Hemolytic anemia

Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (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 or acquired. Treatment depends on the cause and nature of the breakdown.

Symptoms of hemolytic anemia are similar to other forms of anemia (fatigue and shortness of breath), but in addition, the breakdown of red cells leads to jaundice and increases the risk of particular long-term complications, such as gallstones and pulmonary hypertension.

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 level (mainly indirect-reacting) with jaundice
   2. increased fecal and urinary urobilinogen
   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, fatigue, shortness of breath, and potential for heart failure) are present. In small children, failure to thrive may occur in any form of anemia. Certain aspects of the medical history can suggest a cause for hemolysis, such as drugs, consumption of fava beans due to Favism, 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 has been linked with the development of pulmonary hypertension (increased pressure over the pulmonary artery); this, in turn, leads to episodes of syncope (fainting), chest pain, and progressive breathlessness. Pulmonary hypertension eventually causes right ventricular heart failure, the symptoms of which are peripheral edema (fluid accumulation in the skin of the legs) and ascites (fluid accumulation in the abdominal cavity).

Causes

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 (RBC) itself, or extrinsic in cases where factors external to the RBC dominate.^[1] 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 :

• Defects of red blood cell membrane production (as in hereditary spherocytosis and hereditary elliptocytosis)

• Defects in hemoglobin production (as in thalassemia, sickle-cell disease and congenital dyserythropoietic anemia)

• Defective red cell metabolism (as in glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency)

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 infection (cold agglutinin disease) or permanent factors as in autoimmune diseases like autoimmune hemolytic anemia (itself more common in diseases such as systemic lupus erythematosus, rheumatoid arthritis, hodgkin disease and chronic lymphocytic leukemia)
• 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
• Any of the causes of hypersplenism (increased activity of the spleen) such as portal hypertension
• Acquired hemolytic anemia is also encountered in burns and as a result of certain infections.
• Lead poisoning resulting from the environment causes non-immune hemolytic anemia.
• Runners can suffer hemolytic anemia due to "footstrike hemolysis", owing to the destruction of red blood cells in feet at foot impact.^[2][3]
• Low-grade hemolytic anemia occurs in 70% of prosthetic heart valve recipients, and severe hemolytic anemia occurs in 3% ^[4]
• March hemoglobinuria

Pathophysiology

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 (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.

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, a breakdown product of hemoglobin, can accumulate in the blood, causing jaundice, 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.^[5][6][7] 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.^{[8][9][10][11][12][13][14][15][16][17]}

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.^[18][19] Free hemoglobin can bind to haptoglobin, 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.^[18] 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.^[20]

Diagnosis

• Peripheral blood smear microscopy:
  • fragments of the red blood cells ("schistocytes") can be present
  • some red blood cells may appear smaller and rounder than usual (spherocytes)
  • Reticulocytes are present in elevated numbers. This may be overlooked if a special stain is not used.
  • Bite cells may be present due to Heinz body removal by the spleen in G6PD deficiency.
• The level of unconjugated bilirubin in the blood is elevated. This may lead to jaundice.
• The level of lactate dehydrogenase (LDH) in the blood is elevated
• Haptoglobin levels are decreased
• If the direct Coombs test is positive, hemolysis is caused by an immune process (e.g. autoimmune hemolytic anemia).
• Hemosiderin in the urine indicates chronic intravascular hemolysis. There is also urobilinogen in the urine.
• Haemaglobinuria in the morning is suggestive of paroxysmal nocturnal haemoglobinuria.

Treatment

Definitive therapy depends on the cause:

• Symptomatic treatment can be given by blood transfusion, if there is marked anemia.
• In severe immune-related hemolytic anemia, steroid therapy is sometimes necessary.
• Sometimes splenectomy can be helpful where extravascular hemolysis, or hereditary spherocytosis, is predominant (i.e. most of the red blood cells are being removed by the spleen).^[21]

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.^[22]

Some notable cases include hemolytic anemia found in black rhinos kept in captivity, with the disease affecting 20% of the animals in one instance.^[23][24][25] The disease is also found in wild rhinos.^[26]

References