scholarly journals Roles of factor Xa beyond coagulation

2021 ◽  
Author(s):  
Wolfram Ruf
Keyword(s):  
Clinical Evidence ◽  
Inflammatory Diseases ◽  
Oral Anticoagulant Therapy ◽  
Macrophage Polarization ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Therapeutic Benefit ◽  
Pathway Activation ◽  
Excessive Activation

AbstractOral anticoagulant therapy has changed by clinical evidence that coagulation factor Xa (FXa) can be safely and effectively targeted for thromboprophylaxis. Because thrombotic and thrombo-inflammatory diseases are frequently caused by excessive activation of the tissue factor (TF) pathway, activation of FX by the TF-FVIIa complex is of central importance for understanding the roles of FXa in thrombosis and hemostasis and functions beyond blood coagulation. Recent data showed that the nascent product FXa associated with TF-FVIIa not only supports hemostatic cofactor VIII activation, but also broadly influences immune reactions in inflammation, cancer, and autoimmunity. These signaling functions of FXa are mediated through protease activated receptor (PAR) cleavage and PAR2 activation occurs in extravascular environments specifically by macrophage synthesized FX. Cell autonomous FXa-PAR2 signaling is a mechanism for tumor-promoting macrophage polarization in the tumor microenvironment and tissue penetrance of oral FXa inhibitors favors the reprogramming of tumor-associated macrophages for non-coagulant therapeutic benefit. It is necessary to decipher the distinct functions of coagulation factors synthesized by the liver for circulation in blood versus those synthesized by extrahepatic immune cells for activity in tissue milieus. This research will lead to a better understanding of the broader roles of FXa as a central regulator of immune and hematopoietic systems.

scholarly journals Cryo-EM structures of human coagulation factors V and Va

Blood ◽  
2021 ◽  
Author(s):  
Eliza A Ruben ◽  
Michael J Rau ◽  
James Fitzpatrick ◽  
Enrico Di Cera
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Proteolytic Processing ◽  
Coagulation Cascade ◽  
Factor V ◽  
Prothrombinase Complex ◽  
A2 Domain

Coagulation factor V is the precursor of factor Va that, together with factor Xa, Ca2+ and phospholipids, defines the prothrombinase complex and activates prothrombin in the penultimate step of the coagulation cascade. Here we present cryo-EM structures of human factors V and Va at atomic (3.3 Å) and near-atomic (4.4 Å) resolution, respectively. The structure of fV reveals the entire A1-A2-B-A3-C1-C2 assembly but with a surprisingly disordered B domain. The C1 and C2 domains provide a platform for interaction with phospholipid membranes and support the A1 and A3 domains, with the A2 domain sitting on top of them. The B domain is highly dynamic and visible only for short segments connecting to the A2 and A3 domains. The A2 domain reveals all sites of proteolytic processing by thrombin and activated protein C, a partially buried epitope for binding factor Xa and fully exposed epitopes for binding activated protein C and prothrombin. Removal of the B domain and activation to fVa exposes the sites of cleavage by activated protein C at R306 and R506 and produces increased disorder in the A1-A2-A3-C1-C2 assembly, especially in the C-terminal acidic portion of the A2 domain responsible for prothrombin binding. Ordering of this region and full exposure of the factor Xa epitope emerge as a necessary step for the assembly of the prothrombin-prothrombinase complex. These structures offer molecular context for the function of factors V and Va and pioneer the analysis of coagulation factors by cryo-EM.

