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Haemophilia is a bleeding disorder which hinders 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. Complications arising from external wounds pose very little risk, however, difficulties occurring due to internal bleeding or haemorrhaging may demonstrate a larger risk. These haemorrhages are commonly found in major joints, tissues and muscles.3 If bleeding happens in a vital organ, in particular the brain, a haemophiliac's life becomes extremely fragile and death may result. Haemophiliac's experience prolonged bleeding following an injury, surgery, or something as routine as having a tooth removed.1 In severe cases of haemophilia, profuse bleeding can occur after minor trauma or even without injury (spontaneous bleeding).4 Haemophiliacs can be organized into three different categories, severe, moderate, mild. Severe complications can arise due to bleeding into the joints, muscles, brain, or other internal organs, as mentioned above. Milder forms of haemophilia exclude spontaneous bleeding, and the malignity may not become obvious 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 of haemophilia have common 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 depictions and similar patterns of inheritance. The F8 gene supplies directives for synthesizing 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 mutually in blood clotting. After an injury is sustained, blood clots serve the function of protecting the body by creating a seal for 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.3 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.3 Due to the alterations or lack of protein, the coagulation factor cannot participate effectively in the blood clotting process. As a result, blood clots cannot form properly in response to injury, which leads to excessive bleeding that is hard to control. The mutations that are responsible for serious haemophilia near entirely eradicate the activity of coagulation factor VIII or coagulation factor IX. The mutations accountable for mild and moderate haemophilia reduce but do not eliminate the activity of one of these proteins.4 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.3 The bleeding can be caused by a simple bump/twist or at times can occur for no obvious reason. Moderate haemophiliacs bleed less often. These haemorrhages occur more commonly as result of minor trauma, or injury which may be contracted playing sports. Mild haemophiliacs have even fewer haemorrhages. They may be only become aware of their bleeding problem when trauma or injury is inflicted such as one contracted during a tooth extraction or a serious injury. Women with mild haemophilia may bleed more during the menstruation (periods).
One of the main treatments for haemophilia patients is replacement therapy. Replacement therapy works by using concentrates of clotting factor VIII (for haemophilia A) or clotting factor IX (for haemophilia B), which slowly drip in or are injected into the vein.4 These infusions help replace the missing/decreased clotting factor. Clotting factor concentrates can be made from human blood that has been treated to prevent the spread of diseases, such as hepatitis.3 With the current preventative measures and high standards of treating donated blood in place, the risk of contracting an infectious disease from human clotting factors is greatly reduced. To reduce the risk further, clotting factor concentrates can be synthesized from non human blood as an alternative. These are more commonly referred to as recombinant clotting factors.
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 end bleeding whenever it may occur. This use of the treatment, on an as-needed basis, is called demand therapy. 4 Demand therapy is less intensive and less expensive than preventive therapy.4 However bleeding before the administration of demand therapy may cause harm. Although effective complications of replacement therapy do exist, some of these: Antibodies may be created that act in opposition to the clotting factor; viral infections from clotting factors may develop; delays in treatment may cause damage to joints, muscles, or other parts of the body. Antibodies may possibly destroy the clotting factor before it can be effective, posing a severe problem. 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 In rare occasions the antibodies may regress and treatment may prove to be effective again. Researchers are studying ways to deal with antibodies to clotting factors. 1 Studies are also being conducted to determine if a larger single-dose of clotting factor may prove to be more effective than repeated, smaller doses in certain patients. Clotting factors can carry viruses that are transmitted during replacement therapy but this has been nearly abolished by the rigorous screening processes implemented. Desmopressin (DDAVP), a man-made hormone, is widely utilized to care for patients who have mild to moderate haemophilia A. Desmopressin is not given as treatment to patients who are diagnosed with haemophilia B or severe haemophilia A. Desmopressin initiates the discharge of stored factor VIII and von Willebrand factor; it also increased the level of these proteins in your blood.6 Von Willebrand factor carries and binds factor VIII, which can then remains in the patient's bloodstream for a longer period of time. Desmopressin is commonly given by injection or as nasal spray. Although effective, the upshot of this synthesized hormone decreases when used too frequently; hence, it is prescribed only to certain patients in specific situations. For example, this medicine be taken prior to dental work or before playing certain sports to prevent or reduce bleeding.3 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.