Haemophilia- Introduction, Types, Pathophysiology, Diagnostics, Treatment

Introduction:

Haemophilia is a rare hereditary condition that inhibits the capacity of the blood to clot normally. It is caused by a lack of particular proteins known as coagulation factors, which are required for blood to clot. Haemophilia patients may endure prolonged bleeding following an injury, surgery, or dental procedure, as well as spontaneous bleeding into joints or muscles.

Fig: Haemophilia

Types:

Prevalence:

Haemophilia prevalence varies by type and area. Hemophilia A is more prevalent than hemophilia B, accounting for roughly 80% of all cases. Hemophilia A affects roughly 1 in 5,000 males in the general population, while hemophilia B affects about 1 in 25,000 males.

The prevalence of hemophilia, on the other hand, varies substantially by geographic region and ethnic group. In some populations, such as Ashkenazi Jews, the prevalence of hemophilia A might reach 1 in 100 males. Because of greater rates of untreated cases in developing nations with limited access to treatment, the prevalence of hemophilia may be higher.

Generally, hemophilia is a very infrequent disorder that affects a relatively small number of people. It can, however, have a significant impact on the health and quality of life of people affected, and proper treatment and management are essential for optimal outcomes.

Causes:

Hemophilia is a genetic disorder that affects the body’s ability to control bleeding. It is caused by a deficiency or absence of certain proteins in the blood that are needed for blood clotting. Here are some of the main causes of hemophilia:

Genetic mutation

Hemophilia is caused by a mutation in one of two genes, F8 and F9, which produce clotting factors VIII and IX, respectively. The F8 and F9 genes are located on the X chromosome. The F8 gene is located on the long (q) arm of the X chromosome at position 28, and the F9 gene is located on the long (q) arm of the X chromosome at position 27.

A mutation in the F8 gene, which codes for clotting factor VIII, causes hemophilia A. The severity of the illness is determined by the type and location of the mutation in the F8 gene. In certain situations, the mutation entirely prohibits the generation of clotting factor VIII, whereas in others, the protein production is diminished.

A mutation in the F9 gene, which codes for clotting factor IX, causes hemophilia B. Similarly, with Hemophilia A, the severity of Hemophilia B is determined by the kind and location of the mutation in the F9 gene.

Inheritance

Hemophilia is a hereditary illness, which means that it is passed along through the DNA of parents to their children. If one parent has hemophilia, their children have a 50% risk of inheriting it. Hemophilia is an X-linked recessive condition, meaning that the defective gene lies on the X chromosome. Males are more likely to be affected with hemophilia than females since males have only one X chromosome and females have two. Females can have the mutant gene and pass it on to their children, but they are rarely afflicted by the illness.

Fig: X -linked recessive inheritance

Spontaneous mutation

Spontaneous mutations are uncommon, occurring in around one-third of cases of hemophilia A and one-fifth of cases of hemophilia B. In these circumstances, the affected person is usually the only member of their family who has hemophilia, and no family history of the disorder exists.

Even though there is no family history of the disorder, hemophilia can occur in rare cases due to a spontaneous mutation in the F8 or F9 gene during fetal development. They are known as “sporadic” or “non-inherited” hemophilia instances.

Acquired hemophilia

Acquired hemophilia is a rare and serious bleeding illness caused by the immune system attacking blood clotting factors. This causes a lack of clotting factors, which can result in uncontrollable bleeding. Unlike genetic hemophilia, acquired hemophilia develops later in life and is not present at birth.

Liver disease

Liver disease can potentially influence clotting factor levels in the blood, worsening hemophilia symptoms. For example, persons with liver disease may have less clotting factor production, which might increase haemophilia’s bleeding symptoms.

Vitamin K deficiency

Vitamin K is a necessary component that promotes in blood coagulation. Without enough vitamin K, the body is unable to manufacture specific clotting factors required for healthy blood coagulation, such as factors II, VII, IX, and X. A lack of vitamin K can result in bleeding diseases such as hemophilia.

It is crucial to remember, however, that a vitamin K deficit alone cannot cause hemophilia. Hemophilia is a hereditary condition caused by a lack of particular clotting factors, primarily factor VIII (hemophilia A) or factor IX (hemophilia B).

Pathophysiology:

Hemophilia is a hereditary condition caused by abnormalities in the genes responsible for the production of clotting factors, specifically factor VIII (hemophilia A) or factor IX (hemophilia B). These clotting factors are required for normal clotting, which is a complicated set of processes involving many clotting factors, platelets, and blood arteries. When a blood vessel is injured, a chain of events occurs that finally leads to the creation of a blood clot to halt the bleeding. The deficit or lack of clotting factors in persons with hemophilia disturbs this process, resulting in bleeding symptoms that can range from moderate to severe depending on the severity of the deficiency.

Fig: Pathophysiology of Hemophilia

The level of clotting factor in the blood determines the severity of hemophilia, with patients with less than 1% of normal clotting factor levels described as having severe hemophilia. This can result in life-threatening spontaneous bleeding events, as well as long-term joint damage from repeated bleeding episodes. Generally, hemophilia pathophysiology involves a disturbance in the normal clotting process caused by a deficiency or lack of particular clotting factors, which can result in bleeding symptoms and long-term problems.

Signs and symptoms:

The signs and symptoms of hemophilia can vary depending on the severity of the deficiency in clotting factors. In general, people with hemophilia may experience the following:

Unexplained or excessive bleeding: This can occur after an injury, surgery, or dental work. In severe cases, spontaneous bleeding episodes can also occur.

