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NORD gratefully acknowledges Graça D. Almeida-Porada, MD, PhD, Professor of Regenerative Medicine, Director Fetal Research and Therapy Program, Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine and Nigel Key, MB, ChB, FRCP, Harold R Roberts Distinguished Professor of Medicine and Pathology and Laboratory Medicine, Director, UNC Hemophilia and Thrombosis Center, University of North Carolina at Chapel Hill, for assistance in the preparation of this report.
Hemophilia A, also known as classical hemophilia, is a genetic bleeding disorder caused by insufficient levels of a blood protein called factor VIII. Factor VIII is a clotting factor. Clotting factors are specialized proteins that are essential for proper clotting, the process by which blood clumps together to plug the site of a wound to stop bleeding. Individuals with hemophilia A do not bleed faster or more profusely than healthy individuals, but because their blood clots poorly, they have difficulty stopping the flow of blood from a wound. This may be referred to as prolonged bleeding or a prolonged bleeding episode. Hemophilia A can be mild, moderate or severe, depending on the baseline level of factor VIII made by that individual. In mild cases, prolonged bleeding episodes may only occur after surgery, dental procedures or trauma. In more severely affected individuals, symptoms may include prolonged bleeding from minor wounds, painful swollen bruises, and unexplained (spontaneous) bleeding into vital organs as well as joints and muscles (internal bleeding).
Hemophilia A is caused by disruptions or changes (variants or mutations) to the F8 gene located on the X chromosome. This variant may be inherited or occur randomly with no previous family history of the disorder (spontaneously). Hemophilia A is mostly expressed in males but some females who carry the gene variant may have mild or, rarely, severe symptoms of bleeding. Although there is no cure for hemophilia, effective therapies have been developed; most affected individuals can lead full, productive lives by maintaining proper treatment and care.
Hemophilia is a general term for a group of rare bleeding disorders caused by congenital deficiency of certain clotting factors. The most common form of hemophilia is hemophilia A. In rare cases, hemophilia A can be acquired during life (acquired hemophilia A) as a result of an auto-antibody to factor VIII. Although both disorders involve deficiency of the same clotting factor, the bleeding pattern is quite different. The reason the bleeding patterns differ between these disorders is not fully understood. This report only deals with the genetic form of hemophilia A.
The severity and symptoms of hemophilia A can vary greatly from one person to another. Hemophilia A can range from mild to moderate to severe. Factor VIII levels in these categories are 5-40% of normal, 1-5%, and less than 1%, respectively. The age of onset and frequency of bleeding episodes depend upon the amount of factor VIII protein and overall clotting ability of the blood. In most individuals, regardless of severity, bleeding episodes tend to be more frequent in childhood and adolescence than in adulthood.
It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
In mild cases, individuals may experience bruising and bleeding from the mucous membranes such as nosebleeds or bleeding from the gums. More serious, prolonged bleeding episodes may occur only after surgery or dental procedures, injury or trauma. The bleeding in such cases is out of proportion for the procedure or trauma. In many cases, individuals with mild hemophilia A may go undiagnosed until they need a surgical procedure or suffer an injury. In some cases, the first bleeding episode does not occur until well into adulthood. Individuals with a mild form of hemophilia A may go many years without a prolonged bleeding episode. Mild hemophilia A can be associated with anywhere from 5-40% factor VIII clotting activity.
Individuals with moderate hemophilia A seldom have spontaneous bleeding episodes. Spontaneous bleeding refers to bleeding episodes that occur without apparent cause. Individuals with moderate hemophilia A are at risk for prolonged bleeding following surgery, dental procedures or trauma. Easy or excessive bruising may also occur. Moderate hemophilia A is often diagnosed by 5 or 6 years of age. By definition, affected individuals have 1-5% of normal factor VIII clotting activity.
