Hemolytic anemia
Hemolytic anemia is a form of anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...

 due to hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...

, the abnormal breakdown of red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...

s (RBCs), either in the blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

s (intravascular hemolysis) or elsewhere in the human body (extravascular). It has numerous possible causes, ranging from relatively harmless to life-threatening. The general classification of hemolytic anemia is either inherited
Heredity is the passing of traits to offspring . This is the process by which an offspring cell or organism acquires or becomes predisposed to the characteristics of its parent cell or organism. Through heredity, variations exhibited by individuals can accumulate and cause some species to evolve...

 or acquired. Treatment depends on the cause and nature of the breakdown.

Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue
Fatigue (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...

 and shortness of breath), but in addition, the breakdown of red cells leads to jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...

 and increases the risk of particular long-term complications, such as gallstone
A gallstone is a crystalline concretion formed within the gallbladder by accretion of bile components. These calculi are formed in the gallbladder, but may pass distally into other parts of the biliary tract such as the cystic duct, common bile duct, pancreatic duct, or the ampulla of...

s and pulmonary hypertension
Pulmonary hypertension
In medicine, pulmonary hypertension is an increase in blood pressure in the pulmonary artery, pulmonary vein, or pulmonary capillaries, together known as the lung vasculature, leading to shortness of breath, dizziness, fainting, and other symptoms, all of which are exacerbated by exertion...


Basic features

Hemolytic anemia involves the following:
  1. Abnormal and accelerated destruction of red cells and, in some anemias, their precursors
  2. Increased breakdown of hemoglobin, which may result in:
    1. increased bilirubin
      Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...

       level (mainly indirect-reacting) with jaundice
    2. increased fecal and urinary urobilinogen
      Urobilinogen is a colourless product of bilirubin reduction. It is formed in the intestines by bacterial action. Some urobilinogen is reabsorbed, taken up into the circulation and excreted by the kidney. This constitutes the normal "enterohepatic urobilinogen cycle".Increased amounts of bilirubin...

    3. Hemoglobinanemia, methemalbuminemia, hemoglobinuria and hemosiderinuria (where there is significant intravascular hemolysis).
  3. Bone marrow compensatory reaction:
    1. Erythroid hyperplasia with accelerated production of red cells, reflected by reticulocytosis, and slight macrocytosis in peripheral blood
    2. Expansion of bone marrow in infants and children with severe chronic hemolysis - changes in bone configuration visible on X-ray
  4. The balance between red cell destruction and marrow compensation determines the severity of anemias.

Signs and symptoms

In general, signs of anemia (pallor
Pallor is a reduced amount of oxyhaemoglobin in skin or mucous membrane, a pale color which can be caused by illness, emotional shock or stress, stimulant use, lack of exposure to sunlight, anaemia or genetics....

, fatigue, shortness of breath, and potential for heart failure) are present. In small children, failure to thrive
Failure to thrive
Failure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....

 may occur in any form of anemia. Certain aspects of the medical history can suggest a cause for hemolysis, such as drugs
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

, consumption of fava beans, the presence of prosthetic heart valve, or other medical illness.

Chronic hemolysis leads to an increased excretion of bilirubin into the biliary tract, which in turn may lead to gallstones. The continuous release of free hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...

 has been linked with the development of pulmonary hypertension (increased pressure over the pulmonary artery
Pulmonary artery
The pulmonary arteries carry deoxygenated blood from the heart to the lungs. They are the only arteries that carry deoxygenated blood....

); this, in turn, leads to episodes of syncope
In phonology, syncope is the loss of one or more sounds from the interior of a word; especially, the loss of an unstressed vowel. It is found bothin Synchronic analysis of languages and Diachronics .-Found synchronically:...

 (fainting), chest pain
Chest pain
Chest pain may be a symptom of a number of serious conditions and is generally considered a medical emergency. Even though it may be determined that the pain is non-cardiac in origin, this is often a diagnosis of exclusion made after ruling out more serious causes of the pain.-Differential...

, and progressive breathlessness. Pulmonary hypertension eventually causes right ventricular heart failure, the symptoms of which are peripheral edema
Peripheral edema
Peripheral edema is the swelling of tissues, usually in the lower limbs, due to the accumulation of fluids.The condition is commonly associated with aging, but can be caused by many other conditions, including congestive heart failure, trauma, alcoholism, altitude sickness, pregnancy,...

 (fluid accumulation in the skin of the legs) and ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...

 (fluid accumulation in the abdominal cavity).


They may be classified according to the means of hemolysis, being either intrinsic in cases where the cause is related to the red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...

 (RBC) itself, or extrinsic in cases where factors external to the RBC dominate. Intrinsic effects may include problems with RBC proteins or oxidative stress handling, whereas external factors include immune attack and microvascular angiopathies (RBCs are mechanically damaged in circulation).

