Factor FXIII concentrate
Factor XIII represents another major contributor
in achieving clot stability by cross-linking fibrin
monomers, and preventing clot lysis by covalent
binding of α2-plasmin inhibitor to fibrin
molecules. Although congenital FXIII deficiency is
a very rare bleeding disorder, there are clinical
data proving that acquired FXIII deficiency can be
observed frequently during major paediatric
surgery. 37,38 In the latter study, FXIII levels
decreased to minimal levels of activity of 33%
(15–61%), which has been determined to be the
lower threshold in adults to initiate FXIII
supplementation. 3 However, clinical efficacy of
FXIII administration to treat acquired FXIII
deficiency in paediatric surgery is currently based
on clinical observation rather than on evidence-
based data.
Recombinant activated FVII
Management of intractable bleeding has led to
a call for a defined rescue therapy. Although it
is well known that some prerequisites including
normothermia, undisturbed acid–base status,
and normal calcium levels, as well as sufficient
platelet count and plasma fibrinogen levels are
the mainstay for adequate clot building, many
authors have declared a special role in improving
thrombin potential to enable cessation of
bleeding. Therefore, administration of
recombinant activated FVII (rFVIIa) has been
advocated, whereby clinical evidence to support
its use are lacking.
Activated rFVII is licensed for the treatment
of patients with haemophilia A or B with
inhibitors, and patients with congenital FVII
deficiency. In Europe, additional approval was
granted for treatment of Glanzmann’s
thrombasthenia. There are published data for
the off-label treatment using rFVIIa to stop
severe bleeding in children with bleeding
during neurosurgical procedures 39,40 and
cardiac surgery. 41 It has been hypothesised that
administration of rFVIIa for treatment of severe
bleeding in adults may only be efficacious if
critical amounts of fibrinogen and platelets have
been established. 3 As no clear dose has been
established, sound evidence-based data are
lacking, and the treatment using rFVIIa increases
thromboembolic risk considerably, a recent
Cochrane analysis has advocated against the use
of rFVIIa outside its licensed indications. 42
Conclusions
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. The use of coagulation
factors as part of an algorithm offers great
advantages for effective bleeding management,
as it does not require cross-matching or thawing,
is almost immediately available, it does not
alter serum ionised calcium level, it is less
immunogeneic, the increase in desired
coagulation factor levels can be reliably
calculated, and it can be administered in a
significantly less volume than plasma transfusion.
Although more clinical data in children are
needed, this approach seems very likely to permit
rapid and effective targeted management.
References
1 Haas T et al. Management of
dilutional coagulopathy during
pediatric major surgery. Transfus
Med Hemother 2012;39:114–19.
2 American Society of
Anesthesiologists Task Force on
Perioperative Blood M. Practice
guidelines for perioperative
blood management: an updated
report by the American Society
of Anesthesiologists Task
Force on Perioperative Blood
Management. Anesthesiology
2015;122:241–75.
3 Kozek-Langenecker SA et
al. Management of severe
perioperative bleeding:
guidelines from the European
Society of Anaesthesiology: First
update 2016. Eur J Anaesthesiol
2017;34:332–95.
4 El Kady N et al. Perioperative
assessment of coagulation in
paediatric neurosurgical patients
using thromboelastography. Eur
J Anaesthesiol 2009;26:293–7.
5 Romlin BS et al. Earlier
detection of coagulopathy with
thromboelastometry during
pediatric cardiac surgery: a
prospective observational study.
Paediatr Anaesth 2013;23:222–7.
6 Faraoni D et al. Development
of a specific algorithm to guide
haemostatic therapy in children
undergoing cardiac surgery:
a single-centre retrospective
study. Eur J Anaesthesiol
2015;32:320–9.
7 Faraoni D et al. Plasma
fibrinogen concentration is
correlated with postoperative
blood loss in children
undergoing cardiac surgery.
A retrospective review. Eur J
Anaesthesiol 2014;31:317–26.
8 Nakayama Y et al.
Thromboelastometry-guided
intraoperative haemostatic
management reduces bleeding
and red cell transfusion after
paediatric cardiac surgery. Br J
Anaesth 2015;114:91–102.
9 Weber CF et al. Point-of-
care testing: a prospective,
randomized clinical trial of
efficacy in coagulopathic cardiac
surgery patients. Anesthesiology
2012;117:531–47.
10 Haas T et al. Higher fibrinogen
concentrations for reduction
of transfusion requirements
during major paediatric surgery:
A prospective randomised
controlled trial. Br J Anaesth
2015;115:234–43.
11 Levy JH, Welsby I, Goodnough
LT. Fibrinogen as
a therapeutic target for
bleeding: a review of critical
levels and replacement therapy.
Transfusion 2014;54:1389–1405;
quiz 1388.
12 Levy JH et al. Fibrinogen and
hemostasis:
a primary hemostatic target for
the management
of acquired bleeding. Anesth
Analg 2012;114:261–74.
13 Sorensen B et al. Fibrinogen
as a hemostatic agent. Semin
Thromb Haemost 2012;38:
268–73.
14 Fenger-Eriksen C et al.
Mechanisms of hydroxyethyl
starch-induced dilutional
coagulopathy. J Thromb
Haemost 2009;7:1099–105.
15 Levy JH. Massive transfusion
coagulopathy. Semin Hematol
2006;43:S59–S63.
