Hemophilia | Research & Encyclopedia Articles

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Haemophilia Summary

Hemophilia

Hemophilia A and hemophilia B are genetic disorders in the blood-clotting system, characterized by bleeding into joints and soft tissues, and by excessive bleeding into any site experiencing trauma or undergoing surgery. Hemophilia A and B are clinically indistinguishable. Both have the same type of bleeding manifestations, and both affect males almost exclusively.

The coagulation cascade involves multistep conversion of several factors into their active (A) forms. In hemophilia, factors VIII or IX are missing or present in insufficient amounts.

The two conditions can be distinguished by detecting the responsible defective proteins.

Contrary to popular belief, individuals with hemophilia rarely bleed excessively from minor cuts or scratches. Hemophilia A and B are both worldwide in distribution, affecting all racial and ethnic groups. The prevalence of hemophilia A is approximately 1 in 10,000 males, and that of hemophilia B is 1 in 30,000 males.

The disorder was recognized (although not named) in Babylonian times. A second-century Jewish rabbi gave permission for a woman not to have her third son circumcised after her first two sons died from the procedure. No doubt the most famous carrier of hemophilia was the nineteenth-century Queen Victoria, whose son, Prince Leopold, had the disorder, and whose two daughters inherited and passed on the gene. Ultimately several of the European royal families were affected by Queen Victoria's gene.

There are a number of clotting factors that interact to form a stable blood clot following injury or surgery. Each factor has a name and is produced in certain cells (usually in the liver), encoded by a certain gene. Hemophilia is caused by a defect in one of these genes. In the case of hemophilia A, factor VIII (FVIII) is deficient or absent. In hemophilia B, FIX is deficient in amount or absent, or it does not function properly.

The genes encoding FVIII and FIX are on the long arm of the X chromosome. Because males have only one X chromosome, hemophilia A and hemophilia B affect males almost exclusively. If a boy's X chromosome has the defective gene that causes hemophilia A or B, the boy will have hemophilia.

Since boys with hemophilia have only an X chromosome carrying the defective gene that causes hemophilia A or B, and no gene for the production of normal FVIII (or FIX), and since fathers pass an X chromosome on to their daughters, all of their daughters will be "obligate carriers" for hemophilia.Obligate carriers—individuals who are definitely carriers—include daughters of men with hemophilia and women who have a maternal family history of hemophilia and one or more affected sons or grandsons.

In general, such carrier females do not bleed excessively, as their other X chromosome, with a gene for normal FVIII (or FIX) production, results in intermediate levels of FVIII (or FIX). However, carrier females have a fifty-fifty chance of passing their X chromosome that bears the hemophilia gene to each child they might have. A son would have an equal chance of being normal or having hemophilia. A girl would have an equal chance of being normal or being a carrier, like her mother.

Gene Defects Causing Hemophilia

Hundreds of defects in the FVIII gene have been shown to cause hemophilia A. These include deletions of varying sizes in the gene, stop codons, frameshift mutations, and point mutations. Inversion of the gene is the most common mutation. The same types of defects are found in the FIX gene. This makes population screening for hemophilia impractical: There are too many possible mutations to screen for. However, affected members of a given family will all have the same defect.

It is useful to determine (by gene analysis) which defect is present in the FVIII or FIX gene of a particular family with hemophilia, so that one can look for this defect in possible carrier females. Identification of carrier females permits genetic counseling and decision making, on the part of parents, regarding childbearing.

Detection of Fviii or Fix Gene Defect in Family: Carrier Detection

A number of different techniques are available for carrier detection. Linkage analysis using DNA polymorphisms to track defective FVIII or FIX genes is possible in large families. Use of intragenic polymorphisms in both the FVIII and FIX genes allows precise detection of carrier females in most families studied. In persons with hemophilia A, the FVIII gene inversion can be tested for by Southern blotting.

If the gene defect in the family is not known, the inversion mutation in an affected male is generally sought first, as this mutation accounts for at least 20 percent of all cases of hemophilia A, and the test is relatively simple to perform. Although more time-consuming, point-mutation screening also can be done, using a variety of methods. For researchers working on the FVIII or FIX genes, there are sites on the Internet that are valuable resources, as they contain regularly updated listings of all reported mutations in each of these genes, and other useful information.

Because of a high mutation rate, approximately one-third of infants found to have hemophilia A or B have no family history of the disorder, the condition having occurred spontaneously. However, hemophilia is genetically transmitted to future generations.

Differences in Severity of Hemophilia

There are different degrees of severity of hemophilia A and B. Clinical severity usually correlates with the individual's circulating FVIII or FIX level(determined by doing an FVIII or FIX assay on a venous blood sample). The severity is generally the same in all affected members of a family.

Normal values for FVIII and FIX can range between 50 and 150 percent of the mean value, while severely affected individuals generally have levels of less than or equal to 1 percent, moderately affected persons 1 to 5 percent, and mildly affected persons 5 to 35 percent. Severely affected individuals often have spontaneous joint and muscle hemorrhages, whereas mildly affected persons bleed only with trauma or surgery.

Pedigree of hemophilia in the royal families of Europe. Queen Victoria was a carrier of this X-linked trait. Her son Leopold in herited the X chromosome that carried it, while her son Edward VII did not. Adapted from http://ublib.buffalo.edu/libraries/projects/cases/hemo.htm.

Treatment

Treatment for bleeding episodes consists of replacing the missing clotting factor by intravenous infusion of FVIII (or FIX). There are both human plasma-derived FVIII and FIX concentrates and recombinant DNA-derived FVIII and FIX concentrates. The useful life for both proteins (FVIII and FIX) once infused is relatively short (on average, half is degraded within twelve hours for FVIII and within eighteen hours for FIX). Thus for serious bleeding episodes or surgery, frequent repeat dosing (or continuous infusion) is often necessary.

Prophylaxis is also used, particularly in persons with severe hemophilia A or B. This consists of giving FVIII three times weekly, and FIX twice weekly (in view of its longer half-life, once infused). The aim of prophylaxis (which is often begun between age one and three) is to prevent joint bleeding (and the resulting increase in joint destruction and disability).

Persons with mild hemophilia A can often be treated with the synthetic agent DDAVP (1-deamino-8-D-arginine vasopressin). This analogue of the naturally occurring antidiuretic hormone vasopressin results in a rapid release of whatever FVIII (and another large plasma glycoprotein, von Willebrand factor) is in the individual's body storage sites. Thus, following intravenously administered DDAVP, FVIII (and von Willebrand factor) increase (two-to tenfold), but then fall back to baseline within approximately twelve to fifteen hours. This drug comes in several formulations, for intravenous, subcutaneous, and intranasal use.

It is hoped that gene therapy for persons with severe hemophilia may eventually become a realistic option. In early 2002 there were several ongoing phase-one trials (very early research studies) in human subjects with severe hemophilia, using different vectors and different techniques. However, formidable challenges remain.

One form of hemophilia is due to the insertion of a transposable genetic element. (DNA sequence that can be copied and moved in the genome).