Course:MEDG550/Student Activities/Hemophilia A

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Hemophilia is the name for a group of hereditary bleeding disorders where clotting does not occur properly due to low levels of specific coagulation factors, proteins in the blood that promote clot formation. The most common form of Hemophilia is Hemophilia A. In Hemophilia A individuals have decreased amounts of a coagulation factor called factor VIII because of a change that causes the factor VIII gene, F8, not to work properly.[1] Individuals with Hemophilia A may bleed longer than usual when a blood vessel is broken from injury or surgery. In severe cases, prolonged bleeding can occur after minor trauma or spontaneously (without trauma).

Clinical Features

Hemophilia A is caused by a lack of clotting factor VIII (8), which is necessary for normal blood clotting. Blood clotting, or coagulation, is needed to repair blood vessels after damage, to prevent bleeding for long periods of time.[1][2][3] Platelets (small blood cells) and clotting factor proteins, like factor VIII, work together to plug damaged blood vessels.[1][3] Individuals with Hemophilia A will not experience heavier bleeding but will bleed for longer periods of time than individuals without Hemophilia A. Many children with hemophilia A will not show symptoms until they are becoming more active, learning to walk and crawl.[4]

Some of the features of Hemophilia A include[4]:

  • Bleeding for long periods of time after injury, surgery, or tooth extraction
  • Internal bleeding into muscles and joints, particularly ankles, elbows, and knees.
  • Limited joint movement, joint pain and swelling.
  • Bruising easily
  • Blood in the urine
  • Unexplained persistent headaches due to bleeding in the brain
  • Anemia

The severity of symptoms depends on the individual’s level of working factor VIII, with less factor VIII resulting in an earlier age at diagnosis and an increased number of bleeding episodes.

Types

Hemophilia A is classified into 3 groups depending on the amount of factor VIII found in someone's blood:[2]

  1. Mild
    • 6%-40% activity in factor VIII
    • No spontaneous/unexplained bleeding
    • Prolonged or heavy bleeding after major injury, surgery or tooth extraction
    • Often diagnosed later in life
  2. Moderate
    • 1-5% activity in factor VIII
    • Usually no spontaneous/unexplained bleeding
    • Prolonged or heavy bleeding after minor injury, surgery or tooth extraction
    • Usually diagnosed before age 5 or 6
  3. Severe
    • <1% activity factor VIII
    • Spontaneous bleeding (often into joints or bleeding within muscles)
    • Average of 2-5 spontaneous bleeding episodes per month (when untreated)
    • Usually diagnosed in the first year of life

Female Carriers

Hemophilia A is a condition that more frequently occurs in males than females.[4] Females with Hemophilia A often have less severe symptoms than males. This is because females have two copies of the gene responsible for making factor VIII while males only have one as explained in more detail below. Females who have one working copy and one non working copy of the F8 gene are called carriers. Carriers have variable levels of factor VIII activity. A female carrier may have normal levels of clotting factor VIII and therefore show no symptoms of Hemophilia A or may have low levels of factor VIII similar to those seen in men with mild Hemophilia A. Up to 80% of women with one non working copy of the F8 gene will have clotting levels lower than individuals with only working copies and 30% of female carriers will have clotting activity below 40% and be at risk for bleeding.[5] Females who are carriers have been shown to bleed for longer periods of time after minor injuries compared to non carriers, have nosebleeds that last for longer periods of time, and require treatment for bleeding after surgery more often than non carriers. They may experience increased and prolonged bleeding during their menstrual periods. Female carriers may also be at risk for prolonged bleeding following child birth[5] Rarely a female may have two non working copies of the F8 gene and show more severe signs of Hemophilia A.

Prevalence

Hemophilia A typically affects more males than females. An estimated 1/4000 - 1/5000 males will be born with Hemophilia A.[1] In Canada, approximately 31% of individuals with Hemophilia A will have the severe type. [6] Hemophilia A occurs in individuals of all races and ethnic backgrounds.[7]

Genetics

Hemophilia A is caused by a change in the gene that provides the instructions for the body to make factor VIII, which is called F8. This change causes the gene not to work properly resulting in lower than expected levels of factor VIII. All males with a non working copy of the factor VIII gene will have hemophilia A. There are many different different changes in the F8 gene that cause Hemophilia A. The type of change will determine the level of working factor VIII and thus the severity of symptoms.

The change in the gene which causes it not to be working right can occur randomly in an individual. This is the case in about 30% of babies born with Hemophilia A.[4] The rest of the time this change will be inherited. Within a family, all males with the non working copy of the F8 gene will have hemophilia A. Because they share the same exact same change in their F8 gene males within a family will typically have a similar level of severity.[2][8]

Inheritance

X-linked Recessive Inheritance White boxes on the X chromosome represent the mutated copy and blue boxes represent the functional (normal) copy

The F8 gene is located on the X chromosome. Females have two X chromosomes, whereas males have one X chromosome and one Y chromosome. Hemophilia A follows an X-linked recessive pattern of inheritance since the F8 gene is on the X chromosome and the condition occurs when there is no normal copy of F8 gene. This means that males who inherit the mutated copy of the gene on their only X chromosome will be affected with Hemophilia A because they will not have any normal copy of F8 gene to produce regular levels of factor VIII.

