Involvement of fibrinogen(Fg) and fibrin during various pathologies associated with neuroinflammatory diseases associated with memory reduction are well known. Elevated level of Fg, called hyperfibrinogenemia (HFg) (e.g. ≥ 4±0.1 mg/ml of plasma during inflammation vs.~2±0.1 mg/ml of normal plasma ), accompanies inflammatory diseases such as stroke [2,3], hypertension [1,4], diabetes  and traumatic brain injury (TBI) [6-9]. Blood level of Fg increases during inflammation in general . HFg is considered not only a marker of inflammation  but also a cause of inflammatory responses [12-16]. Gradual extravascular deposition of Fg in the brain accelerates neurovascular damage and promotes neuroinflammation [17,18]. It has been shown that Fg is associated with an increased risk of dementia and AD . Derivative of Fg, fibrin have been found postmortem in the brains of patients with TBI [18,20,8], Alzheimer’s Disease (AD) , and multiple sclerosis (MS) . Elevated blood levels of Fg (HFg) are found to be associated with increased risk of AD, cognitive decline, and dementia [19,23]. Furthermore, formations of plaques containing Fg/fibrin were found in inflammatory neurodegenerative diseases associated with memory reduction such as AD , MS , and TBI . Strong association of Fg/fibrin with amyloid beta (Aβ) peptide was linked to severity of AD .
In fact, it has been shown that Aβ mediates formation of clots with abnormal structure and resistance to fibrinolysis . This can be a possible mechanism for Fg-Aβ complex and subsequent plaque formation that is highly resistant to degradation. Although Fg/fibrin  and Aβ [29,30] containing plaque formations are the hallmark of AD [28,31,24], some studies indicate that content of Aβ has limited effect on memory [32,33]. These results suggest that formation of Fg-Aβ complex can have a greater effect on loss of memory than deposition of Fg or Aβ alone. Thus, although Aβ is known to be associated with AD , a greater role of cellular prion protein (PrPC) in memory reduction has been shown [32,33].
There are data indicating that PrPC is involved in TBI-associated memory reduction . We have recently shown that Fg can specifically associate with its receptor PrPC on the surface of astrocyte [35,36] and others have found that Fg interacts with non-digestive PrPSc . Our data showed that Fg can form a complex with PrPC in extravascular space during mild-to-moderate TBI . As for the functional effects, it has been indicated that Fg that escaped from ruptured brain vessels causes astrocyte scar formation  and axonal damage . Our data showed that Fg, which was transcytosed through endothelial cells (ECs) of non-damaged cerebral microvessels deposited in vasculo-astrocyte interfaces . We found that Fg can activate astrocytes [40,41,35]. Furthermore, these effects of extravasated Fg were associated with neurodegeneration  and memory reduction during TBI [9,40,42].
All these data indicate an undoubtful role of Fg in inflammatory neurodegenerative diseases associated with memory impairment. However, blood-clotting proteins generate thrombin, which catalyzes the conversion of Fg (factor I) - a soluble plasma protein - into long, sticky threads of insoluble fibrin (factor Ia). Thrombin is a serine protease that is generated by proteolytic cleavage of its inactive precursor, prothrombin. Neurons and glial cells can release prothrombin and thrombin . Therefore, extravasated Fg that is immobilized in extravascular space, eventually, will be converted to fibrin. In literature, the terms Fg and fibrin are often used interchangeably that creates a confusion: it becomes unclear if effects are caused by soluble Fg or its hardened, insoluble derivative – fibrin (a monomer). It has been shown that Fg does not cross blood brain barrier (BBB) in the normal brain of young mice . However, our data showed that at higher (4 mg/ml) than physiological blood level, Fg not only increases EC layer permeability to albumin but itself moves through the endothelium . Furthermore, we found that cerebrovascular permeability was increased in acute conditions of a HFg . Similarly, cerebrovascular permeability was increased in transgenic mice exhibiting inherent HFg . Using our dualtracer
probing method, we found that HFg-induced cerebrovascular
protein crossing occurred mainly via transcellular pathway [46,45].
Effects of HFg on formation of caveolae and caveolar transcytosis in
vitro , and an increased cerebrovascular permeability mainly
via caveolar transcytosis have been shown [45,48,46]. All these
data indicate that, most likely, blood soluble protein - Fg and not its
insoluble derivative fibrin, crosses walls of small cerebral vessels
during various neuroinflammatory pathologies accompanied with
HFg. Crossing the walls of unruptured cerebral microvessels for
fibrin that is characterized with high aggregative properties and
lesser flexibility is very unlikely.
While in the extravascular space, Fg interacts with its receptors
intercellular adhesion molecule 1 (ICAM-1) and PrPC [49-51] on the
surface of astrocytes . It is possible that Fg can reach neurons
and on their surface interact with its receptors - ICAM-1 and PrPC.
Thus, these interactions will most likely lead to formation of Fg-PrPC
complexes. As Fg is immobilized in extravascular space, it becomes
an easy target for thrombin that is released from neurons and glial
cells . The rate of plasma Fg (0.1 mg/ml) polymerization is
about 23±2 x10-5sec-1, while release of fibrinopeptides A and B from
it via enzymatic (thrombin-catalyzed cleavage) step may take from
40 to 120 min , maybe even faster. As a consequence of Fg’s conversion to fibrin
in Fg-PrPC complex, a highly resistant to enzymatic degradation,
fibrin-PrPC complex will be formed. All further effects, including
possible formation plaques, would be a result of specific properties
of fibrin deposited in the brain extravascular space. Therefore, in
our opinion, we need to be careful in describing effects of Fg, when
in blood, crosses the vascular wall, deposits in extravascular space
and forms complexes with other proteins, and fibrin (which can
be formed in blood but least likely to extravasate) that is formed
in extravascular space and by creating undegradable protein
complexes (and possibly plaques) leads to memory reduction.
Pahatouridis D, Alexiou G, Zigouris A, Mihos E, Drosos D, et al. (2010) Coagulopathy in moderate head injury. The role of early administration of low molecular weight heparin. Brain Injury 24(10): 1189-1192.