Description: Factor VIII, antihemophilc factor (AHF), is a clotting factor that is responsible for increasing the rate of cleavage of factor X by activated factor IX. Native factor VIII is a heterodimer consisting of a light chain in a divalent, cation-dependent complex with a heavy chain. Factor VIII is present in the plasma as a noncovalent complex with von Willebrand factor (vWF). Exogenous AHF is used as replacement therapy to prevent or control bleeding episodes in patients with acquired or inherited factor VIII deficiency (hemophilia A or classic hemophilia). Many factor VIII replacement products are commercially available. These products differ based on purity and source of factor VIII (e.g., recombinant or plasma derived). The purity of factor VIII products is defined in terms of the biologic activity of FVIII (FVIII:C) per mg of total protein. Factor VIII products are labeled in terms of AHF potency (FVIII:C activity) as international units (IU). These units are referenced to a WHO international standard where 1 IU indicates the amount of factor VIII present in 1 ml of fresh-pooled plasma. Purified factor VIII products were first developed in the 1960s and become available as concentrates for reconstitution in the 1970's. Recombinant factor VIII products became available in the early 1990's after the discovery of the factor VIII gene in 1984. •High Purity Antihemophilic Factor (Alphanate®, Humate-P®, Koate®-HP): These products are derived from cyroprecipitate of pooled human plasma and undergo purification. The purification processes differ for each product. All products contain albumin, polyethylene glycol and polysorbate 80 as stabilizers. Alphanate® undergoes solvent detergent and heat treatment to reduce viral transmission. Alphanate® has a final specific purity of at least 5 IU FVIII:C/mg total protein. Alphanate® also contains heparin (<= 1 unit/ml). Koate®-HP undergoes solvent detergent treatment to inactivate virus and then is purified using gel permeation chromatography. The specific AHF purity of Koate®-HP after the addition of human albumin is 9—22 IU FVIII:C/mg total protein. Koate®-HP contains <= 5 units/ml heparin. Humate-P® undergoes a pasturization process that inactivates virus. Humate-P® contains high molecular weight multimers of vWF. The activity of vWF is indicated by von Willebrand factor:Ristocetin Cofactor (vWF:RCof) activity in international units. The purity of Humate-P® is 20—40 IU FVIII:C/mg total protein and 50—100 IU vWF:RCof/mg total protein. These products may contain anti-A and anti-B blood group isoagglutinins. All of these products are indicated for the treatment and prevention of bleeding in hemophilia A patients. Alphanate® and Humate-P® have orphan drug designations for the treatment of von Willebrand's disease (vWD). In April 1999, the FDA approved Humate-P® for the treatment of bleeding episodes in severe vWD and in mild to moderate vWD where the use of desmopressin is known or suspected to be inadequate. •Monoclonal Antibody Purified Antihemophilic Factor (Hemophil® M, Monarc-M™, Monoclate-P®): Using monoclonal antibodies in the purification process, these products provide ultra-pure concentrates of plasma-derived AHF. Hemophil® M and Monarc-M™ undergo purification by the Method M process that utilizes a murine monoclonal antibody in immunoaffinity chromatography followed by an ion exchange chromatography for further purification. The process also involves a solvent detergent virus inactivation step. The purity of Hemophil® M and Monarc-M™ is 2—15 IU FVIII:C/mg total protein. These products also contain 12.5 mg/ml human albumin and trace amounts of polyethylene glycol and murine proteins. Monoclate-P® uses a murine monoclonal antibody to vWF as an affinity ligand to first isolate the factor VIII complex. Factor VIII is then dissociated from vWF, recovered, and formulated. The final product undergoes pasteurization to decrease viral transmission. The final purity of Monoclate-P® is 5—10 IU FVII:C/mg total protein with albumin as a stabilizer; prior to the addition of albumin the purity is > 3000 IU FVIII:C/mg of protein. The final product contains 1—2% albumin and trace amounts of murine protein. These products are indicated for the treatment and prevention of bleeding episodes in patients with hemophilia A. In addition, these products may be useful in patients with acquired inhibitors to factor VIII not exceeding 10 Bethesda units (BU)/ml. The circulating plasma FVIII:C levels should determine the AHF dosage in these patients. These products are not effective in controlling bleeding due to von Willebrand's disease. •Recombinant Anithemophilic Factor (Bioclate™, Helixate® FS, Kogenate® FS, ReFacto®, Recombinate™): Recombinant AHF (rAHF) is produced in a variety of media. These products are glycoproteins that have activity similar to native factor VIII. Bioclate™, ReFacto®, and Recombinate™ are produced by a Chinese hamster ovary cell line. The rAHF is secreted into cell