VA Class:BL500
Anti-inhibitor coagulant complex, also referred to as activated prothrombin complex concentrate (APCC) is a preparation containing precursor and activated forms of blood coagulation factors II, VII, IX, and X prepared from pooled human venous plasma.3, 7, 14, 24
Anti-inhibitor coagulant complex is used for the prevention and control of hemorrhagic episodes in patients with hemophilia A (antihemophilic factor [factor VIII] deficiency; classic hemophilia) or hemophilia B (factor IX deficiency; Christmas disease) who have developed inhibitor antibodies (alloantibodies) to factor VIII or factor IX.2, 3, 4, 5, 7, 11, 12, 14, 15, 16, 20, 23, 24, 25, 28, 29, 33, 34, 35, 38, 42, 65 The drug also is used in the management of bleeding in patients with acquired hemophilia who have spontaneously acquired inhibitors (autoantibodies) to factor VIII, XI, or XII.13, 22, 24, 26, 29, 31, 32 Anti-inhibitor coagulant complex also has been used in patients with von Willebrand disease who have inhibitors.24
Hemophilia A or B with Inhibitors
Anti-inhibitor coagulant complex is one of several alternatives that can be used for the prevention and control of bleeding in patients with hemophilia A or B who have inhibitors (alloantibodies).7, 13, 14, 16, 17, 18, 20, 22, 25, 28, 29, 38, 42, 65 Antihemophilic factor inhibitors are IgG antibodies that neutralize the procoagulant activity of antihemophilic factor.13, 16, 18, 20, 21, 25 The presence of antihemophilic factor inhibitors generally does not increase the frequency or severity of bleeding in patients with hemophilia A; however, patients with inhibitors may not respond to treatment with antihemophilic factor replacement therapy or the response may be much lower than would otherwise be expected.13, 25
Management of hemophilia patients with inhibitors may be difficult and consultation with a hemophilia treatment center is strongly recommended.13, 25, 38, 65 The treatment of choice depends on several factors, including the severity and location of bleeding, type of inhibitor (low- or high-responding), current titer of the inhibitor, patient's history of an anamnestic increase in antihemophilic inhibitor levels following use of preparations containing antihemophilic factor, and product availability.13, 14, 16, 17, 22, 25, 38, 65, 66 Management of bleeding episodes in patients who are low responders with antihemophilic factor antibody levels of 5 Bethesda units/mL or lower is less problematic than in patients who are high responders with a history of anamnestic antibody responses.3, 7, 13, 16, 17, 22, 25, 65, 66 Antihemophilic factor preparations may be effective for the prevention or control of bleeding in hemophilia patients who are low responders and whose inhibitor levels have historically remained less than 5-10 Bethesda units/mL.7, 14, 16, 17, 22, 24, 25 However, use of a bypassing agent such as anti-inhibitor coagulant complex, factor VIIa (recombinant), or certain factor IX complex preparations may be necessary in other patients.13, 14, 16, 18, 25, 26, 28, 29, 32, 37, 65, 66 These agents are able to bypass the need for factor VIII or factor IX while promoting hemostasis.38, 68 The National Hemophilia Foundation's Medical and Scientific Advisory Council (MASAC) currently recommends the use of a bypassing agent in hemophilia A patients with inhibitors to prevent or control bleeding in settings in which antihemophilic factor preparations would otherwise be used, including before and after surgery and physical therapy.68
Although anti-inhibitor coagulant complex can be effective in controlling hemorrhage in patients with inhibitors, clinical response to the drug is not always consistent or predictable and there is no laboratory test that can be used to monitor effectiveness of the drug.4, 14, 16, 20, 22, 24, 25, 29 In addition, anti-inhibitor coagulant complex may be associated with an increased risk of thrombotic complications (e.g., disseminated intravascular coagulation, deep venous thrombosis, myocardial infarction)20, 28, 29 and, because the drug is prepared using pooled human plasma, it is associated with a risk of transmission of human viruses or other infectious agents.20, 32 (See Cautions: Precautions and Contraindications.) Because of these considerations, some clinicians suggest that anti-inhibitor coagulant complex be used only when a response to antihemophilic factor preparations has not been obtained or is unlikely.13, 14, 16, 18, 25, 26, 28, 29, 32 There are no controlled studies to date that directly compare the safety and efficacy of the various options used in the management of hemophilia A patients with inhibitors.66
