Background

Factor VII (FVII) is a vitamin K-dependent coagulation factor synthesized in the liver. In 1986, Novo Nordisk began the development of recombinant activated coagulation factor VII, rFVIIa (eptacog alpha [activated], NovoSeven®). Initially developed to treat haemophilia patients with inhibitors against FVIII and FIX, it was granted an EU license in 1996 and gained FDA approval in the USA in 1999. Its potential to treat other haemorrhagic conditions was recognized soon after its clinical introduction, and it has been used off-label for a wide variety of conditions, predominantly in the emergency setting.

Between 2000 and 2008, off-label (including prophylactic) use of rFVIIa increased more than 140-fold and, in 2008, accounted for more than 97% of in-hospital use of the drug [1]. During this same period, in-hospital use for haemophilia patients increased only fourfold. However, evidence to support its off-label use is lacking with concerns about an increased incidence of thromboembolic events. A recent Cochrane review [2] of 25 randomized controlled trials (RCTs) (of which 11 examined the therapeutic use of rFVIIa) suggested that its off-label use should be restricted to clinical trials only.

Large trials or smaller series have examined the efficacy and safety of rFVIIa in, for example:

• Trauma (blunt and penetrating)
  
• Cerebral haemorrhage
  
• Post-cardiac surgery
  
• Prostatectomy
  
• Cirrhosis with gastrointestinal bleeding
  
• Hepatic surgery
  
• Major vascular surgery
  
• Major spinal surgery
  
• Postpartum haemorrhage
  
• Post-stem cell transplantation
  
• Reversal of anticoagulation

Mechanism of action

Following tissue injury, tissue factor (TF, a lipoprotein expressed in the sub-endothelium) is exposed to the circulation and activates FVII. FVIIa induces haemostasis at the injury site by forming a complex with TF derived from injured vessel wall endothelium. This reaction occurs on the surface of the sub-endothelial cells. FVIIa has little proteolytic activity until this complex forms. This initiation phase activates factor X (FX) independently of FVIII and FIX. FXa then binds to FVa on the cell surface.

In the amplification phase, FXa/FVa complex converts small amounts of prothrombin to thrombin, activating FV, FVIII, FIX and platelets locally. The propagation phase occurs on the surface of activated platelets, which bind these factors, with the FVIIIa/FIXa complex activating further FX. The FXa/FVa (prothrombinase) complex now converts large amounts of prothrombin to thrombin during a thrombin burst, leading to the formation of a stable fibrin clot.

At pharmacological dose, rFVIIa directly activates FX on the surface of locally activated platelets independent of TF. The quality of the resultant clot is dependent upon adequate concentrations of platelets and clotting factors. rFVIIa also mediates the inhibition of fibrinolysis, stabilizing clot formation.

Theoretically, this reaction should therefore be limited to activated platelets at the site of tissue injury. However, systemic activation has been described, and meta-analyses suggest an increased incidence of thromboembolic events when used off-label.

Presentation and dosing

For licensed (on-label) use, it is given as an intravenous bolus as early as possible in the bleeding episode at a dose of 90 mcg/kg. This dose is then repeated every 2–3 h until haemostasis is achieved (rFVIIa half-life is 2.4–3.2 h).

Off-label use of rFVIIa is somewhat more complicated. Although surgical procedures have used a similar dosing regimen, it is unclear to what extent these dosing guidelines can be applied to a heterogeneous, non-haemophiliac patient population. Reports describe doses of between 5 and 300 mcg/kg being administered for a wide variety of clinical indications [2]. It has been administered prophylactically before major surgery (predominantly cardiac and liver but also in prostate, pelvic and spinal surgery) and as a rescue therapy in uncontrolled haemorrhage [2].

Typical regimens have used an initial dose of 100–200 mcg/kg with up to two further doses depending upon response. However, some reports have suggested an absence of dose–response effect, and the optimum dosing regimen is still unclear. Our own guideline (available from the authors) is an initial dose of 100 mcg/kg followed by, if response is inadequate, one further dose of 120 mcg/kg after 2 h. Failure to respond to an initial dose is likely to indicate futility, and no more doses should be administered without careful consideration. A coagulation screen should be checked immediately before and 15 min after administration (due to the expected consumption of clotting factors), and this will direct further coagulation therapy.

Suggested parameters before rFVIIa use include:

• Correction of acidaemia (to a pH >7.2)
  
• Correction of hypothermia (>34 °C)
  
• An adequate number of viable platelets (>50 × 10⁹/L)
  
• Adequate circulating coagulation factors (especially FX, prothrombin, fibrinogen)
  
• Haemoglobin level above 7 g/dL

Following the administration of rFVIIa, rapid consumption of coagulation factors, platelets and fibrinogen typically necessitates replacement.

There is no direct way to monitor rFVIIa efficacy. Surrogate markers include a reduction in transfusion requirements and cessation of bleeding. A significant reduction in PT (often to less than the normal range) has been demonstrated within 15 min of the administration of rFVIIa with a concomitant reduction in activated partial thromboplastin time (APTT). However, reduction in PT does not completely reflect the in vivo effect of rFVIIa on coagulation and is not a reliable monitor of rFVIIa efficacy, although in rFVIIa-treated patients, prolonged PT values greater than or equal to 18 s were associated with significantly higher 24 h mortality.