haemorrhage, and liver surgery. Usually, a
fibrinogen level <1.5 g/dl is considered at risk for
fibrinogen-dependent bleeding, but this value
may change depending on the different clinical
scenarios. DIC is usually accompanied by low
levels of fibrinogen, as a marker of intravascular
coagulation and consumption of coagulation
factors. The existing DIC scores include
a fibrinogen level <1.0g/l within the diagnostic
score. However, it should be considered that
when DIC occurs in the setting of sepsis,
consumption of fibrinogen may be relevant even
when the fibrinogen levels are higher: this is
related to the fact that in the early phases of
bloodstream infection and sepsis, the fibrinogen
levels are increased above the normal levels, as an
effect of the acute phase reaction.
In trauma patients, the main mechanism
leading to low fibrinogen levels is
hyperfibrinolysis. Hyperfibrinolysis is reported in
a significant percentage of severely injured
patients, and is accompanied by a high mortality
rate (>70%). Aggressive treatment of
hyperfibrinolysis with tranexamic acid is the
standard of care for severe trauma patients;
replenishment of fibrinogen is also considered
within the existing treatment algorithms when
low values of fibrinogen are diagnosed (FibTEM
<7mm).
Pregnant women have fibrinogen values
higher than normal before delivery. In presence
of a post-partum haemorrhage (PPH), low
fibrinogen levels have a negative prognostic
value. Values below 2.0g/l or FibTEM <10mm
are predictive of PPH progression and need for
massive transfusions. In liver surgery, and namely
in liver transplant, the fibrinolytic system is
activated during the anhepatic and the
reperfusion phases. Additionally, the fibrinogen
levels in cirrhotic patients are reduced.
Hypofibrinogenemia in these patients is
a determinant of severe bleeding. Values below
1.5–2.0g/l or FibTEM <6mm) should trigger
fibrinogen supplementation.
Cardiac surgery is a common clinical scenario
for acquired hypofibrinogenemia. Dilution and
consumption during cardiopulmonary bypass are
the main determinants, but other mechanisms
may be involved. Extensive use of cell-saver,
with washing of the saved blood, results in
a loss of coagulation factors and fibrinogen.
Patients undergoing ascending aorta surgery
due to acute aortic dissection may form clots
inside the false chamber, leading to fibrinogen
consumption. Finally, postoperative bleeding
from any source (platelet dysfunction,
hyperfibrinolysis, residual heparin, surgical
sources and others) invariably lead to a
fibrinogen loss. A study highlighted that
postoperative bleeding becomes dependent
when fibrinogen levels are below 2.0g/dl, with
a 50% positive predictive value for severe
bleeding when the fibrinogen levels fall below
1.15 g/l.11
Hyperfibrinogenemia
High levels of fibrinogen may depend on genetic
factors (G-455A polymorphism) but is more
commonly the result of concomitant
inflammatory diseases and lifestyle (smoking).
Elderly subjects and females have higher
fibrinogen values; 12 seasonal variations have been
reported. 13
The most important consequence of increased
fibrinogen levels is the concomitant increase in
cardiovascular risk. Many studies demonstrated
an association between elevated plasma
fibrinogen levels and cardiovascular risk. 14–16
Venous thromboembolism can be associated with
high fibrinogen levels. It is also true that
therapies that reduce the cardiovascular risk (ACE
inhibitors) simultaneously reduce fibrinogen
levels. However, it is not fully established that the
link between high fibrinogen levels and
cardiovascular events is causative rather than
associative. There are several pathways by which
fibrinogen triggers acute cardiovascular events.
The most intuitive is that fibrinogen is strongly
involved in local thrombus formation in the
presence of a ruptured atherosclerotic plaque.
There are animal models of induced arterial and
venous thrombosis demonstrating that higher
fibrinogen levels shorten the time to vessel
occlusion, and generate a more stable and
lysis-resistant clot.
Even chronic atherosclerotic plaque formation
can involve fibrinogen. Atherosclerotic plaques
contain fibrin(ogen) deposits. Fibrin is
incorporated in the plaque and contributes to
plaque growth and instability. 5
An important link between fibrin(ogen) and
thrombosis is represented by the contribution of
fibrin to the clot physical properties. Different
degrees of contribution may result in different
clot visco-elastic properties, firmness, and
resistance to lysis. Clots characterised by an
increased fibrin fibre density (usually produced
by LMW fibrinogen) are more likely to be
associated with cardiovascular events. This was
demonstrated in young subjects suffering an
acute coronary syndrome. 5
As already mentioned, fibrinogen levels
are elevated in a number of conditions
characterised by a systemic inflammatory
reaction syndrome. It is still unclear if this
kind of hyperfibrinogenemia increases the risk
of thrombotic events. Of note is that no
reports of an increased thrombogenic risk
exist in case of exogenous fibrinogen
supplementation.
Conclusions
Fibrinogen is certainly involved in a number of
inflammatory, haemorrhagic, and thrombotic
processes. Its peculiar position at the crossroad
between inflammation and coagulation results
in dynamic changes in fibrinogen concentration
and structural changes of the fibrin network.
Many of the conditions where fibrinogen levels
are of clinical interest are acute and emergency
situations, and fibrinogen levels are often
indirectly measured with point-of-care tests in the
emergency room, operating room and intensive
care unit. The number of studies addressing the
role of fibrinogen in both haemorrhagic and
thrombotic syndromes is increasing: in the last
three years more than 270 articles per year have
been published on fibrinogen in bleeding
syndromes, and about 300 per year on fibrinogen
and thrombosis. Despite this, some results are
still conflicting, and there is certainly room
available for further studies.
10
HHE 2018 | hospitalhealthcare.com
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