Anti-inhibitor coagulant complex has been used principally for the prevention and treatment of bleeding episodes in patients with hemophilia A who have antihemophilic factor antibody levels exceeding 10-20 Bethesda units/mL or patients who have a history that indicates that antibody levels increase to greater than 10-20 Bethesda units/mL following treatment with antihemophilic factor (human).14, 22, 24 Although antihemophilic factor (porcine) prepared from porcine plasma also has been used effectively in some patients with hemophilia A and antihemophilic factor inhibitors (especially those with inhibitor levels of 10-50 Bethesda units/mL),20, 22, 40 this drug is no longer commercially available in the US and studies have been initiated to evaluate the safety and efficacy of antihemophilic factor (porcine) prepared using recombinant DNA technology.62 It has been suggested that anti-inhibitor coagulant complex may be more effective in the management of patients with inhibitors than factor IX complex, especially in patients undergoing surgery or patients with life-threatening hemorrhage.2, 4, 5, 13, 14, 29 Factor IX complex is similar to anti-inhibitor coagulant complex except that it contains only precursor forms (not activated forms) of blood coagulation factors II, VII, IX, and X.13 In a few studies in patients with hemophilia A and antihemophilic factor inhibitors, anti-inhibitor coagulant complex was effective in about 65% of bleeding episodes whereas factor IX complex preparations containing only nonactivated factors were effective in about 50% of bleeding episodes.4, 13 However, other controlled studies have found no difference in efficacy between the activated and nonactivated preparations.4, 5, 13, 16, 25, 29
Anti-inhibitor coagulant complex has been used effectively to maintain hemostasis perioperatively and postoperatively in adults11, 12, 42 and children2, 23, 42 with hemophilia A and antihemophilic factor inhibitors who were undergoing surgery (e.g., tooth extraction, synovectomy, placement of ventricular reservoir or ventriculoperitoneal shunt, drainage of subdural, intracerebral, and intracranial hematoma).
Anti-inhibitor coagulant complex can be used in the management of bleeding episodes in patients with acquired hemophilia.13, 16, 20, 24, 25, 26, 29, 30, 32, 64 Acquired hemophilia is a rare disorder characterized by the spontaneous development of antibodies to factor VIII (autoantibodies) in patients who do not have hemophilia A and previously had normal plasma levels of factor VIII.13, 19, 20, 25, 26, 27, 30, 31, 32, 64 Spontaneously acquired factor VIII inhibitors have been reported most frequently in postpartum women; geriatric adults; patients with autoimmune disorders such as rheumatoid arthritis and systemic lupus erythematosus; patients with malignant diseases such as plasma cell dyscrasias and lymphoproliferative disorders; and patients with other conditions such as diabetes, inflammatory bowel disease, dermatologic disorders (e.g., erythema multiforme, dermatitis herpetiformis), or prior anti-infective agent therapy (penicillin, chloramphenicol, sulfonamides).26, 27, 30, 31, 32 Occasionally, inhibitors to factor VIII arise spontaneously in some patients, including young children and geriatric adults, with no apparent condition that would predispose them to inhibitor formation.27, 30, 32
Factor VIII antibodies that develop in patients with acquired hemophilia are predominantly IgG immunoglobulins that are similar to, but more heterogeneous than, those that develop in patients with hemophilia A.26, 27, 30, 32 For further information on these inhibitors, see Uses: Patients with Acquired Hemophilia in Antihemophilic Factor (Recombinant) 20:28.16. Patients with acquired hemophilia may have measurable levels of factor VIII, even though inhibitors may be present in moderately high concentrations; this measured level of factor VIII may be misleading and result in underestimation of antibody activity and the need for replacement therapy.32 Factor VIII inhibitor levels in patients with acquired hemophilia can fluctuate greatly over time13, 19, 32 and, in about one-third of patients (especially postpartum or young patients), acquired factor VIII inhibitors disappear within 12-18 months without treatment.13, 32 In other cases, acquired antihemophilic factor antibodies persist for 48 months or longer and may persist for as long as 20 years.13