culture media and is then purified using a series of chromatography columns. In order to stabilize Bioclate™ and Recombinate™, vWF is co-expressed with it. The final product contains <= 2 ng vWF/rAHF, which will not have any clinically relevant effect in patients with vWD. Refacto® does not contain any vWF or any added human components (i.e., albumin) in the final formulation. Helixate® FS and Kogenate® FS are produced in baby hamster kidney cells and undergo purification via chromatography columns and monoclonal antibody immunoaffinity chromatography. Kogenate® has an orphan drug designation for the treatment of bleeding due to hemophilia A. Kogenate® FS and Helixate® FS do not use albumin in the purification process or as part of the formulation. All of these products are indicated for the prevention and treatment of bleeding due to hemophilia A. In addition, these products may be useful in patients with acquired inhibitors to factor VIII not exceeding 10 Bethesda units (BU)/ml. The circulating plasma FVIII:C levels should determine the AHF dosage in these patients. These products are not effective in controlling bleeding due to von Willebrand's disease. Recombinate™ was the first recombinant AHF approved by the FDA in December 1992. The FDA approved Kogenate® in February 1993. In March 2000, the FDA approved ReFacto®. •Porcine Factor VIII (Hyate:C®): Early porcine formulations were associated with allergic reactions or thrombocytopenia due to the presence of porcine vWF. Hyate:C® is a highly purified form of porcine factor VIII and contains little porcine vWF. The lowered concentration of porcine vWF reduces the incidence of adverse reacitons. The specific activity of porcine factor VIII is > 50 U/mg of protein. Each lot is screened for porcine viruses and is not known to transmit any human viruses. Porcine factor VIII can replace human factor VIII in human coagulation cascade. It is used to treat hemophilia A patients who have inhibitors (> 5 BU/ml) and for previously non-hemophilic patients with spontaneously acquired inhibitors to human factor VIII (acquired hemophilia). Patients with an antibody titer <= 20 BU/ml to porcine factor VIII achieve a good to excellent response to therapy with Hyate:C®. Benefits of porcine factor VIII in patients with inhibitors include minimal cross-reactivity to anti-human factor VIII:C antibodies, ease of laboratory monitoring, viral safety from blood borne pathogens, less anamnestic response potential, and no thrombogenic effects.[2398] Hyate:C® was approved by the FDA in the mid 1980's. Mechanism of Action: Factor VIII (FVIII) acts in the coagulation cascade to accelerate the cleavage of factor X by activated factor IX. FVIII dramatically increases the maximal velocity of the reaction. Low concentrations of FVIII (0.2 ng/ml of plasma) are required for normal hemostasis. A severe decrease (> 80%) or lack of the factor lead to the bleeding disorder known as hemophilia A or classical hemophilia. FVIII circulates in a noncovalent complex with von Willebrand factor (vWF). The complex with vWF increases the synthesis of FVIII, protects FVIII from proteolysis, and concentrates FVIII at the site of active bleeding. FVIII can not become part of the "tenase" complex (the calcium-dependent complex of activated FVIII (FVIIIa), factor IXa and phospholipid) until it is released from vWF since vWF inhibits the binding of FVIII to phospholipid. The release of FVIII from vWF requires cleavage of the FVIII light chain by thrombin or factor Xa. This results in activation of FVIII and binding of FVIIIa to phospholipid surfaces of damaged cells and activated platelets. FVIIIa is unstable and rapidly loses its activity. FVIIIa undergoes subunit disassociation and is inactivated via proteolytic cleavage by activated protein C.[2399] The increase in FVIII:C activity produced by AHF differs by product. One unit of recombinant AHF per kg body weight increases FVIII:C activity approximately 2 units/dl. Each unit per kg body weight porcine AHF increases FVIII:C approximately 1.5 units/dl. One unit per kg body weight of Humate-P® increases the FVIII:C activity level 2 units/dl and increases vWF:RCof activity 3.5—4 units/dl. The increase in FVIII:C activity following one unit per kg body weight of other plasma derived AHF products is 2—2.5 units/dl. Pharmacokinetics: After IV administration, AHF is quickly cleared from the plasma. The distribution of AHF is limited to the plasma. The peak effect of activity occurs 1—2 hours following IV administration. The half-life of plasma-derived AHF and recombinant AHF are similar and is approximately 15 hours (range 8.4—19.3 hours). Porcine AHF (i.e., Hyate:C®) has a half-life of approximately 7 hours (range 2—9 hours). The half life of all AHF products is reduced in patients with factor VIII inhibitors. The median half-life of vWF:RCof in patients receiving Humate-P® is 10.3 hours (range 6.4—13.3 hours). The median in vivo recovery of vWF:RCof is 1.89 units/dl/kg.