The Synthetic Pentasaccharide, Fondaparinux, Reduces Inflammation and Neutrophil Accumulation in Kidney Ischemia-Reperfusion Injury.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 217-217 ◽  
Author(s):  
Gernot Schabbauer ◽  
Rolf D. Frank ◽  
Todd Holscher ◽  
Yuichiro Sato ◽  
Michael Tencati ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Inflammatory Diseases ◽  
Anticoagulant Activity ◽  
Ischemia Reperfusion ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Inflammatory Cells ◽  
Neutrophil Accumulation ◽  
Kidney Ischemia

Abstract Acute inflammatory diseases are often accompanied by coagulation activation leading to local thrombotic complications and disseminated intravascular coagulation. Recent studies support the concept of crosstalk between coagulation and inflammation. The synthetic pentasaccharide, fondaparinux, is a selective antithrombin-dependent inhibitor of coagulation factor Xa. In this study, we investigated the effect of fondaparinux in a lethal murine model of kidney ischemia-reperfusion (I/R) injury that is associated with coagulation and inflammation. Fondaparinux treatment of I/R-injured mice significantly reduced serum creatinine levels and increased survival from 0 to 44% compared with saline treated control mice. In contrast, depletion of fibrinogen with ancrod was not protective, suggesting that fondaparinux may have additional properties beyond its anticoagulant activity. Indeed, fondaparinux significantly reduced IL-6 and MIP-2 expression but did not reduce MCP-1 expression. Furthermore, fondaparinux significantly decreased neutrophil accumulation in the injured kidneys. Finally, we showed that fondaparinux reduced recruitment of neutrophils into the peritoneum in a model of acute peritonitis and inhibited the binding of U937 cells to P-selectin in vitro. Our data indicate that fondaparinux has both anticoagulant and anti-inflammatory activity reducing fibrin deposition and blocking the binding of inflammatory cells to activated endothelium. Fondaparinux may be useful in the treatment of acute inflammatory diseases.

scholarly journals Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1889 ◽  
Author(s):  
Nadezhda Novichikhina ◽  
Ivan Ilin ◽  
Anna Tashchilova ◽  
Alexey Sulimov ◽  
Danil Kutov ◽  
...  
Keyword(s):  
Anticoagulant Activity ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Protein Targets ◽  
Ic50 Value ◽  
Anticoagulant Drugs ◽  
Factor Xia ◽  
Derivatives Of

Coagulation factor Xa and factor XIa are proven to be convenient and crucial protein targets for treatment for thrombotic disorders and thereby their inhibitors can serve as effective anticoagulant drugs. In the present work, we focused on the structure–activity relationships of derivatives of pyrrolo[3,2,1-ij]quinolin-2(1H)-one and an evaluation of their activity against factor Xa and factor XIa. For this, docking-guided synthesis of nine compounds based on pyrrolo[3,2,1-ij]quinolin-2(1H)-one was carried out. For the synthesis of new hybrid hydropyrrolo[3,2,1-ij]quinolin-2(1H)-one derivatives, we used convenient structural modification of both the tetrahydro- and dihydroquinoline moiety by varying the substituents at the C6,8,9 positions. In vitro testing revealed that four derivatives were able to inhibit both coagulation factors and three compounds were selective factor XIa inhibitors. An IC50 value of 3.68 μM for was found for the best factor Xa inhibitor and 2 μM for the best factor XIa inhibitor.

Thrombin-Directed Therapy

2006 ◽  
Author(s):  
Richard C. Becker ◽  
Frederick A. Spencer
Keyword(s):  
Molecular Weight ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Molecular Weights ◽  
Antithrombin Activity ◽  
Term Administration ◽  
Wide Variability ◽  
Physiologic Activity

