Netherlands Journal

netherlands journal of critical care
There have only been some non-significant trends towards an increased
incidence of thromboembolic complications in the treatment
arm.
There is also little evidence describing the existence of a dose-response
effect. However, there did appear to be a dose-response effect
for the treatment of intracerebral haemorrhage (ICH) with doses
of 160mcg/kg producing better outcomes than 40mcg/kg [31]. This
may be due to the unique mechanism that damage is produced by
ICH, which will be discussed later.
Factor VIIa and reversal of oral anticoagulants
The level of factor VII, one of the vitamin K-dependent coagulation
factors, decreases during oral anticoagulant therapy leading to an
increased prothrombin time. This can be reversed with factor VIIa
without producing systemic coagulation [32]. The lowest dose (5
microgram/kg) has been shown to normalize the INR for 12 h and
doses > 120 micro/kg normalized INR for 24 h [32]. Although only
one small study, this rapid reversal could be of benefit in the setting
of oral anti-coagulated patient that requires emergency surgery [32].
Recombinant FVIIa has also been shown to have some effect on
the newer anticoagulants. There is one case report of its efficacy in
reversing the effect of low molecular weight heparin [33]. There is
also evidence showing its benefit reversing the anticoagulant effect
of the pentasaccharide anticoagulants idraparinux and fondaparinux
[34-36]. However, drugs used to maintain anticoagulation after the
diagnosis of heparin-induced thrombocytopaenia – the direct acting
thrombin inhibitors - have been less successfully reversed by rFVIIa
[37].
Factor VIIa and Trauma
In civilian and military trauma, exsanguination accounts for 40% of
the mortality [38,39]. Blood transfusion in trauma is associated with
late complications and has been shown to be an independent risk factor
for the development of infection [40] and multiple organ failure
[41,42]. The coagulopathy associated with trauma is mutifactorial
including acidosis, hypothermia, haemodilution and consumption
– referred to as the ‘bloody vicious cycle’. If a patient develops the
lethal triad of hypothermia, acidosis and coagulopathy, then surgical
control alone is less likely to be effective [43]. These factors must all
be considered when assessing the use of rFVIIa in a trauma setting.
Acidosis
Acidosis affects enzyme activity [44] and platelet function [45,46].
In vitro, a reduction in pH from 7.4 to 7.0 resulted in a 90% reduction
in TF independent activity of rFVIIa and a 60% reduction in TF
dependent activity [44]. However, as rFVIIa administration increases
circulating FVIIa concentrations by 100 fold, it is not known how
the interaction of low pH and high rFVIIa concentration effects coagulation.
Given that the relative importance of TF independent and
dependant activity may vary according to the exact clinical situation,
the effect of acidosis becomes more difficult to quantify. Impaired
platelet function due to acidosis would also be expected to have a detrimental
affect on rFVIIa efficacy.
A retrospective analysis of 81 coagulopathic trauma patients treated
with rFVIIa, found that the mean pH in trauma patients responding
to rFVIIa treatment was 7.29 compared to a mean pH of 7.02 in
non-responders [47]. However, six out of twenty non-responders
had a pH > 7.1 whilst 5 patients with pH ≤ 7.1 did respond to treatment.
The Israeli Multidisciplinary rFVIIa Task Force reported a decline
in clinical response to rFVIIa in trauma patients at a pH below 7.2,
but the effect was only significant below 7.0 [23]. Thus, based on
information available there does appear to be a reduction in efficacy
with declining pH but acidosis can not be used as an absolute indicator
of the likely effectiveness of treatment. The Israeli Taskforce has
recommended a correction of pH to ≥ 7.2 prior to administration to
improve chances of effectiveness.
Hypothermia
Under experimental conditions, TF dependent activity of rFVIIa has
been shown to reduce by 20% with a decline in temperature from 37
to 33 degrees Celsius. However TF independent activity rises with
the fall in temperature [44]. Activity of the TF independent pathway
alone is likely to be limited by the lack of platelet activation under
hypothermic conditions [48].
Martinowitz and Michaelson [23] reported efficacy in trauma patients
with an average core temperature of 34.1 degrees. One study
reports efficacy at a body temperature as low as 30 degrees. Current
information suggests that rFVIIa can be expected to be useful for the
control of non-surgical bleeding under hypothermic conditions encountered
in trauma (e.g. 33 degrees C) but loss of TF activity and decreased
platelet function are likely to lead to reduced rFVIIa efficacy
as the temperature approaches 30 degrees [11].
Haemodilution / consumption
Changes in the concentrations of various components of the system
can greatly alter thrombin generation and the clotting process as a
whole [49]. In the absence of FX or FV, rFVIIa does not shorten in
vitro clotting times [50]. In a study of 13 patients receiving rFVIIa, the
responders had a better coagulation status as measured by fibrinogen
and platelet concentrations, PT and APTT at the time of administration
than the non-responders [51].
In order to optimise the opportunity for rFVIIa to be effective, it
is recommended that coagulation factors and platelets be replaced
as far as possible prior to administration [23, 52-54]. The direct loss
of clotting factors through haemorrhage rapidly reduces the body’s
small stores of fibrinogen and platelets and resuscitation that includes
blood components can still cause further dilution [55]. Haemodilution
and consumption can reach a point where a component
other than FVIIa becomes a rate limiting step and the benefit of rF-
VIIa is lost.
Overall efficacy
To date there is only one published RCT of the use of rFVIIa in trauma.
Boffard and colleagues [56] ran two parallel clinical trials for victims
of blunt (n=143) or penetrating trauma (n=134). Patients receiving
six units of blood in the initial 4 hours of hospital treatment were
randomised to receive 3 doses of rFVIIa (200, 100 and 100 mcg/kg) or
placebo following transfusion of the eighth unit of blood. These were
exceedingly large doses (see section above on dosing) and probably
unnecessarily so in patients with normal coagulation prior to injury.
In blunt trauma, RBC transfusion requirements were significantly
reduced, with the need for massive transfusion (>20 units) in only
14% compared to 33% of patients in placebo group. In penetrating
trauma there was a non-significant trend towards a reduction in RBC
and massive transfusion.
There was a trend in both groups towards a reduction in critical
complications (acute respiratory distress syndrome, multiple organ
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neth j crit care • volume 10 • no 5 • october 2006