Severe hemophilia A occurs in individuals with less than 1% of normal factor VIII clotting activity. In contrast to the mild or moderate forms of the disease, severe hemophilia A is associated with spontaneous bleeding episodes. Such episodes often result in bleeding into the deep muscles or joints (hemarthroses), which will acutely cause pain and swelling and early restricted movement of the joint. If not treated in a timely manner or at all, bleeding may result in longer term arthritis (pain and restricted movement) of the affected joint. The joints and muscles are the most common sites for spontaneous bleeding episodes in individuals with severe hemophilia A.
Severe cases of hemophilia A usually become apparent early during infancy and a diagnosis is often made by two years of age. Without prophylactic treatment, these infants may experience bleeding from minor mouth injuries. Common symptoms in untreated infants are large swellings or “goose eggs” that form after a bump on the head. In rare cases, infants with severe hemophilia A have extra- or intracranial bleeding following birth. Untreated infants and children may also develop hematomas under the skin. Hematomas are solid swellings or masses of congealed blood. As infants and children grow older, spontaneous joint bleeds may become more frequent.
If untreated, infants and children with severe hemophilia A may have approximately two to five spontaneous bleeding episodes per month. Without treatment, affected individuals are at risk for prolonged bleeding from minor injuries, surgery and dental procedures such as tooth extractions.
Individuals with the severe form of hemophilia A can experience spontaneous bleeding into any organ system including the kidneys, the gastrointestinal tract, and the brain (intracranial bleeding). Genitourinary and gastrointestinal bleeding may respectively cause blood in the urine (hematuria) and black or bloody stools (melena, hematochezia). Intracranial bleeding may cause headaches, stiff neck, vomiting, seizures, mental status changes including excessive sleepiness and poor arousability. If untreated, these frequently occurring spontaneous bleeding events can be life-threatening.
Hemophilia A is caused by disruptions or changes (variants or mutations) of the F8 gene. The F8 gene contains instructions for creating (encoding) factor VIII. Factor VIII is one of the essential blood proteins and plays a role in aiding the blood to clot in response to injury. Mutations of the F8 gene result in deficient levels of functional factor VIII. The symptoms of hemophilia A occur due to this deficiency.
The F8 gene is located on the X chromosome. Approximately 70% of cases are inherited in an X-linked pattern. In the remaining 30%, cases occur spontaneously (i.e., as a result of a de novo mutation) without a previous family history of the disorder.
X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder can reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.
Females have two X chromosomes, but one of the X chromosomes is “turned off” or inactivated and all of the genes on that chromosome are inactivated. Carrier females, known as heterozygotes, inherit a single copy of the disease-causing variant, such as the gene for hemophilia A, and a normal copy of the F8 gene which compensates for the copy with the hemophilia-causing variant. If a female has a large proportion of the X chromosome with the normal gene inactivated, she may have symptoms of the disorder. Depending on the proportion of the X-chromosome with the disease-causing copy of the gene, a female may exhibit symptoms of the disorder, most commonly appearing to have mild hemophilia. There are other rare mechanisms which can cause a female to have hemophilia or other conditions caused by genes on the X chromosome.
Hemophilia A is the most common X-linked recessive disorder and the second most common inherited clotting factor deficiency after von Willebrand disease. Hemophilia A mostly affects males but females can also be affected. Approximately 1 in 5,000 newborn males have hemophilia A. Approximately 60% of individuals with hemophilia A have a severe form of the disorder. All racial and ethnic groups are equally affected by hemophilia.
A diagnosis of hemophilia A is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized laboratory tests.
Clinical Testing and Workup
Laboratory studies should include a complete blood count (CBC), coagulation tests and measurement of the level of specific factors (e.g. factor VIII). Screening coagulation tests that measure how long it takes the blood to clot include the activated partial thromboplastin time (aPTT) and prothrombin time (PT). Typically, the PT is normal, whereas the aPTT is prolonged in hemophilia A when the factor VIII level is less than 30% of normal. In such cases, a diagnosis of hemophilia A must be confirmed through a clotting activity assay. This assay can determine whether the cause of the abnormal aPTT is deficiency of factor VIII (hemophilia A), factor IX (hemophilia B) or another blood clotting factor deficiency. This specific test will also determine the severity of the factor VIII deficiency. Even if an aPTT test is normal this does not rule out mild cases of hemophilia A because of the relative insensitivity of the test.
