Jessica Cordeiro Isidoro & Alyssa Goulart
What is Hemophilia?
-Hemophilia is an X-linked recessive bleeding disorder that slows or prevents the blood clotting process.
-People with this condition experience prolonged bleeding after an injury or surgery.
-In severe cases of hemophilia, continuous bleeding occurs after minor trauma or even without injury (spontaneous bleeding).
-The major types of this condition are hemophilia A (factor VIII (8) deficiency) and hemophilia B (factor IX (9) deficiency).
-Although the two types have very similar signs and symptoms, they are caused by mutations in different genes.
-Hemophilia C is very rare and is much more mild that hemophilia A or B. It is caused by a defective clotting factor known as factor XI.
-Individuals with more than 5 percent of normal factor VIII have mild hemophilia A (experience bleeding problems only when having surgery or dental procedures)
-Individuals with 1 to 5 percent of normal factor VIII have moderate hemophilia A (experience bleeding problems if they have a minor injury, such as a fall)
-Individuals with less than 1 percent of normal factor VIII have severe hemophilia A (may begin bleeding for no reason at all. Surgery and dental procedures can be very dangerous)
-About half of all hemophiliacs have this form of the disorder.
-The range of symptoms of hemophilia B is similar to that of hemophilia A.
It is usually diagnosed in infancy or childhood.
It is confirmed with blood tests which are able to measure how much of various clotting factors are present in the blood and how quickly they work to produce clots. These tests can be used to diagnose the type of hemophilia a person has and the seriousness of the condition.
-Acquired hemophilia is not caused by inherited gene mutations.
-It is a rare condition characterized by abnormal bleeding into the skin, muscles, or other soft tissues, usually beginning in adulthood.
-Results when the body makes specialized proteins called autoantibodies (inhibitors) that attack and disable coagulation factor VIII (8).
-The production of autoantibodies is sometimes associated with pregnancy, immune system disorders, cancer, or allergic reactions to certain drugs.
Hemophilia and Genetics
-The genes for producing coagulation factors are located on X chromosomes.
-This means that males are more likely to have hemophilia than females. A female always has two X chromosomes. She may inherit one defective X chromosome, but will rarely inherit two defective X chromosomes. Her normal X chromosome will still carry the correct instructions for making clotting factors.
-Males, however, carry only one X chromosome. If the X chromosome a male inherits is defective, he will not have a normal X chromosome to compensate for the defective one. His cells will not receive the correct instructions for making clotting factors.
Hereditary Hemophilia Video
Review: How does blood clot?
-Blood clotting involves two major features- platelets and the thrombin system.
-When bleeding occurs, platelets activate and adhere to the wall of the blood vessel.
-The thrombin system consists of blood proteins that become activated when bleeding occurs and engage in many chemical reactions that results in a substance called fibrin.
-Fibrin resembles a long sticky string which sticks to the vessel wall binding platelets together stabilizing the clot.
What Cause Hemophilia?
-Coagulation factors are proteins that work together in the blood clotting process.
-The F8 gene provides instructions for making a protein called coagulation factor VIII.
-The F9 gene provides instructions for producing a related protein called coagulation factor IX.
-Mutations in the F8 gene are responsible for hemophilia A, while mutations in the F9 gene cause hemophilia B. Mutations in the F8 or F9 gene lead to the production of an abnormal version of coagulation factors.
-The mutated protein cannot participate effectively in the blood clotting process which means blood clots cannot form properly in response to injury.
-This gene is known as “coagulation factor VIII, procoagulant component” because it provides instructions for making a protein called coagulation factor VIII.
-The protein circulates in the bloodstream in an inactive form. In response to injury, coagulation factor VIII is activated and interacts with another coagulation factor called factor IX.
-This interaction sets off a chain of additional chemical reactions that form a blood clot.