Intrinsic causes

Hereditary (inherited) hemolytic anemia can be due to membrane defects:
  • Defects of red blood cell membrane production (as in hereditary spherocytosis
    Hereditary spherocytosis
    Hereditary spherocytosis is a genetically-transmitted form of spherocytosis, an auto-hemolytic anemia characterized by the production of red blood cells that are sphere-shaped rather than bi-concave disk shaped , and therefore more prone to hemolysis.-Symptoms:As in non-hereditary spherocytosis,...

     and hereditary elliptocytosis
    Hereditary elliptocytosis
    Hereditary elliptocytosis, also known as ovalocytosis, is an inherited blood disorder in which an abnormally large number of the sufferer's erythrocytes are elliptical rather than the typical biconcave disc shape. It is one of many red-cell membrane defects. In its severe forms, this disorder...


Hereditary (inherited) hemolytic anemia can be due to defects in hemoglobin :
  • Defects in hemoglobin production (as in thalassemia
    Thalassemia is an inherited autosomal recessive blood disease that originated in the Mediterranean region. In thalassemia the genetic defect, which could be either mutation or deletion, results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin...

    , sickle-cell disease
    Sickle-cell disease
    Sickle-cell disease , or sickle-cell anaemia or drepanocytosis, is an autosomal recessive genetic blood disorder with overdominance, characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various...

     and congenital dyserythropoietic anemia
    Congenital dyserythropoietic anemia
    Congenital dyserythropoietic anemia is a rare blood disorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells in the body and a less than normal quantity of hemoglobin in...


Hereditary (inherited) hemolytic anemia can be due to enzyme defects:
  • Defective red cell metabolism (as in glucose-6-phosphate dehydrogenase deficiency
    Glucose-6-phosphate dehydrogenase deficiency
    Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive hereditary disease characterised by abnormally low levels of glucose-6-phosphate dehydrogenase , a metabolic enzyme involved in the pentose phosphate pathway, especially important in red blood cell metabolism. G6PD deficiency is...

     and pyruvate kinase deficiency
    Pyruvate kinase deficiency
    Pyruvate kinase deficiency, also called erythrocyte pyruvate kinase deficiency, is an inherited metabolic disorder of the enzyme pyruvate kinase which affects the survival of red blood cells and causes them to deform into echinocytes on peripheral blood smears.Both autosomal dominant and recessive...


Acquired due to Paroxysmal nocturnal hemoglobinuria:
  • Paroxysmal nocturnal hemoglobinuria
    Paroxysmal nocturnal hemoglobinuria
    Paroxysmal nocturnal hemoglobinuria , sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterised by complement-induced intravascular hemolytic anemia , red urine and thrombosis...

     (PNH), sometimes referred to as Marchiafava-Micheli syndrome, is a rare, acquired, potentially life-threatening disease of the blood characterised by complement-induced intravascular hemolytic anemia

Extrinsic causes

Acquired hemolytic anemia may be caused by immune-mediated causes, drugs and other miscellaneous causes.
  • Immune-mediated causes could include transient factors as in Mycoplasma pneumoniae
    Mycoplasma pneumoniae
    Mycoplasma pneumoniae is a very small bacterium in the class Mollicutes.It causes the disease mycoplasma pneumonia, a form of atypical bacterial pneumonia, and is related to cold agglutinin disease.-Cell wall/Treatment:...

    infection (cold agglutinin disease) or permanent factors as in autoimmune disease
    Autoimmune disease
    Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...

    s like autoimmune hemolytic anemia
    Autoimmune hemolytic anemia
    Autoimmune hemolytic anemia occurs when antibodies directed against the person's own red blood cells cause the RBCs to burst , leading to insufficient plasma concentration. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases...

     (itself more common in diseases such as systemic lupus erythematosus
    Systemic lupus erythematosus
    Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...

     and chronic lymphocytic leukemia)
  • Any of the causes of hypersplenism (increased activity of the spleen) such as portal hypertension
    Portal hypertension
    In medicine, portal hypertension is hypertension in the portal vein and its tributaries.It is often defined as a portal pressure gradient of 10 mmHg or greater.-Causes:Causes can be divided into prehepatic, intrahepatic, and posthepatic...