Anticoagulant therapy in general is designed to prevent either the generation or activity of thrombin; however, a cell-based model of coagulation provides a physiologic view of individual phases of the process, allowing more specific targets for attenuating the initiation, priming, or propagation of thrombus formation. Future categorization schemes will consider individual coagulation factors, individual sites on a given coagulation factor, and specific phases of coagulation to better identify an agent’s biochemical and physiologic activity. Unfractionated heparin (UFH) is a heterogeneous, negatively charged mucopolysaccharide consisting of approximately 18 to 50 saccharide units (molecular weight 5000–30,000 Da). Antithrombin (AT), required for the interaction (and subsequent neutralization) of UFH with thrombin and coagulation proteases including factors Xa, IXa, XIa, and XIIa, is bound by one third of administered drug (only molecules containing the critical pentasaccharide sequence can bind AT). Following IV administration, UFH binds to a variety of plasma proteins, endothelial cells, and macrophages, explaining, in part, the wide variability in anticoagulant effects for a given dose. It is cleared from the circulation through both a rapid saturable mechanism and a slower first-order mechanism. As a result, there is a dose-dependent half-life ranging from 60 minutes after a dose of 100 U/kg to 180 minutes for a dose of 400 U/kg (Beguin et al., 1988; Lam et al., 1976). Heparin-induced thrombocytopenia and hemorrhage are the most feared complications of UFH administration (see Chapter 29). Other adverse effects include osteopenia (with long-term administration). Low-molecular-weight heparin (LMWH) is prepared by the depolymerization of porcine UFH. A variety of processes are used, giving distinctive products whose molecular weights range from 4,000 to 6,500 Da (Hirsh and Levine, 1992). Like UFH, approximately one third of LMWH polysaccharide chains contain the pentasaccharide binding site for antithrombin. The LMWH–antithrombin complex (consisting of a predominance of shorter chain polysaccharides) has relatively weak antithrombin activity but retains the ability to inactivate factor Xa. The ratio of anti-Xa activity to anti-IIa (antithrombin) activity varies from 2:1 to 4:1. Similar to UFH, LMWH is not able to inhibit thrombin bound to fibrin (Weitz, 1997).

Differential cellular effects of old and new oral anticoagulants: consequences to the genesis and progression of atherosclerosis

2014 ◽  
Vol 112 (11) ◽  
pp. 909-917 ◽  
Author(s):  
Henri Spronk ◽  
Leon Schurgers
Keyword(s):  
Oral Anticoagulant Therapy ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factors ◽  
New Oral Anticoagulants ◽  
Fixed Dose ◽  
Direct Inhibition ◽  
Thrombotic Risk ◽  
Cellular Effects ◽  
Fibrin Formation

SummaryThe main purpose of anticoagulants is to diminish fibrin formation, thereby decreasing the risk of venous or arterial thrombosis. Vitamin K antagonist have been used for many decades in order to achieve reduced thrombotic risk, despite major drawbacks of this class of drugs such as cumbersome dossing and monitoring of anticoagulant status. To overcome these drawbacks of VKA, new classes of anticoagulants have been developed including oral anticoagulants for direct inhibition of either thrombin or factor Xa, which can be administrated in a fixed dose without monitoring. Coagulation factors can activate cellular protease-activated receptors, thereby inducing cellular processes as inflammation, apoptosis, migration, and fibrosis. Therefore, inhibition of coagulation proteases not only attenuates fibrin formation, but may also influence pathophysiological processes like vascular calcification and atherosclerosis. Animal models revealed that VKA therapy induced both intima and media calcification and accelerated plaque vulnerability, whereas specific and direct inhibition of thrombin or factor Xa attenuated atherosclerosis. In this review we provide an overview of old and new oral anticoagulants, as well discuss potential pleiotropic effects with regard to calcification and atherosclerosis. Although translation from animal model to clinical patients seems difficult at first sight, effort should be made to fully understand the clinical implications of long-term oral anticoagulant therapy on vascular side effects.

Anticoagulation beyond direct thrombin and factor Xa inhibitors: indications for targeting the intrinsic pathway?