Acquired hemophilia generally is suspected when there is an unexplained prolongation of the activated partial thromboplastin time (aPTT) in a patient with a normal prothrombin time or when there is a spontaneous bleeding episode (e.g., ecchymoses, soft-tissue hematomas, intractable epistaxis) in a patient who does not have hemophilia A.27 Patients with acquired hemophilia frequently develop hematomas in muscles or have soft tissue ecchymoses, mucosal bleeding, or GI bleeding; hemarthroses occur less frequently in patients with acquired hemophilia than in patients with hemophilia A.19, 26, 30, 31 Because of the unpredictable nature of bleeding that can occur in patients with acquired hemophilia, these patients may be at increased risk of major bleeding episodes and fatal hemorrhage.26, 27, 30, 32, 43
The management of patients with acquired hemophilia is not well established.26, 30, 31, 32 Although there are various therapeutic options available, no one treatment has been found to be suitable for the management of bleeding in all patients who have spontaneously acquired factor VIII inhibitors.26, 30, 31, 32 Immunosuppressive therapy that includes use of corticosteroids with or without other agents (e.g., cyclophosphamide, vincristine, cyclosporine, interferon alfa) has been used effectively to suppress formation of the autoantibodies in some patients, especially those with low levels of inhibitors.19, 26, 31, 64 However, because these spontaneously acquired autoantibodies also may disappear spontaneously, it is difficult to evaluate effectiveness of immunosuppressive therapy or to identify which patients may respond to such therapy.19, 26, 31 Some patients with acquired hemophilia who have low levels of inhibitors and mild to moderate hemorrhage may respond to therapy with desmopressin (DDAVP).16, 25, 43, 25 However, many patients with acquired hemophilia, especially those with higher levels of inhibitors and more severe hemorrhage, generally are managed with antihemophilic factor (recombinant) or antihemophilic factor (human).16, 20, 22, 25, 30, 31, 32, 40 Antihemophilic factor (recombinant) or antihemophilic factor (human) may be used effectively in patients with low levels of acquired antihemophilic factor inhibitors.22, 30, 31, 40 Although antihemophilic factor (porcine) prepared from porcine plasma also has been used in patients with acquired hemophilia, especially those with high levels of inhibitor, this drug is no longer commercially available in the US and studies have been initiated to evaluate the safety and efficacy of antihemophilic factor (porcine) prepared using recombinant DNA technology.62 Other therapeutic options for patients with acquired hemophilia include anti-inhibitor coagulant complex,16, 20, 25, 26, 29, 30, 32 certain factor IX complex preparations,25, 26, 29, 30, 32 or factor VIIa (recombinant).63, 64
Reconstitution and Administration
Anti-inhibitor coagulant complex is administered by slow IV injection or by IV infusion.24 The drug has been used as part of medically supervised home treatment programs for patients with hemophilia†.44
Prior to reconstitution, lyophilized anti-inhibitor coagulant complex powder for injection and the sterile water for injection diluent provided by the manufacturer should be warmed to room temperature.24 The drug should be reconstituted according to the manufacturer's directions.24 Reconstituted solutions should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.24 The filter needle provided by the manufacturer should be used to withdraw the reconstituted anti-inhibitor coagulant complex solution from the vial into a syrin the filter needle is then replaced with a sterile injection needle for administration.24 Reconstituted solutions of anti-inhibitor coagulant complex should not be refrigerated and should be administered as soon as possible.24 Infusions of the drug should be completed within 3 hours following reconstitution.24
The rate of administration of anti-inhibitor coagulant complex should be individualized according to the patient's response.24
The manufacturer of Feiba® VH states that the infusion rate should not exceed 2 units/kg per minute; depending on the number of units of drug contained in the vial, this corresponds to an infusion rate of 2.5-7.5 mL/minute in a patient weighing 75 kg.24
Dosage of anti-inhibitor coagulant complex is not well defined and therefore should be individualized carefully based on clinical response.22, 24, 29, 41 Response to anti-inhibitor coagulant complex varies depending on the type of hemorrhage and shows considerable interindividual variation; response to the drug does not necessarily correlate with the patient's plasma levels of inhibitor.3, 24, 41 There is no laboratory test that can reliably be used to monitor effectiveness of anti-inhibitor coagulant complex therapy.16, 22, 24, 29, 41
Dosage of Feiba® VH is expressed in terms of Feiba® VH units of activity.9, 24
