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Hemophilia A is a bleeding disorder caused by factor VIII deficiency and is the third most common X-linked genetic disorder. Approximately 1 in 5000 male births are affected. Typical laboratory findings include prolonged aPTT, normal protime and normal fibrinogen. The prolonged aPTT is due to Factor VIII deficiency. Factor VIII concentrate is the preferred treatment for patients with hemophilia A. Factor VIII concentrates are either purified from large pools of plasma collected from paid or volunteer donors or synthesized in vitro by recombinant DNA techniques. Improved donor screening and viral depletion processes have resulted in plasma derived Factor VIII concentrates with greatly reduced risk for viral transmission compared to older methods. Three methods of viral inactivation are used in the United States including:
Recombinant Factor VIII (rFVIII) is produced in hamster cell lines that have been transfected with a human Factor VIII gene. Recombinant factor VIII concentrates are considered safer than plasma derived concentrates because they are produced from large pools of human plasma. However, some investigators have expressed concern because they still use bovine or human serum albumin in the cell culture medium or have human serum albumin added as a stabilizer. In spite of these concerns, the risk of disease transmission by human or bovine albumin appears to be very small. Pasteurized human serum albumin has an excellent 50-year safety record. Bovine serum albumin is purchased from countries that are not endemic for bovine spongiform encephalopathy. None of the currently available recombinant Factor VIII concentrates has been reported to transmit any animal or human viruses or prions. Because of the concern of potential infections with bovine or human serum albumin, pharmaceutical companies have devised other ways of stabilizing recombinant factor VIII. The most recent products are stabilized with sucrose and only use pasteurized human serum albumin in the cell culture medium. A second-generation recombinant Factor VIII product (Refacto) has the B domain of the factor VIII gene deleted before insertion into hamster ovary cells. The resulting protein lacks the heavily glycosylated B domain, which is not needed for hemostasis. This modified protein is more easily secreted by hamster cells and less prone to proteolytic degradation. It does not prevent the formation of inhibitors to Factor VIII. In November 2001 the National Hemophilia Foundation made the following recommendation.
Factor VIII Concentrates
Some studies have suggested that lower purity products cause immune suppression. HIV infected patients receiving ultra-high purity concentrates have a slower rate of decline of CD4 lymphocyte counts than patients receiving lower purity products. Recombinant or affinity purified concentrates are preferable for HIV infected persons with hemophilia. Some data has suggested that patients with advanced liver disease do not respond as well clinically to ultra-high purity concentrates as they do to intermediate purity products containing vWF. Humate P, Alphanate SD or Koate DVI may be more effective for hemophiliac patients with liver disease. Assessing Hemophilia A Severity Factor VIII therapy is based on an assessment of the severity of hemophilia along with the source and extent of bleeding. Disease severity correlates with Factor VIII activity. Patients with severe hemophilia are at risk of spontaneous hemarthrosis and bleeding into soft tissues. Patients with moderate or mild hemophilia are at little risk of spontaneous hemorrhage, but may bleed excessively after trauma or surgery. Severity of Hemophilia A
Treatment Guidelines Desmopressin (DDAVP) results in a transient fourfold increase in plasma Factor VIII levels by stimulating the release of Factor VIII and von Willebrand's factor from storage sites. Most mild hemophiliacs with Factor VIII levels greater than 8% will respond to DDAVP. Therefore, it provides an alternative therapy for less severe hemorrhage in most patients with mild hemophilia A. DDAVP is administered intravenously at a dose of 0.3 ug/ kg of body weight in 30 to 50 mL of normal saline over 15 to 20 minutes. The peak effect occurs in 30 to 60 minutes. Repeat doses can be given at 12 to 24 hour intervals. Tachyphylaxis, a decreased observable response, may develop following 2-3 consecutive daily doses due to the depletion of storage sites. Hyponatremia induced seizures have been reported in infants and surgical patients treated with multiple doses of DDAVP. Fluid and electrolytes should be monitored closely. Patients with moderate or severe hemophilia A usually require treatment with Factor VIII concentrate. In general, plasma Factor VIII levels of 70 to 100% are required to treat serious hemorrhages, while plasma levels of 30 to 50% are required for less severe bleeding in individuals without factor VIII inhibitors.
