07 August 2011

Sickle Cell Anemia

Sickle cell anemia is an inherited syndrome effecting primarily people in sub-Saharan Africa, but also in the Mediterranean basin, the Caribbean, South and Central America, as well as those whose ancestors are from those regions. In the United States, sickle cell disease afflicts almost solely African-Americans, of whom one in six hundred are homozygous for the mutation and are affected by sickle cell anemia while 40% of that population group are heterozygous carriers who lead mostly normal lives.

The “sickle cell” belt is nearly contiguous with the “malarial belt”, the reason for the existence of the latter being that it lies along vast stretches of swampy, marshy territory where mosquitoes, the females of which are the carriers of the malarial parasites which they inject into those they bite, flourish.

Five haplotypes of the HbS mutation have been identified, four arising in Africa and one in southwest Asia, all in regions with widespread epidemic malaria, with the mutations in the Mediterranean traced to those in Africa.

Scientists believe the reason for the mutation’s survival, and possibly its origin, lies in the fact that it provides a defense against infection by malaria, and they have proven that heterozygous individuals, while not immune to infection by various species of the protozoa genus Plasmodium, are more likely to survive an infection than those with HbA alone, the former showing resistance even to P. falciparum and P. vivax, the most virulent malarial parasites.

Biologists refer to this kind of evolutionary selection as “balanced polymorphism”. Homozygous individuals, on the other hand, are those have inherited an allele for the HbS mutation from each parent, and these are the unfortunate ones who develop sickle cell anemia.

Sickle cell anemia occurs because of substitution of the nucleotide thymine for that of adenine between the two nucleotides of guanine in the sixth triplet of chromosome 11, which results in the encoding of valine rather than glutamic acid in the beta-chains of the hemoglobin molecule. The resulting hemoglobin molecule is called hemoglobin-S (HbS) as opposed to normal hemoglobin-A (HbA).

Where the normal glutamate is hydrophilic, the valine mutation is hydrophobic and becomes, in essence, “sticky”. In heterozygous individuals, this is rarely a problem because their other beta-chain is normal, but in those homozygous for HbS, the hemoglobin molecules within their erythrocytes (RBC’s) are attracted to each other and polymerize.

Eventually the linked HbS molecules join together to form long polymerized chains and deoxygenate, which causes them to deform, or “sickle”, so-called because of their unique shape. The mishapen cells return to their original shape once they regain oxygen, but will inevitably deoxygenate once again and re-sickle. This continual cycle weakens the membrane of the RBC, which eventually ruptures, and this hemolysis is what causes the anemia.

The immediate problem of a single sickle cell is that just one can completely block a capillary, and that several sickle cells clumped together can block venuous pathways, especially if the clump adheres to the vascular epithelium. These vasculo-occlusions can cause severe pain, which effects 70% of all sickle cell anemia victims.

Furthermore, sickled RBC’s are much more likely to get stuck in the spleen, though such splenic sequestration generally occurs only in children, and only 10% of those, or in the liver, causing a heptic sequestration crisis in which the liver enlarges and levels of serum bilirubin becomes critical, and can even lead to acute liver failure, though this effects less than 2% of victims.

A much more common affliction, though less deadly, is acute chest syndrome, which effects 40% of victims. Other conditions that can result from vasculo-epithelial occlusion include stroke (mostly in children under 5), slow brain damage, priapism in men, miscarriage in women, leg ulcers, osteonecrosis, and insufficent function of the kidneys.

Vasculo-occlusion can damage all the organs of the body and eventually lead to pneumonia (because of damage to the lungs), paralysis (due to damage to the central nervous system), rheumatic joints, bone marrow necrosis, and/or failure of the heart, kidneys, or liver.

As mentioned before, excessive hemolysis of sickled RBC’s leads to severe anemia, which can contribute to any of the above conditions, in addition to fatigue and mishapen bones in children, and if combined with infection by the B19 parvovirus, brings about aplastic crisis in which erythropoeisis is shut down entirely. Susceptibility to infections the immune systems of others easily fight off are another feature of sickle cell anemia, especially by Staphylococcus pneumonia and E. coli, as well as those which lead to osteomyelitis.

Clinical laboratory indications of sickle cell anemia are multitude and can include:

· Decreased hemoglobin (5 to 9.5 g/dL)
· Decreased hematocrit
· Decreased erythrocyte count
· Increase in leukocyte count (12,000 to 15,000 x 10^9/L)
· Reticulocytosis (8-12%)
· Increased MCV up to 100 fL
· Elevated serum
· Unconjugated bilirubin methabulin
· Decreased serum haptoglobin and hemopexin
· Increased serum LDH
· Increased AST
· Increased urine urobilirubin

RBC’s on a peripheral blood smear will show anisocytosis, poikilocytosis, and hypochromia, with abnormalities including drepanocytes (sickle cells), microcytes, polychromataphilia, and basophilic stipling. Hemoglobin electrophoresis will show 80-95% HbS, up to 20% HbF, and normal HbA2. [1]

Prenatal screening includes amniocentesis at or around the 14th week of pregnancy, but there is also increased use of chorionic villus biopsy at the 7th to 10th week. For newborns, the umbilical cord blood can be tested, though care must be taken to prevent contamination by maternal blood, and blood taken from a heel stick, both of which are usually tested by electrophoresis on cellulose acetate. [2]

Treatment for sickle cell anemia currently includes blood transfusions for severe cases, and, since approved by the FDA in 1998, the drug hydroxyurea, which stimulates production of HbF, which retards the formation of HbS polymers and in addition reduces the amount of neutrophils, monocytes, and reticulocytes in the blood.[3]

Beginning in the 1990’s, some fortunate victims of sickle cell disease have been cured by bone marrow transplants, though only 1% have been fortunate enough to have a suitable sibling donor.

However, in December 2007, Rudolph Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, along with his coworker Jacob Hanna and Tim Downes of the University of Alabama Schools of Medicine and Denstistry at Birmingham announced that they had cured sickle cell anemia in mice using “induced pluripotent stem” (iPS) cells.

The scientists created the iPS cells by removing skin cells from the affected mice and inducing them to become stem cells by injecting them with four different viruses specifically engineered to turn the skin cells into ones almost exactly matching embryonic stem cells. They then spliced the DNA to remove the genetic code that caused production of HbS and filled the gaps with the proper sequence, treated these with another virus designed to create healthy hematopoietic stem cells which they injected back into the marrow of the mice from which they came. Once there, the newly made cells began producing healthy HbA while the mice ceased producing HbS.

The major advantage to this approach is that since the cells from which the iPS cells are made come from the individual mouse into which they are returned after being converted, there is virtually no chance of rejection, and anti-rejection drugs are not needed. The only drawback before the technique can be used on humans is that something other than viruses will have to be found to induce the changes in the skin cells since human physiology is much different than that of mice.


Bridges, Kenneth R., M.D., and Maureen Okam, M.D. Management of Patients with Sickle Cell Disease. Retrieved 22 March 2008 from Information Center for Sickle Cell and Thalassemic Disorders website: http://sickle.bwh.harvard.edu/scdmanage.html.

Steinberg, Martin H., M.D. (1999). Management of Sickle Cell Disease. The New
England Journal of Medicine, 340 (13), 1021-1030.

Turgeon, Mary Louise. (2005). Clinical Hematology: Theories and Procedures.
Baltimore: Lippincott, Williams, & Wilkins.

Weiss, Rick. (2007, December 7). Scientists Cure Mice Of Sickle Cell Using Stem Cell Technique: New Approach Is From Skin, Not Embryos. Washington Post, p. A02.

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