ANAEMIAS DUE TO EXCESSIVE DESTRUCTION OF RBC’S- HAEMOLYTIC ANAEMIAS

The haemolytic anemias are characterised by

• premature destruction of red cells
• accumulation of the products of haemoglobin catabolism
• a marked increase in erythropoiesis in the bone marrow

Intravascular haemolysis is manifested as

• hamoglobinaemia
• haemoglobinuria
• methaemoglobinaemia
• jaundice
• haemosiderinuria

When haemoglobin escapes into the plasma it is bound to to an alpha 2 globulin called haptoglobin. The heme-haptoglobin complex is not excreted into urine. A decrease in serum haptoglobin is characteristic of intravascular haemolysis. When the haptoglobin is depleted the unbound or free haemoglobin is oxidized to methaemoglobin and both haemoglobin and metahemoglobin are excreted through the kidney imparting a reddish brown colour to the urine. When the excretory capacity of the kidney is exceeded the free methomoglobin complexes with albumin to form methaemoalbuminaemia which imparts a reddish brown colour to the blood. Within the tubular cells of the kidney iron released form heme produces haemosiderosis of the renal cells. When the cells are shed into the urine they stain with special iron stains producing haemosiderinuria.
In haemolytic anemias excessive breakdown of heme leads to a unconjugated bilirubinaemia.
Hemoglobinaemia and haemoglobinuria do not occur with extra vascular haemolysis. Excessive destruction of Red Blood Cells occurs both as a hereditary condition or as a hereditary condition or as an acquired disorder.
This increased red cell destruction results in an increased level of bilirubin in the blood leading to jaundice. Bilirubin is a breakdown product of haemoglobin.To compensate for the increased destruction of red cells the bone marrow increases the production of red cells which results in the appearance of some immature cell forms in the peripheral blood- reticulocytosis.

Reticulocyte-
Increased bone marrow expansion when present in early childhood produces bony deformities which are most commonly seen in the cranial bones, ribs and facial bones.

Haemolytic anaemias can be classified into two groups-

• Hereditary
• Acquired

The common hereditary causes for haemolysis result from the abnormalities of Red blood cell membrane, defects in the enzymes of red blood cells, abnormal Haemoglobins and quantitative reductions in Globin chain synthesis. Membrane abnormalities include Hereditary Spherocytosis.

HEREDITARY SPHEROCYTOSIS-

The red cells assume a globular shape in hereditary sphaerocytosis as a result of Which they easily get destroyed –“ bruised “ while passing through the sinusoids of the liver and spleen. These cells have an increased influx and efflux of Sodium. This disease is inherited in an autosomal dominant pattern. The sphaerocytes are densely staining without a central pallor.

Sphaerocytes are not conclusive for the diagnosis of hereditary sphaerocytosis as they could also occur in autoimmune haemolytic anemias and allo immune haemolytic anemia ( heamolytic disease of the newborn or delayed transfusion reactions ).

Patients are usually anaemic and jaundiced as well. The spleen is usually enlarged. The disease could manifest anytime either in early childhood or in old age. The manifestations of the disease process also tend to be variable.

Associated infections can produce HAEMOLYTIC crises resulting in both an increased anaemia and jaundice or an APLASTIC crisis with marked anaemia. Patients tend to develop pigment gall stones.The treatment depends on the severity of the condition and ranges from the administration of Folic acid, blood transfusion and Splenectomy. In severe crisis splenectomy is done early after the age of six years.

After a splenectomy the child is especially prone to infection with capsulated organisms like Pneumococci, H. Influenzae and Meningococci and should be protected by way of vaccination against these organisms at least three weeks prior to the splenectomy.

Microsphaerocytes are cells that are both small in size and hyperchromic and are seen with hereditary sphaerocytosis and is characteristic of burns and MAHA- microangiopathic haemolytic anemia which could occur with a number of conditions like DIC, pregnancy induced hypertension, disseminated cancer, Haemolytic uremic syndrome, Thrombotic thrombocytopenic purpura etc.

Other Membrane disorders are Hereditary Ovalocytosis wherein the red cells have an oval shape and Hereditary Elliptocytosis where the red cells are elliptical. Haemolytic anaemia is rare in these conditions.

ENZYME DEFECTS-

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY-

The most common of the red cell enzyme deficiency leading to haemolysis is Glucose-6-Phosphate dehydrogenase deficiency. This is an X-linked recessive disorder seen in male children with the defective X chromosome and in female children with the homozygous state. About 3% of the world population has this defect and is more common in the Mediterranean region, South East Asia and in blacks.

