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Haemophilia C

Symptoms

Unlike individuals with Haemophilia A and B, patients affected by Haemophilia C are not ones to bleed spontaneously. In these cases, haemorrhages tend to happen after a major surgery or injury. However, people affected with Haemophilia C might experience symptoms closely related to those of other forms of haemophilia such as:

• Brusing.
• Nosebleeds.
• Traces of blood in the urine.
• Heavy menstrual bleeding in females.

The drug Cyklokapron is often used for both treatment after an incident of bleeding and as a preventative measure to avoid excessive bleeding during oral surgery.

Genetics

Factor XI

Visual representation of the structure of the Factor XI clotting protein.

The F11 gene is located on the long arm (denoted as the q arm) of chromosome 4, or 4q35. This gene encodes Factor XI, which is a blood protein necessary for proper blood clotting. When a harmful mutation is present in the gene, this causes the gene to be unable to produce functional Factor XI proteins. Generally, the amount of left over protein product directly correlates with the severity of Haemophilia C. However, due to environmental factors, the severity of the symptoms of Haemophilia C may differ between patients.

Inheritance

Haemophilia C is, most of the time, inherited as an autosomal recessive trait. However, because of the two-part structure of Factor XI, a mutation that causes one part of the protein to act antagonistically to the other may occur instead (see dominant-negative effect). This eventually leads to a dominant pattern of inheritance. 

Molecular Genetics

The F11 gene is 23kb in length and contains 15 exons. Most of the mutations recorded for this gene are missense or nonsense. There are two particularly common mutations: Glu117stop in exon 5, which means that a glutamate is substituted for a stop codon. This mutation results in early chain termination. The other common mutation is Phe283Leu in exon 9, which is phenylalanine substituted for a leucine. This causes a lack of ability to dimerize, leading to a monomer (single unit) of the protein within the cell. Since two units of the protein are required for proper functioning, individuals homozygous for the glutamine substitution mutation do not have Factor XI coagulation activity. On the other hand, those who are homozygous for the phenylalanine substitution mutation have little activity.

Diagnosis

In order to diagnose a patient suffering from Haemophilia C, health care workers obtain information about personal and family bleeding history. The family history and background will also help determine the patient’s ethnicity. Although Haemophilia C is found in all racial and ethnic groups, this information may give an indication of the probability of developing the disorder.

Partial Thromboplastin Time (APTT) and Factor XI activity assay are also common coagulation tests that are used to diagnose Haemophilia C after birth.

Epidemiology

Haemophilia C occurs in 1 in 100,000 Americans, with the highest Factor XI deficiencies in individuals of Jewish descent. These statistics indicate that while Haemophilia C is less common than Haemophilia A, it is found more frequently than Haemophilia B. Concerning gender and age, Haemophilia C equally affects males and females of every age. However, studies have found that normal newborns tend to have lower levels of Factor XI until they reach the age of 6 months. After this time, their Factor XI levels are comparable to that of a normal adult and will likely not develop the disease.