The Battle Against the Royal
Disease, Hemophilia A
From the beginning of time…
Dubbed the “Royal Disease” because Queen
Victoria was a carrier, our enemy has been characterized as one of the oldest genetic diseases known to mankind. The earliest records date back to rabbinical writings of the
Talmud documented in the second century. A law was present that stated that if two sons of a woman die from circumcision then her third would not be required to be circumcised. This was an illustration that the Jewish were aware that mothers passed it on to their sons. Up until 1937, the cause of this disease remained unknown.
Modern studies began in
1803 when a Philadelphia physician named Dr. John
Conrad Otto wrote a review about a hemorrhagic disposition that occurred in families affecting males.
Following that, Nasse gave the first review in 1820 and
Wright demonstrated evidence of laboratory defects in blood clotting in

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1893. Our forces strengthened exponentially in 1937 after Patek and Taylor found the role of the soon to be named factor VIII describing its action in hemostasis. They characterized and named it an “antihemophilic globulin substance”. Not long after, the protein was purified and the gene was open to study for many scientists.

The root of this evil
The mastermind behind Hemophilia A is the gene coagulant factor VIII. The factor VIII gene sits on the long arm of chromosome 10 at location 28, more specifically, from base pairs
154,064,062 to 154,255,350. Its protein sequence is 2351 amino acids long transcribed from a 191,288 mRNA. This gene produces two alternatively spliced transcripts.
Transcript variant 1 consists of 26 exons that encodes a large glycoprotein called isoform a, which circulates in the plasma and undergoes multiple cleavage events. Transcript variant 2 encodes a small protein, isoform b, which consists of a unique 5' exon located within intron 22 of transcript variant 1. This exon codes for eight amino acids and is spliced to exons 2326 maintaining the reading frame. It is composed primarily of the phospholipid-binding domain of factor VIIIc. This binding domain is essential

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for coagulant activity. Normally this gene, an important ally of the human body, is what helps with stopping hemorrhages through the production of factor VIII clotting proteins; however a mutation resulting in deficient production soon turns this beneficent gene into a deadly enemy.

The enemies’ whereabouts

Our enemies’ headquarters has been spotted in numerous locations including the liver, kidneys, testis, spleen, ovaries, lungs, brain, heart, muscles, and even skin. (Hollestelle et al. 2001) Studies have reached different results but the general consensus is that gene expression occurs primarily in the liver. More specifically, they are found expressed in hepatocytes and endothelial cells of the liver. (Yaday et al. 2012) After the production of the protein, the enemy has been reported travelling away from the liver towards the placenta, megakaryocytes, and fibroblasts. (Fear et al.
1984) Staining techniques have also shown protein localisation in the endothelial cells of the kidney, spleen, lymph nodes, cardiac muscle, smooth muscle, thyroid, umbilical cord, arteries, veins, capillaries, splenic and hepatic sinusoids and skin. (Hoyer et al. 1973) Interestingly enough, the factor VIII protein has not been seen where gene expression is the highest i.e. the liver.
(Fear et al. 1984)

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Be weary, other living things…
It has been noted that the blood coagulation network, including factor VIII is present in all jawed vertebrates and evolved before the divergence of tetrapods and teleosts. All three domains of the protein - A1, A2, and A3 are found in dogs, pigs, mouse, fugu, and chicken. (Davidson et al. 2003) Other studies have determined the presence of the protein in rats, rabbits and the whole bovine family. So where exactly did the gene coagulant factor VIII come from?
Evolutionary studies on the coagulation network of vertebrates and inflammation have shown that these evolved in parallel with a rapid change during the divergence of jawless fish and the appearance of mammals. Both of these systems have been suggested to extend up to the primordial protochordates. (Doolittle 2011) In fact, comparisons between the factor VIII gene to that of a sea-quirt, an invertebrate tunicate and the puffer fish, a close relative of the ancient lamprey show many conserved gene portions and identical protein sequences. (Doolittle et al. 2008)

The enemies’ strategy of attack
This gene holds the information necessary for the transcription and translation of coagulation factor VIII, which plays a crucial role in the blood coagulation pathway. Under ordinary circumstances, when blood vessels are damaged from injury, bleeding occurs, the vessels constrict and numerous clotting factors are activated. The injury results in a signal transduction changing the

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concentration of calcium ions and phospholipids and causes factor VIII to convert factor X to its active form factor Xa. Together with factor V, they convert prothrombin to thrombin, which in turn converts fibrinogen to fibrin. This creates platelet plugs over which a stable fibrin clots form at the damaged sites and bleeding stops.
Individuals with a recessive mutation in the gene cannot form proper blood clots in response to injury because there is an insufficient or even complete lack of the factor VIII protein; this is known formally as
Hemophilia A. This leads to complications involving disproportionate bleeding that is both painful and difficult to control. To date more than 1300 different types of mutations have been identified. Some are single substitutions, others insertions or deletions of multiple base pairs but the most common and severe form of Hemophilia A occur when there is an inversion of a large segment. The severity of the disorder thus depends on the degree to which function is impaired. Aaron Chan

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Our strategies of attack
Although currently there is no cure, experimental trials are underway and soon humans will be able to rid themselves of the disease. Our best weapon of attack is gene therapy. Gene therapy involves the manipulation of genes to treat or prevent diseases. Theoretically, treating people with Hemophilia A would involve the removal of cells that would normally produce the factor VIII protein at normal levels, alter the genetic material of the cells to produce the clotting factor, and reinsert the cells back into the patient. Many experiments are underway as hemophilic dogs, mice and humans are being studied. It has been determined that this type of therapy works. The only problem is that after a certain period of time the levels of factor VIII drop back down. Interestingly enough, it was published on Wednesday, November 20th 2013 that a team of scientists lead by Dr. David Wilcox of the Medical College of Wisconsin,
Milwaukee have successfully treated hemophilic dogs and that they have remained normal for more than two years. They determined that performing gene replacement therapy on a patient's bone marrow cells can lead to production, storage and release of factor VIII from platelets directly at the site of an injured blood vessel to prevent uncontrolled bleeding for several years after treatment. This team is currently applying for a patent to start clinical trials in the US. The Hemophilia society expects the cure to come within 10 years. Will this finally mark our victory and end the long war?

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Images

"Clotting Cascade." almostadoctor.com. N.p., n.d. Web. 20 Nov. 2013.
.
Doolittle, R. F. (2011). Coagulation in vertebrates with a focus on evolution and inflammation.
Journal of Innate Immunity, 3(1), 9-16. doi:10.1159/000321005
"F8." - coagulation factor VIII, procoagulant component. N.p., n.d. Web. 18 Nov. 2013.
.
"Hemophilia A." Look for Diagnosis. N.p., n.d. Web. 20 Nov. 2014.
.
Hollestelle, M. J., Thinnes, T., Crain, K., Stiko, A., Kruijt, J. K., van Berkel, T. J., . . . van
Mourik, J. A. (2001). Tissue distribution of factor VIII gene expression in vivo-a closer look.
Thrombosis and Haemostasis-Stuttgart-, 86(3), 855-861.
"What is hemophilia." - Canadian Hemophilia Society. N.p., n.d. Web. 20 Nov. 2013.
.

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