Pathophysiology
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-
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 includes sepsis,
chronic inflammatory states in
atherosclerosis, pregnancy, smoking,
acute exercise, exposure to extracorporeal
membrane oxygenation, or
cardiopulmonary bypass (after an initial
decline).
“Coagulation and complement systems descend
from a common ancestral pathway and have
an extensive crosstalk”
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).
8
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
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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 procedures,
trauma and delivery. Clinical
manifestations of dysfibrinogenemia are
very heterogeneous, ranging from
absence of clinically relevant symptoms to
major bleeding, and even thrombosis.
The evidence of thromboembolic
complications in patients with fibrinogen
deficiency (in around 30% of the
subjects 5 ) is difficult to explain, given the
pro-coagulant properties of fibrinogen.
The main interpretation is that the low
levels of fibrinogen may promote a weak
clot, more susceptible to the lytic effects
of plasmin. This could result in a partial
or total clot breakdown, with
embolisation of clot parts.
More common are the acquired
conditions, which may derive from liver
disease, disseminated intravascular
coagulation (DIC), thrombolytic therapy,
haemodilution or consumption. Basically,
acquired hypofibrinogenemia results
from a reduced synthesis (liver disease),
excessive activation of the haemostatic
system with consumption of the
substrates (disseminated intravascular
coagulation), severe haemodilution (heart