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Recombinant Factor VIIa

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 binds 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.

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.

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.

  • If the patient’s plasma FVII level is >25%, they can usually be managed with 15 mL/kg of FFP. Factor VIIa may be necessary if the patient is undergoing cardiothoracic, neurologic, ophthalmologic, or trauma surgery.
  • If the patients plasma FVII level is <25% and they are undergoing minor surgery, they should be initially treated with 15 mL/kg of FFP. Doses of 5 mL/kg of FFP can be repeated at 6 hour intervals until hemostasis is achieved.
  • If the patient’s plasma FVII level is <25% and they have a serious bleeding episode or are undergoing undergoing cardiothoracic, neurologic, ophthalmologic, or trauma surgery, they should be treated initially with rFVIIa at a dose of 15 – 30 ug/kg every 2 hours until hemostasis is achieved. Once bleeding is controlled, this dose can be administered every 6 to 12 hours as needed. This dose corresponds to a 1.2 mg vial for a 70 kg adult.

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.

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.

Factor VII is the first vitamin K dependent coagulation factor to be decreased by warfarin. Sometimes patients require urgent reversal of their prolonged INR for an intracerebral hemorrhage. Patients with life threatening or intracranial bleeding can be treated with 20 mL/kg of FFP and a single dose of rFVIIa. A single dose of 80 ug/kg of rFVIIa given within 4 hours after the onset of symptoms reduces hematoma growth, but does not improve mortality.

Off label use of rFVIIa has been associated with thromboembolic events, especially within the first 24 hours after the last dose. 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.

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