ndications...Dosage For the prophylaxis and management of hemorrhage or hemarthrosis in patients with hemophilia A (classical hemophilia): NOTE: Humate®, Kogenate®, and Refacto® have been designated by the FDA as orphan drugs for this indication. •for bleeding prophylaxis: Intravenous bolus dosage (human, plasma-derived and recombinant AHF): Adults, adolescents, children and infants weighing < 50 kg: 250 units or 10 units/kg IV once daily in the morning. Goal is to obtain a plasma FVIII activity level of 15—20%. Adults, adolescents, and children weighing >= 50 kg: 500 units/day or 10 units/kg IV once daily in the morning. Goal is to obtain a plasma FVIII activity level of 15—20%. •for minor bleeding including early muscle bleed and severe epistaxis: Intravenous bolus dosage (human, plasma-derived and recombinant AHF): Adults, adolescents, children and infants: 10—15 units/kg IV to achieve a FVIII activity level of approximately 20—40%. One dose is usually all that is required. If bleeding or pain continues, half the initial dose may be given 1—2 times a day for 1—3 days. In all cases, the dose of antihemophilic factor should be individualized taking into consideration the seriousness of the bleed, the clinical status of the patient, and the factor VIII activity level. •for moderate bleeding including advanced muscle bleed, neck, tongue or pharyngeal hemotoma (without airway obstruction), tooth extraction, and severe abdominal pain: Intravenous bolus dosage (human, plasma-derived and recombinant AHF): Adults, adolescents, children and infants: 25 units/kg IV to achieve a FVIII activity level of approximately 30—60%, followed by 15 units/kg IV every 8—12 hours for the first 1—2 days to maintain a FVIII activity level of about 30%, then continue maintenance dose 1—2 times per day for a up to 7 days or until adequate wound healing. In all cases, the dose of antihemophilic factor should be individualized taking into consideration the seriousness of the bleed, the clinical status of the patient, and the factor VIII activity level. •for life-threatening bleeding including surgical bleeding, gastrointestinal bleeding, neck, tongue or pharyngeal hemotoma with potential for airway compromise, intracranial, intraabdominal, or intrathoracic bleeding or fractures: Intravenous bolus dosage (human, plasma-derived and recombinant AHF): Adults, adolescents, children and infants: 40—50 units/kg IV followed by 20—25 units/kg IV every 8 hours to maintain FVIII activity levels of 80—100% for 7 days then continue the same dose 1—2 times per day to maintain the FVIII activity level at 30—50% for 7 days or until adequate healing. In all cases, the dose of antihemophilic factor should be individualized taking into consideration the seriousness of the bleed, the clinical status of the patient, and the factor VIII activity level. Continuous infusion dosage†: Adults, adolescents, children and infants: 50 units/kg IV loading dose to achieve FVIII activity level of 80-100% then a continuous IV infusion of AHF is begun. An initial rate of 2 units/kg/hour IV adjusted based upon the plasma FVIII activity levels has been used. For the first 7 days or until bleeding resolves, the goal is a FVIII activity level of 80—100%. Once bleeding resolves, the rate of the infusion may be decreased to maintain FVIII activity levels of 30—50% depending upon the clinical status of the patient.