Today we are going to discuss on pathology of sickle cell anemia. Like hereditary spherocytosis, sickle cell anemia is one type of hemoglobinopathy. Hemoglobinopathy? What is that?
Hemoglobinopathy is a hereditary disease characterized by structurally abnormal hemoglobin.
We are going to discuss on pathogenesis, morphology and maybe few additional infos which be important in this topic.
Sickle cell anemia is a autosomal recessive genetic disorder. It affects the BETA GLOBIN gene on the CHROMOSOME 16.
Before we go into deep, let us do some simple revision on Molecular Medicine about hemoglobin.
1) Hemoglobin is a tetrameric structure in which it has two pairs of similar globin chains
2) Arrangement of globin
+ HBF (Fetus)
(this HBF will gradually replace by HBA until the age of 5 months)
+ Adult hemoglobin
- HBA1 (96%)
+2 alpha globins
+2 beta globins
- HBA2 (3%)
+ 2 alpha globins
+ 2 delta globins
- HBF (1%)
3) Let us concentrate on the HBA1, since its the most prominent one. It consists of:
+ 2 alpha globins
- Encoded by 2 loci at chromosome 11
+ 2 beta globins
- Encoded by a single loci at chromosome 16
Enough with molecular medicine, let us get back to our main topic – sickle cell anemia. What goes wrong then?
1) There is a point mutation happens at the beta globin gene in chromosome 16.
2) SUBSTITUTION of GLUTAMIC ACID to VALINE. This substitution leads to sickling of the red cells.
3) Why it sickles then? In the beta globin, there is a normally occuring HYDROPHOBIC POCKET at the sixth position of amino acid in the beta globin chain.
4) At the same time, the normal constituent at the sixth position is GLUTAMIC ACID which is HYDROPHILIC in nature. Due to that, it couldnt fit into the hydrophobic pocket.
5) But, in sickle cell, the glutamic acid is replaced by VALINE which is HYDROPHOBIC in nature. Therefore, it fits the hydrophobic pocket.
6) We agreed that sickle cell is an autosomal recessive disorder, so below is its genetic characteristic:
- 50% of HBA1 are replaced by sickle hemoglobin (HBS)
- 100% of HBA1 are replaced by HBS
Ok, that is pretty much about milecular pathology of sickle cel anemia. Now its time for histopathology of sickle cell anemia.
Sickle RBC doesnt express its crescentic shape upon release from red marrow. Sickling only happens during DEOXYGENATION. The process is called polymerization.
It must be clear that, during the first few deoxygenations, sickling is reversible. Buy after countless deoxygenation that the RBCs undergo, the sickling starts to become irreversible. This is due to :-
1) Lost of
2) Accumulation of Calcium
The rate of sickling is influenced by 3 major factors :-
1) Pressence of other type of hemoglobin other than HBS
+ There is a weak interaction between HBA1 and HBS
- This is why rate of sickling is longer in patient with heterozygous HBS
- Homozygous HBS still has 50% of HBA1 in which significant enough to reduce the rate of sickling
+ Increased interaction with HBC ( just another mutant beta chain)
- Patient having HBC has a significant increment in sickling rate
2) Concentration of HBS in red cells
+ The higher the amount of HBS, the higher the rate of sickling
+ Homozygous has higher rate compared to heterozygous
- Homozygous has higher amound of HBS
3) Transit time of red cell during deoxygenation
+ When the transit time of RBC in the capillary higher deoxygenation rate
+ Increase deoxygenation rate increase sickling ( sikling happens during deoxy)
+ Difference in transit time at different sites
- Capilary has less transit time, so less sickling happens
- Sinusoidal capillary of liver and spleeb has higher transit time, high sickling
- Acute inflammation, increase transit time, thus increases sickling
Irreversible sickling somehow makes the sickle RBCs ‘sticky’. These RBCs deposited at the arterial walls and lead to microinfarction of tissue especially the lungs. This triggers pain crisis.
In severe cases, microvascular occlusion leads to stroke.
1) Severe chronic hemolytic anemia
2) Increased production of bilirubin which eventually leads to hyperbillirubinemia
3) Microvascular occlusion leads to tissue ischemia and infarction
4) Sickle cell is cresentic or pencil shape
5) Increased compensatory erythropoeisis leads to erythroid tissue hyperplasia
6) Bone marrow expansion leads to bone deformity
+ Prominent cheek bone deformity
+ Crew-cut skull
7) Simultaneous extramedullary erythropoeisis and hemolysis leads to splenomegaly
Those are pretty much about the pathology of sickle cell anemia.
Next we are going to discuss on Thalassemia. Until then thanks!!