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Recombinant Factor VIIa (rFVIIa, NovoSeven) received FDA approval for the treatment of bleeding in hemophilia patients with inhibitors to Factor VIII or Factor IX on April 19, 1999. More recently, it has been used off-label for a variety of bleeding disorders. Factor VIIa complexes with tissue factor at the site of injury and induces activation of Factor X, resulting in clot formation. Supraphysiologic doses of rFVIIa bind directly to tissue factor that is exposed on damaged endothelium and directly activates Factor X, bypassing the intrinsic pathway of coagulation. It also bindings directly to thrombin activated platelets. Recombinant Factor VIIa is supplied in three sizes: 1.2, 2.4 and 4.8 mg per vial. The product is supplied as a freeze-dried powder that is reconstituted in sterile water. It should be administered by IV push over a period of one to two minutes within 3 hours after reconstitution. Currently, there is no satisfactory laboratory test to monitor the clinical effectiveness of rFVIIa. Protime and aPTT shorten, but do not necessarily reflect clinical effectiveness. Indications for rFVIIaHemophilia A or B with an inhibitor Recombinant FVIIa is appropriate for management of acute hemorrhage in hemophilia patients with high-titer inhibitors (>5 BU). The recommended dose of rFVIIa is 90 ug/kg by IV bolus given every two hours for 24 hours or until hemostasis is achieved. Once the patient is stabilized, the interval between treatments can be lengthened to 3-6 hours. This dosage schedule can be used for patients undergoing major surgery or treatment of serious CNS, intraperitoneal, retroperitoneal or intramuscular (compartment syndrome) bleeding. For major surgery, a dose of 90 to 120 ug/kg is given every 2 hours for the first 48 hours. The dose can often be decreased to every 4 hours during the third and fourth postoperative days and then to every 6 hours for another week. A dosage of 90 ug/kg corresponds to plasma levels of 2 ug per mL, assuming 100% recovery. The goal of therapy is to increase peak levels of FVII functional clotting activity (FVII: C), measured immediately after the initial dose, to above 30 U/mL and preferably between 60 and 90 U/mL. Steady state levels measured 2 hours after 90 ug/kg NovoSeven administration following two days of dosing at 2-hour intervals average 28 U/mL. The protime shortens significantly and often plateaus around 7 seconds. The aPTT may shorten as much as 15 to 20 seconds, but usually does not completely normalize. An advantage of Factor VIIa is its lower risk of DIC. However, DIC may occur if a patient is first treated with activated prothrombin complex concentrate (APCC) and then switched to rFVIIa. DIC can be prevented by waiting several hours between discontinuing APCC and starting rFVIIa infusions. Congenital FVII Deficiency FVII deficiency is a rare coagulation disorder that may be associated with spontaneous bleeding episodes in severely deficient patients or bleeding after surgery in mildly affected patients.
Patients with thrombocytopenia have impaired thrombin generation. FVIIa enhances thrombin generation on already activated platelets and may be useful in patients with profuse bleeding who are not responding to platelet transfusions. Patients should first be transfused with platelets, cryoprecipitate and RBCs. DDAVP and Amicar may also be indicated. Dialysis is recommended if the patient is uremic. If all of these measures do not control the bleeding, a single 4.8 mg vial of rFVIIa may be helpful. Patients with Glanzman's thrombasthenia have been successfully treated with rFVIIa for surgical prophylaxis or to control excessive menstrual bleeding. This therapy is especially effective for those patients who have developed platelet alloantibody from previous platelet transfusions. The dosage needed to control hemostasis has varied from 90 to120 ug/kg. Complex Surgery and Trauma Patients undergoing extensive surgery and patients bleeding after severe trauma develop multiple hemostatic defects. Coagulation factors and platelets are both consumed and diluted by massive transfusion and infusion of volume expanders. Coagulation is impaired by hypothermia and acidosis Patients should first be transfused with platelets, FFP, cryoprecipitate and RBCs. Criteria for rFVIIa usage in trauma patients have been developed by the University of Southern California and include:
Liver Disease A dose of 15 to 30 ug/kg is often sufficient, but a dose of 90 ug/kg may be necessary if bleeding is severe. The use of rFVIIa should be reserved for those cases where bleeding cannot be controlled by standard blood component therapy. Factor XI Deficiency rFVIIa has been used to treat patients with factor XI deficiency either with or without an inhibitor. Doses of 90 to 120 ug/kg every 2 to 3 hours until bleeding has ceased have been effective. Warfarin Reversal Factor VII is the first vitamin K dependent coagulation factor to be decreased by warfarin. Sometimes patients require urgent reversal of their prolonged INR after head trauma or prior to an invasive procedure.
Studies have shown that rFVIIa can control the expansion of of intracranial hematomas, thereby improving neurologic outcome and decreasing mortality. For nontraumatic intracranial bleeding, rFVIIa is beneficial if it is administered within 4 hours of the onset of symptoms. A single dose of 90 ug/kg body weight is recommended. Severe arterial and venous thromboembolic events occurred in 7% of the rFVIIa treated groups, compared to 2% of the placebo group. Patients with a medical history of thrombotic or vaso-occlusive disease, should probably be excluded from treatment with rFVIIa. Cardiac Surgery Recombinant FVIIa was studied in 51 cardiac surgery patients with intractable blood loss at Toronto General Hospital. Blood loss was considered massive if it exceeded 2000 mL. Blood loss and blood component usage were significantly reduced after a single vial of 2.4 mg of rFVIIa. A second dose was given if blood loss continued at >100 mL per hour. The median time interval between doses was 2.5 hours. One third of cases required a second dose of 2.4 mg. Patients treated with rFVIIa had a higher incidence of acute renal failure, a trend toward higher incidence of stroke, and a longer length of stay in the ICU and the hospital. Preterm and Term Infants The smallest vial of rFVIIa is 1.2 mg. For a 1.5 kg preterm infant, this dose would give an extremely high dose of 800 ug/kg if an entire vial were administered. Therefore, it is necessary to ask pharmacy to reconstitute a 1.2 mg vial and then divide it into 4 or 6 aliquots. One aliquot is infused at a time, with a goal of using all of the aliquots within 24 hours. Adverse Effects A review of adverse events reported to the FDA from 1999 through December 31, 2004 documented 185 thromboembolic events. Most of these events occurred within the first 24 hours after the last dose in patients being treated for off-label uses. Many of the patients who experienced an adverse event were elderly with existing atherosclerotic disease. Thromboembolic events included cerebrovascular, acute myocardial infarction, other arterial thrombosis, pulmonary embolism, other venous thrombosis, and clotted devices. In 50 cases, thromboembolism was the probable cause of death. Updated March 16, 2007 |
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