  • Acquired hemolytic anemia is also encountered in burn
    A burn is an injury to flesh caused by heat, electricity, chemicals, light, radiation, or friction.Burn may also refer to:*Combustion*Burn , type of watercourses so named in Scotland and north-eastern England...

    s and as a result of certain infections.
  • Lead poisoning
    Lead poisoning
    Lead poisoning is a medical condition caused by increased levels of the heavy metal lead in the body. Lead interferes with a variety of body processes and is toxic to many organs and tissues including the heart, bones, intestines, kidneys, and reproductive and nervous systems...

     resulting from the environment causes non-immune hemolytic anemia.
  • Runners
    Running is a means of terrestrial locomotion allowing humans and other animals to move rapidly on foot. It is simply defined in athletics terms as a gait in which at regular points during the running cycle both feet are off the ground...

     can suffer hemolytic anemia due to "footstrike hemolysis
    Mechanical hemolytic anemia
    Mechanical hemolytic anemia is a form of hemolytic anemia due to mechanically induced damage to red blood cells. Red blood cells, while flexible, may in some circumstances succumb to physical shear and compression. This may result in hemoglobinuria. Some forms are self-inflicted , if not...

    ", owing to the destruction of red blood cells in feet at foot impact.
  • Low-grade hemolytic anemia occurs in 70% of prosthetic heart valve recipients, and severe hemolytic anemia occurs in 3%
  • March hemoglobinuria


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. The spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...

 (part of the reticulo-endothelial system) is the main organ that removes old and damaged RBCs from the circulation. In healthy individuals, the breakdown and removal of RBCs from the circulation is matched by the production of new RBCs in the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...


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. Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...

, a breakdown product of hemoglobin, can accumulate in the blood, causing jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...

, and be excreted in the urine causing the urine to become a dark brown color.

In general, hemolytic anemia occurs as a modification of the RBC life cycle. 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. It is perhaps then helpful to understand the physiology of the RBC and things that can go wrong to cause it to "die" prematurely. With their complete lack of mitochondria, RBCs rely on glycolysis for the materials needed to reduce oxidative damage. Any limitations of glycolysis can result in more susceptibility to oxidative damage and a short or abnormal lifecycle. If the cell is unable to signal to the reticuloendothelial phagocytes by externalizing phosphatidylserine, it is likely to lyse through uncontrolled means. Dogs and cats differ slightly from humans in some details of their RBC composition and have altered susceptibility to damage, notably, increased susceptibility to oxidative damage from onion or garlic.

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. Free hemoglobin can bind to haptoglobin
Haptoglobin is a protein that in humans is encoded by the HP gene. In blood plasma, haptoglobin binds free hemoglobin released from erythrocytes with high affinity and thereby inhibits its oxidative activity. The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system...

, or it 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. 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.


  • Peripheral blood smear microscopy:
    • fragments of the red blood cells ("schistocyte
      A schistocyte or schizocyte is a fragmented part of a red blood cell. Schistocytes are typically irregularly shaped, jagged, and asymmetrical. A true schistocyte does not have central pallor...

      s") can be present
    • some red blood cells may appear smaller and rounder than usual (spherocytes)
    • Reticulocyte
      Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells,...

      s are present in elevated numbers. This may be overlooked if a special stain
      Staining (biology)
      Staining is an auxiliary technique used in microscopy to enhance contrast in the microscopic image. Stains and dyes are frequently used in biology and medicine to highlight structures in biological tissues for viewing, often with the aid of different microscopes...

       is not used.
  • The level of unconjugated bilirubin in the blood is elevated. This may lead to jaundice.
  • The level of lactate dehydrogenase
    Lactate dehydrogenase
    Lactate dehydrogenase is an enzyme present in a wide variety of organisms, including plants and animals.Lactate dehydrogenases exist in four distinct enzyme classes. Two of them are cytochrome c-dependent enzymes, each acting on either D-lactate or L-lactate...

     (LDH) in the blood is elevated
  • Haptoglobin levels are decreased
  • If the direct Coombs test
    Coombs test
    Coombs test refers to two clinical blood tests used in immunohematology and immunology...

     is positive, hemolysis is caused by an immune process.
  • Hemosiderin
    thumb|Hemosiderin image of a kidney viewed under a microscope. The brown areas represent hemosiderinHemosiderin or haemosiderin is an iron-storage complex. It is always found within cells and appears to be a complex of ferritin, denatured ferritin and other material...

     in the urine indicates chronic intravascular hemolysis. There is also urobilinogen in the urine.


Definitive therapy depends on the cause:
  • Symptomatic treatment can be given by blood transfusion
    Blood transfusion
    Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...

    , if there is marked anemia.
  • In severe immune-related hemolytic anemia, steroid
    A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...

     therapy is sometimes necessary.
  • Sometimes splenectomy
    A splenectomy is a surgical procedure that partially or completely removes the spleen.-Indications:The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the removal of old red blood cells and platelets, and the detection and fight...

     can be helpful where extravascular hemolysis is predominant (i.e. most of the red blood cells are being removed by the spleen).

Veterinary cases

Hemolytic anemia may affect non human species as well. It has been found in a number of animal species to result from specific triggers.

Some notable cases include hemolytic anemia found in black rhinos kept in captivity, with the disease affecting 20% of the animals in one instance. The disease is also found in wild rhinos.
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