Introduction

 

What is Hemophilia A?

Hemophilia A is a genetic disorder that effects blood clotting. It disproportionately effects males due to its X-linked nature. It is most common in cases where there is a family history of Hemophilia. It is typically diagnosed at a young age via blood testing.

Symptoms

Hemophilia A is caused by a mutation in the coagulation factor VIII, abbreviated as F8C. F8C is a clotting factor gene, so any significant changes in F8C result in the body’s inability to stop bleeding and results in the following symptoms:

• • unexplained bruising
• • excessive bleeding
• • bleeding in joints and organs
• • joint pain or stiffness
• • possible bleeding around the head or brain

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Brief History

Molecular Genetics

 

Hemophilia A is an X-linked recessive disorder caused by a mutation in the F8 gene. The specific location of the gene is referred to as Xq28, meaning that it is on the 28 th band of the q region of the 28 th chromosome. This band is located right on the telomere of the chromosome. The F8 gene consists of 26 exons and 25 introns. It codes for 2351 total amino acids, and these amino acids are what come together to form the Human Coagulation Factor VIII protein. The Human Coagulation Factor VIII protein is very important because of its role in the coagulation cascade, which is what allows blood clotting in humans to occur. In order for coagulation to occur, Factor VIII has to be activated to become Factor VIIIa. Factor VIIIa is then used as a co- factor to Factor IX in the cascade, which ultimately produces Factor X and leads to clotting. A lack of this Factor VIII protein, which is what occurs when the F8 gene is mutated in hemophilia A patients, thus leads to an inability of blood clotting to occur. This causes what would be minor cuts and scrapes in unaffected people to be fatal wounds in patients with hemophilia A. In some severe cases, spontaneous internal bleeding may occur, and often times, this is also fatal. The Factor VIII protein that the F8 gene codes for consists of six domains in the inactive form, and these domains are as follows: A1, A2, A3, B, C1, and C2. However, there are only five domains in the active form. This is because the cleavage and release of the B domain is what causes the active form of the protein to be produced. The A domains are important because they give the protein a copper-binding ability, while the C domains are important because they are what allow the protein to bind to phospholipids and thus have cell membrane activity. The severity of hemophilia A depends on what sort of mutation the affected individual has in their F8 gene. The most common mutation that leads to a severe form of hemophilia A is characterized by an inversion of intron 22 with intron 1. This accounts for roughly 50% of severe hemophilia A cases. Other severe hemophilia A cases are mostly caused by the deletion of certain exons, and there are also mutations that can lead to less severe forms of the disorder.

Environmental Interactions

 

Conclusion

 

New gene therapy technologies are on the verge of being developed for hemophilia A treatment. One example can be seen with the combination of CRISPR/Cas9 and stem cell technologies that has been used in experiments with mice. Promising results have been seen with regard to treating hemophilia B in mice, but there is still a lot of work that has to be done before any of these technologies can be used in humans. Not as much work has been done with hemophilia A, but there is also hope that these technologies can eventually be used to treat it as well. In addition to the CRISPR/Cas9 treatment that is being developed, there has also been work done that involves inserting the Factor VIII protein into human genomes through the use of vectors. This is also still being perfected, but there will likely be some progress made on this front very soon.

 

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