Coagulation
and complement
systems descend
from a common
ancestral
pathway
and have
an extensive
crosstalk
(HMW) and low-molecular weight (LMW)
fibrinogen. They act differently in terms of fibrin
network characteristics and wound healing. HMW
fibrinogen produces a fibrin clot with thick fibres
and limited fibre density, whereas the LMW
fibrinogen produces clots with thin fibres at
higher density. 5 The low-density clots produced
by HMW fibrinogen promote angiogenesis in
wound healing at a better rate than high-density
clots.
A second very important role of fibrinogen is
its ability to cross-link platelets, promoting the
platelet aggregation process. Silent platelets may
be activated through a number of different
receptors and pathways; the protease-activating
receptors (PAR) are one of the most powerful
activating receptors, and PAR-dependent platelet
activation is triggered by thrombin. Once
activated, platelets express the integrin αIIb β3
(better known as the GP IIb/IIIa receptor) on their
surface. The GP IIb/IIIa receptor binds fibrinogen,
producing a cross-link between platelets (platelet
aggregation).
The haemostatic process is promoted by
a thrombin burst which, in turn, results in fibrin
polymerisation and platelet aggregation: in both
processes, fibrinogen is an essential player.
Thrombin is essential to trigger fibrinogen
conversion into fibrin; reptile venoms (reptilase,
botropase) are able to convert fibrinogen into
fibrin independently from thrombin, and
this property is used in some point-of-care tests
(platelet-mapping thromboelastography) to create
a fibrin-dependent, thrombin-independent clot.
Fibrinogen-dependent platelet aggregation is
blunted by GP IIb/IIIa inhibitors (commonly used
in clinical practice). Again, this mechanism is
used to separate fibrin(ogen)-dependent and
platelet-dependent clot firmness contribution in
some visco-elastic, whole blood point-of-care tests
(FibTEM at thromboelastometry and Functional
Fibrinogen at thromboelastography).
Fibrinogen and inflammation
Coagulation and complement systems descend
from a common ancestral pathway and have an
extensive cross-talk. 6 Within this interaction of
different pathways, factor XIII has a specific role:
it is responsible for generation of complement
C5a during plasma clotting. Fibrinogen enhances
the activity of the lectin complement pathway. 7
Through this and other mechanisms, coagulation
may trigger inflammation. Inflammation, in turn,
has important effects on the coagulation process
and namely on fibrinogen-dependent processes.
Pro-inflammatory cytokines promote tissue factor
release from monocytes and endothelial cells 8
and reduce thrombomodulin expression on
endothelial cells, decreasing its anticoagulant
properties. 9
Fibrinogen synthesis is strongly enhanced by
inflammation and is considered an acute-phase
protein. Transcription of the three genes
producing the fibrinogen chains is enhanced in
the early phases of inflammation, in presence
of interleukin-6 and glucocorticoids. 2 Fibrinogen
levels are increased in patients with elevated
levels of C-reactive protein. 10
In the clinical environment, it is common
to find elevated fibrinogen levels whenever
a systemic inflammatory reaction is present; this
8
HHE 2018 | hospitalhealthcare.com
includes sepsis, chronic inflammatory states
in atherosclerosis, pregnancy, smoking, acute
exercise, exposure to extracorporeal membrane
oxygenation, or cardiopulmonary bypass (after an
initial decline).
Hypofibrinogenemia
There are inherited and acquired conditions
leading to hypofibrinogenemia. Afibrinogenemia
is usually diagnosed at birth following prolonged
umbilical cord bleeding. This severe condition is
characterised by spontaneous bleeding in all
tissues and may not be compatible with life.
Hypofibrinogenemia symptoms depend on the
severity of the disease, and may be asymptomatic
or accompanied by spontaneous bleeding events
or severe bleeding following surgical