Once the diagnosis of hemophilia A is made, the specific mutation in the F8 gene is often determined to ascertain the affected person’s risk of developing an uncommon but serious complication, i.e., the development of neutralizing anti-factor VIII antibodies, sometimes accompanied by allergic reactions, to the treatment outlined below. This complication is otherwise known as “inhibitor” development, since these antibodies can seriously inhibit the effectiveness of standard replacement treatment (see below).
Molecular genetic testing, which can identify mutations in the F8 gene is available on a clinical basis. Understanding the specific F8 gene variant can also be helpful in identifying female carriers in the family as well as in the prenatal diagnosis of hemophilia A, which is not only feasible, but is also available and encouraged in most Western and developing countries. Importantly, the development of digital PCR now allows analysis of cell-free fetal DNA present in maternal plasma and can diagnose hemophilia A in utero non-invasively as early as 7 weeks of gestation.
Individuals with hemophilia A will benefit from referral to federally-funded hemophilia treatment centers. These specialized centers can provide comprehensive care for individuals with hemophilia including the development of specific treatment plans, monitoring and follow up of affected individuals and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapist, social worker and genetic counselor) experienced in the treatment of individuals with hemophilia. Genetic counseling is recommended for affected individuals and their families.
Although there is no cure for hemophilia A, current treatments are very effective. Treatment consists of replacing the missing clotting protein (factor VIII) and preventing the complications associated with the disorder. Replacement of this protein may be obtained through recombinant factor VIII, which is artificially created in a lab. Many physicians and voluntary health organizations favor the use of recombinant factor VIII because it does not contain components derived from human blood. Factor VIII can also be obtained from frozen plasma (i.e., blood donations). Human blood donations do carry a risk of transmitting viral infection such as hepatitis. However, newer techniques for screening and treating blood donations have made such a risk extremely low.
The U.S. Food and Drug Administration (FDA) has approved several recombinant forms of factor VIII for the treatment of hemophilia A including Helixate FS, Recombinate, Kogenate FS, Advate, ReFacto, Eloctate, Nuwiq, Adynovate, Kovaltry, Jivi, and Xyntha. Human plasma-derived preparations include Monarc-M, Monoclate-P, Hemofil M, and Koate-DVI.
Individuals with mild or moderate hemophilia A may be treated with replacement therapy as needed (i.e., to treat specific bleeding episodes). This is referred to as ‘on demand’ therapy. Ideally, individuals with severe hemophilia A are treated prophylactically, meaning they receive periodic factor VIII infusions at regular intervals to prevent bleeding episodes and associated complications such as joint damage.
Parents and affected individuals can be trained to administer infusions at home. This is especially important for individuals with severe disease because infusion of factor VIII concentrate is most effective within one hour of the onset of a bleeding episode. In general, rapid treatment is important because it reduces pain and damage to the joints, muscle or other affected tissues or organs.
Some individuals with mild hemophilia A may be treated with desmopressin (DDAVP), a synthetic agent that is a derivative of the hormone vasopressin. Desmopressin raises the plasma levels of factor VIII. Desmopressin may be administered intravenously or through a nasal spray. Drugs known as antifibrinolytics, which slow the breakdown of clotting factors in the blood, can also be used to treat individuals with mild hemophilia A.
In some cases (approximately 30% of individuals with severe disease), people with hemophilia A may develop “inhibitors” against the replacement factor VIII. Inhibitors are antibodies, which are specialized proteins created by the body’s immune system to combat foreign or invading substances such as toxins or bacteria. The immune system may recognize replacement factor VIII as “foreign” and create these antibodies (inhibitors), which target and destroy the replacement factor. Inhibitor development can sometimes be accompanied by mild or serious allergic reactions. Inhibitors may also be known as alloantibodies. The reasons a person develops an inhibitor are complex, not fully understood and most likely due to a variety of both genetic and environmental factors. The risk of developing an inhibitor may change during an affected individual’s life. More research is necessary to determine the exact underlying mechanisms that ultimately cause inhibitor development in some individuals with hemophilia A.