The dosage range of Feiba® VH recommended by the manufacturer is 50-100 units/kg.24 Because laboratory and/or clinical signs of disseminated intravascular coagulation (DIC) have been reported in patients receiving high doses of Feiba® VH, the manufacturer states that single doses of the drug should not exceed 100 units/kg and daily dosages should not exceed 200 units/kg.24 Patients receiving more than 100 units/kg should be monitored for the development of DIC and/or symptoms of acute coronary ischemia.24 High doses of Feiba® VH should be given only as long as absolutely necessary to stop bleeding.24
For the management of joint hemorrhage, the manufacturer of Feiba® VH recommends that a dose of 50 units/kg be given every 12 hours; dosage may be increased to 100 units/kg every 12 hours if necessary.24 Treatment should be continued until there are clear signs of clinical improvement (e.g., relief of pain, reduction of swelling, mobilization of the joint).24
For the management of mucous membrane bleeding, the manufacturer of Feiba® VH states that 50 units/kg may be given every 6 hours while monitoring the patient's hematocrit and observing carefully for visible bleeding.24 If this dosage is insufficient and hemorrhage does not stop, the manufacturer states that dosage may be increased to 100 units/kg every 6 hours for 2 doses; however, dosage should not exceed 200 units/kg daily.24
For the management of serious soft tissue hemorrhage, such as retroperitoneal bleeding, Feiba® VH doses of 100 units/kg may be given every 12 hours up to a maximum daily dosage of 200 units/kg.24 Severe hemorrhages, such as CNS bleeding, have been managed effectively with doses of 100 units/kg given every 12 hours; if necessary, these doses may be given every 6 hours until clear evidence of clinical improvement is achieved.24
Anti-inhibitor coagulant complex generally is well tolerated;7, 34, 35, 42 however, there is a risk that thromboembolic complications may occur if high doses of the drug are used, especially in patients with risk factors for thromboembolic complications.22, 24, 41
As with most blood products, infusion reactions consisting of fever, chills, dizziness, and nausea may occur in patients receiving anti-inhibitor coagulant complex.5, 35, 42
Hypersensitivity reactions, ranging from mild, transient urticarial rash to anaphylaxis, may occur following administration of anti-inhibitor coagulant complex.24, 42 If a severe hypersensitivity reaction occurs, anti-inhibitor coagulant complex should be discontinued and the patient given appropriate treatment (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen) as indicated.24
Laboratory and/or clinical signs of disseminated intravascular coagulation (DIC) have been reported occasionally in patients receiving high doses of Feiba® VH (e.g., single infusions exceeding 100 units/kg or daily dosage of 200 units/kg).24 Acute myocardial infarction has occurred rarely in patients receiving prolonged therapy with anti-inhibitor coagulant complex and has been reported in several adolescents receiving the drug.4, 36 Myocardial infarction has occurred in patients receiving high doses and/or prolonged therapy with anti-inhibitor coagulant complex and/or in the presence of risk factors predisposing to myocardial infarction.24
Administration of anti-inhibitor coagulant complex may result in increased plasma levels of inhibitors to antihemophilic factor (alloantibodies) in 15-20% of patients;6, 13, 25, 34, 35, 42 anamnestic responses have been reported occasionally following administration of the drug to patients with hemophilia A and antihemophilic factor inhibitors.6, 24, 25, 34, 35, 41, 42 This increase in antihemophilic factor inhibitors presumably occurs because low levels of antihemophilic factor antigen may be present in preparations of anti-inhibitor coagulant complex.6, 13, 24, 35, 41 Therefore, some clinicians caution that, if anti-inhibitor coagulant complex is used in critical situations in patients with inhibitors, it should be used early in the course of the bleeding episode.41, 45
Precautions and Contraindications
Risk of Transmissible Agents in Plasma-derived Preparations
