Beyond Anticoagulation: A Comprehensive Review of Non-Vitamin K Oral Anticoagulants (NOACs) in Inflammation and Protease-Activated Receptor Signaling

Abstract

Non-vitamin K oral anticoagulants (NOACs) have revolutionized anticoagulant therapy, offering improved safety and efficacy over traditional agents like warfarin. This review comprehensively examines the dual roles of NOACs-apixaban, rivaroxaban, edoxaban, and dabigatran-not only as anticoagulants, but also as modulators of inflammation via protease-activated receptor (PAR) signaling. We highlight the unique pharmacotherapeutic properties of each NOAC, supported by key clinical trials demonstrating their effectiveness in preventing thromboembolic events. Beyond their established anticoagulant roles, emerging research suggests that NOACs influence inflammation through PAR signaling pathways, implicating factors such as factor Xa (FXa) and thrombin in the modulation of inflammatory responses. This review synthesizes current evidence on the anti-inflammatory potential of NOACs, exploring their impact on inflammatory markers and conditions like atherosclerosis and diabetes. By delineating the mechanisms by which NOACs mediate anti-inflammatory effects, this work aims to expand their therapeutic utility, offering new perspectives for managing inflammatory diseases. Our findings underscore the broader clinical implications of NOACs, advocating for their consideration in therapeutic strategies aimed at addressing inflammation-related pathologies. This comprehensive synthesis not only enhances understanding of NOACs' multifaceted roles, but also paves the way for future research and clinical applications in inflammation and cardiovascular health.

Keywords: NOAC; anti-inflammation; factor Xa; protease-activated-receptor signaling; thrombin.

Figure 1

The current model of the blood coagulation cascade, depicting NOACs’ mechanism of action. There are two pathways, the intrinsic pathway and the extrinsic pathway. These multicomponent processes are illustrated as enzymes, inhibitors, zymogens, or complexes. On injury to the vessel wall, tissue factor, the cofactor for the extrinsic tenase complex, is exposed to circulating FVIIa and forms the extrinsic tenase. FIX and FX are converted to their serine proteases FIXa and FXa, which then form the intrinsic tenase and the prothrombinase complexes, respectively. The combined actions of the intrinsic and extrinsic tenase and the prothrombinase complexes lead to an explosive burst of the enzyme thrombin (IIa). In addition to its multiple procoagulant roles, thrombin also acts in an anticoagulant capacity when combined with the cofactor thrombomodulin in the protein Case complex. The product of the protein Case reaction, activated protein C (APC), inactivates the cofactors FVa and FVIIIa. The cleaved species, FVai and FVIIIai, no longer support the respective procoagulant activities. Once thrombin is generated through procoagulant mechanisms, thrombin cleaves fibrinogen (releasing fibrinopeptide A and B [FPA and FPB]), as well as activating FXIII to form a cross-linked fibrin clot. Thrombin–thrombomodulin also activates thrombin activate-able fibrinolysis inhibitor, which slows fibrin degradation by plasmin. The procoagulant response is downregulated by the stoichiometric inhibitor tissue factor pathway inhibitor (TFPI) and antithrombin III (AT-III). TFPI serves to attenuate the activity of the extrinsic tenase trigger of coagulation. AT-III directly inhibits thrombin, FIXa, and FXa. The accessory pathway provides an alternate route for the generation of FIXa. Thrombin has also been shown to activate FXI. The fibrin clot is eventually degraded by plasmin, yielding soluble fibrin peptides. Factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) act by binding to the active site of factor Xa, inhibiting the conversion of prothrombin to thrombin, the final enzyme in the coagulation cascade. Dabigatran, conversely, functions as a direct thrombin inhibitor. It binds with high affinity to the active site of thrombin, inhibiting its ability to convert fibrinogen to fibrin, thereby preventing clot formation.

