Activated factor XI and tissue factor in aortic stenosis

Abstract Factor XI (FXI) may be activated in a purified system by thrombin and by autoactivation in the presence of negatively charged substances such as dextran sulfate or sulfatides. The current studies were performed to determine if these processes occur during the coagulation of plasma. FXII--deficient plasma was supplemented with 125I-FXI and clot formation was induced with tissue factor and/or sulfatides. Cleavage of FXI was studied by standard polyacrylamide gel electrophoresis and autoradiography. Activated FXI (FXIa) was detected after 20 minutes of incubation with sulfatides alone and this process was markedly accelerated by the addition of tissue factor (TF). The enhancing effect of TF was blocked by hirudin, which indicated thrombin involvement in FXI activation. The contribution of FXIa to FIX activation in this system was studied using a 3H-FIX activation peptide release assay. Sulfatides increased FIX activation about twofold in plasma induced to clot with TF but had no effect if the plasma was immunodepleted of FXI. FIX activation was also increased in plasma induced to clot with FXa if sulfatides were present. The enhanced generation of FIXa was dependent on FXI and was blocked by hirudin. Some activation was seen in the reactions with sulfatides and hirudin and is likely solely caused by FXI autoactivation. The data indicate that during the coagulation of plasma in the presence of sulfatides, FXI is activated by a mechanism that is thrombin dependent and does not require FXII.

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The Role of Factor XI in Thrombin Generation Induced by Low Concentrations of Tissue Factor

Thrombosis and Haemostasis ◽

10.1055/s-0037-1615964 ◽

2001 ◽

Vol 85 (06) ◽

pp. 1060-1065 ◽

Cited By ~ 66

Author(s):

Irene Keularts ◽

Ariella Zivelin ◽

Uri Seligsohn ◽

H. Coenraad Hemker ◽

Suzette Béguin

Keyword(s):

Tissue Factor ◽

Thrombin Generation ◽

Contact Activation ◽

Factor Xi ◽

Platelet Poor Plasma ◽

Low Concentrations ◽

Time Determination ◽

Thrombin Formation

SummaryThrombin generation has been studied in the plasma of severely factor XI deficient patients under conditions in which contact activation did not play a role. In platelet-rich as well as platelet-poor plasma, thrombin generation was dependent upon the presence of factor XI at tissue factor concentrations of between 1 and 20 pg/ml i.e. ~ 0.01 to 0.20% of the concentration normally present in the thromboplastin time determination. The requirement for factor XI is low; significant thrombin generation was seen at 1% factor XI; at 10%, thrombin formation was nearly normalised. A suspension of normal platelets in severely factor XI deficient plasma did not increase thrombin generation. This implies that there is no significant factor XI activity carried by normal platelets, although the presence of factor XI and factor XI inhibitors in platelets cannot be ruled out.

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Factor XI enhances fibrin generation and inhibits fibrinolysis in a coagulation model initiated by surface-coated tissue factor

Blood Coagulation & Fibrinolysis ◽

10.1097/01.mbc.0000224843.33216.5f ◽

2006 ◽

Vol 17 (4) ◽

pp. 251-257 ◽

Cited By ~ 26

Author(s):

Peter A von dem Borne ◽

Linda MP Cox ◽

Bonno N Bouma

Keyword(s):

Tissue Factor ◽

Factor Xi

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Activated factor XI increases the procoagulant activity of the extrinsic pathway by inactivating tissue factor pathway inhibitor

Blood ◽

10.1182/blood-2014-10-604587 ◽

2015 ◽

Vol 125 (9) ◽

pp. 1488-1496 ◽

Cited By ~ 34

Author(s):

Cristina Puy ◽

Erik I. Tucker ◽

Anton Matafonov ◽

Qiufang Cheng ◽

Keith D. Zientek ◽

...

Keyword(s):

Endothelial Cells ◽

Tissue Factor ◽

Tissue Factor Pathway Inhibitor ◽

Factor X ◽

Factor Xi ◽

Extrinsic Pathway ◽

Fibrin Formation ◽

Key Points ◽

Tissue Factor Pathway ◽

Factor X Activation

Key Points Activated factor XI binds and proteolyzes tissue factor pathway inhibitor. Activated factor XI promotes factor X activation generation and fibrin formation through the inactivation of tissue factor pathway inhibitor from platelets and on endothelial cells.

