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Hemolytic anemia is anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs) either in the blood vessels (intravascular hemolysis) or elsewhere in the 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.

Signs and symptoms

Signs of anemia (pallor, fatigue, shortness of breath, and potentially heart failure) are generally 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, 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) and 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 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 while external factors include immune attack and microvascular angiopathies ( RBC's are mechnically damaged in circulation).

Hereditary (inherited) hemolytic anemia can be due to:

• Defects in hemoglobin production (as in thalassemia and sickle-cell disease)
• Defects of red blood cell membrane production (as in hereditary spherocytosis and hereditary elliptocytosis)
• Defective red cell metabolism (as in glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency).

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 and chronic lymphocytic leukemia)
• Any of the causes of hypersplenism (increased activity of the spleen) such as portal hypertension
• Acquired hemolytic anemia is also encountered in burns and certain infections

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 which 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 colour.

Hemolytic anemia generally occurs as a modification of the RBC lifecycle. 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, RBC's 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.^[2][3][4] Dogs and cats differ slightly from humans in some details of their RBC composition and have altered susceptibility to damage, notably increased susceptbility to oxidative damage from onion or garlic.^{[5][6][7][8][9][10][11][12][13][14]}

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.^[15][16] Free hemoglobin can bind to haptoglobin or it may oxidize and release the heme group which is able to bind to either albumin or hemopexin. The heme is ultimately converted to bilirubin and removed in stool and urine.^[15] 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.^[17]

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

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 is predominant (ie most of the red blood cells are being removed by the spleen).

References