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Advanced Neurology Anticoagulants as neuroprotective therapeutics

This vasculopathy is particularly evident from recent with protease factor VII (FVII), activating it to FVIIa. This
transcriptome analyses of human vascular cells, which TF-FVIIa complex initiates a protease cascade by activating
identified 30 of the top 45 AD risk genes as being linked factor IX (FIX) and factor X (FX), ultimately leading to
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to the vascular system and dysregulated CBF. Therefore, the generation of thrombin, a key serine protease in the
drugs that preserve vascular integrity, normalize blood coagulation process. The intrinsic coagulation pathway
pressure and procoagulant states, and maintain CBF and is triggered by damage to the cell surface, leading to the
brain perfusion are believed to offer beneficial effects on activation of the serine protease factor XII (FXII) into
neurovascular function and cognitive abilities in AD FXIIa as part of the plasma contact system. 15,16,25,28 FXIIa
patients. 5-10,15,16 Approved cardiovascular drugs, due to their then drives the intrinsic protease cascade by activating
known safety profiles and established efficacy, are attractive factor XI (FXI) and subsequently FIX, also culminating
candidates for repurposing as AD therapies, potentially in the production of thrombin. Both the extrinsic and
offering significant savings in developmental time and intrinsic coagulation pathways converge at the activation
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costs. For example, antiplatelet drugs and diuretic of FIX to FIXa, which, through the subsequent activation
bumetanide have been explored as repurposed treatments of FX to FXa, forms the prothrombinase complex. This
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for AD. Anticoagulants are also increasingly discussed complex cleaves prothrombin into thrombin. Numerous
as potential candidates for targeting vascular-driven coagulation factors require vitamin K and calcium for their
neuronal dysfunction in AD. 15,16,22-27 These drugs have been activation and function. 15,16,25,28,32
used in antithrombotic therapies for decades. 15,16,28 As early Hemostasis is tightly regulated by various inhibitors,
as 60 years ago, there was speculation that anticoagulants including antithrombin III, which inactivates thrombin,
could also be used to combat dementia. 29-31 Mechanistically, and alpha-2-antiplasmin, which inhibits plasmin in the
thrombin-inhibiting anticoagulants are particularly well fibrinolytic system. 15,16,28 Collectively, thrombin synthesis
suited to counteract key factors driving neurovascular through the coagulation cascade ensures the generation
dysfunction in AD. 15,16,22-27 Recent findings suggest that of active thrombin in the blood. Thrombin production is
these anticoagulants may mitigate the proinflammatory further amplified by a thrombin-driven positive feedback
and prothrombotic states present in the blood vessels of loop in the coagulation cascade involving factors V, VIII, and
the AD brain, which are caused by Aβ-induced thrombin XI. 15,16,28 Procoagulant thrombin plays several critical roles,
and fibrin production. 6,15,16,25,27 including the activation of factor XIII (FXIII) and platelets,
This review provides an update on the potential of oral as well as the conversion of soluble fibrinogen into insoluble
anticoagulants (OACs), specifically direct OACs (DOACs), fibrin protofibrils. Together, these processes lead to the
as a disease-modifying therapy for early AD. The focus formation of a blood clot or thrombus. A thrombus primarily
is on preventing excessive thrombin production caused consists of cross-linked fibrin, platelets, and red blood cells,
by Aβ pathology and addressing its associated vascular, forming the final product of the blood coagulation process
neuronal, and cognitive sequelae. in hemostasis. 15,16,28 At the same time, the fibrinolytic system
initiates the cessation of thrombus growth and its subsequent
2. Hemostasis, thrombosis, and the benefit degradation to support wound healing. This process is
of anticoagulant drugs mediated by the activation of the serine protease plasmin,

Hemostasis is a complex biochemical process involving the although plasmin activation occurs relatively slowly.
blood vessel wall, platelets, and various blood factors from The release of plasminogen activators, such as urokinase
the coagulation and fibrinolytic systems. 15,28 Its primary plasminogen activator (uPA) and tissue plasminogen
function is to form a temporary plug to seal vessel injuries, activator (tPA), induces the conversion of plasminogen into
15,16,28
arrest bleeding, and facilitate wound healing. In addition, fibrin-degrading plasmin. For a detailed illustration of
hemostasis regulates the removal of clots once the the coagulation cascade and the fibrinolytic system, reference
healing process is complete. 15,28 Hemostasis involves three is made to additional sources. 16,25,28
interrelated biochemical pathways: the extrinsic, intrinsic, Disruption of the hemostatic process can have
and common coagulation cascades, all of which ultimately fatal consequences. In individuals with hemophilia,
lead to fibrinolysis. 15,16,28 characterized by coagulation factor deficiencies, there
is an increased risk of uncontrolled bleeding. 15,28 On the
2.1. Blood coagulation and fibrinolytic system other hand, excessive thrombus formation can occur
The extrinsic coagulation pathway is activated by the in individuals who experience major trauma or have
subendothelial tissue factor (TF), which is exposed to the conditions that lead to slow blood flow, such as vascular
blood only after vessel injury. 15,16,25,28 TF forms a complex disorders, heart arrhythmias, or physical inactivity. 15,28

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