2013 ◽  
Vol 110 (08) ◽  
pp. 223-232 ◽  
Author(s):  
Maurits van Montfoort ◽  
Joost Meijers
Keyword(s):  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Xa Inhibitors ◽  
Therapeutic Window ◽  
Intrinsic Pathway ◽  
Antithrombotic Drugs

SummaryAntithrombotic drugs like vitamin K antagonists and heparin have been the gold standard for the treatment and prevention of thromboembolic disease for many years. Unfortunately, there are several disadvantages of these antithrombotic drugs: they are accompanied by serious bleeding problems, it is necessary to monitor the therapeutic window, and there are various interactions with food and other drugs. This has led to the development of new oral anticoagulants, specifically inhibiting either thrombin or factor Xa. In terms of effectiveness, these drugs are comparable to the currently available anticoagulants; however, they are still associated with issues such as bleeding, reversal of the drug and complicated laboratory monitoring. Vitamin K antagonists, heparin, direct thrombin and factor Xa inhibitors have in common that they target key proteins of the haemostatic system. In an attempt to overcome these difficulties we investigated whether the intrinsic coagulation factors (VIII, IX, XI, XII, prekallikrein and high-molecular-weight kininogen) are superior targets for anticoagulation. We analysed epidemiological data concerning thrombosis and bleeding in patients deficient in one of the intrinsic pathway proteins. Furthermore, we discuss several thrombotic models in intrinsic coagulation factor-deficient animals. The combined results suggest that intrinsic coagulation factors could be suitable targets for anticoagulant drugs.

scholarly journals A clinical case of the successful use of recombinant activated VII coagulation factor in a newborn with sepsis

2020 ◽  
Vol 7 (3) ◽  
pp. 132-137
Author(s):  
I. G. Trukhanova ◽  
L. V. Krugova ◽  
Yu. G. Kutyreva
Keyword(s):  
Clinical Case ◽  
High Titer ◽  
Intensive Therapy ◽  
Active Form ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Fibrin Clot ◽  
Blood Coagulation Factors ◽  
Important Place

Recently, in the intensive care of acquired coagulopathies in children and newborns, synthetic coagulation factors have occupied an important place, with recombinant VII activated coagulation factor (rFVIIa) being used more often. It initiates hemostasis at the site of vascular damage, forms a complex with tissue factor, and ensures maximum platelet activation. The resulting complex stimulates the transition of blood coagulation factors IX and X to the active form IXa and Xa, then factor Xa leads to increased synthesis thrombin and the formation of a stable fibrin clot. Initially, rFVIIa was developed and used to treat bleeding and surgery in patients with hereditary or acquired hemophilia and a high titer of an inhibitor to coagulation factors VIII or IX. Currently, indications for its use have expanded significantly and it is effective in intensive therapy of other acquired coagulopathy, including the occurrence of coagulopathy due to sepsis. This article presents a clinical case of the successful use of rFVIIa in a newborn with sepsis and hemocogulation disorders. The description of each case is important for the accumulation of experience and the development of further algorithms for the treatment of newborns with sepsis, accompanied by impaired hemocoagulation, since there is currently no single effective management strategy for such patients.

scholarly journals A Structure Based Study of Selective Inhibition of Factor IXa over Factor Xa

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5372
Author(s):  
Sibsankar Kundu ◽  
Sangwook Wu
Keyword(s):  
Structural Alignment ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Selective Inhibition ◽  
Binding Mode ◽  
Pharmacophore Modeling ◽  
Coagulation Cascade ◽  
Modern World ◽  
Factor Ixa

Blood coagulation is an essential physiological process for hemostasis; however, abnormal coagulation can lead to various potentially fatal disorders, generally known as thromboembolic disorders, which are a major cause of mortality in the modern world. Recently, the FDA has approved several anticoagulant drugs for Factor Xa (FXa) which work via the common pathway of the coagulation cascade. A main side effect of these drugs is the potential risk for bleeding in patients. Coagulation Factor IXa (FIXa) has recently emerged as the strategic target to ease these risks as it selectively regulates the intrinsic pathway. These aforementioned coagulation factors are highly similar in structure, functional architecture, and inhibitor binding mode. Therefore, it remains a challenge to design a selective inhibitor which may affect only FIXa. With the availability of a number of X-ray co-crystal structures of these two coagulation factors as protein–ligand complexes, structural alignment, molecular docking, and pharmacophore modeling were employed to derive the relevant criteria for selective inhibition of FIXa over FXa. In this study, six ligands (three potent, two selective, and one inactive) were selected for FIXa inhibition and six potent ligands (four FDA approved drugs) were considered for FXa. The pharmacophore hypotheses provide the distribution patterns for the principal interactions that take place in the binding site. None of the pharmacophoric patterns of the FXa inhibitors matched with any of the patterns of FIXa inhibitors. Based on pharmacophore analysis, a selectivity of a ligand for FIXa over FXa may be defined quantitatively as a docking score of lower than −8.0 kcal/mol in the FIXa-grids and higher than −7.5 kcal/mol in the FXa-grids.

