Hemophilia A
by: Julian Raffoul

Hemophilia A is an X-linked recessive, hereditary blood clotting disorder, that affects approximately 20,000 Americans (Hoyer, 1994). Because of its genetic makeup, hemophilia A is carried by females, but those affected are almost always males. There is no cure; people with hemophilia require lifelong treatment. Contrary to popular belief, people with hemophilia do not bleed to death from minor cuts or injuries, nor do they bleed faster than what is considered normal. People with hemophilia bleed longer, because their blood cannot develop a firm clot. Often bleeding is internal, into joints, and results in arthritis or crippling.

In some cases hemophilia A is ìhiddenî for many generations if no affected male children are born. The gene for hemophilia in such cases is carried through several generations of females who, because they have a second X chromosome that is normal, do not suffer from the disease themselves. Other cases may have no family history, meaning that the change in the X chromosome is a new one. This would be a mutation of the gene. Most mothers of children with hemophilia, however, have fathers, grandfathers, brothers, or other male relatives on the maternal side of their families who were born with hemophilia. Very rarely, a female with hemophilia is born if her mother is a carrier and her father has hemophilia.

It is important to realize that hemophilia A is a clinically heterogeneous disorder. This is expected because of the large number of different molecular defects in the factor VIII gene. It is also important to distinguish patients with severe hemophilia A, whose plasma has no detectable factor VIII, from patients who have moderate (1 to 4 percent of the normal factor VIII level) or mild (5 to 25 percent of the normal level) hemophilia. The distinction of severe disease from disease that is not is relevant since mild or moderate hemophilia A is rarely complicated by episodes of apparently unprovoked bleeding (Hoyer, 1994). The level of coagulation factors present in a patientís plasma aids in clinical determination of the severity of the disease.

Blood coagulation normally proceeds through a series of sequential enzymatic reactions in which protein cofactors (i.e. factor VIII) have an essential role (Hoyer, 1994). A very low concentration of factor VIII (0.2 micrograms per milliliter of plasma) ensures adequate coagulant function in normal persons; a substantial (>80 percent) reduction in or absence of the factor leads to a bleeding disorder (Hoyer, 1994).

A person with hemophilia A has either an inactive or inadequate supply of the factor VIII protein which is needed for blood to clot normally. Sequences within intron 22 of the factor VIII gene have been implicated in the cause of hemophilia in almost 50 percent of severely affected patients (Goodeve et al., 1994). The changes result from intrachromosomal rearrangements of the tip of the long arm of the X chromosome, one break-point being within the intron 22 of the factor VIII gene (Goodeve et al., 1994).

Carrier detection and prenatal diagnosis are important aspects of care in hemophilia A and are based on intragenic or extragenic polymorphism factor VIII gene tracking or by detection of the causative mutation in potential carriers or in the unborn male at risk (Peake et al., 1993). The size and complexity of the factor VIII gene makes comprehensive analysis difficult. The gene is located at the tip of the long arm of the X chromosome. It compromises nearly 186 kilobases (kb) and constitutes nearly 0.1 percent of the X chromosome. The coding DNA is distributed in 26 exons, approximately 9 kb in all (Hoyer, 1994). The techniques used to analyze the complete coding region of the factor VIII gene come from genomic DNA and are used to detect mutations in the gene.

The molecular characterization of mutations in hemophilia A can be carried out by using PCR-SSCP, Southern blotting, and reverse transcribed-PCR (Pieneman, 1995). A multiplex PCR in which four to eight exons are co-amplified is used to reduce the time needed for screening the coding region of the factor VIII gene. PCR-SSCP is used to screen small molecular defects, and reverse transcriptase PCR combined with Southern blotting is used to screen DNA for the inversions that occur frequently in intron 22 of the factor VIII gene. These methods of detection assist in identifying deletions or insertions that result in a frameshift in the coding DNA sequence, inversions that are a result in a disruption of the gene, and ultimately elucidating an abnormality in the factor VIII gene in the patient being tested (Pieneman, 1995).

Current products used to treat hemophilia are either manufactured from fresh frozen plasma and cryoprecipitate, which are from single blood donors and require special freezing, or are ìfreeze driedî factor VIII concentrates. These concentrates are made in large lots, come in small bottles and may be kept at room temperature or in the regular refrigerator allowing for a patient to use this method of treatment at home. Although this type of treatment may prove effective, it may also prove harmful. The possibility of viral transmission by plasma-derived products has spurred efforts to produce factor VIII by recombinant DNA technology. Following pre-clinical evaluations, clinical trials demonstrated that factor VIII produced by recombinant technology has no immediate side effects, is comparable to plasma-derived factor VIII in its recovery and half-life characteristics, and is effective in treating bleeding episodes (White et al., 1989). Ongoing clinical studies are monitoring patients receiving factor VIII for increasingly long periods and special attention is being placed on the possibility that these products might cause a higher incidence of antibodies to factor VIII than do plasma-derived factor VIII concentrates (Lusher et al., 1993).

Recombinant blood coagulant factor VIII appears to be an effective, well- tolerated treatment for patients with hemophilia A. Use of plasma-derived clotting factor in hemophiliacs risks the transmission of blood-borne viral diseases such as hepatitis B, hepatitis C, HIV, or any other viruses that could be present in human plasma (Lusher et al., 1993). Recombinant DNA-derived clotting factor, however, contains no virus and is thus potentially advantageous to hemophiliacs. Another advantage of recombinant factor VIII would be the unlimited supply, however, the cost may be prohibitive.

Regardless of the risk involved, if any, in the treatment of hemophilia A, not treating can be very painful and may lead to other serious medical complications. Physicians caring for patients with hemophilia A recognize that improved care is increasingly available. Factor VIII concentrates, effectively treated to inactivate viruses, can prevent or control bleeding in most patients, comprehensive care programs make available the range of necessary resources, and the availability of recombinant factor VIII will free patients from the possibility of infection by human-derived viruses. Recombinant factor VIII will not cure the disease, however, and inhibitor formation will be an ongoing concern. Moreover, this potential will only be reached if cost issues are addressed so that concentrates can be used as medically indicated and access to care is broadened to include all patients with hemophilia.


Goodeve AC, Preston FE, Oeake IR (1994). Factor VIII gene rearrangements in patients with severe hemophilia A. The Lancet . v 343. p329 (2).

Hoyer LW (1994). Hemophilia A (review article). N Engl J Med. v 330. p38 (10).

Hughes-Jones NC (1995). Risk Assessment and factor VIII concentrates. The Lancet. v 345. p 502 (2).

Klug WS & Cummings MR (1994). Concepts of Genetics. NewJersey Prentice-Hall.

Lusher JM, Arkin S, Abilgaard CF, and Schwartz RS (1993). Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A: safety, efficacy, and development of inhibitors. N Engl J Med. v 328. p453 (7).

Pieneman WC (1995). Screening for mutations in hemophilia A patients by multiplex PCR-SSCP, Southern blotting and RNA analysis: the detection of a genetic abnormality in the factor VIII gene in 30 out of 35 patients. Br J Haematol. v 90. p442 (8).

White GC, McMillan CW, Kingdon HS, and Shoemaker CB (1989). Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia. N Eng J Med. v 320. p166 (4).

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