-Mutations in this gene cause hemophilia A
-Over 1,300 alterations of this gene has been identified; some involve a change in single DNA base pairs while others delete or insert multiple base pairs (POINT MUTATION)
- In a study of 83 patients with hemophilia A, Youssoufian (1986) identified 2 different point mutations, one in exon 18 and one in exon 22, that recurred independently in unrelated families. Each mutation produced a nonsense codon by a change of CG to TG
-The most common mutation in people with Hemophilia A is the rearrangement of genetic material (INVERSION) in the F8 gene.
Where is the F8 Gene Located?
-Cytogenetic Location: Xq28 (long (q) arm of the X chromosome at position 28)
-Molecular Location on the X chromosome: base pairs 154,835,787 to 155,026,
-Provides instructions for making the protein coagulation factor IX.
-Works alongside coagulation factor VIII in the formation of blood clots.
-Mutations in the F9 gene cause hemophilia B
-Over 900 alterations in this gene have been identified.
-The most common mutation in the F9 gene is single base pair mutations.
-A small percentage of mutations that cause hemophilia B insert or delete multiple case pairs and rearrange sequence of DNA within the gene.
-Mutations that completely eliminate the activity of coagulation factor IX results in severe hemophilia.
-Mutations that reduce but do not eliminate the proteins activity usually cause mild or moderate hemophilia.
Where is the F9 Gene Located
-Cytogenetic Location: Xq27.1-q27.2 long (q) arm of the X chromosome between positions 27.1 and 27.2.
-Molecular Location on the X chromosome: base pairs 139,530,733 to 139,563,463
Signs and Symptoms
-Easy and excessive bleeding
-Bleeding in muscles cause pressure on nerves which leads to pain numbness and damage to nerves
-Joints can become deformed and permanently damaged
-Many people receive blows to the head, but rarely suffer serious damage. In the case of hemophilia, a blow to the head can cause extensive bleeding in the brain. Since the skull cannot expand, the bleeding causes pressure on delicate brain tissue. Permanent brain damage may occur.
-Bleeding in internal organs may lead to DEATH!
-As of yet, there is no cure for people with hemophilia
-The standard therapy is frequent infusions with blood-clotting promoters
-Desmopressin (dDVAP) is used to treat hemophilia A
-Prophylaxis is used to prevent bleeding episodes and is used for patients with severe or moderate hemophilia.
-Several longer-lasting clotting factors have been developed however many people have developed an immune resistance to these infused factors.
-Research is developing an alternative treatment strategy to remove or disable the body's anticoagulants rather than adding clotting factors.
-Gene therapy could provide a cure by correcting the underlying genetic defect.
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F8. (2015, May 11). Retrieved from http://ghr.nlm.nih.gov/gene/F8
F9. (2015, May 11). Retrieved from http://ghr.nlm.nih.gov/gene/F9
"Hemophilia." Sick! Detroit: UXL, 2007. Science in Context. Web. 16 May 2015.
Hemophilia.(2015,May 11). Retrieved from http://ghr.nlm.nih.gov/condition/hemophilia
Purrello, M., Alhadeff, B., Esposito, D., Szabo, P., Rocchi, M., Truett, M., … Siniscalco, M. (1985). The human genes for hemophilia A and hemophilia B flank the X chromosome fragile site at Xq27.3. The EMBO Journal, 4(3), 725–729.
Reininger, Armin J., et al. "Pushing The Frontiers Of Medicine: Innovations In Haemophilia Care." Scientific American 312.1 (2015): W1. Science Reference Center. Web. 16 May 2015.
Reininger, A. J., Gringeri, A., Valentino, L. A., Spotts, G., Romanov, V., Numerof, R., & ... Ewenstein, B. M. (2015). Pushing the frontiers of medicine: innovations in haemophilia care. Scientific American, 312(1), W1.
Sung Ho Hwang, Hee-Jin Kim and Hye Sun Kim (2012). Chapter 1 Profiling of Mutations in the F8 and F9, Causative Genes of Hemophilia A and Hemophilia B", Hemophilia, Dr. Angelika Batorova (Ed.), ISBN: 978-953- 51-0429-2, InTech, Available from: http://www.intechopen.com/books/hemophilia/profiling-of-mutations-in-thef8-and-f9-causative-genes-of-hemophilia-a-and-hemophilia-b