Inflammation
George Feuer, Felix A. de la Iglesia in Molecular Biochemistry of Human Disease, 2020
Factor X deficiency disease has also been described, and individuals with this deficiency have a bleeding tendency similar to that of classic hemophilia.99,143 The congenital defect of Factor II (thrombin) is very rare. Most of the individuals with this disorder have 2 to 10% prothrombin activity, and the susceptibility to bleeding shows some parallelism to the level of prothrombin.238,251,415 Factor XI and Factor XII deficiencies have also been observed. Deficiency of Factor XI is a relatively uncommon disorder and is manifested as a hemorrhagic disorder. The hemorrhagic tendency is, however, much less severe than in hemophilia.129 Congenital deficiency of Factor V is also rare, and the associated bleeding tendency is only moderately severe.354
Briefing Therapeutic Approaches in Anticoagulant, Thrombolytic, and Antiplatelet Therapy
Debarshi Kar Mahapatra, Sanjay Kumar Bharti in Medicinal Chemistry with Pharmaceutical Product Development, 2019
Currently available direct factor Xa inhibitors are rivaroxaban, apixaban, and edoxaban (Figure 7.7). Rivaroxaban is given orally. It can inhibit both free factor Xa and factor Xa bound in the prothrombinase complex. Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade by inhibiting both thrombin formation and development of thrombi [48]. Apixaban is a highly selective; orally bioavailable and reversible direct inhibitor of free and clot-bound factor Xa. It was approved in Europe in 2012. Subsequently, it was approved in the U.S. in 2014 for treatment and secondary prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE) [49].
Inflammation and immunology
C. Simon Herrington in Muir's Textbook of Pathology, 2020
Although the major function of the clotting system is haemostatic control there are intimate links with the inflammatory response and many clotting factors are involved with either the complement or the kinin cascades. Particularly important in inflammation is the activation of the Hageman factor, a protein synthesized in its inactive form by the liver as part of the acute-phase response (Figure 4.11). When the Hageman factor is exposed to collagen in basement membranes or activated by platelets it undergoes a conformational change to become factor XIIa, exposing an enzymatically active site that can act on downstream components of both the clotting and the kinin cascades. Two further components of the coagulation system provide links between blood clotting and inflammation. Thrombin, which is the cleavage product of the inactive precursor prothrombin, cleaves the plasma protein fibrinogen to form fibrin, an important component of blood clot formation. However, during this process, small fibrin peptides are formed that can increase vascular permeability and are chemotactic for leukocytes. Thrombin itself may activate leukocytes, directly causing increased leukocyte adhesion to endothelial cells, and may cause fibroblast proliferation during the healing response. Factor X, when activated to factor Xa, may also increase vascular permeability and enhance leukocyte exudation. During the activation of the coagulation cascade, the fibrinolytic regulatory mechanism is activated. This second cascade generates the proteolytic enzyme plasmin to degrade fibrin, but it is also capable of activating the complement cascade.
Rivaroxaban for the treatment of venous thromboembolism in pediatric patients
Published in Expert Review of Cardiovascular Therapy, 2020
Omri Cohen, Sarina Levy-Mendelovich, Walter Ageno
Factor Xa (FXa) has been known to have a pivotal role in hemostasis by catalyzing the production of thrombin leading to clot formation [12]. The first FXa inhibitor, antistasin, was isolated from salivary glands of the Mexican Leech Haementeria officinalis in 1987 [13]. Tick anticoagulant peptide is another naturally occurring FXa inhibitor [14]. The development of these compounds was discontinued for unknown reasons [9]. Direct and indirect FXa inhibitors showed that inhibition of FXa produces its antithrombotic effect via decreasing the generation of thrombin. The residual thrombin generated seems to be sufficient to ensure normal systemic hemostasis, thus contributing to a favorable efficacy/safety ratio. On the basis of these findings, in the mid-1990s several direct FXa inhibitor small molecules were being developed [9]. In 1998 the FXa program at Bayer Healthcare was started. Over 200,000 compounds were tested and eventually rivaroxaban was selected.
Rivaroxaban protects from the oxysterol-induced damage and inflammatory activation of the vascular endothelium
Published in Tissue Barriers, 2021
Paulina Gorzelak-Pabis, Marlena Broncel, Katarzyna Wojdan, Adrian Gajewski, Maciej Chalubinski, Mateusz Gawrysiak, Ewelina Wozniak
Dysfunction of the vascular endothelium is an important contributor to the pathobiology of atherosclerotic cardiovascular disease.3 Molecular studies have shown that both factor Xa (FXa) and thrombin are involved in inflammatory processes and endothelial activities, including inflammation, vascular remodeling, and atherosclerosis, presumably mediated through protease activated receptors (PARs). Thrombin is an activator of PAR1, whereas FXa activates PAR1, −2, and −3 alone or in complex with TF-FVIIa.4,5 It should be noted that Factor X is not converted to FXa constitutively but is only activated by intrinsic clotting factors and during a cellular injury. The function of rivaroxaban in the inactivated coagulation cascade is unclear. Seki et al. suggest that rivaroxaban per se may not influence gene modulation in the inactivated coagulation state, while rivaroxaban may suppress the expression of pro-inflammatory genes such as MCP-1, ICAM-1, and IL-8, but only in endothelial cells activated by FXa. Interestingly, Daci et al. imply that pre-treatment with rivaroxaban attenuates LPS-induced acute vascular inflammation by a significant reduction of IL-6, MCP-1 and VCAM-1 levels in rat plasma. These anti-inflammatory effects might perhaps have an impact on vascular functions and prevent the development of atherosclerosis.6
A drug safety evaluation of apixaban for the treatment of atrial fibrillation, acute coronary syndrome, and percutaneous coronary intervention
Published in Expert Opinion on Drug Safety, 2019
Jakub Gumprecht, Magdalena Domek, Gregory Y. H. Lip
Apixaban is a highly selective, oral acting, free and prothrombinase-bound factor Xa inhibitor. Factor Xa is an enzyme for the conversion of prothrombin to thrombin in the clot formation process. Apixaban has no direct effect on thrombocytes aggregation, but indirectly inhibits the clot formation caused by thrombin [13]. The drug has a selective high affinity for human Xa factor. Those features might correlate with improved pharmacologic characteristics compared to other factor Xa inhibitors [14,15]. The bioavailability of apixaban is around 50% and maximum concentration is between 3 and 4 h after oral administration. Apixaban can be taken regardless of meals and its elimination pathways include both metabolism and renal excretion. The drug seems to be relatively safe for subjects with mild to moderate kidney disease [14].
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