SICKLE CELL ANEMIA AND HEMOGLOBINOPATHIES

Sickle cell anemia are a class of Hemoglobinopathies -  set of inherited disorder that are either due to 

1) Structural abnormality

2)Deficiency in hemoglobin production

SICKLE CELL DISEASE

         Also known as hemoglobin S disease (HbS), this is an autosomal recessive disease that is predominantly found in Africans. it is caused by a point mutation in the genes that code for Beta-globin chain of hemoglobin. New borns typically do not experience any symptoms as they have predominantly HbF (fetal hemoglobin). this HbF fades as they grow, causing them to experience life long pain crisis and hemolytic anaemia as a result of instability of the red blood cell- RBCs (lifespan of 20days).

patients also have risk of  infections and may experience acute chest syndrome, stroke and splenic infarctions.

PATHOGENESIS

         Patients undergo point mutation in the gene that codes for beta-globin chain, the mutation is caused by removing the negatively charged Glutamate in the gene and replacing it with a neutral valine. Therefore both beta-globin chain of a single molecule of hemoglobin have these mutations.

As a result of having a less negatively charged hemoglobin compared to the normal hemoglobin A. The HbS migrates slowly on electrophoresis. HbS obtained after lysis of RBCs can be used for diagnosis.

         The replacement of a polar glutamate with a non polar valine creates a pocket in the structure that make it more readily able to interact with the alpha chains of nearby hemoglobin. at low oxygen, hemoglobin S forms fibrous polymers that stiffen and distort the shape of the RBCs. The sickled cells can clump together and block blood flow in small vesicles. This will lead to anoxia in humans and thereby causing pain and eventual cell infarction.

Any factor that decrease oxygen tension and make levels of deoxy hemoglobin will predispose to sickling. This includes high altitudes, exercise and levels of 2,3 bisphosphoglycerate.

TREATMENT

      Involves hydration therapy, analgesics for pain coated with antibiotics for infection control, intermittent transfusion may be done in patients with high risk of vasoelusive episodes, however recurrent transfusion may cause iron overload. In addition, patients may be given a drug called hydroxyurea. This meditation works to decrease sickling by increasing fetal Hemoglobin levels.

HEMOGLOBIN C DISEASE

     This condition is due to point mutation in the 6th position of beta-globulin that replaces glutamate with lysine. Since lysine carries a positive charge, it moves the slowest on electrophoresis. patient with this condition typically have mild, chronic hemolytic anaemia, abdominal and joint pain, mild jaundice.

HEMOGLOBIN SC DISEASE

       In this disorder, some of the beta-globulin have the sickle cell mutation while others have the HbC mutation. These patients have hemoglobin levels higher than sickle cell patients and typically remain asymmptomatic until some major stimulus i.e surgery, child birth. causes an infarctive crisis.

METHEMOGLOBINEMIA

       Heme groups that have iron in the ferrous state (Fe2+) can bind oxygen. certain medications such as nitrates as well as endogenous metabolites such as reactive oxygen species can oxidize the iron in the ferric state (Fe3+). Heme in the ferric state cant bind oxygen well and this can lead to a state of chocolate cyanosis characterized by brownish-blue skin and chocolate coloured blood.

Symptoms are related to tissue hypoxia and include headache, fatigue, anxiety and dysnia. Treatment involves using methylene blue and vitamin C.

THALASSEMIAS

       Normally, our cells regulate the production of alpha chain and beta chain in such a way as to produce a one-to-one ratio.

In a group of disorder called thalassemia, there is a defect in either the alpha chain production or the beta chain production. This can be caused by a variety of mutations including single nucleotide deletions, substitutions and even entire gene deletions. The type of mutation determines the type and severity of the thalassemia.