Females who inherit one non working copy of the gene are called carriers because they have one working copy of the gene and one non working copy. While the levels of factor VIII activity may vary, female carriers typically do not show symptoms of hemophilia A because they have one working copy of factor VIII gene that can compensate for the mutated, abnormally functioning copy. However, they have a 50% chance to pass on the non working copy to their children. Males with hemophilia A will pass on the non working copy to their daughters and thus all of their daughters will be carriers. Carrier daughters may show mild symptoms of hemophilia A and will be able to pass on the non working copy to their own children. Males with hemophilia A do not pass on the non working copy to their sons because they only pass on their Y chromosome.[1]

  • Female carrier mother:
    • 50% chance that her sons will have hemophilia A
    • 50% chance that her daughters will be carriers
  • Father with hemophilia A:
    • None of his sons will have hemophilia A
    • All of his daughters will be carriers

Diagnosis

The diagnosis of hemophilia A can be made by a combination of the clinical symptoms, and factor VIII levels. Factor VIII activity levels below 40% will lead to a diagnosis with hemophilia A and the exact activity level can help predict disease severity in an individual with symptoms. Individuals with severe hemophilia A will usually be diagnosed by two years of age, individuals with moderate hemophilia A by five or six years, and individuals with mild hemophilia A are often not diagnosed until later in life when there is no known family history.[1] Genetic testing of the F8 gene can help confirm the diagnosis and determine the change in the F8 gene responsible for causing hemophilia A in the individual. This test result may have implications for the rest of that person’s family because certain family members may also have a non working copy of the F8 gene. These individuals may also have hemophilia A or be at risk for having children with hemophilia A .[2]

Women with the possibility of being carriers for hemophilia A should have their levels of factor VIII tested. However, normal factor VIII levels do not eliminate the possibility of being a carrier. The only way to determine carrier status is through genetic testing.[9]

Prenatal diagnosis may be available when there is a family history of hemophilia A and the specific genetic cause has already been identified in the family.[10]

Management

There is currently no cure for hemophilia A, however, the symptoms can be well managed. Infusion (injection into the blood) of factor VIII concentrates is the main treatment option. The idea is that the concentrates help to increase the level of working factor VIII in the patient's blood. Infusions may be required on a continuous basis to prevent bleeding episodes or may only be required to stop bleeding once it occurs.[1][3]

Prevention of injuries can also help manage the frequency of bleeding episodes. This may include avoiding contact sports and protecting young children with kneepads, elbow pads and helmets. It is also important that doctors, dentists and other health care providers be aware of a diagnosis or a family history of hemophilia A to ensure proper care is provided.

Medications to avoid

Some medications affect body's ability to clot blood therefore individuals with hemophilia A are advised to avoid medications that can increase the risk of bleeding. For example, aspirin and other drugs that contain aspirin (i.e. Alka Seltzer, Excedrin, etc.) may disrupt platelet function which is necessary for clotting. Non-steroidal anti-inflammatory drugs such as ibuprofen and naproxen should be avoided unless prescribed by physician [1][11]. Furthermore, individuals with hemophilia A should avoid blood thinning medications such as warfarin and heparin which will lengthen the time it takes for blood to clot [11]

Pregnancy Management

During pregnancy factor VIII levels typically increase leading to a reduced chance of bleeding episodes.[9] However, women who are carriers of hemophilia A may be at an increased risk for prolonged bleeding postpartum. Factor VIII levels should be measured during the third trimester of pregnancy. If they are low a plan can be made for delivery. Factor VIII levels typically return to normal about a week after delivery.[9]

Genetic Counselling

Genetic counselling should be available to individuals and families with hemophilia A. A genetic counsellor can help determine who is at risk for hemophilia A in the family and organize testing if desired. A genetic counsellor will also be able to provide support and information when making decisions prior to and during pregnancy. See the resources below for more information and support.

Genetic Testing for Individuals with Hemophilia A

Genetic testing in individuals with hemophilia A aims to identify the specific change in the F8 gene that is responsible for causing symptoms. This testing could serve to confirm a diagnosis of hemophilia A but would likely not change the care or medical management of an individual who has been shown to have low factor VIII activity. Instead this testing would allow for family members to pursue testing to determine if they have a chance of being carriers, or would allow for prenatal testing.

Carrier Testing

Women with a family history of hemophilia A may choose to pursue genetic testing to determine whether they have a non working copy of the gene responsible for Hemophilia. These women may or may not have symptoms of hemophilia A but would have a chance of having a son with hemophilia A or a daughter who is also a carrier.