Coagulation factor concentrates prepared from pooled human plasma (e.g., antihemophilic factor [human], factor IX [human], factor IX complex, anti-inhibitor coagulant complex) are potential vehicles for transmission of viruses, including the causative agents of viral hepatitis.4, 20, 24, 26, 32, 38 Although currently available preparations of anti-inhibitor coagulant complex have undergone vapor- or dry-heat treatment procedures during manufacturing in an attempt to reduce viral infectious potential, no method has been shown to be totally effective in removing hepatitis infectivity.4, 20, 22, 24, 26, 32, 38 Available data regarding plasma-derived antihemophilic factor and plasma-derived factor IX indicate that improved methods of viral inactivation and improved donor screening practices have substantially reduced the risk of human viral transmission; however, there is still a possibility of transmission of hepatitis A virus (HAV) or hepatitis B virus (HBV) from currently available plasma-derived preparations.38 Transmission of nonenveloped viruses, including HAV38, 46 and parvovirus B19,38 has been documented following administration of plasma-derived clotting factors, but the risk has been reduced with further viral attenuation methods.46 The risk of hepatitis associated with use of plasma-derived preparations should be weighed against the risks of withholding treatment with anti-inhibitor coagulant complex.4, 32
Active immunization against HBV infection using hepatitis B vaccine is recommended by the American Academy of Pediatrics (AAP) for all children and is particularly important for patients with hemophilia and other congenital bleeding disorders.38, 47 It is recommended that hepatitis B vaccination be initiated at birth or at the time of diagnosis.38 Although postvaccination serologic testing to confirm immunity is not usually indicated after routine vaccination of infants, children, or adolescents, the National Hemophilia Foundation's Medical and Scientific Advisory Council (MASAC) recommends that such testing be performed 1-6 months following completion of hepatitis B vaccination in individuals with hemophilia and that nonresponders receive one or more additional doses of the vaccine.47 MASAC states that subsequent booster doses or additional serologic testing to assess antibody levels is not necessary in immunocompetent children and adults.47 (See Hepatitis B Vaccine 80:12.)
It has been recommended that susceptible patients who are receiving clotting factors be vaccinated against HAV infection.38, 46 MASAC recommends that all unvaccinated individuals with hemophilia or other bleeding disorders who are HAV seronegative receive hepatitis A vaccine at 2 years of age or older.38, 47 Although postvaccination serologic testing to confirm immunity is not usually indicated because of the high rate of vaccine response, MASAC strongly recommends such testing following hepatitis A vaccination in adults and children with hemophilia.47 (See Hepatitis A Virus Vaccine Inactivated 80:12.)
Coagulation factor concentrates prepared from pooled human plasma (e.g., antihemophilic factor [human], factor IX [human], factor IX complex, anti-inhibitor coagulant complex) are potential vehicles for transmission of human immunodeficiency virus (HIV).4, 26, 38 There is now considerable evidence that improved viral-depleting processes and improved donor screening practices used in the manufacture of currently available plasma-derived preparations have resulted in preparations with greatly reduced risk for transmission of HIV4, 26, 38 and there have been no reports of HIV seroconversion associated with any currently available plasma-derived clotting factor preparations.38 However, the possibility of transmission of HIV-1 or HIV-2 with use of viral-inactivated plasma-derived products still remains.38
Risk of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease
Because anti-inhibitor coagulant complex is prepared from human blood, it theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD).48, 53 There have been 3 reports of probable cases of vCJD acquired through transfusion of human red blood cells (RBCs) identified by an ongoing epidemiologic review being conducted in the United Kingdom.53, 69 One of these patients developed symptoms of vCJD 6.5 and 7.8 years, respectively, after receiving non-leukodepleted RBCs from 2 different donors; the donors developed clinical symptoms approximately 40 and 21 months after donating.69 The third probable case of transfusion-associated vCJD had no clinical symptoms of the disease prior to death, but abnormal prion protein was found in postmortem lymphoid tissue (5 years after RBC transfusion); the donor involved in this case had made the RBC donation 18 months before the onset of their clinical symptoms.69 Although attempts to transmit CJD to nonhuman primates via blood transfusion have failed, bovine spongiform encephalopathy (BSE) has been transmitted to at least one sheep through blood transfusion.48, 49
