| Recombinant
Factor VIIa (NovoSeven) for Traumatic Coagulopathy
Introduction
Recombinant
Factor VIIa (FVIIa) is currently licensed for use in haemophiliacs
with antibodies to Factor VIII. At present, its use in
trauma and haemorrhage is on a 'compassionate' basis.
The first published account of the use of Factor VIIa
in trauma was published by Gili Kenet in 1999. She described
the successful use of FVIIa in a soldier with traumatic
coagulopathy following a high velocity gunshot wound to
the inferior vena cava, near its bifurcation.
Structure
Factor VIIa is a trypsin-like serine
protease.
Recombinant Factor VIIa is produced
by Novo Nordisk AG, Copenhagen, Denmark and marketed as
Novoseven.
Function
Factor VIIa is an initiator of thrombin
generation. Factor VIIa acts primarily via two pathways
to activate Factor Xa. One pathway is at the site of tissue
injury complexed with Tissue Factor, and the other is
on the surface of platelets, independent of tissue factor.
1. Factor VIIa (FVIIa) forms an active
complex with Tissue Factor (TF). Tissue Factor is present
in the subendothelial layer of the vascular wall, and
hence is not normally free to complex with circulating
Factor VIIa. Following injury, the subendothelium is exposed
and Tissue Factor is free to bind FVIIa. This TF:VIIa
complex activates Factors IX & X.
2. Factor VIIa can also activate factors
IX & X on the platelet membrane, in the absence of
Tissue Factor. Although this is a lower affinity reaction
for generation of Factor Xa, Factor IXa subsequently activates
Factor Xa and amplifies this pathway dramatically. This
reaction is often referred to as the 'Thombin Burst' and
is thought to be responsible for the majority of fibrin
generated in response to a local injury.
Factor Xa, complexed with Factor V forms
a complex called Prothrombinase. Prothrombinase cleaves
Prothrombin to form Thrombin, which then generates Fibrin
from Fibrinogen.
Tissue Factor - VIIa to Thrombin Pathway
Theoretically, both of these mechanisms
localise the action of Factor VIIa to the site of injury,
and hence avoid the complications of thromboses occurring
in other vascular beds and leading to Acute Respiratory
Distress Syndrome, Acute Renal Failure and Multiple Organ
Dysfunction Syndrome.
Clinical Studies
Most reports of Factor VIIa use in trauma
are anecdotal in nature and comprise small case series.
To date there has been one prospective, randomized, double-blind
controlled trial of Factor VIIa in trauma, conducted by
Novo NorDisk.
Novo Nordisk conducted a Phase II multicentre,
multinational prospective randomised placebo-controlled
trial of Factor VIIa in traumatic shock in 2001-2003.
The final results have not yet been published, but results
were presented in part at the 6th World Congress on Shock,
Inflammation & Sepsis in Munich on 5th February 2004,
and at the American Association for the Surgery of Trauma
annual meeting in Maui, on the 1st October 2004.
Study Design
- Trauma patients who received 6 units
of red blood cells within the first 12 hours of admission
were randomised into the study, and the drug given after
the 8th unit of blood had been administered.
- Major traumatic brain injury was
excluded from the study.
- Blunt and penetrating injuries were
randomized separately.
- Study dosing was 200micrograms/kg
initially followed by 100micrograms/kg at 1 and 3 hours
after the first dose.
- The primary endpoint for the study
was transfusion requirement. Secondary endpoints were
mortality and organ failure.
Outcome
301 trauma patients were enrolled.
277 were analysed. Withdrawals were primarily for protocol
violations and data collection issues
143 blunt, 137 penetrating.
Overall, there was no significant difference
in outcome measures between the Factor VIIa and Placebo
groups.
Blood transfusions
After excluding early deaths (before
48 hours) from the analyses, there was a significant difference
in blood transfusion requirements within in the blunt
trauma group, and a trend towards decreased use in the
penetrating trauma patients.
Blunt trauma patients receiving Factor
VIIa were transfused a median of 2.6 units less blood
than patients receiving placebo (90% CI: 0.7-4.6 units).
There was also a significant reduction in FFP, platelet
and cryoprecipitate transfusions in the blunt trauma group.
