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Haemophilia is a bleeding disorder that slows the blood clotting process. It is important to note that the patient does not bleed more profusely or more quickly than a non-diagnosed person but rather bleeds for a longer duration. It is falsely perceived that haemophiliacs tend to bleed excessively from minor cuts, which generally is not the case. External wounds are usually not serious. Far more important is internal bleeding or haemorrhaging. These haemorrhages are commonly found in joints, especially the knees, ankles and elbows; and into tissues and muscles.3 If bleeding occurs in a vital organ, especially the brain, a haemophiliac's life becomes extremely fragile and death may result. Haemophiliac's experience prolonged bleeding following an injury, surgery, or having a tooth pulled out.1 In severe cases of haemophilia, heavy bleeding occurs after minor trauma or even in the absence of injury (spontaneous bleeding).4 Haemophiliacs can be organized into three different categories, severe, moderate, mild. Serious complications can result from bleeding into the joints, muscles, brain, or other internal organs, as mentioned above. Milder forms of haemophilia do not involve spontaneous bleeding, and the condition may not become apparent until abnormal bleeding occurs following surgery or serious injury. Mild haemophiliacs have clotting times which may go unnoticed during a person's life. The major types of this condition are haemophilia A (also known as classic haemophilia, since it is the more common form) and haemophilia B ( also known as Christmas disease, named after Steven Christmas, a Canadian who in 1952 was the first person to be diagnosed with this distinct form of haemophilia). 2 Although, the two types have very similar signs and symptoms, they are caused by mutations in different genes. Patients with an unusual form of haemophilia B, known as haemophilia B Leyden, experience episodes of excessive bleeding in childhood but have few bleeding problems after adolescence/puberty. 1 Another form of the disorder, acquired haemophilia is not caused by inherited gene mutations. This rare condition is characterized by abnormal bleeding into the skin, muscles, or other soft tissues, usually beginning in adulthood. 3
Haemophilia A and B are inherited bleeding disorders caused by deficiencies of clotting factors VIII (FVIII) and factor IX (FIX), respectively. 2 They account for 90-95% of severe congenital coagulation deficiencies. 1 Haemophilia A and B are categorized together based on their similar clinical depeictions and similar patterns of inheritance. The F8 gene provides instructions for making a protein called coagulation factor VIII. A related protein, coagulation factor IX, is produced from the F9 gene. 2 These proteins or coagulation factors work together in the blood clotting process. After an injury is sustained, blood clots protect the body by sealing off damaged blood vessels and preventing further blood loss. Coagulation factors are a group of related proteins that are essential for the formation of blood clots. The role of the coagulation system, as depicted in the image below, is to produce stable fibrin clot at sites of injury. The clotting mechanism has 2 pathways: intrinsic and extrinsic.
"The intrinsic system is initiated when factor XII is activated by contact with damaged endothelium. In conjunction with high-molecular-weight kininogen (HMWK), factor XIIa converts prekallikrein (PK) to kallikrein and activates factor XI. Activated factor XI, in turn, activates factor IX in a calcium-dependent reaction. Factor IXa can bind phospholipids. Then, factor X is activated on the cell surface; activation of factor X involves a complex (tenase complex) of factor IXa, thrombin-activated FVIII, calcium ions, and phospholipids. In the extrinsic system, the conversion of factor X to factor Xa involves tissue factor (TF), or thromboplastin; factor VII; and calcium ions. TF is released from the damaged cells. It is thought to be a lipoprotein complex that acts as a cell surface receptor for FVII, with its resultant activation. It also adsorbs factor X to enhance the reaction between factor VIIa, factor X, and calcium ions. Factor IXa and factor XII fragments can also activate factor VII. FVIII and FIX circulate in an inactive form. When activated, these 2 factors cooperate to cleave and activate factor X, a key enzyme that controls the conversion of fibrinogen to fibrin. Therefore, the lack of either of these factors may significantly alter clot formation and, as a consequence, result in clinical bleeding." 5
Mutations in the F8 or F9 gene lead to the production of an abnormal version of coagulation factor VIII or coagulation factor IX, or reduce the amount of one of these proteins. The altered or missing protein cannot participate effectively in the blood clotting process. As a result, blood clots cannot form properly in response to injury. These problems with blood clotting lead to excessive bleeding that can be difficult to control. The mutations that cause severe haemophilia almost completely eliminate the activity of coagulation factor VIII or coagulation factor IX. The mutations responsible for mild and moderate haemophilia reduce but do not eliminate the activity of one of these proteins. The genes for FVIII and factor IX (FIX) are located on the long arm of the X chromosome in bands q28 and q27, respectively; hence haemophilia A and B can be classified as inherited X-linked recessive trait. Females have two copies of the X chromosome, so if the factor VIII gene on one chromosome doesn't work, the gene on the other chromosome can do the job of making enough factor VIII. Males, however, have only one X chromosome, so if the factor VIII gene on that chromosome is defective, they will have haemophilia A. The two major forms of haemophilia occur much more commonly in males than in females. 3 Haemophilia A is the most common type of the condition; 1 in 4,000 to 1 in 5,000 males worldwide are born with this disorder. Haemophilia B occurs in approximately 1 in 20,000 newborn males' worldwide. 4 If a woman has a defective factor VIII gene, she is considered a carrier. In women who carry the defective gene, any of her male children will have a 50% chance of having haemophilia A, while any of her female children will have a 50% chance of being a carrier. All female children of men with haemophilia carry the defective gene, since only the defective x chromosome will be passed down to the daughter. This is depicted in the pedigree below.
