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Advanced Neurology Anticoagulants as neuroprotective therapeutics

formation of thrombotic fibrin clots and inflammatory oligomerization domain-like receptor family, pyridine
reactions in cerebral vessels, working in conjunction with domain containing 3 inflammasome, a key component of
Aβ to promote the development of vasculopathies, such the innate immune system. 7,15,27,78,80,105 Ultimately, blood-
as Aβ-CAA (Figure 1). Moreover, thrombin activates borne proinflammatory mediators, such as thrombin, can
procoagulant factors V, VIII, and XI, further amplifying its damage healthy neurons in the brain parenchyma, resulting
own production. Thrombin also activates fibrin-stabilizing in neuronal structural loss and functional impairment, as
FXIII and, in conjunction with fibrin(ogen) and platelets, observed in AD and other neurodegenerative diseases. 27,105
promotes the formation of cross-linked fibrin clots (c) Thrombin’s role in triggering neurotoxicity
containing platelets and erythrocytes. 16,27,28,44,107,109 In both
AD patients and mouse models, elevated platelet activation, In addition to its procoagulant and proinflammatory
adhesion, and aggregation have been found in the early activities, thrombin has been found to be an important
44
stages of AD, correlating with disease progression. trigger for neurotoxic effects (Figure 1). 14,27,110 Through
The prothrombotic state induced by thrombin is further multiple signaling pathways, including those mediated by
aggravated by its ability to stabilize existing fibrin clots PARs, thrombin can induce neuronal cell death, which is
through the activation of thrombin-activatable fibrinolysis associated with cognitive decline. 14,27 Thrombin has been
inhibitor and FXI. 16,27,28 shown to disrupt CA3 hippocampal neurons, leading to
epileptic and cognitive dysfunction. In addition, thrombin
(b) Thrombin’s role in generating a proinflammatory state can indirectly cause neuronal damage by activating

Beyond its procoagulant activity, thrombin, a astrocytes and microglia. 27,105,110 In microglia, thrombin has
multifunctional protease, activates a diverse array of been found to induce oxidative stress by activating NADPH
signaling pathways that mediate systemic inflammatory oxidase, a response linked to the death of hippocampal
110
responses and affect vascular and neuronal functions in neurons in vivo. Thrombin’s role in hippocampal
the brain (Figure 1). 15,27,76,77 Through signaling through neurodegeneration is also related to both Aβ and tau
PARs, thrombin acts on multiple cellular targets, including pathologies. 27,76,80 Recent studies in neuronal cell cultures
blood platelets, vascular endothelial cells, pericytes, have revealed that thrombin enhances the expression and
as well as parenchymal glial cells and neurons. 27,107 activity of key AD markers, including Aβ, APP, BACE1,
PARs, which are G-protein-coupled receptors, regulate tau, and the pro-apoptotic mediator caspase 3. 111
important cellular processes such as platelet activation, 4.3.3. Fibrin(ogen) as a proteinopathic factor
cell adhesion and migration, angiogenesis, inflammation,
and neurotoxicity. 27,107 In the vasculature, thrombin can In the final phase of the coagulation cascade, thrombin
elicit inflammatory reactions that affect vessel diameter, converts soluble fibrinogen into fibrin dimers and
endothelial cell morphology, and BBB permeability. 27,77 activates platelets and FXIII, resulting in the formation of
Elevated thrombin levels, often seen in AD and under cross-linked fibrin clots containing aggregated platelets
hypoxic conditions, have been associated with the onset and other components (Figure 1). 28,44 Beyond its role in
of cerebrovascular inflammation and dysfunction. 27,105 blood clotting, fibrinogen also plays an important role in
Pathologically, thrombin can induce endothelial cells inflammation and tissue repair. 106,109 Fibrinogen is a fibrous
to adopt a proinflammatory phenotype, releasing glycoprotein comprised of two sets of disulfide-bridged
inflammatory mediators, such as cytokines, ROS, NO, polypeptide chains (Aα, Bβ, and γ), 28,109 and it is expressed
and additional thrombin, resulting in damage to the and secreted into the blood by platelets, endothelial cells,
endothelial cell layer and BBB. 27,76,77 Cytokines can further and hepatocytes in response to tissue injury. 28,109
upregulate the extrinsic coagulation pathway through In a variety of neurodegenerative diseases, fibrinogen
TF activation, 27,105 which promotes additional thrombin has been found to infiltrate from the blood into the brain
production, exacerbating the proinflammatory and parenchyma. There, it can interact with various proteins
procoagulant state. In the CNS, thrombin also contributes and cells, such as neurons, astrocytes, and microglia,
to neuroinflammation, particularly due to increased which have been associated with neuronal and cognitive
BBB permeability, allowing blood-borne proteins, such dysfunction. 106,109 In AD, enhanced deposition of
as thrombin, prothrombin, and fibrin(ogen), to enter fibrin(ogen) has been observed particularly around and
and accumulate in the brain parenchyma. 7,27,78,80,105 within cerebral vessel walls, colocalizing with Aβ, especially
Through PAR involvement, parenchymal thrombin in small capillaries and arterioles, often in association with
can convert astrocytes and microglia into an activated, Aβ-CAA. 6,27,53,61,96-99,106,109 In addition, fibrin(ogen) deposits
proinflammatory state, leading to the release of have been detected in the perivascular spaces of the brain
cytokines, ROS, and the activation of nucleotide-binding parenchyma.

Volume 3 Issue 4 (2024) 14 doi: 10.36922/an.3799