Family Planning

For individuals who are affected with hemophilia A, or a family member who is affected a genetic counsellor will be able to discuss with you the chance of having a child who has hemophilia A. There is also the possibility of preimplantation genetic testing, a process which requires the use of in vitro fertilization (IVF) to test embryos for the gene change responsible for causing hemophilia A. The goal of this process is to prevent or greatly reduce the chance of having a child with hemophilia A.

Prenatal Testing

Testing is available in pregnancy to determine if the baby has Hemophilia A. An ultrasound may be able to determine the sex of the baby, and since only males are likely to have the severe form of hemophilia A this might provide useful information. Diagnostic testing for hemophilia A is also possible in pregnancy. A sample of fetal tissue from the placenta or the amniotic fluid is necessary for this type of testing. There are risks associated with this procedure. Genetic counselling can provide more information about this type of testing.

Living with Hemophilia A

Without treatment Hemophilia A can be a serious disease that is debilitating. With treatment options available today most individuals with hemophilia A live full and active lives.

Individuals with hemophilia A may experience feelings of worry regarding possibly injury and spontaneous bleeding.[12] Parents of individuals with Hemophilia A may feel a sense of protectiveness and experience similar feelings of worry. The time required for infusion treatments and medical appointments may interfere with other activities though infusion therapies are able to be done at home.[12] Individuals with mild and moderate hemophilia A have been shown to have similar health related quality of life as the general population.[13]

Resources

Living with Hemophilia: http://www.livingwithhemophilia.ca/

Canadian Hemophilia Society: http://www.hemophilia.ca/en/

National Hemophilia Foundation: https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Hemophilia-A

Hemophilia Federation of America: http://www.hemophiliafed.org/

World Federation of Hemophilia: http://www.wfh.org/en/page.aspx?pid=492

Canadian Association of Genetic Counsellors- Find a clinic page: https://www.cagc-accg.ca/?page=225

National Society of Genetic Counselors- Find a genetic counselor page: http://nsgc.org/p/cm/ld/fid=164

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 http://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia.
  2. ↑ 2.0 2.1 2.2 2.3 Konkle BA, Josephson NC, Nakaya Fletcher S. Hemophilia A. 2000 Sept 21 [Updated 2014 June 5]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1404/.
  3. ↑ 3.0 3.1 3.2 http://www.hematology.org/Patients/Clots/.
  4. ↑ 4.0 4.1 4.2 4.3 Franchini, M; Mannucci, P.M. (2013). "Hemophilia A in the third millennium". Blood Reviews. 27 (4): 179–184.
  5. ↑ 5.0 5.1 Plug, I., Mauser-Bunschoten, E. P., Bröcker-Vriends, A. H., van Amstel, H. K. P., van der Bom, J. G., van Diemen-Homan, J. E., ... & Rosendaal, F. R. (2006). Bleeding in carriers of hemophilia. Blood, 108(1), 52-56.
  6. ↑ Stonebraker, J.S.; Bolton-Maggs, P.H.B.; Michael Soucie, J; Walker, I; Brooker, M (2010). "A study of variations in the reported haemophilia A prevalence around the world". Haemophilia. 16 (1): 20–32.
  7. ↑ Bolton-Maggs, P.H.; Pasi, K.J. (2003). "Haemophilia a and b". The Lancet. 361 (9371): 1801–1809.
  8. ↑ Oldenburg K, Pezeshkpoor B, Pavlova A. (2014). Historical review on genetic analysis in hemophilia A. Semin Thromb Hemost 40:895-902.
  9. ↑ 9.0 9.1 9.2 Street, A.M.; Ljung, R.; Lavery, S.A. (2008). "Management of carriers and babies with haemophilia". Haemophilia. 14 (Suppl. 3): 181–187.
  10. ↑ Kessler L, Adams R, Mighion L, Walther S, Ganguly A. (2014). Prenatal diagnosis in haemophilia A: Experience of the genetic diagnostic laboratory. Haemophilia 20:e384-391
  11. ↑ 11.0 11.1 Srivastava, A., Brewer, A. K., Mauser-Bunschoten, E. P., Key, N. S., Kitchen, S., Llinas, A., Ludlam, C. A., Mahlangu, J. N., Mulder, K., Poon, M. C., Street, A. and Treatment Guidelines Working Group The World Federation Of Hemophilia (2013) Guidelines for the management of hemophilia. Haemophilia, 19: e1–e47. doi: 10.1111/j.1365-2516.2012.02909.x
  12. ↑ 12.0 12.1 Katz, AH (1963). "Social adaptation in chronic illness: A study of hemophilia". American Journal of Public Health and the Nations Health. 53 (10).
  13. ↑ Poon, J.L.; Zhou, Z.Y.; Doctor, J.N.; Wu, J; et al. (2012). "Quality of life in haemophilia A: Hemophilia Utilization Group Study Va (HUGS-Va)". Haemophilia. line feed character in |title= at position 57 (help)
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