Protocol for use of rVIIa (NovoSeven) in uncontrolled haemorrhage

(except obstetric haemorrhage –see separate guideline)

Caution:Recent thrombosis or high risk (eg PE, MI, thrombotic stroke in last 6months; prosthetic heart valve) Discuss risks vs benefits of rVIIa with haematologist.

Instructions for reconstitution and injection of rVIIa (NovoSeven)

  1. If time allows, bring powder and water to room temperature (i.e. by holding in hands).
  1. Remove plastic stoppers on vials and wipe stoppers with alcohol swab.
  1. Open syringe package.
  1. Open vial adapter packet and screw on to syringe, taking care not to touch the tip of vial adapter.
  1. Pull plunger to draw in a volume of air equal to water in vial.
  1. Click the vial adapter on to the water vial.
  1. Push the plunger until you feel resistance.
  1. Hold syringe with water vial upside down and pull plunger to draw water in the syringe.
  1. Remove empty water vial, by tipping syringe with water adapter.
  1. Holding the syringe slightly tilted, click vial adapter on to powder vial.
  1. Inject the water into the powder vial.
  1. Gently swirl the vial until the powder is dissolved. Do not shake.
  1. Check solution for particulates and discolouration.
  1. Turn syringe upside down and pull plunger to draw up NovoSeven.
  1. Unscrew vial adapter from the empty vial.
  1. Attach to needle and dispose of sharps safely.
  1. NovoSeven should be administered intravenously over 2-3 minutes.
  1. Unused vials must be refrigerated and returned to Blood Bank as soon as possible.

Background and rationale for the protocol

Recombinant activated factor VIIa (rFVIIa) is licensed for the treatment of haemophilia with inhibitors, FVII deficiency and Glanzmann’s thrombasthenia with platelet refractoriness.

It’s off label use as a haemostatic agent in massive uncontrolled bleeding in a wide range of clinical scenarios is rapidly expanding, but no evidence-based guidelines are available.

Uncontrolled massive bleeding after trauma or complicated surgical procedures is frequently a combination of surgical and coagulopathic bleeding. Treatment of coagulopathic bleeding centres on replacement therapy with appropriate blood products, but may be unsuccessful in some cases of massive blood loss, predicting a poor outcome.

Mechanism of action of rVIIa

rVIIa is identical to the human plasma protein with only minor difference in post-translational carboxylation, hydroxylation and glycosylation. Its half-life is short: 2-3 hours in haemophiliacs with inhibitors, and less in children and bleeding individuals.

Coagulation models suggest that rVIIa enhances haemostasis at the site of injury without a systemic hypercoagulable effect. This is thought to explain the good safety profile of rVIIa with respect to thrombosis.

Its haemostatic effects are mediated by the thrombin it generates by both tissue factor dependent and independent mechanisms. The TF independent mechanism requires platelets for the direct activation of Factor X on their surface by rVIIa. It is likely that in the presence of TF, the more efficient TF-dependent mechanism predominates.

It is probable that the action of rVIIa requires the presence of adequate substrate for the reactions involved in securing adequate haemostasis. The minimum levels of other coagulation factors required are not known, but some authors have suggested minimum levels of fibrinogen required for an adequate response. Although there are case reports of the successful use of rVIIa in severe thrombocytopenia, the only randomised controlled trial in thrombocytopenic individuals suggested that a low platelet count is likely to predict a poor response to rVIIa therapy.

Both clinical and experimental data suggest that acidosis inhibits response to rVIIa treatment. Significant acidosis is very likely in severely ill bleeding patients, and may predict a poor response to rVIIa. There is currently no evidence that correction of acidosis prior to treatment improves the response to rVIIa.

Clinical studies of rVIIa treatment

Currently there is no good evidence that the use of rVIIa in uncontrolled haemorrhage as a result of trauma or surgery reduces mortality. The limited randomised controlled trial data available seem to suggest a trend towards lower transfusion requirements, but so far do not provide sufficient evidence to make firm recommendations for the use of rVIIa in ‘last ditch’ therapy situations.

Clinical decision making in these situations remains very difficult. This protocol is based on guidelines derived mainly from use of rVIIa in trauma patients, and is an attempt to provide practical guidance pending the availability of better evidence from well designed randomised controlled trials.

References:

Martinowitz U et al. Guidelines for the use of recomnbinant activated factor VII (r FVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary Task Force. J Thromb and Haemost, 2005; 3: 640-648

Mittal S and Watson HG. A critical appraisal of the use of recombinant factor VIIa in acquired bleeding conditions. BJ Haem, 2006; 133: 355-363