Haemophilia A is a genetic disorder characterised by defficiency of Factor VIII in the blood. The factor VIII gene is located on the X chromosome . Thus this disorder is a sex linked disorder.
- One in 10,000 males is born with deficiency or dysfunction of the factor VIII molecule.
- Although normal hemostasis requires at least 25 percent factor VIII activity, symptomatic patients usually have factor VIII levels below 5 percent.
- Patients with <1 percent factor VIII activity have severe disease.
- Patients with levels between 1 and 5 percent have moderatedisease with less frequent bleeding episodes.
- Those with levels over 5 percent have mild disease with infrequent bleeding that is usually secondary to trauma.
- Occasional patients with factor VIII levels as high as 25 percent are discovered when they bleed after major trauma or surgery.
- The majority of patients with Haemophilia A have factor VIII below 5 %
- All daughters of haemophilics are carriers and sisters have a 50 % chance of being a carrier.
- If a carrier has a son he has 50 % chance of having haemophilia, and a daughter has 50 % chance of of being a carrier.
- Haemophilia ‘breeds true’ within a family. All members of a family will have same abnormality of factor VIII gene, i.e. if one member has severe form of the disease all other affected would have severe form of the disease.
- In carrriers of this disease, Ratio of factor VIIIC : von Willibrand factor (vWF) is reduced compared to the normal.
- Tracing of the haemophilia gene within families can be done using gene probes which detect restriction fragment length polymorphism (RFLPs).
- Antenatal diagnosis can be done in females having high degree of probability of being a carrier. This is done by doing chorion villus sampling at 8-9 weeks of gestation.
Hemophilia B is similar to Hemophilia A. Both are abnormality of blood coagulation. Hemophilia B is caused by the deficiency of Factor IX. It is also known as Christmas disease. It occurs in 1 in 100,000 male births. It has to be diagnosed accurately because clinically it is indistinguishable from factor VIII deficiency – Hemophilia A.
Factor IX is one of a group of six proteins synthesized in the liver that require vitamin K for biologic activity.
Treatment of Haemophilia A
Plasma products enriched in factor VIII have revolutionized the care of hemophilia patients, reduced the degree of orthopedic deformity, and permitted virtually any form of elective and emergency surgery. Now this mode of treatment is being widely used.
The widespread use of factor VIII concentrates also has produced some serious complications, including viral hepatitis, chronic liver disease, and AIDS.
Cryoprecipitate, which contains about half the factor VIII activity of fresh frozen plasma in one-tenth the original volume, is simple to prepare and is produced in hospital or regional blood banks. It must be stored frozen and is thawed and pooled before administration. Partially purified factor VIII concentrate, which is prepared from multiple donors and supplied as a lyophilized powder, can be refrigerated and reconstituted just before use.
There had been immense problem with the safety of these products. Three major developments have increased the safety of factor VIII therapy. First, heating of lyophilized factor VIII concentrates under carefully controlled conditions can inactivate human immunodeficiency virus (HIV) without destroying factor VIII coagulant activity. Second, highly purified factor VIII can be produced by adsorbing and eluting factor VIII from monoclonal antibody columns. Third, recombinant factor VIII is now available.
Patients with hemophilia should receive either monoclonal purified or recombinant factor VIII to minimize viral infections and other complications.
It has been determined empirically that each unit of factor VIII infused, defined as the amount present in 1 ml normal plasma, will raise the plasma level of the recipient by 2 percent per kilogram of body weight. Factor VIII has a half-life of 8 to 12 h, making it necessary to infuse it continuously or at least twice daily to sustain a chosen factor VIII level. In patients with mild hemophilia, an alternative to the use of plasma products is desmopressin (DDAVP), which transiently increases the factor VIII level. Desmopressin, in general, will increase the factor level two- to threefold. Although generally safe, it occasionally causes hyponatremia or may precipitate thrombosis in elderly patients.
- An uncomplicated episode of soft tissue bleeding or an early bleeding into a joint can be treated with one infusion of sufficient factor VIII concentrate to raise the factor VIII level to 15 or 20 percent. A more extensive bleeding requires twice-daily or continuous infusions in order to keep the factor VIII level between 25 and 50 percent for at least 72 h. Life-threatening bleeding into the central nervous system or major surgery may require therapy for 2 weeks with levels kept at a minimum of 50 percent of normal.
- Patients with joint involvement also need skilled orthopedic care with immobilization of inflamed joints to promote healing and to prevent contractures and physical therapy to strengthen muscles and maintain joint mobility.
- Hemophiliacs also require treatment before dental procedures. Filling of a carious tooth can be managed by a single infusion of cryoprecipitate or factor VIII concentrate coupled with the administration of 4 to 6 g of e-aminocaproic acid (EACA) four times daily for 72 to 96 h after the dental procedure. EACA is a potent antifibrinolytic agent that will inhibit plasminogen activators present in oral secretions and stabilize clot formation in oral tissue.
Most hemophiliac patients have had multiple episodes of hepatitis, and a majority have elevated hepatocellular enzyme levels and abnormalities on liver biopsy. Between 10 and 20 percent of patients also have hepatosplenomegaly, and a small number develop chronic active or persistent hepatitis or cirrhosis. A few patients with hemophilia have received liver transplants with cure of both diseases.
Following multiple transfusions, between 10 and 20 percent of patients with severe hemophilia develop inhibitors to factor VIII. Inhibitors are, generally, IgG antibodies that rapidly neutralize factor VIII activity. Before surgery, every patient should be screened for the presence of an inhibitor to factor VIII.
Female carriers of hemophilia, who are heterozygotes, usually produce sufficient factor VIII from the factor VIII allele on their normal X chromosome for normal hemostasis. However, occasional hemophilia carriers will have factor VIII levels far below 50 percent due to random inactivation of normal X chromosomes in tissue producing factor VIII. These symptomatic carriers may bleed with major surgery or bleed occasionally with menses. Rarely, true female hemophiliacs arise from consanguinity within families with hemophilia or from concomitant Turner’s syndrome or XO mosaicism in a carrier female.