Bruising easily: People with hemophilia may experience bruises that are larger than usual or occur without an obvious cause.

Prolonged bleeding: Bleeding may continue for a longer period of time than usual, and it may take longer for bleeding to stop.

Joint pain and swelling: Repeated bleeding episodes in the joints can lead to long-term joint damage, causing pain, swelling, and stiffness.

Blood in urine or stool: In severe cases, bleeding may occur in the urinary or gastrointestinal tract, leading to blood in the urine or stool.

Headaches or neurological symptoms: Bleeding in the brain can cause headaches, seizures, and other neurological symptoms.

It’s important to note that the severity of symptoms can vary widely, even among people with the same type of hemophilia. Some people with mild hemophilia may only experience bleeding symptoms in response to trauma or surgery, while those with severe hemophilia may experience spontaneous bleeding episodes that can be life-threatening. If you suspect you or a loved one has hemophilia, it’s important to seek medical attention for proper diagnosis and treatment.

Diagnosis:

The clinical diagnosis of hemophilia is based on a combination of medical history, physical examination, and laboratory tests. Here are some of the steps involved in the clinical diagnosis of hemophilia:

Medical history: Your doctor will ask about your personal and family medical history, including any bleeding symptoms you or your family members have experienced.

Physical examination: Your doctor will examine you for signs of bleeding or bruising, as well as any joint damage that may have occurred as a result of repeated bleeding episodes.

Laboratory tests: Laboratory tests are used to measure the levels of clotting factors in the blood. The most common tests are the activated partial thromboplastin time (aPTT) and the prothrombin time (PT). If the results of these tests are abnormal, additional tests may be done to determine the specific clotting factor deficiency.

Factor assay: Factor assays are used to measure the levels of specific clotting factors in the blood. This test can help identify the type and severity of hemophilia.

Genetic testing: There are various forms of genetic tests that can be used to diagnose and treat hemophilia. One popular strategy is to analyse the DNA sequence of the F8 or F9 genes to find mutations or variations linked with hemophilia. Another method is deletion/duplication analysis, which searches for large-scale alterations in the DNA sequence that can lead to hemophilia. Another sort of genetic testing is linkage analysis, which can be used to track the inheritance of genetic markers in families with a known history of hemophilia. Furthermore, prenatal testing can be done during pregnancy to identify if a fetus has hemophilia.

PCR testing amplifies specific segments of DNA, allowing for the detection of mutations or variants in the F8 or F9 genes that are associated with hemophilia.

Finally, carrier testing can be performed on those who have a family history of hemophilia but do not have symptoms. Individuals and families impacted by hemophilia can benefit from several forms of genetic testing to confirm a diagnosis, identify carriers, and guide treatment options and genetic counseling.

Prenatal Testing: Prenatal testing for hemophilia can be done in a variety of ways, including chorionic villus sampling (CVS) and amniocentesis. CVS entails collecting a tiny sample of placental tissue, which contains fetal cells with DNA that may be examined for mutations in the F8 or F9 genes. This test is often administered between 10 and 12 weeks of pregnancy. Amniocentesis is the procedure of collecting a sample of the amniotic fluid that surrounds the fetus in the pregnancy. Mutations in the F8 or F9 genes can be detected in fetal cells in amniotic fluid. This test is often administered between 15 and 20 weeks of pregnancy.

Treatments:

The most frequent treatment for hemophilia is replacement therapy, which involves injecting the missing clotting factor into the patient’s bloodstream.

Desmopressin, a synthetic version of vasopressin, a natural antidiuretic hormone, is a drug that increases the release of coagulation factors, can be used to treat people with moderate hemophilia.

Gene therapy is a promising treatment that involves delivering a normal copy of the clotting factor gene to the patient’s liver cells.

Antifibrinolytic medicines can be used to prevent the breaking of blood clots.

Physical therapy and surgery may also be utilized to prevent joint injury and heal damage caused by bleeding.

Individuals with hemophilia should collaborate with their healthcare team to design an individualized treatment strategy based on the severity of their condition and their lifestyle.

Recent Advances in the Treatment of Haemophilia:

Current breakthroughs in the treatment of hemophilia include gene therapy, longer half-life factor replacement medicines, non-factor therapeutics, customized treatment, and comprehensive care models. Gene therapy includes inserting a functioning copy of the missing clotting factor gene into the patient’s cells, offering a long-term cure for haemophilia. Longer half-life factor replacement therapies allow for less frequent infusions, lowering the therapeutic burden on patients. Non-factor therapies are being explored as alternate therapy choices, providing a more tailored approach to treatment. Customized treatment approaches that take an individual’s unique genetic composition into consideration are becoming increasingly widespread, improving patient results. Holistic care approaches that incorporate education, psychological support, and social services are being created to provide a more holistic approach to haemophilia management.

References:

• Tkacs, N. C., Herrmann, L. L., & Johnson, R. L. (2020). Advanced physiology and pathophysiology: Essentials for clinical practice. Springer Publishing.
• U.S. National Library of Medicine. (2020, August 18). Hemophilia: Medlineplus Genetics. MedlinePlus.
• Okaygoun, D., Oliveira, D.D., Soman, S. et al. Advances in the management of haemophilia: emerging treatments and their mechanisms. J Biomed Sci 28, 64 (2021).
• Marchesini E, Morfini M, Valentino L. Recent Advances in the Treatment of Hemophilia: A Review. Biologics. 2021 Jun 15; 15:221-235.