Figure 2

Schematic representation of structural domains of FXa and binding sites of FXa inhibitors. A schematic representation of FXa protein structural domains and the location of the binding sites of FXa inhibitors (apixaban, edoxaban, and rivaroxaban) are depicted. (A) illustrates the domain organization of FXa, highlighting the serine protease domain in the heavy chain (indicated by green) where the binding site is located. (B–D) depict the structures of apixaban, edoxaban, and rivaroxaban, respectively, as obtained from the Protein Data Bank, indicating their binding sites with FXa, which exhibit enzyme kinetics similar to competitive inhibitors.

Figure 3

Schematic representation of PAR1- and PAR2-mediated signal transduction. PAR1 and PAR2 are G protein-coupled receptors that can be activated by thrombin and FXa, initiating a cascade of cellular responses. Upon cleavage, PAR1/2 interact with different G proteins like Gα_i, Gα_12/13, Gα_s, and Gα_q. Gα_12/13 leads to Ras homolog family member A (RhoA) activation, via Rho guanine nucleotide exchange factors (RhoGEFs) influencing cell hypertrophy. Gα_q activates phospholipase C-β, generating second messengers that trigger calcium release and Protein Kinase C (PKC) activation. PKC can further activate the nuclear factor kappa B (NF-κB) signaling pathway to upregulate production of SRY-box transcription factor 4 (SOX4) and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5). Gα_i can inhibit adenylate cyclase (AC) to regulate downstream cAMP, whereas Gα_s can increase cAMP. β-arrestin can activate the ERK1/2 signaling pathway but exhibits inhibitory effects on PKC and calcium release. Anticoagulants like dabigatran (thrombin inhibitor) and apixaban, edoxaban, and rivaroxaban (FXa inhibitors) can potentially disrupt this signaling by preventing PAR activation. Ultimately, these signal transduction pathways can trigger physiological changes like inflammatory and immune responses, cell hypertrophy, and cell migration.

Figure 4

Schematic representation of PAR4-mediated signal transduction. PAR4 can activate signaling pathways involving Gα_12/13 and Gα_q. Gα_12/13 prompts RhoGEFs to activate RhoA, while Gα_q -Phospholipase C- β (PLC- β) leads to downstream effects such as upregulation of inositol triphosphate (IP3) and diacylglycerol (DAG), resulting in calcium alterations and PKC upregulation, which ultimately leads to activation of the NF-κB signaling pathway. Additionally, β-arrestin can facilitate ERK1/2 phosphorylation but has inhibitory effects on PKC. Thrombin, known for its ability to cleave PAR4, can influence these pathways, therefore dabigatran (thrombin inhibitor) can modulate signal transduction by attenuating thrombin’s effects. As seen, PAR4 activation can cause physiological alterations such as inflammatory and immune response, endothelial barrier dysfunction, and platelet activation.

Figure 5

Proposed mechanism of apixaban’s modulatory effects on factor Xa and associated inflammatory signaling pathways in an osteoarthritic chondrocyte model. This illustration delineates the pathways through which apixaban may exert anti-inflammation in the context of osteoarthritis. Apixaban targets FXa, inhibiting its ability to bind and activate PAR2, which is represented by the red inhibitory line. This intervention most likely attenuates the downstream signaling cascades involved in OA pathophysiology: 1. PAR2 inhibition: The blockage of PAR2 activation by apixaban may ameliorate the downstream signaling events mediated by ERK1/2 that lead to the production of pro-inflammatory cytokines, such as TNF-α and IL-1β, potentially alleviating chronic pain associated with OA. 2. Cytokine modulation: The expected reduction in TNF-α and IL-1β due to apixaban’s action on FXa mitigates the upregulation of molecules like MCP-1, which are involved in monocyte recruitment and the NF-κB signaling pathway, both key contributors to inflammation and osteoclastogenesis. 3. Protein expression: The illustration also indicates the potential effects of apixaban on the expression of regulatory proteins, including SOX4 and ADAMTS5, and their impact on critical components like aggrecan, which is essential for cartilage integrity. 4. Chondrocyte integrity and bone health: By modulating these inflammatory and catabolic pathways, apixaban may help preserve chondrocyte integrity, mitigate the generation of reactive oxygen species (ROS), and contribute to maintaining joint health by potentially impacting the RANK/RANKL pathway, which is crucial for osteoclast activity and bone resorption.