Penetrating trauma patients had an estimated
reduction of blood transfusion requirements of one unit
(90% CI: 0-2.6 units) which did not reach significance.
Mortality
There was no significant difference
in mortality in the two groups:
Blunt: FVIIa 25%, Placebo: 30% (p=0.58)
Penetrating: Factor VIIa: 24%, Placebo: 28% (p=0.69)
Multiple Organ failure &
ARDS
There was a trend towards a reduced
incidence of multiple organ failure & ARDS in the
FVIIa group:
Blunt: FVIIa 10%, Placebo: 23% (p=0.07)
Penetrating: Factor VIIa: 7%, Placebo: 17% (p=0.11)
There was a similar trend to increased
ICU- and Ventilator- free days (30-day)
ICU-Free Days (30-day):
Blunt: FVIIa 13, Placebo: 8 (p=0.18)
Penetrating: Factor VIIa: 24 Placebo: 20 (p=0.26)
Ventilator-free days:
Blunt: FVIIa 17, Placebo: 14 (p=0.44)
Penetrating: Factor VIIa: 26, Placebo: 22 (p=0.17)
Comments
One of the main criticisms of the study
design has been the failure to identify a need for on-going
blood transfusion at the time of drug dosing. That is,
there was a possibility that patients receiving their
8th unit of blood had their haemorrhage controlled at
this point, were not coagulopathic and hence would not
have required procoagulant therapy under normal clinical
conditions.
Although blunt and penetrating groups
were randomized separately, it is possible to analyse
the two groups as one, as the study protocol was not different
between the groups. Analysing the 277 patients as a whole
cohort gives a signficant difference to the incidence
of ARDS/MOF, but mortality remains unchanged.
ARDS / Multiple Organ Failure:
Factor VIIa: 8.6%, Placebo: 20.3% (p=0.006)
To date, the largest cohort study is
from the Maryland Shock Trauma Institute. Dutton and coworkers
present a case series of 81 patients in which Factor VIIa
was given to trauma patients on a compassionate use basis.
This is rather a mixed bag of patients. 2 patients received
FVIIa for Factor VII deficiency, and 9 patients received
FVIIa for reversal of Warfarin anticoagulation in the
setting of 'life-threatening' haemorrhage.. Only 59 patients
received Factor VIIa within the first 24 hours of admission.
The authors found that PT was reduced
in all patients following administration. However, they
classified 20 of the 81 patients as 'non-responders' given
their continued requirement for blood & blood product
administration. However these non-responders had received
significantly more blood & fluid administration prior
to dosing with FVIIa, and were also more acidotic. at
the time of dosing. The authors attempted to compare their
results with historical controls matched for degree of
coagulopathy, injury type & severity. It is difficult
to draw any conclusions from this process, but mortality
was higher in the groups receiving FVIIa than in matched
controls.
Other smaller case series have mirrored
these findings.
Current studies of Factor VIIa include
a study by the Western Trauma Association to collect information
in trauma cases where Factor VIIa has been used. This
study is being coordinated by Dr. Peggy Knudson at San
Francisco General Hospital.
You can download the data entry form
here: FactorVIIa
DataSheet (pdf)
A Phase II/III trial of Factor VIIa
in the USA is currently in the design phase and should
start enrolling patients some time in 2005.
Pre-clinical studies
Meng and co-workers have studied the
effect of temperature and acidosis on the activity of
Factor VIIa with in-vitro studies of human volunteer blood.
They found that TF:VIIa activity was
reduced linearly with reduced temperature, retaining approximately
50% of its activity at temperatures of 28oC. However Factor
VIIa activity on platelet surface membranes rose as temperature
falls, probably due to increased stability of the protein
at lower temperatures. Thus hypothermia should have little
effect on FVIIa activity.
VIIa & TF:VIIa - Hypothermia
Factor VIIa activity falls dramatically
over the pH range 7.4 to 6.8, such that TF:VIIa activity
is reduced to 50% of normal at pH 7.0 and activity of
VIIa on platelet surfaces reduces even faster.