The activity of the enzyme could be normal in young cells and falls rapidly with ageing of the red cells. Subjects taking drugs like anti-malarials, sulpha drugs, analgesics including aspirin, phenacetin, viral infections, consumption of fava beans could all precipitate a haemolytic episode. During periods of haemolysis the diagnosis could be difficult as newly formed red cells contain normal enzyme levels. A repeat study after about a month would show the enzyme deficiency then.

Features of haemolysis are – Jaundice, reticulocytosis, circulating nucleated red cells. Special staining techniques would show up “ HEINZ” bodies which would help establish the diagnosis. Heinz bodies are precipitated globin chains seen in the red cells.

Treatment consists of stopping the offending drug and administration of Folate. Keratocytes or bite cells and Blister cells which are cells with an irregular Contour is characteristic of acute haemolysis induced by oxidant stress. These irregularly contracted cells share with sphaerocytes the lack of central pallor but differ in that they have an irregular outline.

PYRUVATE KINASE DEFICIENCY- Is a rare condition but produces severe haemolysis.

HAEMOGLOBINOPATHIES AND THALASSAEMIA-

The three crises associated with Sickle Cell disease are

• Infarction producing painful crisis. Dehydration and hypoxia resulting from infections like pneumonia precipitate these attacks
• Haemolytic crisis associated with infections.
• Aplastic crisis results from bone marrow failure resulting from infections commonly due to the Parvo B 19 strain.

DIAGNOSIS- An examination of the peripheral smear would show sickled cells in the homozygous state. Haemoglobin electrophoresis would reveal the slow migration of Hb S as compared to Hb A.
TREATMENT- Prevention of dehydration, adequate analgesia, treatment of inter current infections, Folic acid supplementation, avoidance of hypoxic states are the main stay of treatment.

Hypoxic states
In emergency situations like CNS crises, priaprism, aplastic crisis, and acute coronary syndromes exchange transfusions could be given.

Anti sickling agents largely have not been found useful in preventing the various crises. It has been observed that some of the Mediterranean patients have an increased level of HbF and correspondingly the crisis rate has been seen to be low in them. So Hydroxyurea which helps in switching to an increased HbF production has been found to be useful in reducing crisis rates among patients with the sickle cell disease.

Subjects with the Sickle Cell Trait are usually aymptomatic. They may occasionally have haematuria. Painful crises are rare except when severe hypoxaemia develops.

The HbS trait can be diagnosed by doing a Haemoglobin electrophoresis. It can also be tested for by inducing sickling with reducing agents like sodium metabisulphite.

Other haemoglobinopathies like HbC,HbE,HbD are seen but are not clinically very important.

THE THALASSAEMIAS-

There are three main forma of Beta Thalassaemia

• Thalassaemia Major-
  This is the severe form with anaemia being present from early infancy. This is associated with hepatosplenomegaly and the facila bony changes of haemolysis resulting in a mongoloid facies. The main haemoglobin present is HbF ( the foetal Haemoglobin ) which may range from 50-100%.
• Thalassaemia Intermedia-
  In this clinical entity the severity of disease is less than in Thalassaemia Major. These patients too are anaemic, have splenomegaly and have jaundice.Transfusion requirements are variable in this group of patients
• Thalassaemia Minor-
  This is a heterozygous state in which subjects usually show no symptoms with the underlying condition usually being picked up during investigation of families with the Thalassaemia gene.
  
  The clinical features in severe forms are a failure to thrive, microcytic anaemia, jaundice, mongoloid facies, hepato-splenomegaly and growth retardation.

TREATMENT-

1. Blood transfusions so as to keep the level of Haemoglobin above 10 gm%. This type of a hypertransfusion program helps the child attain a normal physical and mental status for age and also helps lead an active life. This mode of treatment also results in transfusional haemosiderosis due to the increase in the body iron stores. Haemosiderosis leads to diabetes, impotence, cirrhosis etc due to deposition in various organs.

Transfusion haemosiderosis is treated with iron chelation therapy using subcutaneous infusion of Desferal using a pump for delivery. The pump is attached to the body using a belt. This is usually transfused during night five days a week. New chealting agents using oral drugs like Kelfer is now available.

Thalassaemia Trait or Thalassaemia Minor-

Heterozygous state. Anaemia is minimal. Red cells are microcytic with many target ceels. HbA2 levels are slightly increased

ALPHA THALASSAEMIA-

ACQUIRED HAEMOLYTIC ANAEMIAS-