[2400] •for treatment of bleeding in patients with factor VIII inhibitor titers < 10 Bethesada Units and with low anamnestic responses: Intravenous dosage (monoclonal antibody-purified or recombinant AHF): Adults, adolescents, children and infants: The actual dose of recombinant AHF appropriate to treat hemorrhages in patients with low levels of inhibitors has not been established. In general, higher doses than those normally required for a particular bleed episode are needed. Doses should be based upon the clinical situation and the inhibitor status of the patient. Initial doses of 50—100 units/kg IV may be required. Close monitoring of FVIII activity levels are needed. Repeat doses as needed until desired FVIII activity level is reached, then doses continue every 8—12 hours to maintain the FVIII activity in the therapeutic range. •for treatment of bleeding in patients with factor VIII inhibitor titers < 50 Bethesda units or with high anamnestic inhibitor responses: Intravenous dosage (porcine AHF, Hyate:C®): Adults, adolescents, children and infants:: Prior to treatment determine the activity of antibody against porcine AHF. If the antibody titer is > 20 Bethesda units, then the patient will be unlikely to benefit from treatment with porcine AHF. For patients with porcine AHF antibody titers < 20 Bethesda units, the recommended initial dose is 100—150 porcine units/kg IV and then check FVIII activity levels, repeat dose immediately until acceptable activity levels are reached. Prior therapy with Hyate:C® may serve as an indication of appropriate doses in patients. Once acceptable FVIII activity levels are achieved, administer subsequent doses every 6—8 hours. Actual amount of subsequent doses should be based upon FVIII activity post-infusion or clinical status. An initial dose may be calculated using the following method. Determine the patient's antibody titer to porcine factor VIII in Bethesda units. Determine patients blood volume: patients body weight x average blood volume (80 ml/kg) x (1 — hematocrit). Then calculate the neutralizing dose of Hyate:C®: plasma volume x porcine antibody titer. Then calculate the incremental dose required to increase the FVIII activity level to the appropriate level: (desired FVIII activity level x body weight) divided by 1.5. The total dose equals the neutralizing dose + incremental dose. For the treatment and prevention of hemorrhage in patients with von Willebrand's disease (vWD): NOTE: Alphanate® and Humate-P® have been designated by the FDA as orphan drugs for this indication. Intravenous bolus dosage (only Humate-P® indicated): Adults, adolescents, children and infants: In general, 40—80 vWF:RCof/kg (16—32 units/kg Humate-P®) IV are given every 8—12 hours. Doses are repeated every 8—12 hours as needed based on appropriate clinical and laboratory parameters. •for mild Type I vWD patients with major hemorrhage such as severe or refractory epistaxis, GI bleeding, CNS trauma or traumatic hemorrhage or for moderate to severe Type I vWD patients with minor hemorrhage such as epistaxis, oral bleeding or menorrhagia: Intravenous bolus dosage (only Humate-P® indicated): Adults, adolescents, children and infants: 40—60 units vWF:RCof/kg (16—24 units/kg Humate-P®) IV loading dose then 40—50 units vWF:RCof/kg (16—20 units/kg Humate-P®) IV every 8—12 hours for 3 days to keep the nadir level of vWF:RCof > 50%. Continue same dose 1—2 times per day for up to a total of 7 days. •for moderate to severe Type I vWD patients with major hemorrhage such as severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, or traumatic hemorrhage: Intravenous bolus dosage (only Humate-P® indicated): Adults, adolescents, children and infants: 50—75 units vWF:RCof/kg (20—30 units/kg Humate-P®) IV loading dose then 40—60 units vWF:RCof/kg (16—24 units/kg Humate-P®/kg) IV every 8—12 hours for 3 days to keep the nadir level of vWF:RCof > 50%. Continue this dose 1—2 times per day for a total of 7 days. FVIII levels should be monitored and maintained as appropriate (60—100%) depending upon the severity of the bleed. •for type 2 and 3 vWD patients with minor hemorrhage such as epistaxis, oral bleeding or menorrhagia: Intravenous bolus dosage (only Humate-P® indicated): Adults, adolescents, children and infants: 40—50 units vWF:RCof/kg (16—20 units/kg Humate-P®) IV for 1—2 doses. •for type 2 and 3 vWD patients with major hemorrhage such as severe or refractory epistaxis, GI bleeding, CNS trauma, hemarthrosis, or traumatic hemorrhage: Intravenous bolus dosage (only Humate-P® indicated): Adults, adolescents, children and infants: 60—80 units vWF:RCof/kg (24—32 units/kg Humate-P®) IV loading dose then 40—60 units vWF:RCof/kg (16—24 units/kg Humate-P®) IV every 8—12 hours for 3 days to keep the nadir level of vWF:RCof > 50%. Continue this dose 1—2 times per day for a total of 7 days. FVIII levels should be monitored and maintained as appropriate (60—100%) depending upon the severity of the bleed. Patients with hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. †non-FDA-approved indication