An inhibitor can seriously “inhibit” the effectiveness of replacement clotting factors, placing the patient at risk of life-threatening bleeding events. In such cases, alternate treatment is used to prevent and/or treat bleeding and additional therapy to eradicate these antibodies is sometimes instituted (immune tolerance induction).
The amount of antibody (inhibitor) in an individual can be measured and is referred to as the titer. The inhibitor titer is expressed in a specific measurement called a Bethesda unit. The higher the number of Bethesda units, the more inhibitor that is present. An inhibitor can also be classified as low-responding or high-responding depending on how an individual’s immune system is stimulated based on repeated exposure to factor VIII. If the immune response is strong, inhibitor levels can rise to high levels. This is called high-responding. Alternatively, the immune system response can be weaker; this is classified as low-responding.
If the inhibitor titer is very low (i.e., < 5 Bethesda units) and low-responding, then bleeding episodes in affected individuals can often be treated with replacement factor VIII in higher doses. However, replacement factor VIII is not effective in individuals with a high inhibitor titer (i.e., > 5 Bethesda units).
In individuals with higher titer levels, bypassing agents (concentrates of other coagulation factors that bypass the step in the clotting cascade affected by the factor deficiency) are often used to control bleeding episodes. The bypassing agents that are presently available are recombinant activated factor VII or activated prothrombin complex concentrate. Neither of these therapies is effective in all individuals.
The U.S. Food and Drug Administration (FDA) has approved NovoSeven RT, a genetically engineered (recombinant) version of activated coagulation factor VII (factor VIIa), for the treatment of inhibitors in hemophilia A. Because it is artificially created in a lab, it does not contain human blood or plasma and, consequently, there is no risk of blood-borne viruses or other such pathogens. NovoSeven has been well-tolerated and associated with few side effects. Risk of thrombotic adverse effects (thrombosis) is below 1% for individuals with hemophilia.
In 2020, FDA approved Sevenfact (recombinant human coagulation factor VIIa expressed in the mammary gland of genetically engineered rabbits and secreted into the rabbits’ milk) for treatment and control of bleeding in adults and adolescents age 12 and older with hemophilia A or B with inhibitors (neutralizing antibodies).
Activated prothrombin complex concentrate (aPCC) is a plasma-derived, anti-inhibitor complex that contains various activated clotting factors. These factors allow the drug to bypass certain steps in the formation of blood clots (including the steps that require factor VIII). aPCC is treated to inactivate any potential viruses or similar pathogens and adverse thrombotic events are rare. The only form of aPCC currently available in the United States is FEIBA (Factor eight inhibitor bypassing activity).
In 2017, the first monoclonal antibody treatment for hemophilia A, Hemlibra (emicizumab-kxwh) was approved to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients who have developed inhibitors. Hemlibra is a bispecific monoclonal antibody that bridges activated coagulation factor 9 and 10 (FIX and FX) to replace the function of activated FVIII and thereby restore blood clotting.
While the aforementioned therapies treat bleeding episodes, some individuals with inhibitors may undergo a process known as immune tolerance induction. This type of therapy is designed to eradicate the inhibitor, allowing individuals to be treated with replacement factor VIII. Immune tolerance induction involves exposing an affected individual to high doses of replacement factor VIII over a period of time that can range from months to years. The process is designed to train the immune system to accept therapy with replacement factor VIII without producing more inhibitors. Drawbacks to immune tolerance induction are its very high cost, its inconvenience, and the fact that it is time-consuming. In addition, immune tolerance induction has only proven to be effective in eradicating inhibitors in approximately 70% of patients.
In 2023, a one time gene therapy called Roctavian was approved by the FDA to treat adults with severe hemophilia A who do not have pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test. Roctavian contains a viral vector carrying a normal F8 gene. The gene is expressed in the liver to increase blood levels of FVIII and reduce the risk of uncontrolled bleeding.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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