Recombinant Factor VII (NovoSeven)

This beast is new to appear on the scene of haemostatic pharmacotherapy. As far as the exam goes, Novoseven has been mentioned in some detail as a part of Question 12 from the first  paper of 2007. It is a vitamin K dependent factor which is available as a stand-alone infusion. As a means of reversing any specific coagulopathy, it is a weak actor. However, in the presence of bleeding, and with other factors normal, it promotes haemostasis by a strange mechanism.

It appears the Factor 7 is only useful in massive quantities, many times the amount which would normally be required to saturate the coagulation cascade. The dose is 100-400mcg/kg; historically most patients seem to receive about 90mcg/kg on average, and 80% of them receive only one dose. In the linked trial, this dose followed the transfusion of the eighth unit of packed cells, with additional doses 1 and 3 hours later. Its effect appears to come not from the supplementation of depleted factor 7 levels, but from a tissue-factor-independent activation of Factor X. Thus, it causes fibrin deposition and platelet aggregation at the site of injury, without causing a widespread prothrombotic state. This is supported by evidence of safety - the use of Factor 7 in the critically ill population does not seem to be associated with an increase in adverse thrombotic events.

The key feature of Factor 7 is its complete disregard for hypothermia. At a temperature of 33°, it will continue working while other coagulation factors fail. In a study by Martinowitz et al (2005), it retained its full activity at patient core temperatures around 34°C (+/- 2.5°C). It does, however, become inactivated by low pH, and in the acidotic patient at a pH of 7.00 it loses almost 90% of its activity. Its half life is short in trauma patients- about 2-3 hours, as opposed to 4-6 hours for normal subjects.

Interestingly, it is not licenced for use in acute trauma - and as there are not that many haemophiliacs around, 95% of its use seems to be off-label. The most recent PI states that NovoSeven is now indicated "for control of bleeding and surgical prophylaxis" in patients with Factor 7 inhibitors or a Factor 7 deficiency.

So, is it safe to use?

Probably, yes. It is difficult to observe mortality outcome statistics for this susbstance, because the patients who have received Factor 7 have traditionally been very ill patients with serious lifethreatenig problems. Naturally, they tend to die. So overall the mortality of patients receving Factor 7 is increased in comparison to the general ICU population.

The most recent published data seems to support the use of Factor 7 in acute refractory haemorrhage. Unfortunately, we are very good at managing trauma, and the mortality from it is so low that the investigators of the CONTROL trial lamented the difficulty of studying mortality in the era of modern trauma management. Because of awesome trauma skillz, their study turned out to be underpowered to detect a mortality benefit (and they didn't find one).

The canonical NBA guidelines on the management of massive transfusion make no specific recommendations for the use of Factor 7, and merely point out that the product seems to decrease RBC transfusion requirements in patients with blunt trauma, but not in penetrating trauma.


For details of reversal of anticoagulation, I direct you all to the NHMRC guidelines:

Clinical practice guidelines on the use of blood components (2001)

Boffard, Kenneth David, et al. "Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials." Journal of Trauma-Injury Infection and Critical Care 59.1 (2005): 8-18.

Klitgaard, Thomas, and Tina G. Nielsen. "Overview of the human pharmacokinetics of recombinant activated factor VII." British journal of clinical pharmacology 65.1 (2008): 3-11.

The propaganda PI pamphlet of the Novo Nordisk corporation who distrbute NovoSeven is available for review.

Brophy, Gretchen M., et al. "Recombinant Activated Factor VII Use in Critically III Patients: Clinical Outcomes and Thromboembolic Events." Annals of Pharmacotherapy 47.4 (2013): 447-454.

Hauser, Carl J., et al. "Results of the CONTROL trial: efficacy and safety of recombinant activated Factor VII in the management of refractory traumatic hemorrhage." Journal of Trauma-Injury, Infection, and Critical Care 69.3 (2010): 489-500.

Martinowitz, U., and M. Michaelson. "Guidelines for the use of recombinant activated factor VII (rFVIIa) in uncontrolled bleeding: a report by the Israeli Multidisciplinary rFVIIa Task Force." Journal of Thrombosis and Haemostasis 3.4 (2005): 640-648.