Administration Intravenous Administration •Antihemophilic factor, AHF is administered intravenously. •These products should be administered to patients under the direct supervision of a physician experienced in the treatment of hemophilia. •Use only plastic syringes to prepare and administer antihemophilic factor. •Monitor patients for allergic and infusion-related reactions. Stop infusions for severe reactions. •Coagulation parameters do not necessarily correlate with or predict the effectiveness of treatment. These parameters should be used to adjust treatment schedules, if necessary. •Store unopened vials under refrigeration. Avoiding freezing, which may damage the diluent bottle. Do not use past the expiration date. Reconstitution of human plasma-derived or recombinant antihemophilic factor products: •Warm vials to room temperature prior to reconstitution. Do not use artificial methods of warming. •Using aspectic technique, remove the covering from one end of the double-ended needle, and completely insert the exposed end through the diluent stopper. •Remove the protective covering from the other end of the double-ended needle. Invert the diluent vial over the concentrate vial, and then rapidly insert the free end of the needle to its full length through the concentrate stopper. The diluent will be drawn into the concentrate vial by vacuum. •Disconnect the two vials by removing the needle from the concentrate vial. Gently swirl the concentrate vial until all the material is dissolved. •Attach a filter needle (provided) to a sterile disposable syringe or insert filter spike into concentrate vial. Withdraw the solution into the syringe. If more than one vial is required, use a different filter needle or spike to withdraw the contents of each vial. All vials may be withdrawn into the same syringe or empty IV bag. Discard the filter needle and attach an appropriate intravenous needle or infusion set. •Do not refrigerate after reconstitution. Per manufacturer recommendations, the reconstituted monoclonal antibody-purified products should be used within 1 hour and all other products should be used within 3 hours. Reconstituted solutions should not be refrigerated. Reconstitution of porcine antihemophilic factor (Hyate:C®): •Warm vials to room temperature prior to reconstitution. Do not use artificial methods of warming. •Reconstitute by slowly adding 20 ml of sterile water for injection to the concentrate vial. Gently shake the vial until the powder is completely dissolved which usually takes less than 5 minutes. •Withdraw solution into a plastic syringe using a disposable filter needle (supplied). Discard the filter needle and attach an appropriate intravenous needle or infusion set. •Administer reconstituted solution within 3 hours. Reconstituted solutions should not be frozen. Direct IV injection or infusion: •May infuse using a controlled infusion device. •Alphanate®, Bioclate®, Hemophil® M, Monarc-M™, or Recombinate™: Administer IV at a rate not to exceed 10 ml/minute. •Humate-P®: Administer IV at a rate of 4 ml/minute. •Helixate® FS, Koate®-HP, Kogenate® FS: Administer IV over 5—10 minutes. •Hycate:C®: Administer IV at a rate not to exceed 2—5 ml/minute. •Monoclate-P®: Administer IV at a rate of 2 ml/minute. •ReFacto®: Administer IV over several minutes. The rate should be determined by the patient's comfort level. Continuous intravenous infusion†: •Infuse using a controlled infusion device. •The following factor VIII agents have been shown to maintain activity > 80% above baseline in a polypropylene container at 20—23 degrees C for at least 24 hours: Hemophil® M, Humate-P®, Monoclate-P®, and Recombinate™.[1045] †non-FDA-approved indication