Dosage Guidelines for Factor VIII Replacement
Hemarthrosis is the most common bleeding problem in hemophiliacs. Prompt treatment stops the bleeding and avoids long term complications. Older children and adults are able to detect early hemarthrosis, which is first evident as a paresthesia-like sensation in the joint. Factor VIII dose for treatment of early hemarthrosis is10 units/kg. Repeat doses are usually not required. Younger children may not appreciate early symptoms and present with a swollen, immobile painful joint. Treatment of late presenting hemarthrosis requires larger doses. Loading dose is 20 to 40 units/kg. This dose should be repeated every 12 hours to maintain the factor VIII level between 30 and 50%. Patients with hip and knee hemorrhages may require prolonged treatment to keep their Factor VIII level between 15 and 25% for several weeks. Lacerations in hemophiliacs usually do not require factor administration. Prolonged application of direct pressure to the wound is usually adequate. If direct pressure fails or a more serious laceration is incurred, then factor administration is helpful. A loading dose of 20 units/kg is given to raise plasma Factor VIII level to between 30 and 50%. Repeat administration is usually not necessary. DDAVP can sometimes be used for mild hemophiliacs. Subcutaneous hematomas are usually self-limited and do not require treatment. Intramuscular hemorrhage is usually associated with mechanical trauma and requires prompt treatment. Common sites include the extremities and iliopsoas muscles. Extremity intramuscular hemorrhage can be complicated by the development of compartment syndrome. Intramuscular hemorrhages require higher loading doses and a longer duration of treatment than hemarthrosis. Loading doses are 20-40 units/kg. The general goal is to obtain a Factor VIII level of 50%, but higher levels may be required with more extensive bleeds. Repeat doses of 20 units/kg should be given every 12 hours. Treatment should be continued for several days until the muscle group becomes soft and decreases in size. Spontaneous and painless hematuria can occur as a complication in hemophilia. Treatment is usually not required outside of ensuring adequate fluid intake. Normally, hematuria will resolve in two to three days. Some refractory cases may require factor administration. Hematuria resulting from trauma should be treated with Factor VIII concentrate. Hemorrhage in the neck region should also be treated promptly to avoid airway compression. This recommendation applies to any patient with pharyngitis or prolonged coughing whom complains of swelling in his neck. The initial dose is 50 units/kg in order to obtain a Factor VIII level close to 100%. The maintenance dose should be high enough to maintain the Factor VIII level above 70%. Intracranial hemorrhage is a life-threatening complication of hemophilia. Prior history of head trauma or physical evidence, such as scalp lacerations or abrasions, requires immediate factor infusion. Even mild cases of head trauma should receive prompt treatment. An initial dose of at least 50 units/kg should be given to raise the patient's factor VIII level to 100%. If follow up CT scan confirms intracranial hemorrhage, then a continuous intravenous infusion of factor VIII for 21 days is recommended. Continuous infusion is used to keep the patient's Factor VIII level above70% at all times. Hemophiliac patients who have suffered an intracranial bleed are at high risk of developing a subsequent hemorrhage. These patients require prophylactic Factor VIII concentrate every other day for 6 months. Gastrointestinal tract bleeding occurs no more frequently in hemophiliacs than in the normal population. A loading dose of 40 to 50 units/kg may be required, depending on the severity of bleeding. The goal is to obtain an initial Factor VIII level of 100% and then maintain it at 30% until healing occurs. Patients with severe abdominal pain, with or without a history of trauma, should be treated promptly until internal hemorrhage is ruled out. The recommended initial dose is 20 to 40 U/kg and the goal is to obtain a Factor VIII level between 30 and 50%. Hemophiliac patients undergoing surgery should receive a loading dose of 50 units/ kg 30 to 40 minutes before the procedure. They should then receive a maintenance dose of 25 to 30 units/kg every 8 to 12 hours. Ideally, the maintenance dose should be given as a continuous infusion at a rate of 3 to 4 units/kg per hour. The goal is to increase the patient's Factor VIII level to 100% intraoperatively, keep it at 50% until wound healing begins, and then maintain the level at 30% until would healing is complete. Hemophiliac patients undergoing dental procedures such as tooth extractions should be treated with aminocaproic acid (Amicar) the evening prior to the procedure and for 5 to 10 days thereafter. The recommended Amicar loading dose is 200 mg/kg. A maintenance dose of 100 mg/Kg should be given every six hours. The total loading dose should not exceed 10g and the maintenance dose should not exceed 30g per day. Complicated extractions may require a Factor VIII concentrate dose of 20 units/kg just prior to the procedure and at 12 hour intervals. DDAVP should be considered in mild hemophiliacs prior to surgery and dental procedures. Newborn hemophiliac males may bleed with circumcision. This procedure should be avoided whenever possible or delayed until after Factor VIII replacement. Toddlers are particularly prone to lip, tongue, and mouth lacerations. Factor replacement is usually required to control this bleeding. The Factor VIII loading dose for these lacerations is 20 U/Kg. This dose should be repeated every 12 hours to maintain a Factor VIII level of 30-50%. Children with hemophilia A should begin receiving prophylactic treatment at a young age prior to the onset of frequent bleeding. The goal is to keep their Factor VIII trough level above 1% in between doses. This goal can usually be accomplished by giving 25- 40 FVIII units/kg three times per week or every other day. Asymptomatic female carriers of hemophilia A with factor VIII levels between 30 and 50% may require prophylactic Factor VIII concentrate prior to surgery or after trauma. Family members of hemophilia A patients should have their Factor VIII levels evaluated prior to planned surgical procedures. Factor VIII Dosage Calculation The patient's plasma factor VIII level should be measured prior to the loading dose to calculate dosage and after the loading dose to determine adequacy. Trough levels should be measured prior to each maintenance dose. Doses are usually scheduled at 12-hour intervals because the circulating half-life of Factor VIII: C is 8 to 12 hours. One unit of infused Factor VIII should raise the plasma level by approximately 0.02 U/mL (2%). The following formula is used to calculate Factor VIII dosage: # Factor VIII units = (wt(kg) x desired % increase)/2 For example, if a severe hemophiliac weighs 70 Kg and has a baseline factor VIII level of < 1% and it needs to be increased to 50% the following calculation would be used: # Factor VIII units = 70 kg X 50 /2= 1750 units of Factor VIII Lyophilized Factor VIII should be reconstituted with sterile water and given within 3 hours. The concentrate should be infused by syringe equipped with a filter at a maximum rate of 2 mL/min. Patients infused with ReFacto cannot be monitored with the usual Factor VIII assay based on the one stage aPTT assay, because Factor VIII levels will be < 50% of the expected value. This falsely low value would result in over-treatment of patients. |
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