Factor VIIa - Acidosis
Decreasing the pH of the reactions decreased
the rate of FXa formation by the FVIIa/TF complex (solid
circles) and even more dramatically decreased the activity
of FVIIa alone on phospholipid vesicles (open diamonds).
Factor Xa Activity - Acidosis
Decreasing the pH also decreases the
rate of prothrombin activation by the FXa/FVa complex
on phospholipid vesicles.
There have been several animal studies
performed to evaluate dose and efficacy of recombinant
Factor VIIa in haemorrhagic shock & trauma. These
may be summarized as follows:
- No efficacy in non-coagulopathic
animals
- Reduction in blood loss and prothrombin
time (PT)
- No difference in mortality (but increased
time to death)
- Saturation of system at dose of 180micrograms/kg
(porcine)
Summary of FVIIa Studies
Factor VIIa lowers the Prothrombin Time
and reduces visible coagulopathic haemorrhage following
trauma. Factor VIIa reduces blood transfusion requirements
in blunt trauma patients (who have already received 8
units of blood) and there is a similar trend in penetrating
injury.
An outcome benefit in terms of mortality,
morbidity, ICU stay and cost has not been demonstrated,
although there was a trend to reduction in the incidence
of Multiple Organ Failure & ARDS. Cohort studies have
also not demonstrated improved survival from FVIIa administration.
There are several possible reasons for this, including
study methodology. It is conceivable that the drug was
given as salvage therapy too late, or with too severe
a metabolic derangement, for potential benefit to be seen
in this group of patients. Alternatively, FVIIa may have
adverse effects that counterbalance its effects in reducing
transfusion requirements.
There are two main safety concerns with
FVIIa:
1. FVIIa will lead to a hypercoagulable
state and increase the incidence of Deep Venous Thrombosis
and Pulmonary Embolism.
This has not been borne out in studies
in trauma, nor where FVIIa has been used for non-trauma
conditions.
1. FVIIa will lead to microvascular
coagulation and subsequent Acute Lung Injury (ALI), Acute
Renal Failure and the Multiple Organ Dysfunction Syndrome
(MODS). There are anecdotal reports of severe ARDS following
the use of FVIIa. However the Phase II trial above showed
an overall trend to reduced incidence of ARDS & MODS.
Concerns still exist however and should be addressed by
subsequent studies.
The dosing regimen in the Phase II trial
was 200mcg/kg initially followed by repeat dosing of 100mcg/kg
at 1 hour and 3 hours. The half-life of FVIIa is 2 hours,
so repeat dosing may be required, especially in the patient
with significant on-going haemorrhage.
Some investigators believe the initial
dose to be too high, and subsequent studies will likely
be conducted with reduced dosing. The recommended dose
of FVIIa in haemophiliacs in 90mcg/kg.
Recommendations
At this point there can be no firm recommendations
for the use of Factor VIIa in severe traumatic haemorrhage.
Factor VIIa is not yet licensed in any country for this
condition, and its use proceeds on a 'compassionate' basis.
Given the high cost associated with using Factor VIIa,
its use should be restricted to those situations where
it is likely to be of maximum benefit. Additionally, evidence
is emerging that the coagulant and metabolic milieu must
be favourable, or made favourable, for the drug to work.
At this stage the following recommendations
can be made:
- Where the use of Factor VIIa is
being considered, hospitals should have a set of guidelines
in place for the availability and use of Factor VIIa.
- The use of Factor VIIa should be
closely monitored and ideally submitted to a national
or international registry.
- Factor VIIa will not stop surgical
haemorrhage.
- Factor VIIa should not be given instead
of other blood product administration. Adequate FFP,
Cryoprecipitate and Platelets need to be present for
full effect.
- Factor VIIa should not be used too
early, but neither should it be used only after 'super-massive'
transfusions of 40-60 units. Therapy at between 8 and
20 red blood cell infusions is probably appropriate.
(opinion only)
- The current recommended dose is 100micrograms/kg.
This dose should be repeated at 1-2 hourly intervals
if required.
- The Prothrombin time is used to monitor
drug effect
- When the pH is below 7.2, consideration
should be given to:
- not using FVIIa (futility)
- increasing the dose of FVIIa
- Treating the patient with bicarbonate
or THAM to raise the pH (no evidence to support
this)
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