Contraindications All antihemophilic factor (AHF) products are classified as FDA pregnancy category C agents. AHF should be used with caution during pregnancy because its effects on the fetus and reproduction capacity are not known. Animal studies have not been done to determine the affects of AHF during pregnancy. AHF should be used during pregnancy only if clearly needed. It is not known if antihemophilic factor (AHF) is excreted in breast milk. Because many drugs are excreted in breast milk and the potential for serious adverse reaction in nursing infants, a decision should be made whether to discontinue breast-feeding or to discontinue AHF considering the importance of the drug to the mother. As with other products derived from or purified with human blood components, the possibility of contamination with hepatitis and other viral or bacterial infections exists in patients receiving plasma-derived antihemophilic factor products (i.e., Alphanate®, Hemophil® M Humate-P®, Koate®-HP, Monarc-M™, and Monoclate-P®). Screening plasma donors for prior exposure to certain viruses, testing for the presence of viruses, and inactivating and/or reducing viruses has reduced the risk of transmission of infectious agents. The manufacturing processes are designed to reduce the risk of transmitting viral infection; however, none of the processes are completely effective. There is also the possibility that unknown infectious agents may be present in these products. It is recommended that all patients with hemophilia receive vaccination against hepatitis A and B at birth or at diagnosis of hemophilia. Alphanate®, Humate-P®, Koate-HP® contain small amounts of isoagglutinins for blood groups A and B. Caution and frequent monitoring (hematocrit and Coombs' test) is advised when giving large or frequently repeated doses to patients with blood groups A, B, and AB due to the possibility of developing anemia and intravascular hemolysis. Monoclonal antibody-purified and recombinant antihemophilic factor products contain varying amounts of animal protein and should be used with caution in patients with bovine protein hypersensitivity, hamster protein hypersensitivity, and murine protein hypersensitivity. Hemophil® M, Monarc-M™ and Monoclate-P® contain trace amounts of murine proteins from the purification process. Bioclate™ and Recombinate™ contain trace amounts of bovine, hamster and mouse proteins. Helixate®, Kogenate®, and ReFacto® contain trace amounts of hamster and mouse proteins. Hyate:C® should be used cautiously in patients with porcine protein hypersensitivity. Patients with porcine AHF titers > 20 Bethesda units are unlikely to benefit from treatment with Hyate:C®. In hemophilic patients, the development of inhibitors (i.e., antibody formation) to factor VIII can occur. These antibodies are reported to be present in 5—15% of patients with severe hemophilia and a few with mild hemophilia. Patients with inhibitors present may or may not respond to treatment with AHF. These patients can have bleeding problems that are difficult to control and require careful monitoring and, possibly, other treatments, especially when surgery is required. Hemophilia A patients with human immunodeficiency virus (HIV) infection or who are HIV seropositive may benefit from treatment with ultra-pure, antihemophilic factor (AHF) products (i.e., monoclonal antibody purified or recombinant products). Studies have shown improved immune function in hemophilia A patients receiving high purity factor VIII products.[2214]

No clinically-significant drug interactions are noted for this drug.

