Netherlands Journal

netherlands journal of critical care
thrombin generated in the initiation phase activates the platelets
forming a platelet plug and their surface is primed with factors Va,
VIIIa and XIa.
Factor IX is activated by both tissue-factors—factor VIIa complex
and factor XIa, so the coagulation cascade has moved to the platelet
surface where all the necessary factors are assembled ready for the
propagation stage [10].
Propagation
Factor IXa produced in both the initiation and amplification phases,
binds to the platelet surface and combines with FVIIIa to form the
tenase complex (FIXa/FVIIIa/calcium). This activates FX which combines
with FVa to form prothrombinase complex leading to the large
scale production of thrombin. Thrombin cleaves fibrinogen to fibrin
monomers, which polymerise to consolidate the initial platelet plug
and form a stable clot. This thrombin generation also exerts positive
feedback into the coagulation process by activating factors V, VIII, XI
and Thrombin Activatable Fibrinolysis Inhibitor (TAFI).
This process is localised to the site of injury by localised exposure
of TF causing localised binding and activation of FVII and platelets.
Factor VIIa Mechanism of Action
Normal circulating levels of FVII and FVIIa are in the ratio of 100:1
(10nmol/l and 0.10nmol/l respectively). Administration of rFVIIa increases
the circulating concentration of activated factor 100 fold (to
3-20nmol/l) [11]. Although it is widely agreed that rFVIIa acts by local
activation of thrombin production there is disagreement regarding
the exact mechanism by which this is achieved.
There are two principal pathways – TF-dependent and TF-independent
[12]. However both require the initial interaction of rFVIIa
with TF, which leads to the activation of FX and thrombin formation.
In the TF-dependent pathway, higher concentrations of FVIIa/TF
complex go on to enhance FXa production and subsequent thrombin
formation [13].
In the TF-independent pathway, rFVIIa itself activates FX on the
platelet surface. As platelets accumulate at the site of injury, FXa production
is independent of TF [10,14]. Although this reaction is less
efficient than activation by the FVIIa/TF complex, the pharmacological
concentration of factor offsets this inefficiency.
The continuation of both pathways requires the combination of
FXa with FVa on the platelet surface to form the prothrombinase
complex, which converts prothrombin to thrombin. This localised
generation of large amounts of thrombin may carry the additional
benefits of enhanced platelet adhesion and aggregation [15] as well
as producing thinner, more tightly packed fibrin fibres and increased
activation of thrombin activatable fibrinolysis inhibitor (TAFI) making
the clots more resistant to fibrinolysis [16,17].
It is worth noting, that since the process of haemostasis involves
both coagulation and anti-fibrinolysis (as stimulated in the propagation
phase described above), rFVIIa will never replace the rational
use of appropriately dosed antifibrinolytic drugs. The authors believe
the use of tranexamic acid should be considered in conjunction with
rFVIIa administration.
Laboratory Monitoring of the Effects of Factor VIIa
There is no definitive laboratory test that is satisfactory for monitoring
the efficacy of rFVIIa treatment. The use of Prothrombin Time (PT) is
recommended but a reduction in PT does not predict clinical haemostasis.
The improved clotting time reflects only the enzymatic activity
of FVIIa. It is not a marker of the therapeutic efficacy of FVIIa [18].
It can only be suggested that the correction of the PT to within
a normal range is an indicator that the drug was administered and
therefore may be beneficial [11]. The failure to reduce PT may also
predict non-responders.
Thromboelastography has been used to assess the effect of rFVIIa
[19]. It was found that the speed of clot formation and the physical
properties of the clot are improved, both of which cannot be detected
by routine coagulation tests. This correlates with the mechanism of
action being most probably dependant on the presence of activated
platelets which are localised to the site of the injury [20]. This would
also explain why there is little systemic activation of coagulation because
the maximum effect of rFVIIa occurs at the site of injury. The
best test of efficacy remains the observation of haemostasis.
Blood Product Management.
There are no universal guidelines or evidence for the efficacy of a
particular regime for fresh frozen plasma (FFP), platelets, fibrinogen
and cryoprecipitate replacement [21]. There is also very little information
to guide the use of rFVIIa outside its licensed indications.
Due to rFVIIa’s mechanism of action, severe thrombocytopaenia
(