Tests are being developed to detect CJD and vCJD infection in blood and plasma donors.48 Until such donor screening tests are available for these diseases, the US Food and Drug Administration (FDA) has recommended interim preventive measures that include specific guidelines for deferral of blood and plasma donors with possible exposure to CJD and vCJD that are based on geographic considerations and guidelines for product retrieval, quarantine, and disposition that are based on consideration of risk in the donor and product and the effect that withdrawals and deferrals might have on the supply of blood, blood components, and plasma derivatives.48 For further information on CJD and vCJD precautions related to blood and blood products, the FDA's guidance for industry should be consulted ([Web]).48
Risk of West Nile Virus Infection
There is evidence that West Nile Virus (WNV) can be transmitted in transplanted organs (e.g., heart, liver, kidney) and blood products (e.g., whole blood, packed red blood cells, fresh frozen plasma).51, 52, 55, 56 WNV has been isolated from frozen plasma obtained from a blood donor subsequently found to have WNV, indicating that the virus can survive in frozen blood components.52 It is unlikely that WNV would be transmitted through commercially available plasma-derived preparations of clotting factors since WNV is an enveloped virus, like hepatitis C, which is known to be inactivated by the heat and solvent/detergent viral inactivation procedures used in the manufacture of these preparations.52, 54
During 2003, a specific test to screen donated blood for WNV became available under an investigational new drug (IND) protocol,57, 58 and this test has been used at all US blood centers since July 2003.58 The FDA also recommends additional measures to assess donor suitability to help screen out potential blood donors who have past or present manifestations that suggest WNV illness.52 All potential donors with a medical diagnosis of WNV infection (including diagnosis based on symptoms and laboratory results) should be deferred from blood donation for at least 28 days from onset of manifestations or until 14 days after the condition is considered to be resolved, whichever is later.52 In addition, the FDA recommends that between June 1 and November 30 of each year, potential donors should be asked if they have a history of headache and fever within the last week and they should be deferred for 28 days if the answer is yes.52 This donor questioning should begin earlier in the year if there are local reports of epizootic activity or human transmission of WNV and should end later in states where human infection with WNV is reported in November.52 These recommendations apply to whole blood and blood components intended for transfusion and blood components, including recovered plasma, source leukocytes, and source plasma intended for use in further manufacturing into injectable or noninjectable products.52
Because of the possible transmission of WNV through organ transplants and blood transfusions, any case of WNV that occurs in a patient who received organs, blood, or blood products within the 4 weeks preceding onset of the illness should be reported to CDC through state and local health authorities and serum or tissue samples should be retained for later studies.51, 52 In addition, cases of WNV infection occurring in blood or organ donors within 2 weeks after their donation should be reported to CDC.51, 52 Prompt reporting of such individuals will facilitate withdrawal of potentially infected products.51, 52
For further information on WNV precautions related to blood and blood products, the FDA's guidance for industry should be consulted ([Web]).52
Other Precautions and Contraindications
Anti-inhibitor coagulant complex is indicated only for the management of bleeding episodes in patients who have inhibitors and should not be used in the management of bleeding episodes resulting from coagulation deficiencies.22, 24, 28
Patients receiving anti-inhibitor coagulant complex should be observed closely for signs and symptoms of thromboembolic complications, including DIC.7, 22, 24 The fact that thromboembolic effects may occur during anti-inhibitor coagulant complex therapy, especially following high doses and/or in patients with thrombotic risk factors, should be considered.22, 24, 41 If any sign or symptom of thromboembolic complication occurs (e.g., changes in blood pressure or pulse rate, respiratory distress, chest pain, cough), anti-inhibitor coagulant complex therapy should be discontinued immediately and appropriate diagnostic and therapeutic measures initiated.24 The patient should be monitored for DIC with appropriate laboratory tests.24 Laboratory indicators of DIC include prolonged thrombin time, prothrombin time, and partial thromboplastin time test results, decreased fibrinogen concentration, decreased platelet count, and/or the presence of fibrin split products.24 Patients who do not have hemophilia but have acquired inhibitors to factors VIII, IX, or XII may have both a bleeding tendency and an increased risk of thrombosis at the same time.24