16 Fries D. [Dilutional
coagulopathy: development,
diagnostic options
and management].
Haemostaseologie 2006;26:
S15–S19.
17 Kozek-Langenecker S.
21
HHE 2018 | hospitalhealthcare.com
Management of massive
operative blood loss. Minerva
Anestesiol 2007;73:401–15.
18 Innerhofer P, Kienast J.
Principles of perioperative
coagulopathy. Best practice
and research. Clin Anaesthesiol
2010;24:1–14.
19 Rossaint R et al. Management
of bleeding following major
trauma: an updated European
guideline. Crit Care 2010;14:R52.
20 Haas T et al. Fibrinogen in
craniosynostosis surgery. Anesth
Analg 2008;106:725–31.
21 Rahe-Meyer N et al.
Thromboelastometry-guided
administration of fibrinogen
concentrate for the treatment
of excessive intraoperative
bleeding in thoracoabdominal
aortic aneurysm surgery.
J Thorac Cardiovasc Surg
2009;138:694–702.
22 Fenger-Eriksen C et al.
Fibrinogen substitution
improves whole blood clot
firmness after dilution with
hydroxyethyl starch in bleeding
patients undergoing radical
cystectomy: a randomized,
placebo-controlled clinical
trial. J Thromb Haemost
2009;7:795–802.
23 Fenger-Eriksen C et al.
Fibrinogen concentrate
substitution therapy in patients
with massive haemorrhage
and low plasma fibrinogen
concentrations. Br J Anaesth
2008;101:769–73.
24 Danes AF et al. Efficacy and
tolerability of human fibrinogen
concentrate administration
to patients with acquired
fibrinogen deficiency and active
or in high-risk severe bleeding.
Vox Sang 2008;94:221–6.
25 Weinkove R, Rangarajan
S. Fibrinogen concentrate for
acquired hypofibrinogenaemic
states. Transfus Med
2008;18:151–7.
26 Dickneite G et al. Animal
model and clinical evidence
indicating low thrombogenic
potential of fibrinogen
concentrate (Haemocomplettan
P). Blood Coagul Fibrinolysis
2009;20:535–40.
27 Manco-Johnson MJ et al.
Pharmacokinetics and safety
of fibrinogen concentrate. J
Thromb Haemost 2009;7:2064–9.
28 Haas T et al. Economic aspects
of intraoperative coagulation
management targeting higher
fibrinogen concentrations
during major craniosynostosis
surgery. Paediatr Anaesth
2016;26:77–83.
29 Galas FR et al. Hemostatic
effects of fibrinogen concentrate
compared with cryoprecipitate
in children after cardiac surgery:
a randomized pilot trial.
J Thorac Cardiovasc Surg
2014;148:1647–55.
30 Tirotta C et al. Use of human
fibrinogen concentrate in
pediatric cardiac surgery. Int
J Anesthetic Anesthesiol
2015;2:1–6.
31 Fominskiy E et al. Efficacy
and safety of fibrinogen
concentrate in surgical patients:
A meta-analysis of randomized
controlled trials. J Cardiothorac
Vasc Anesth 2016;30:1196–1204.
32 Despotis G, Eby C, Lublin
DM. A review of transfusion
risks and optimal management
of perioperative bleeding with
cardiac surgery. Transfusion
2008;48:2S–30S.
33 Butchart EG et al.
Exercise Physiology ESoC.
Recommendations for the
management of patients after
heart valve surgery. Eur Heart
J 2005;26:2463–71.
34 Noga T et al. Four-factor
prothrombin complex
concentrates in paediatric
patients – a retrospective case
series. Vox Sang 2016;110:253–7.
35 Franklin SW et al. Optimizing
thrombin generation with
4-Factor prothrombin complex
concentrates in neonatal plasma
after cardiopulmonary bypass.
Anesth Analg 2016;122:935–42.
36 Rech MA et al. Prothrombin
complex concentrate for
intracerebral hemorrhage
secondary to vitamin K
deficiency bleeding in
a 6-week-old child. J Pediatr
2015;167:1443–4.
37 Korte W. [Fibrin monomer
and factor XIII: a new concept
for unexplained intraoperative
coagulopathy]. Hamostaseologie
2006;26:S30–35.
38 Haas T et al. Perioperative
course of FXIII in children
undergoing major
surgery. Paediatr Anaesth
2012;22(7):641–6.
39 Uhrig L et al. Use of
recombinant activated factor
VII in intractable bleeding
during pediatric neurosurgical
procedures. Pediatr Crit Care
Med 2007;8:576–9.
40 Heisel M et al. Use of
recombinant factor VIIa (rFVIIa)
to control intraoperative
bleeding in pediatric brain tumor
patients. Pediatr Blood Cancer
2004;43:703–05.
41 Ekert H et al. Elective
administration in infants
of low-dose recombinant
activated factor VII (rFVIIa) in
cardiopulmonary bypass surgery
for congenital heart disease does
not shorten time to chest closure
or reduce blood loss and need
for transfusions:
a randomized, double-blind,
parallel group, placebo-
controlled study of rFVIIa
and standard haemostatic
replacement therapy versus
standard haemostatic
replacement therapy. Blood
Coagul Fibrinolysis 2006;17:
389–95.
42 Simpson E et al. Recombinant
factor VIIa for the prevention
and treatment of bleeding in
patients without haemophilia.
Cochrane Database Sys Rev
2012;3:CD005011.