Ancylostoma caninum Anticoagulant Peptide Blocks Metastasis In Vivo and Inhibits Factor Xa Binding to Melanoma Cells In Vitro

1998 ◽  
Vol 79 (05) ◽  
pp. 1041-1047 ◽  
Author(s):  
Kathleen M. Donnelly ◽  
Michael E. Bromberg ◽  
Aaron Milstone ◽  
Jennifer Madison McNiff ◽  
Gordon Terwilliger ◽  
...  
Keyword(s):  
Active Site ◽  
Thrombin Generation ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Melanoma Cells ◽  
Factor V ◽  
Ancylostoma Caninum ◽  
Metastatic Activity

SummaryWe evaluated the in vivo anti-metastatic activity of recombinant Ancylostoma caninum Anticoagulant Peptide (rAcAP), a potent (Ki = 265 pM) and specific active site inhibitor of human coagulation factor Xa originally isolated from bloodfeeding hookworms. Subcutaneous injection of SCID mice with rAcAP (0.01-0.2 mg/mouse) prior to tail vein injection of LOX human melanoma cells resulted in a dose dependent reduction in pulmonary metastases. In order to elucidate potential mechanisms of rAcAP’s anti-metastatic activity, experiments were carried out to identify specific interactions between factor Xa and LOX. Binding of biotinylated factor Xa to LOX monolayers was both specific and saturable (Kd = 15 nM). Competition experiments using antibodies to previously identified factor Xa binding proteins, including factor V/Va, effector cell protease receptor-1, and tissue factor pathway inhibitor failed to implicate any of these molecules as significant binding sites for Factor Xa. Functional prothrombinase activity was also supported by LOX, with a half maximal rate of thrombin generation detected at a factor Xa concentration of 2.4 nM. Additional competition experiments using an excess of either rAcAP or active site blocked factor Xa (EGR-Xa) revealed that most of the total factor Xa binding to LOX is mediated via interaction with the enzyme’s active site, predicting that the vast majority of cell-associated factor Xa does not participate directly in thrombin generation. In addition to establishing two distinct mechanisms of factor Xa binding to melanoma, these data raise the possibility that rAcAP’s antimetastatic effect in vivo might involve novel non-coagulant pathways, perhaps via inhibition of active-site mediated interactions between factor Xa and tumor cells.

The Effect of Antithrombin III on the Activity of the Coagulation Factors VII, IX and X

1976 ◽  
Vol 35 (02) ◽  
pp. 295-304 ◽  
Author(s):  
B Østerud ◽  
M Miller-Andersson ◽  
U Abildgaard ◽  
H Prydz
Keyword(s):  
Antithrombin Iii ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Disc Electrophoresis ◽  
Polyacrylamide Gel ◽  
Factor Vii ◽  
Native Form ◽  
Factor Ixa ◽  
Plasma Factor

SummaryAntithrombin III, purified to homogeneity according to Polyacrylamide gel disc electrophoresis and immunoelectrophoresis, inhibited the activity of purified factor IXa and Xa, whereas factor VII was not inhibited either in the active or in the native form.Antithrombin III is the single most important inhibitor of factor Xa in plasma. Factor Xa does not, however, reduce the activity of antithrombin III against thrombin.

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