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Roles of Platelets and Factor XI in the Initiation of Blood Coagulation by Thrombin

Thrombosis and Haemostasis ◽

10.1055/s-0037-1616203 ◽

2001 ◽

Vol 86 (07) ◽

pp. 75-82 ◽

Cited By ~ 58

Author(s):

Peter Walsh

Keyword(s):

Binding Site ◽

Tissue Factor ◽

Vascular Injury ◽

Factor Xi ◽

Platelet Surface ◽

Proteolytic Activation ◽

Activated Platelets ◽

Tissue Factor Pathway ◽

Protease Nexin ◽

Normal Hemostasis

SummaryTo account for the variable hemostatic defect in patients with factor XI (FXI) deficiency, with normal hemostasis in contact factor deficiencies, a coagulation paradigm is presented whereby trace quantities of thrombin, generated transiently by exposure of tissue factor at sites of vascular injury, activates FXI bound to the platelet surface in the presence of prothrombin or high Mr kininogen (HK). Tissue factor pathway inhibitor (TFPI) limits the flux of thrombin generated by the tissue factor pathway, and protease nexin II (PNII), released from activated platelets, inhibits solution phase FXIa and localizes FIX activation to the platelet surface where FXIa is protected from inactivation by PNII. Either prothrombin or HK binds to the Apple 1 (A1) domain of FXI, thereby exposing a platelet-binding site in the FXI A3 domain. Dimeric FXI binds to activated platelets directly through the A3 domain of one monomer. After proteolytic activation of platelet-bound FXI by thrombin (or FXIIa), a substrate binding site for FIX is exposed in the opposite monomer that promotes FIX activation on the platelet surface resulting in the local explosive generation of thrombin and the formation of hemostatic thrombi at sites of vascular injury.

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Protective Roles for Fibrin, Tissue Factor, Plasminogen Activator Inhibitor-1, and Thrombin Activatable Fibrinolysis Inhibitor, but Not Factor XI, during Defense against the Gram-Negative BacteriumYersinia enterocolitica

The Journal of Immunology ◽

10.4049/jimmunol.1101094 ◽

2011 ◽

Vol 187 (4) ◽

pp. 1866-1876 ◽

Cited By ~ 47

Author(s):

Deyan Luo ◽

Frank M. Szaba ◽

Lawrence W. Kummer ◽

Edward F. Plow ◽

Nigel Mackman ◽

...

Keyword(s):

Tissue Factor ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

Thrombin Activatable Fibrinolysis Inhibitor ◽

Factor Xi ◽

Gram Negative ◽

Fibrinolysis Inhibitor ◽

Activator Inhibitor

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Atherosclerotic-like process in aortic stenosis: Activation of the tissue factor–thrombin pathway and potential role through osteopontin alteration

Atherosclerosis ◽

10.1016/j.atherosclerosis.2010.07.047 ◽

2010 ◽

Vol 213 (2) ◽

pp. 369-376 ◽

Cited By ~ 44

Author(s):

Joke Breyne ◽

Francis Juthier ◽

Delphine Corseaux ◽

Sylvestre Marechaux ◽

Christophe Zawadzki ◽

...

Keyword(s):

Aortic Stenosis ◽

Tissue Factor ◽

Potential Role

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Factor XI contributes to thrombin generation in the absence of factor XII

Blood ◽

10.1182/blood-2009-02-203604 ◽

2009 ◽

Vol 114 (2) ◽

pp. 452-458 ◽

Cited By ~ 96

Author(s):

Dmitri V. Kravtsov ◽

Anton Matafonov ◽

Erik I. Tucker ◽

Mao-fu Sun ◽

Peter N. Walsh ◽

...

Keyword(s):

Tissue Factor ◽

Thrombin Generation ◽

Factor Xa ◽

Factor Ix ◽

Factor Xii ◽

Factor Xi ◽

Factor Xii Deficiency ◽

Low Concentrations

Abstract During surface-initiated blood coagulation in vitro, activated factor XII (fXIIa) converts factor XI (fXI) to fXIa. Whereas fXI deficiency is associated with a hemorrhagic disorder, factor XII deficiency is not, suggesting that fXI can be activated by other mechanisms in vivo. Thrombin activates fXI, and several studies suggest that fXI promotes coagulation independent of fXII. However, a recent study failed to find evidence for fXII-independent activation of fXI in plasma. Using plasma in which fXII is either inhibited or absent, we show that fXI contributes to plasma thrombin generation when coagulation is initiated with low concentrations of tissue factor, factor Xa, or α-thrombin. The results could not be accounted for by fXIa contamination of the plasma systems. Replacing fXI with recombinant fXI that activates factor IX poorly, or fXI that is activated poorly by thrombin, reduced thrombin generation. An antibody that blocks fXIa activation of factor IX reduced thrombin generation; however, an antibody that specifically interferes with fXI activation by fXIIa did not. The results support a model in which fXI is activated by thrombin or another protease generated early in coagulation, with the resulting fXIa contributing to sustained thrombin generation through activation of factor IX.

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