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Advanced Neurology Anticoagulants as neuroprotective therapeutics

BBB disruption. 25,96,100 In addition to FXII, Aβ also activates plasma levels of thrombin and fibrin(ogen). 25,52 In
HK, which is essential for both the intrinsic coagulation AD mice, anti-FXII oligonucleotide treatment also
(through FXI activation by FXIIa) and the inflammatory reduced vascular damage, neuroinflammation,
kallikrein-kinin pathway (through PK activation by FXIIa). neuronal loss, and cognitive impairment. 25
Both FXI and PK must bind to HK to be activated by FXIIa (iv) Inhibition of thrombin and fibrin production
(Figure 1). 25,96 by anticoagulants normalized procoagulant
and proinflammatory states, reducing disease
4.3.1. Evidence for a causative role progression and associated sequelae in AD mouse
In recent years, studies have provided evidence of the models. 15,16,25,90,96,101-103 Long-term thrombin blockage
importance of the Aβ-induced activation of the contact was able to slow cerebrovascular and parenchymal
system in generating procoagulant and proinflammatory disease progression and cognitive decline. 90,101-103
states in AD. 6,16,25,51,52,96,100 Collectively, these investigations Similarly, anticoagulant treatment in patients with AF
have yielded the following findings: was found to benefit the cerebrovascular and neuronal
(i) In patients with sporadic and genetic AD, as well as systems, reducing the incidence of dementia by up
in AD mouse models, accumulations of FXII, HK, to 48%. 15,16,27,104
bradykinin, thrombin, fibrinogen, and fibrin were
found to be associated with the activation of the plasma 4.3.2. Thrombin as a proteinopathic factor
contact system by Aβ (Figure 1). The pathological A substantial body of evidence supports the role of the
sequelae observed included inflammation, multifunctional protease thrombin as a key mediator
neurovascular dysfunction, neurodegeneration, and of neuroinflammatory and neurotoxic processes in
cognitive impairment. 6,25,27,51-53,61,96-100 AD and other neurodegenerative diseases, such as
(ii) Biochemical studies suggest a causal connection Parkinson’s disease, multiple sclerosis, and amyotrophic
between Aβ-triggered FXII activation and the lateral sclerosis. 15,27,105 In both sporadic and familial AD,
upregulation of bradykinin synthesis (Figure 1). 16,25,96 Aβ-induced proinflammatory and procoagulant states,
The severity of cognitive impairment in AD patients characterized by increased thrombin production, are
correlated with elevated plasma levels of FXIIa, implicated in vasculopathic and neurodegenerative events
increased kallikrein activity, cleaved HK levels, and (Figure 1). 6,16,25,27,52,53,61,77,97-99 In the brain of AD patients,
bradykinin levels, while FXII levels decreased. 25,51,52,100 elevated levels of thrombin, prothrombin, and protease-
In wild-type mice, the injection of Aβ increased activated receptors (PARs) involved in thrombin signaling
plasma kallikrein activity and HK cleavage. 25,51 have been detected, particularly in microvessels, neurons,
Similarly, normal human plasma treated with Aβ42 and glial cells. 27,76,77,80,105 Thrombin has also been identified
responded with FXII activation to FXIIa, HK cleavage, in senile Aβ-plaques and NFTs in AD patients. Similarly,
and bradykinin synthesis. 25,51 Antibody blockage of increased thrombin expression levels have been found in
HK prevented HK cleavage and bradykinin synthesis, the brain vasculature. 27,76,105 These findings have led to the
as well as HK-mediated FXI activation in Aβ-induced suggestion of a key role for thrombin in the pathological
intrinsic coagulation. 16,25 interactions between coagulation, vascular disease,
(iii) Additional biochemical studies suggest a causal inflammation, and neurotoxicity (Figure 1). 27,76,77,105 Recent
connection between Aβ-induced FXII activation, studies have demonstrated that elevated thrombin levels,
subsequent FXI activation, and increased thrombin directly and indirectly, trigger inflammatory, vasculopathic,
production in the coagulation cascade, leading to and neurodegenerative changes in cardiovascular disease
thrombosis (Figure 1). 16,25,52,96 In the plasma of AD and AD. Both diseases are multifactorial and exhibit
27
patients, increased FXIIa and decreased FXI levels long asymptomatic phases, sharing vascular risk factors,
(suggesting enhanced FXI activation to FXIa) were such as CAA, atherosclerosis, diabetes, and traumatic
found alongside elevated fibrin levels, 25,51,52,96 indicating brain injury. 27,42 In AD, thrombin is now considered a
increased activation of the intrinsic clotting system. The proteinopathic factor alongside Aβ and tau. 15,16,27,77,105
addition of Aβ42 to in vitro protein systems or normal
human plasma triggered the production of thrombin (a) Thrombin’s role in generating a prothrombotic state
and fibrin. 16,52 In FXII-deficient human plasma, these Aβ has been shown to trigger FXII activation in the
effects were abolished, indicating that Aβ-induced plasma contact system (Figure 1). 6,16,25,51,52,96 The resulting
52
FXII activation triggers thrombin synthesis. Blocking dysregulation of the coagulation cascade leads to elevated
FXII activation, either with antibodies in plasma or thrombin levels, which enhance fibrin production and
with anti-FXII oligonucleotides in AD mice, decreased inflammation. 6,15,16,25,27,53,96,105-108 Fibrin contributes to the

Volume 3 Issue 4 (2024) 13 doi: 10.36922/an.3799