Hemolysis

Hemolysis refers to the lysis, or breakdown, of red blood cells. Physiologically, mature red blood cells, or erythrocytes, have a relatively long lifespan during which they travel in the bloodstream and carry oxygen to body tissues. After about 120 days the aged cells become exhausted and damaged, and are then recognized by macrophages in the spleen, liver, and bone marrow to undergo phagocytosis. After digestion, the cell contents are either recycled to be used again or eliminated. Meanwhile, new erythrocytes are continuously produced in the bone marrow to replace the aged cells. 

Hemolysis becomes abnormal when it’s due to a premature destruction of red blood cells. Normally, when hemolysis occurs, new red blood cells are made in the bone marrow by a protein called erythropoietin (EPO), produced by the kidneys when they sense cellular hypoxia to stimulate erythropoiesis. If this compensation system manages to replenish the red blood cells adequately, the condition is termed compensated hemolysis. But if the destruction is excessive and cannot be compensated by erythropoiesis, hemolytic anemia can occur. Hemolytic anemia occurs when erythrocytes are destroyed at a faster rate than they can be replenished and can either inherited or acquired. It can present clinically from mild to very severe, usually depending on if the presentation is more chronic or acute.  

The rupture of red blood cells, or hemolysis, can be intravascular or extravascular.  

In intravascular hemolysis, the red blood cells are destroyed within blood vessels, usually due to mechanical damage (e.g., prosthetic heart valves, thrombotic microangiopathy), infections (e.g., malaria), toxins (e.g., Clostridium perfringens), or immune reactions, including targeting of the cells by autoantibodies. This causes a release of the cells’ contents into the bloodstream, consequently leading to high levels of hemoglobin, called hemoglobinemia, and the product of its breakdown, bilirubin, called hyperbilirubinemia, in the blood, which can lead to jaundice (i.e., yellowing of the eyes and skin). 

In extravascular hemolysis, the erythrocytes are removed by macrophages outside of vessels, in the bone marrow or organs like the spleen and liver. In these cases, they are broken down by macrophages because of inherited structural defects in the red blood cells (e.g., hereditary spherocytosis, sickle cell anemia) or because they are marked for destruction by antibodies on their cell membrane, like in autoimmune hemolytic anemia.

There are many possible reasons for hemolysis, which can be classified into intrinsic or extrinsic causes. Intrinsic causes involve cell rupture due to defects in the red blood cells themselves whereas extrinsic causes are related to the cells’ environment. The causes may or may not be immune-mediated.  

Intrinsic causes are related to issues in the components or functions of red blood cells. For example, in hereditary spherocytosis or hereditary elliptocytosis, there are defects in the cell membrane structure, leading to atypical shapes instead of the essential biconcave shape of the erythrocytes. There are defects in hemoglobin production in sickle-cell disease, thalassemia, and congenital dyserythropoietic anemia that can cause hemolysis. There may also be defects in the cells’ metabolism, like in pyruvate kinase deficiency and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Hemolysis is quite common in preterm infants, because they are usually born with low stores of vitamin E, which protect red blood cells from oxidative stress. Next, a rare, acquired, and potentially-life threatening blood condition known as paroxysmal nocturnal hemoglobinuria (PNH) can cause hemolysis and hemolytic anemia due to a genetic variant that leads to a problem in production of proteins that normally protect the red blood cells from attacks by the immune system. Finally, hemolysis may rarely be triggered by spur cell anemia, which is an acquired condition that can occur in advanced liver disease. It’s characterized by spike-like red blood cells called spur cells, or acanthocytes, which are more prone to rupture in the spleen, leading to anemia. 