Some packaging components (e.g., vial closures, needle covers, syringe plungers) of Feiba® VH may contain natural latex proteins in the form of dry natural rubber and/or natural rubber latex (see the manufacturer's labeling).60, 61 Some individuals may be hypersensitive to natural latex proteins found in a wide range of medical devices, including such packaging components, and the level of sensitivity may vary depending on the form of natural rubber present;60, 61 rarely, hypersensitivity reactions to natural latex proteins have been fatal.61 Therefore, while the specific risk cannot necessarily be predicted,60 health-care professionals should take appropriate precautions when administration of such anti-inhibitor coagulant complex preparations is considered for individuals with a history of natural latex sensitivity.60, 61
Anti-inhibitor coagulant complex is contraindicated in patients with signs of fibrinolysis and in patients with disseminated intravascular coagulation (DIC).22, 24
The manufacturer of Feiba® VH states that there currently are no data available concerning use of the drug in neonates.24 Some clinicians suggest that anti-inhibitor coagulant complex be used with caution in neonates since there is a risk of thrombosis.43
Transient hypofibrinogenemia has been reported in a few children receiving anti-inhibitor coagulant complex.7, 22 There was no evidence of DIC in these children, and the hypofibrinogenemia was corrected by infusion of cryoprecipitate.7 Some clinicians recommend that fibrinogen levels be determined prior to the initial infusion and monitored throughout therapy when anti-inhibitor coagulant complex is used in children.43, 44, 45
Animal reproduction studies have not been performed to date with anti-inhibitor coagulant complex.24 It is not known whether anti-inhibitor coagulant complex can affect reproductive capacity or can cause fetal harm when administered to pregnant women, and the drug should be used during pregnancy only when clearly needed.24
The manufacturer states that because only limited data are available on concomitant administration of highly activated prothrombin complex preparations and antifibrinolytic agents such as aminocaproic acid or tranexamic acid, these agents probably should not be used concomitantly.24 The manufacturer of Feiba® VH suggests that antifibrinolytics be administered no sooner than 12 hours after administration of anti-inhibitor coagulant complex.24 It has been suggested by some clinicians that, although parenteral tranexamic acid should be avoided in patients receiving anti-inhibitor coagulant complex, a mouthwash containing the drug (10 mL of 4.8% tranexamic acid) probably can be used safely and effectively in patients receiving anti-inhibitor coagulant complex.4, 33
Anti-inhibitor coagulant complex contains varying amounts of factors II (prothrombin), VII (proconvertin or serum prothrombin conversion accelerator), IX (Christmas factor or plasma thromboplastin component), and X (Stuart-Prower factor).13, 14, 24, 25 Unlike commercially available factor IX complex (prothrombin complex concentrate, PCC), anti-inhibitor coagulant complex contains activated or partially activated forms of factor VII and factor X.13, 14, 16, 18, 24, 25 The mechanism by which anti-inhibitor coagulant complex temporarily reestablishes hemostasis in patients with hemophilia A who have antihemophilic factor inhibitors is unclear; however, the term “inhibitor bypassing activity” has been used to describe the effect.7, 9, 13, 14, 16, 18, 22, 25, 42 It has been suggested that efficacy of anti-inhibitor coagulant complex may be related in part to the presence of the activated factors (e.g., factor Xa and/or factor VIIa), which leads to more complete factor X activation in conjunction with tissue factor, phospholipid, and ionic calcium and allows the coagulation process to proceed beyond those stages where factor VIII is needed.13, 22, 24, 42 In addition, it has been suggested that factor IXa and phospholipids contained in the formulations may form a complex with factor VIII and delay its inactivation by antihemophilic factor inhibitors.6, 42
