormalities indicative of intravascular hemolysis include increased serum lactate dehydrogenase (LDH) released from RBC cytoplasm, decreased serum haptoglobin (rapidly removed from the circulation upon binding to heme), and increased serum bilirubin. When bilirubin is measured in the laboratory, a distinction is made between soluble (direct) and insoluble (indirect) forms of bilirubin. Hemolysis, whether intravascular or extravascular, is associated with an increase in unconjugated (indirect) bilirubin . Indirect bilirubin is converted to direct bilirubin by the liver and normally excreted in the bile. In the small bowel, gut bacteria reduce bilirubin to urobilinogen . A small amount of urobilinogen is absorbed by the small bowel and excreted in the urine.

Extravascular hemolysis results from phagocytosis of circulating damaged or senescent RBCs by macrophages in the spleen, liver, and marrow. Under normal circumstances, aged RBCs progressively lose the ability to prevent and repair oxidative damage to the cell membrane, cytoskeleton, and hemoglobin. A certain degree of extravascular hemolysis is normal, related to the physiological removal of senescent RBCs from the circulation, primarily by splenic macrophages.

The susceptibility of aged RBCs to removal results from changes in cell membrane composition, with consequent decreased deformability and physical entrapment within the splenic red pulp, and phagocytosis by splenic macrophages. Aged or senescent RBCs are recognized by splenic macrophages by several mechanisms. Expression of phosphatidyl serine (PS) is normally confined to the inner leaflet of the RBC plasma membrane, maintained as such by the enzyme flippase . Expression of the enzyme scramblase by aged RBCs leads to expression of PS on the RBC surface and removal from the circulation by PS receptor-bearing splenic macrophages. Loss of terminal sialic acid residues on aged RBC surface glycoproteins exposes galactosyl residues that bind to macrophage galactosyl receptors. CD47 loss from old RBCs prevents SIRP1-alpha –mediated “don’t eat me” signaling of macrophages. Aggregates of damaged Band 3 cytoskeletal protein are recognized by natural antibodies, inducing immunoglobulin (Fc) receptor–mediated phagocytosis.

Engulfed RBCs are degraded within macrophage phagolysosomes. Heme is degraded by heme oxidase to biliverdin, reduced to bilirubin, enters the blood bound to albumin, conjugated in the liver to bilirubin diglucuronide, and excreted in the bile. Several pathologic conditions are characterized by an abnormal degree of extravascular hemolysis, leading to anemia. Although extravascular hemolysis often accompanies intravascular hemolysis—for example, damaged RBCs that escape intravascular lysis are phagocytosed and destroyed by splenic and liver macrophages—this term is more commonly applied to situations in which little to no intravascular hemolysis occurs. Examples of such situations include hypersplenism and autoimmune hemolytic anemia (AIHA) .

Laboratory abnormalities in hemolytic anemia of any cause may include normochromic normocytic anemia, elevated reticulocyte count, increased serum LDH, hyperbilirubinemia, decreased serum haptoglobin, increased plasma hemoglobin, hemoglobinuria, and hemosiderinuria. In severe cases, the anemia may be macrocytic because of the compensatory release from the marrow of larger immature RBCs (reticulocytes). In contrast to other forms of macrocytic anemia, the heterogeneity in RBC size caused by admixed erythrocytes and reticulocytes may yield an increased RBC distribution width (RDW) on the complete blood count.

Hemolytic anemia can be broadly classified into two etiologic types, extrinsic hemolytic anemia resulting from extracorpuscular factors and intrinsic hemolytic anemia resulting from RBC defects.