Question 12

College Answer

a)   Recombinant activated protein C (drotrecogin alpha)

a)   endogenous human protein, a component of natural anti-coagulant system b)  Recombinant version shown to improve survival in septic shock in a RCT. c)  Indications for use:septic shoe2 system failure, APACHE II> 25
d)  Possible   mechanisms:   Sepsis   decreases    APC   levels   and    therefore
administration increases levels, Improved microcirculation through alteration 
of coagulation, Anti-inflammatory and antiapoptotic e)  Side effects:Bleeding
f)  Controversies:  Not   proven   in   immunocompromised  patients, increases mortality in paediatric population
g)  Expensive

b)  Recombinant coagulation Factor VIIa

a)   Novel agent for control of intractable hemorrhage
b)  Evidence   base:   hemophilia,   trauma,   post  cardiac  bypass,   intracranial hemorhage
c)   Mechanism: Causes a thrombin burst  which in tum  converts fibrinogen  to fibrin to form a clot
d)  Complications:DVT risk

e)   Expensive

Discussion

Following the shameful worldwide withdrawal of Drotrecogin Alpha, it seems unlikely that the candidates would ever be expected to "write short notes" on it in the ultra-pragmatic CICM fellowship exam. Thus, I will leave the discussion of its merits and demerits to the historians. Moreover, given the changing nature of the fellowship exam (trending further towards easy-to-mark data interpretation questions and tabulated comparisons), it is unlikely the candidates will ever be asked to write short notes on any topic whatsoever.

Recombinant Factor VIIa remains a possibly examinable topic. One might someday be expected to tabulate its advantages and limitations, or to critically evaluate its use.

Thus:

Rationale

• Factor VIIa is thought to act locally, binding to exposed tissue factor at the site of injury and promoting plateet binding.

Advantages

• According to RCTs, it decreases transfusion requirements in trauma
• "Relatively safe" according to a 2005 meta-analysis

Disadvantages

• Insanely expensive
• May promote thrombosis, eg. DVTs
• Not actually approved for use in lifethreatening haemorrhage; most use is thus off-licence.
• No improvement in mortality has ever been found.

Guidelines for practice

• Currently, in Australia the recombinant Factor VIIa is licenced for use only in the treatment of bleeding in patients with haemophilia A and B, who have a circulating inhibitor of the coagulation factor.
• Multiple guidelines for the off-licence use of this drug have emerged.
• After reviewing the available evidence, J.L Vincent's group have suggested that Factor VIIa can be used blunt trauma, post-partum hemorrhage, uncontrolled bleeding in surgical patients, and bleeding after cardiac surgery.
• Surgical haemostasis needs to have been achieved, say the haematologists who in Australia act as the curators of our FVIIa supplies. However, it is not clear that this is a mandatory component.  The Israeli guidelines (Martinowtz et al, 2005) specifically include as one of their indications "Failure to arrest the hemorrhage despite...  application of all accepted and available surgical measures (e.g. ligation of damaged vessels, tamponading, or packing of the bleeding site, and induction of localized thrombosis)". In short, surgical haemostasis is viewed by some to be a contraindication to the use of FVIIa. In contrast, the 2006 European guidelines (Vincent et al, 2006) recommend that "rFVIIa should be used only as an adjunctive therapy to surgical control", and there is some data that some intervention to control the haemorrhage improves mortality (Payen et al, 2016)

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.

O’Connell, Kathryn A., et al. "Thromboembolic adverse events after use of recombinant human coagulation factor VIIa." Jama 295.3 (2006): 293-298.

Levi, Marcel, Marjolein Peters, and Harry R. Büller. "Efficacy and safety of recombinant factor VIIa for treatment of severe bleeding: a systematic review."Critical care medicine 33.4 (2005): 883-890.

Yank, Veronica, et al. "Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications." Annals of Internal Medicine154.8 (2011): 529-540.

Willis, Cameron David, Peter A. Cameron, and L. E. Phillips. "Clinical guidelines and off‐license recombinant activated factor VII: content, use, and association with patient outcomes." Journal of Thrombosis and Haemostasis7.12 (2009): 2016-2022.

Vincent, Jean-Louis, et al. "Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding–a European perspective." Critical Care 10.4 (2006): R120.

Martinowitz, U., M. Michaelson, and Israeli Multidisciplinary rFVIIa Task Force. "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.

Payen, J-F., et al. "Reduced mortality by meeting guideline criteria before using recombinant activated factor VII in severe trauma patients with massive bleeding." BJA: British Journal of Anaesthesia 117.4 (2016): 470-476.