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Advanced Neurology Anticoagulants as neuroprotective therapeutics

include delayed onset of anticoagulation, a slow offset of antidotes are now available for most DOACs, allowing for
effect in bleeding situations despite the use of vitamin K rapid reversal of anticoagulation in bleeding emergencies. 15,28
antidote, and interaction with other drugs and vitamin For example, idarucizumab (Praxbind ) specifically binds
®
K-containing diet. 15,28,32,164 These factors necessitate close dabigatran, reversing its effect. 15,28 In addition, andexanet
medical supervision to ensure effective antithrombotic alfa (Ondexxya ), a human FXa variant, acts as a decoy
®
therapy while minimizing the risk of bleeding from protein to intercept FXa inhibitors, such as apixaban and
overdose – a particularly concerning side effect in elderly rivaroxaban, thereby restoring coagulation. 15,28 However,
patients. Other potential side effects of VKAs include andexanet alfa is not yet approved for use as an antidote
VKA-induced skin necrosis and disruption of vitamin for betrixaban and edoxaban. For long-term therapy AD
K-dependent proteins involved in vascular and neuronal patients, having access to a fast-acting and efficient antidote
functions. 15,28,32 is particularly important, given the increased bleeding risk
in elderly patients due to more vulnerable vasculature. 91
However, VKAs have certain advantages. They can be
used in patients with severe renal dysfunction, as they are Mechanistically, dabigatran, released from its pro-drug
not eliminated through the kidneys, and in individuals form, directly binds to both soluble and fibrin-bound
with mechanical heart valve implants. 28,164 In addition, the thrombin, inhibiting their activity in the blood. 15,16,24,27,28,32
cost of VKA treatment is considerably lower than that of On the other hand, FXa-inhibitors, such as apixaban
DOACs. 15,28,164 and rivaroxaban, prevent thrombin synthesis by directly
inhibiting free and prothrombinase-bound FXa in the
5.3.1. Superior suitability of DOACs coagulation cascade. 15],16,24,27,28,32 Consequently, thrombin
At present, available DOACs include the direct thrombin levels in the blood decrease, preventing excessive thrombin
inhibitor dabigatran and the direct FXa inhibitors accumulation, while the activity of existing thrombin
rivaroxaban, apixaban, edoxaban, and betrixaban. 15,28 remains unaffected. Therapeutically, both types of DOACs
Unlike VKAs, these DOACs offer predictable may reduce thrombin-mediated fibrin formation, prevent
pharmacological efficacy, with a rapid onset of action degradation-resistant fibrin-Aβ clot formation, and inhibit
and a short half-life at fixed dosing. 15,22,24,28,32,151 DOACs inflammation and vasculopathic sequelae in the AD brain,
are favored due to their ease of administration, improved as demonstrated in proof-of-concept studies in AD mouse
treatment adherence, minimal variations in antithrombotic models (Section 5.1 and Figure 2). 15,16,27,90,101,111,122,123
effect, and enhanced safety (with a lower incidence of stroke With regard to preventing thromboembolism,
and intracranial bleeding). Additional benefits include an minimizing intracranial hemorrhage, and enabling
efficient antidote strategy, lack of interference with vitamin rapid reversal of bleeding through antidotes, dabigatran,
K-dependent metabolism, fewer drug–drug interactions, apixaban, and rivaroxaban currently meet the criteria
no dietary restrictions, and reduced need for medical for potential use as anti-dementia agents. As reviewed
supervision. These advantages make DOACs especially in Section 5.2.1., protective effects against dementia
suitable for elderly and often vulnerable patients. However, (including AD, vascular dementia, and other/unspecific
in patients with severe renal dysfunction, DOACs require dementia) have been demonstrated for dabigatran,
dose adjustment or may be contraindicated due to renal apixaban, rivaroxaban, and edoxaban, though no single
elimination. 15,28,164 DOAC has shown a distinct advantage over the others.
The bleeding risk associated with DOAC use, as reviewed 6. DOACs as potential neuroprotective
in Section 5.2.2, has been assessed in a multitude of global
observational studies, especially in elderly patients with therapeutics in AD
AF. Collectively, these studies suggest that DOACs reliably Thrombin-inhibiting OACs of the DOAC type, introduced
prevent stroke and systemic thromboembolic events while over the past 15 years, have become the preferred
reducing the risk of severe intracranial hemorrhage by anticoagulants in millions of patients for preventing
approximately 50% compared to VKAs. 15,153,156,157,164 Among thromboembolic events. 15,34 The main reason for this
DOACs, dabigatran and apixaban appear to present preference is their significantly lower risk of severe
the lowest risk of intracranial hemorrhage, followed by intracranial bleeding in long-term treatments compared to
edoxaban and rivaroxaban. Apixaban has shown particular traditional VKAs or heparins. 15,16,129,153-160,163,164
benefit in AF patients with dementia. 163
Beyond their antithrombotic use, clinical observational
On the other hand, DOACs increase the risk of studies in AF patients have revealed that OACs can reduce
gastrointestinal bleeding in a dose-dependent manner the risk of dementia 15,16,104,124-149 by up to 48% in some
compared to VKAs. 15,16,24,153,155,157,164 Fortunately, effective studies. 104,140 Most study participants were elderly, over the

Volume 3 Issue 4 (2024) 23 doi: 10.36922/an.3799