Diagnoses of the condition can be done as early as ten weeks in neonatal life, but it is usually overlooked unless it is known the mother is a carrier or an infected individual. Most tests are conducted in adolescent years when the toddler first gets trauma and abnormalities in blood clotting are noticed. Some indications of haemophilia are; the activated partial thromboplastin time (aPTT) is prolonged; however, normal aPTT does not exclude mild or even moderate haemophilia because of the relative insensitivity of the test. Severe haemophilia is easily identified with a significantly prolonged aPTT.2 Bleeding times, prothrombin times, and platelet counts are normal. Another test that the physician may conduct is the factor VIII blood test. The factor VIII assay is a blood test that measures the activity of factor VIII.
Without proper treatment, haemophilia is crippling and often fatal. With modern treatment, most people with haemophilia can lead full, active lives. Haemophilia is classified as severe, moderate or mild.
LEVEL OF FACTOR VIII
OR IX IN THE BLOOD
Less than 1% of normal
1 to 5% of normal
5 to 30% of normal
Severe haemophiliacs with less than 1% of the normal level of factor VIII or IX in the blood have haemorrhages several times a month. The bleeding is often the result of a minor bump or twist. Sometimes, there is often no apparent cause for the bleeding. Moderate haemophiliacs bleed less often. Their haemorrhages are often the result of minor trauma, such as a sports injury. Mild haemophiliacs have even fewer haemorrhages. They may be aware of their bleeding problem only in the case of surgery, a tooth extraction or a serious injury. Women with mild haemophilia may bleed more during the menstruation (periods).
The main treatment for haemophilia is called replacement therapy. Concentrates of clotting factor VIII (for haemophilia A) or clotting factor IX (for haemophilia B) are slowly dripped in or injected into the vein.4 These infusions help replace the clotting factor that's missing or low. Clotting factor concentrates can be made from human blood that has been treated to prevent the spread of diseases, such as hepatitis. With the current methods of screening and treating donated blood, the risk of getting an infectious disease from human clotting factors is very small. To further reduce that risk, clotting factor concentrates can be synthesized from non human blood. These are called recombinant clotting factors. Clotting factors are easy to store, mix, and use at home.
Another form of treatment is replacement therapy, which prevents bleeding. This is called preventative or prophylactic therapy. In some cases replacement therapy may only be required to stop bleeding when it occurs. This use of the treatment, on an as-needed basis, is called demand therapy. 3 Demand therapy is less intensive and less expensive than preventive therapy.3 However, there's a risk that bleeding will cause damage before the demand therapy is given. Complications of replacement therapy include: Developing antibodies (proteins) that act against the clotting factor, developing viral infections from human clotting factors, damage to joints, muscles, or other parts of the body resulting from delays in treatment. Antibodies can destroy the clotting factor before it has a chance to work. This is a very serious problem. It prevents the main treatment for haemophilia (replacement therapy) from working.3 Antibodies to clotting factor, also called inhibitors, develop in about 20 percent of people who have severe haemophilia A and 1 percent of people who have haemophilia B. When antibodies develop, doctors may use larger doses of clotting factor or try different clotting factor sources.1 Sometimes, the antibodies go away. Researchers are studying ways to deal with antibodies to clotting factors. 1 They also are studying whether a larger single-dose of clotting factor may be better than repeated, smaller doses for some patients. Clotting factors can carry the viruses being transmitted during replacement therapy has occurred for about a decade.4 Desmopressin (DDAVP) is a man-made hormone used to treat people who have mild to moderate haemophilia A. DDAVP isn't used to treat haemophilia B or severe haemophilia A. DDAVP stimulates the release of stored factor VIII and von Willebrand factor; it also increased the level of these proteins in your blood.2 Von Willebrand factor carries and binds factor VIII, which can then stay in the bloodstream longer. DDAVP usually is given by injection or as nasal spray. Although effective, the effect of this medicine wears off when used often; it's given only in certain situations. For example, this medicine be taken prior to dental work or before playing certain sports to prevent or reduce bleeding. Women who are haemophilia carriers also can have "preimplantation diagnosis" to have children who don't have haemophilia.5 For this process, women have their eggs removed and then fertilized by sperm in a laboratory. The embryos that result from this fertilization are then tested for haemophilia. Only embryos that lack the condition will be implanted in the womb.