The duration of the inhibitor bypassing activity of anti-inhibitor coagulant complex following administration of the drug has not been determined.7 There is no evidence that administration of anti-inhibitor coagulant complex results in any change in factor XII or prekallikrein levels.14
Because anti-inhibitor coagulant complex contains procoagulant and activated coagulation factors, there is a risk that thromboembolic complications may be initiated in patients receiving the drug.14 However, thrombin formation apparently is mitigated by the presence of antithrombin III and other serine protease inhibitors that ultimately neutralize factors IXa and Xa and by the fact that factors VII and VIIa have short biologic half-lives.1 In addition, the presence of circulating antihemophilic factor inhibitors in these patients probably also helps control overactivation of the intrinsic coagulation system.1
The pharmacokinetics of anti-inhibitor coagulant complex after IV administration in patients with factor VIII inhibitors has not been fully evaluated.44, 45 Following IV administration of anti-inhibitor coagulant complex, increased levels of coagulation factors are evident within 10-30 minutes.14 Administration of Feiba® generally results in approximately equivalent increases in levels of II, VII, IX, and X.14
Anti-inhibitor coagulant complex, also referred to as activated prothrombin complex concentrate (APCC), is a sterile, lyophilized powder containing precursor and activated forms of blood coagulation factors II, VII, IX, and X prepared from pooled human venous plasma.3, 7, 14, 24
Feiba® VH is standardized by its ability to shorten the activated partial thromboplastin time (aPTT) of plasma containing antihemophilic factor inhibitors; potency is expressed in terms of Feiba® units of activity.9, 24 One unit of activity is that amount of Feiba® VH that shortens the aPTT of reference plasma containing a high titer of antihemophilic factor inhibitor to 50% of the blank value.24
Feiba® VH undergoes a 2-step vapor-heat treatment to reduce the risk of transmission of viral infection.24 The process involves vapor-heating for 10 hours at 60°C under excess pressure of 190 mbar followed by 1 hour at 80°C under excess pressure of 370 mbar.22, 24, 34 No method, however, has been shown to be totally effective in removing the risk of viral infectivity from coagulation factor preparations.6, 24, 38 (See Cautions: Precautions and Contraindications.)
When reconstituted as directed, Feiba® VH contains 4 mg of trisodium citrate and 8 mg of sodium chloride per mL.24 Feiba® VH also contains 1-6 units of antihemophilic factor antigen (VIII:Ag, VIII:C Ag) per mL and only trace amounts of factors of the kinin generating system; the preparation does not contain heparin.24
Anti-inhibitor coagulant complex powder for injection should be stored at 2-8°C.24 Alternatively, the powder for injection may be stored at room temperature (up to 25°C) for up to 6 months; after storage at room temperature, the powder should not be returned to a refrigerator.24 Freezing of the sterile water for injection diluent should be avoided to prevent breakage of the diluent bottle.24
The manufacturer of Feiba® VH states that reconstituted solutions of the drug should not be refrigerated and should be used within 3 hours following reconstitution.24, 44
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Nabi. Anti-inhibitor coagulant complex heat treated) Autoplex® T prescribing information. Glendale, CA; 1998 Apr.
2. Hutchinson RJ, Penner JA, Hensinger RN. Anti-inhibitor coagulant complex (Autoplex) in hemophilia inhibitor patients undergoing synovectomy. Pediatrics . 1983; 71:631-3. [PubMed 6601258]
3. Aronstam A, McLellan DS, Mbatha PS et al. The use of activated factor IX complex (Autoplex) in the management of haemarthroses in haemophiliacs with antibodies to factor VIII. Clin Lab Haemat . 1982; 4:231-8.
4. Lusher JM. Use of prothrombin complex concentrates in management of bleeding in hemophiliacs with inhibitors: benefits and limitations. Semin Hematol . 1994; 31(Suppl 4):49-52. [PubMed 7939776]
5. Lusher JM, Blatt PM, Penner JA et al. Autoplex versus Proplex: a controlled, double-blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII. Blood . 1983; 62:1135-8. [PubMed 6414555]
6. Laurian Y, Girma JP, Lambert T et al. Incidence of immune responses following 102 infusions of Autoplex in 18 hemophilic patients with antibody to factor VIII. Blood . 1984; 63:457-62. [PubMed 6419798]
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8. Piszkiewicz D, Thomas W, Lieu M et al. Heat inactivation of human immunodeficiency virus in lyophilized anti-inhibitor coagulant complex (Autoplex®). Thromb Res . 1986; 44:701-7. [PubMed 3492776]
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