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Advanced Neurology Anticoagulants as neuroprotective therapeutics

When occlusive thrombi form inside blood vessels, related to heart abnormalities (cardiogenic dementia),
blocking blood flow, life-threatening arterial or venous alongside conditions such as coronary artery disease,
thrombosis may develop. If a thrombus detaches from the heart failure, and myocardial infarction. However, the
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vessel wall and travels through the vascular system, it may use of anticoagulants carries a risk of intracranial and
result in pulmonary embolism, myocardial infarction, or gastrointestinal bleeding. 15,16,28,32 In Germany, DOAC
ischemic stroke. 15,28 treatment is currently prescribed to nearly 2 million
patients, who are predominantly over the age of 70.
2.2. Anticoagulant drugs for the prevention of In contrast, the use of VKAs has been declining, with
thromboembolic incidents approximately 1 million patients currently using them. 15,28
To prevent fatal thromboembolic events, anticoagulants A similar trend is observed in France, where DOACs are
have been used in prophylactic and therapeutic more frequently prescribed than VKAs for ambulatory
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cardiovascular medicine for decades. 15,16,28,32 They individuals aged 80 years and older. This preference also
interfere with the coagulation cascade and prevent the extends to AD patients at risk of thrombosis, as DOACs offer
formation of thrombotic fibrin clots through various a more favorable benefit-risk profile compared to VKAs.
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mechanisms. 15,16,28,32 Parenteral heparins (e.g., enoxaparin) The primary advantages of DOACs include consistent
activate antithrombin III, which inhibits coagulation therapeutic efficacy, a more favorable safety profile with
factors, such as FXIIa, FXIa, FXa, FIXa, thrombin, and a lower risk of intracranial hemorrhage, and the absence
kallikrein in the inflammatory bradykinin pathway. of vitamin K-related complications. 15,22,28,32 Recently, there
Small-molecule OACs include classical vitamin K has been growing interest in whether DOACs could serve
antagonists (VKAs), such as warfarin (Coumadin ) and as disease-modifying therapies in AD, where procoagulant

phenprocoumon (Marcumar ). They block the vitamin and proinflammatory states contribute to neurovascular

K-dependent synthesis of various coagulation factors, dysfunction. 15,16,22-24,27 Emerging studies suggest that
including FX, FIX, FVII, and FII, as well as the proteins DOACs could be an appropriate therapeutic option for
prothrombin, C, and S. VKAs are derivatives of the plant repurposing in AD. 15,16,19,22-24,26,27 This idea seems plausible,
substance dicumarol, originally isolated from spoiled sweet given the extensive clinical experience with antithrombotic
clover hay. In addition to VKAs, a newer class of OACs, drugs and the current lack of effective treatments for AD.
15
known as DOACs, acts independently of vitamin K by
directly inhibiting key serine proteases in the coagulation 3. Pathogenic proteins in AD
cascade. These DOACs, introduced in the 2010s, include It was not until the last three decades that research
the thrombin inhibitor dabigatran (Pradaxa ) and the FXa confirmed Alois Alzheimer’s conclusion that AD is a

inhibitors rivaroxaban (Xarelto ), apixaban (Eliquis ), proteopathic neurodegenerative disease. 1-5,11,20 During


edoxaban (Lixiana ), and betrixaban (Bevyxxa ). A the progression of AD, extracellular amyloid plaques,

 15,16,28
further class of DOACs is currently under development, composed of misfolded Aβ, are formed in the brain
targeting FXIa in the intrinsic coagulation pathway. These parenchyma, followed by intraneural deposits of NFTs,
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inhibitors, such as asundexian and milvexian, are believed which are composed of hyperphosphorylated tau protein.
to have a reduced risk of bleeding since FXIa appears to be The presence of these pathogenic proteins is associated
essential for thrombosis but less crucial for hemostasis. 33 with the initiation of oxidative stress, inflammation,
DOACs are used temporarily in situations such as neurodegeneration, and subsequent loss of memory and
acute vein thrombosis and thromboembolism prevention cognitive functions. 2-5,15,20,35-38 The progression of AD can be
in patients hospitalized for medical illness or after total traced using biomarkers, such as Aβ or neurofilament light
hip or knee replacement. Permanent anticoagulant chain protein – a marker derived from neuron death – which
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therapy is indicated in cases where long-term prevention reveals that the pathogenesis begins 10 – 20 years before
of thromboembolic events is required, such as in cognitive impairment becomes evident. 39,40 In particular,
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patients with recurrent deep vein thrombosis, pulmonary studies using mouse models have made significant
embolism, heart arrhythmias like atrial fibrillation progress in elucidating the proteopathic mechanisms
(AF), or cardiovascular risk factors such as heart failure underlying AD. 2-5,12,15,16,25,41 These animal models provide
and hypertension. Patients with AF particularly a detailed systems biology perspective on the genetic,
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benefit from anticoagulant use due to their increased biochemical, structural, and physiological processes
risk of thromboembolic events. Their likelihood of involved in AD. The models often carry human risk genes,
experiencing a heart attack or ischemic stroke leading to which replicate the Aβ- and tau-associated parenchymal
disability or death is five times higher than in the general and vascular pathologies observed in the human brain. 12,41
population. AF is also a major risk factor for dementia In addition, advances in cryo-electron microscopy have
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Volume 3 Issue 4 (2024) 4 doi: 10.36922/an.3799