The term "hemophilia" refers to the following two disorders:
Hemophilia A and B are X-linked recessive diseases. They exhibit a range of clinical severity that correlates well with assayed factor levels. Severe disease is defined as <1 percent factor activity, whereas 1 to 5 percent and >5 percent of normal are defined as moderate and mild disease, respectively. Males within a family have the same level of deficiency because they share the same genetic defect.
The combined incidence of hemophilia A and B is 1 in 5,000 live male births. Approximately 80 percent have hemophilia A, two-thirds of whom have severe disease. Bleeding may occur anywhere in patients with hemophilia. The most common sites are into joints and muscles and from the gastrointestinal tract. Approximately 80 percent of hemorrhage occurs in the joints; the ankles are most commonly affected in children, and the knees, elbows, and ankles in adolescents and adults. Spontaneous hemarthroses are so characteristic of severe hemophilia as to be almost diagnostic. This pattern is different from the mucosal and cutaneous bleeding characteristic of platelet dysfunction or von Willebrand disease. Mucosal bleeding may manifest as epistaxis and gingival bleeding, and bullous hemorrhages may appear on the buccal mucosa.
REPLACEMENT THERAPY: Clotting factor concentrates are given to prevent bleeding and to limit existing hemorrhage. The current standard of therapy is to use factor concentrates. Recombinant factor VIII products are purified from the cell culture of transfected hamster-derived cell lines and require no further viral attenuation. Human derived factor concentrate subjected to viral inactivation also available and has not been associated with transmission of HIV, HCV, and HBV. Inhibitor development in previously untransfused patients has averaged approximately 25 to 30 percent. Many of the inhibitors in these patients are transient or responsive to immune tolerance induction. The two other therapeutic options in addition to factor replacement are desmopressin and antifibrinolytic agents.
DOSING: Early treatment of bleeding episodes with appropriate dosing decreases the duration of required therapy and the predisposition to rebleeding, and improves the quality of life. One unit of clotting factor is that amount present in 1 mL of pooled normal plasma. An individual with a plasma volume of 3000 mL would have 3000 units of clotting factor in his or her circulation. Thus, a dose of 3000 U of factor VIII would be required to raise the plasma level to normal in a patient with severe disease and baseline levels of less than 1 percent of the normal concentration of factor VIII.
The number of units required is calculated from the body weight (kg), the volume of distribution, and the desired factor level. The volume of distribution for factor VIII is approximately 0.5. Initial doses are calculated using the following formula:
The desired factor level is a function of severity and location of the bleeding episode. Early joint or muscle bleeding episodes are treated to achieve factor levels of 30 to 40 percent. The usual hemarthrosis typically responds to a single injection if treated early. Patients with more severe muscle hematomas and those undergoing dental surgery usually are treated to achieve levels of 50 percent. Severe or potentially serious episodes such as intracranial or intraabdominal hemorrhage or bleeding in areas such as the face, neck, and hip require correction to 80 to 100 percent for longer periods of time, usually until the hemorrhage has resolved. Most orthopedic surgery can be managed with initial levels of 80 to 100 percent followed in a few days by minimum levels of at least 30 percent; an exception occurs at times of wound or joint manipulation when a level of at least 50 percent is necessary. To achieve hemostasis for major surgical procedures, an initial level of 60 to 100 percent is achieved. This level is followed by a prophylactic level of 30 to 50 percent until the wound is healed, typically 10 to 14 days.
Factor levels should be checked to ensure the effectiveness of the calculated dose. The half-life of recombinant human factor VIII is approximately 8 to 12 hours. For this reason, doses are repeated on a 12-hour basis and assays are performed near the end of the 12-hour period.
Concentrates also can be given by continuous infusion. A continuous infusion of factor VIII concentrate at a dose of 2 to 4 U/kg per hour will often maintain the level initially achieved by bolus infusion. This method offers the advantage of consistent levels, less frequent monitoring, and decreased factor utilization. Patients undergoing major surgery or those with major hemorrhage at risk of rebleed may benefit from continuous therapy.
Prophylactic therapy - The regular administration of replacement therapy with the object of reducing spontaneous bleeding is a theoretically logical approach to the treatment of severe hemophilia. The goal of such an approach is to maintain the factor VIII or IX level above 1 percent, which should convert the patient to a moderate phenotype. This level can be achieved by factor concentrate administration two to three times per week. Patients who started prophylaxis soon after the first joint bleed showed little arthropathy in adulthood, whereas the longer the start of prophylaxis was postponed, the higher was the risk of developing arthropathy. Treatment of all patients may result in unnecessary treatment for a subset of patients that would ultimately have fewer musculoskeletal complications with on-demand therapy.
Contributed by Franklin Sedarat MD MSc, Lirong Qu MD PhD, Darrell J. Triulzi MD