blood loss, whereas all other factors seem to be
less affected by haemodilution and blood loss; 11
this has been observed in both adult and
paediatric perioperative settings. 1
Fibrinogen plays several key roles in the
maintenance of haemostasis. 12,13 Fibrinogen acts
by crosslinking platelets via glycoprotein IIb–IIIa
receptors, which builds the surface for the
following haemostatic process, and is the key
substrate for activated thrombin, which converts
it to fibrin, the key component of the
mechanically stable clot. It is well known that
acquired hypofibrinogenaemia seems to be the
leading determinant in dilutional coagulopathy
in adults and children. 1,14–18
Plasma and cryoprecipitate are alternative
sources of fibrinogen. Cryoprecipitate contains
higher concentrations of fibrinogen than plasma,
but was withdrawn from several European
countries because of the risk of immunologic
reactions and potential transmission of infectious
agents. It should be acknowledged that
recommended doses for plasma of 10–15ml/kg
might not be adequate to achieve a clinically
meaningful improvement in haemostatic
potential. 11
Fibrinogen activity can be assessed by the
Clauss assay, and current recommendations
emphasise a trigger level of 150–200mg/dl for
initiating fibrinogen substitution therapy in
a bleeding patient. 19 Ideally, functional fibrinogen
activity can be assessed reliably and much faster
using the ROTEM ® or TEG ® . As such, fibrinogen
substitution can be initiated if maximum clot
firmness (MCF) at 10 minutes (A10) is ≤ 7mm,
which approximates to a Clauss assay of ≤ 150
mg/dl. 3
Clinical studies in adults have demonstrated
a beneficial role for intraoperative substitution
with human fibrinogen concentrate to treat
hypofibrinogenaemia 20–25 with a very good safety
profile. 26,27 A randomised clinical trial in children
who underwent major craniofacial surgery has
demonstrated that early intraoperative fibrinogen
substitution at a dose of 30mg/kg using a
threshold of ROTEM ® FIBTEM MCF <13mm has
led to a significant and clinically relevant
reduction of transfused red blood cell
concentrates compared with a lower threshold of
a FIBTEM MCF <8mm. 10 Although blood loss was
still considerable, neither transfusion of plasma
nor platelet was necessary. At the same time,
earlier substitution with fibrinogen decreased
calculated blood loss from a median of 156.9% to
89.7%. No postoperative RBC transfusion in any
child was necessary, which is in sharp contrast
to published data for children who underwent
major craniofacial surgeries, where postoperative
transfusion occurred relatively frequently
(26–40%). Notably, this management was not
linked to a significant increase in total costs for
transfused allogeneic blood products and
coagulation factors thus offering an economically
equivalent approach to coagulation
management. 28
Data from a randomised clinical trial in
children undergoing cardiac surgery showed that
fibrinogen concentrate was as efficient and safe as
transfusion of cryoprecipitate in the management
of bleeding after cardiopulmonary bypass
weaning. 29 In the same setting, a retrospective
Prompt
and timely
identification of
the underlying
coagulopathy
and,
consequently,
individualised
treatment of
depleted factors
are the mainstay
of a modern
and advanced
coagulation
management
data analysis in children who underwent
cardiopulmonary bypass surgery revealed a
significant reduction in transfusion requirements
for cryoprecipitate and fresh frozen plasma, if
fibrinogen concentrate at a dose of 70mg/kg was
given in the rewarming phase. 30 A meta-analysis
of 14 randomised clinical trials in adult and
paediatric cardiosurgical patients demonstrated
that all-cause mortality was lower in the
fibrinogen concentrate group, and bleeding and
transfusion requirements were significantly lower
versus placebo or a comparator group. 31 There
were no differences in the rates of thrombotic
events and myocardial infarction.
Analysis of our own data showed that a dose
of 30mg/kg can increase FIBTEM clot firmness
approximately 3mm, which may be insufficient
in most cases of more severe bleeding conditions
with acquired hypofibrinogenaemia. Thus, a dose
of 50mg/kg has become standard in our hospital,
which is likely to increase the FIBTEM MCF at
least 5mm.
In summary, fibrinogen concentrate is highly
efficient in treating acquired hypofibrinogenaemia,
offers a good safety profile, is almost immediately
available, can be stored at room temperature, can
be timely and reliably guided by viscoelastic
testing, and can be administered in a very short
time.
Prothrombin complex concentrate
Prothrombin complex concentrates (PCCs) are
licensed for rapid reversal of low vitamin
K-dependent coagulation factor levels due to
vitamin K antagonists in the setting of active
bleeding and for urgent prophylaxis of bleeding.
Besides that, PCC is frequently used in adult
patients to correct coagulopathy with low vitamin
K-dependent coagulation factor levels and
perioperative bleeding. 32,33 However, data on its
off-label use in children are very limited. Analysis
of a 5-year retrospective case series in patients
aged from 0–16 years has demonstrated
favourable efficacy and safety of PCCs. 34 In that
study, 11 patients were treated for vitamin K
antagonist-related reversal of high international
normalised ratio (INR), two children were treated
for elevated INR not related to vitamin K
antagonist use, and for intractable bleeding
post-cardiopulmonary bypass surgery in three
children. However, total sample size was small,
and dosing regimen was not based on evidence-
based data. One thrombotic event was
documented, but true contribution to PCC was
unclear. Data from ex vivo supplemention of PCC
to blood samples obtained from neonates after
cardiopulmonary bypass showed that even a very
low dose of 4.7–14U/kg was sufficient to enhance
lag time, the peak amount, and the rate of
thrombin generation. 35 A case report has
described the effective use of PCC in a newborn
suffering from spontaneous intracranial bleeding,
and who did not receive vitamin K
supplementation at birth. 36
As a result, there is little evidence on the safety
and efficacy of PCC in children. However, for
treatment of severe bleeding episodes, where
plasma is unavailable as a source of coagulation
factors, or where there is a risk of hypervolaemia
due to large amounts of plasma, use of PCC might
offer a useful approach.
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