Extrinsic causes of hemolysis include acquired causes such as infections (e.g., malaria, babesiosis, or a specific strain of Shiga toxin-producing E. coli); burns; poisoning by certain toxic agents (e.g., lead, copper, arsine, stibine, and hyperbaric oxygen); medications (e.g., alpha-methyldopa or methylene blue); mechanical causes, such as prosthetic heart valves; and hypersplenism and its various etiologies (e.g., cirrhosis and portal hypertension). Infections (e.g., Mycoplasma pneumoniae); autoimmune diseases (e.g., autoimmune hemolytic anemia); or hemolytic disease of the newborn, in which maternal IgG antibodies that cross the placenta mark the fetus’ red blood cells for destruction due to Rh or ABO incompatibility, are immune-mediated causes of red blood cell destruction. Similarly, incompatibility of ABO or other minor antigens (e.g., Rh, Kidd, or Kell) between a donor and a recipient during a blood transfusion can also lead to an acute or delayed hemolytic transfusion reaction, as the transfused red blood cells are sensed as foreign by the recipient’s immune system. Another cause of extrinsic hemolysis, foot strike hemolysis, has been observed in long-distance runners, who repetitively and forcefully strike their feet on the ground, leading to red blood cell rupture in the feet, though it is largely clinically insignificant.   

Individuals may not experience any symptoms at all, however, those with hemolytic anemia may experience varying levels of fatigue, dizziness, pale skin, tachycardia, dyspnea, enlarged spleen (i.e., splenomegaly), an enlarged liver (i.e., hepatomegaly), and jaundice. In more severe cases, the excess levels of bilirubin or hemoglobin can also lead to hyperchromic (i.e., dark-colored) urine. Symptoms largely depend on the type and severity of the anemia. If it develops slowly over time, the body’s ability to compensate is greater, and the symptoms are milder but often persist or recur. If it develops suddenly and quickly, signs and symptoms can be more severe, requiring immediate care. In more extreme cases, presentation can include chills, fever, back pain, abdominal pain, shock, and cardiac conditions such as cardiomegaly, arrhythmias, and heart failure.  

Furthermore, depending on the specific cause of the hemolysis, additional specific symptoms may appear. For example, in severe congenital cases of hemolytic anemia, skeletal changes can be present, due to the excessive activity of the bone marrow.   

In fetuses or newborns with hemolytic disease due to the release of numerous heme molecules from the erythrocytes, bilirubin accumulates leading to unconjugated hyperbilirubinemia and jaundice. If the unconjugated bilirubin blood levels become remarkably high, the lipid-soluble molecules can cross the blood brain barrier and accumulate in brain tissue leading to bilirubin encephalopathy (i.e., kernicterus) with neurological damage. Fetuses may also experience a serious complication called hydrops fetalis, which is characterized by fluid accumulation in at least two compartments, such as the skin, abdomen, or chest.  

Hemolysis is diagnosed through a thorough investigation of medical history, physical examination, and laboratory and diagnostic tests. Healthcare providers may ask about personal and familial medical history and the experience of symptoms such as dyspnea and fatigue. In the physical exam, they may look for skin discoloration and signs of anemia. Blood tests, including a complete blood count, and urine and stool analysis may be completed. Typical findings of hemolysis include increased serum levels of lactate dehydrogenase (LDH), unconjugated bilirubin, and aspartate amino transferase (AST); low serum haptoglobin; normal or slightly high bilirubin in the serum; and high urobilinogen in both urine and stools. If anemia develops, hemoglobin serum levels will be low for age and sex.  

More particularly, in a predominantly intravascular hemolysis, hemoglobinuria that is often associated with hemosiderinuria which is the presence of hemosiderin, an iron-storage complex in the urine, may be present. Additional lab tests that can demonstrate the erythropoietic response of the bone marrow include an increased reticulocyte percentage and absolute count, as well as an associated elevation in mean corpuscular volume (MCV). If a peripheral blood smear is done, the erythropoiesis compensation process, with red cells in different stages of maturation, will be indicated by some red blood cells that appear large (i.e., macrocytosis), some that are nucleated, and others with varying colors (i.e., polychromasia). Usually, bone marrow aspiration, which is a more invasive test, is unnecessary, but if performed, it can reveal erythroid hyperplasia, or an abundance of erythroid lineage cells.  

Once hemolysis is diagnosed, further testing may be done to determine the etiology.