Adverse Reactions Adverse reactions to antihemophilic factor are rare. Those that occur are related to the injection or are allergic reactions. Adverse reactions include flushing, somnolence, clouding or loss of consciousness, chest tightness, rigors, headache, elevated hepatic enzymes, lethargy, nausea/vomiting, paresthesias, sinus tachycardia, and visual disturbances. Injection site reactions include erythema, pain, and phlebitis. Symptoms of allergic and anaphylactoid reactions include chills, back pain, fever, hypotension, rash (unspecified), urticaria, and wheezing. Rarely, following large doses of antihemophilic factor (AHF), acute hemolytic anemia, increased bleeding tendency, or hyperfibrinogenemia have been reported. Certain AHF products (Alphanate®, Humate-P® and Koate®-HP) in large and/or frequent doses in patients with A, B, or AB blood types may result in intravascular hemolysis and hemolytic anemia. Should this occur, the administration of serologically compatible type O red blood cells or the administration of AHF produced from group-specific plasma should be considered. Mild thrombocytopenia has been reported with the use of porcine antihemophilic factor. Thrombocytopenia is usually mild and does not appear to affect the patients overall hemostasis. Severity and incidence of platelet affect is not appear to be dose related and may be due to the presence of porcine von Willebrand factor. All plasma-derived, human antihemophilic factor (AHF) products carry the possibility of causing iatrogenic infection via bloodborne pathogens. The risk of infection associated with plasma-derived AHF products produced since the mid 1980's is considered to be low due to the careful screening of plasma donors and manufacturing processes, which includes heat-inactivation, solvent detergent viral inactivation process, and monoclonal antibody purification that effectively remove HIV-1, HIV-2, hepatitis B, and hepatitis C. However, new bloodborne pathogens not controlled by present measures can theoretically emerge at any time. Transmission of parvovirus B19, hepatitis, and HIV infection through the use of plasma-derived AHF products has been documented. Antibody formation (inhibitors) to factor VIII may be seen in 8—10% of hemophilia A patients following exposure to antihemophilic factor (AHF) products. Inhibitors to factor VIII are immunoglobulins of the IgG heavy chain class. Light chains of factor VIII inhibitors are either solely kappa (most common), solely lambda, or both. The reaction between factor VIII and factor VIII inhibitors seems to be time-dependent and leads to the production of two types of inhibitors, Type I and Type II. Type I or simple inhibitors have second-order kinetics where the amount of antibody is related linearly to the residual factor VIII after incubation of factor VIII and inhibitor plasma. Type II inhibitors are usually autoantibodies rather than hemophilic alloantibodies. With Type II inhibitors, the interaction between the inhibitor and factor VIII is variable and does not reach a stable endpoint. Some factor VIII may remain measurable, but if more factor VIII is added it may be partially inactivated. This may be due to the partial dissociation of the factor VIII-inhibitor complex. The most common screening test for inhibitors is the activated partial thromboplastin time (aPTT); the clotting time compared to controls is prolonged in the presence of inhibitors. Quantitiative assays measure the amount of factor VIII inactivated by patient plasma under certain conditions. An inhibitor unit is defined as the reciprocal of the dilution of patient plasma that neutralized a specific portion of the factor VIII. The most common test of this type is the Bethesda method. Type I inhibitors can be quantified by this method. The quantity of Type II inhibitors can only be approximated. Administration of high bolus doses or continuous infusions of AHF is usually successful in patients with an inhibitor level < 5 Bethesda units (BU)/ml and is sometimes successful in patients with inhibitor levels of 10—20 BU/ml. In some cases high doses of AHF, rapidly administered, may be able to act in coagulation process before it is neutralized by inhibitors. Patients with inhibitors require close monitoring of the plasma factor VIII concentration to determine the appropriate dose of AHF.[2401]

Antihemophilic Factor, AHF, Factor VIII Alphanate®, Bioclate®, Helixate® FS, Hemofil®, Humate-P®, Hyate:C®, Koate®-HP, Kogenate® FS, Monarc-M™, Monoclate-P®, Recombinate™, ReFacto® | Alphanate®, Bioclate®, Helixate®, Hemofil®, Humate-P®, Hyate:C®, Koate®-HP, Kogenate

®, Monarc-M™, Monoclate-P®, Recombinate™ | Profilate Osd™ | Profilate Sd™

2398. Kessler CM. Factor VIII inhibitors - an algorithmic approach to treatment. Semin Hematol 1994;31 (2 Suppl 4):33—36.

1045. chulman S, Gitel S,m Martinowitz U. Stability of factor VIII concentrates after reconstitution. Am J Hematol 1994;45:217—23.

2214. de Biasi R, Rocine A, Quirino A, et al. The impact of a very high purity factor VIII concentrate on the immune system of HIV-infected haemophiliacs: a randomized, two-year comparison with a high purity concentrate. Haemophilia 1996;2:82—7.