Regulation of Fibrinolysis by Thrombin Activatable Fibrinolysis Inhibitor, an Unstable Carboxypeptidase B That Unites the Pathways of Coagulation and Fibrinolysis

Mosnier, Laurent O.; Bouma, Bonno N.

doi:10.1161/01.atv.0000244680.14653.9a

Cited by 137 publications

(113 citation statements)

References 94 publications

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“…5c). Thrombin forms a complex with rThm with great affinity for thrombin-activatable fibrinolysis inhibitor (TAFI) [24], which inhibits fibrinolysis and thus may be responsible for the prolongation of the clot lysis time in our experiment (Fig. 5d), as well as a previous report [25].…”

Section: Discussionsupporting

confidence: 90%

Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation

et al. 2018

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The effect of direct oral anticoagulants (DOACs) on turbidimetric measurements of plasma clot formation and susceptibility to fibrinolysis may facilitate a comparison between different classes of anticoagulants in plasma samples. We obtained 424 citrate plasma samples from 226 atrial fibrillation patients on anticoagulation and 24 samples without anticoagulation serving as controls. As comparators, we measured the international normalized ratio (INR) for phenprocoumon samples (N = 166), anti-Xa for low molecular weight heparin (LMWH) samples (N = 42), and DOAC levels with mass spectrometry (dabigatran N = 40, rivaroxaban N = 110, apixaban N = 42). Plasma clot formation and lysis were recorded continuously on a photometer after addition of an activation mix (tissue factor 2 pmol/l and tissue plasminogen activator 333 ng/ml). We used linear regression and ANCOVA for correlation analysis. Clot formation lag phase was prolonged in the presence of anticoagulants in a concentration-dependent manner for DOACs (dabigatran Spearman r = 0.74; rivaroxaban r = 0.78; apixaban r = 0.72, all p < 0.0001), INR dependent for phenprocoumon (r = 0.59, p < 0.0001), anti-Xa level dependent in LMWH samples (r = 0.90, p < 0.0001). Maximum rate of clot formation and peak clot turbidity were reduced in the presence of anticoagulants, but correlated only moderately with the comparator measures of anticoagulation. The clot lysis time was inversely correlated with DOAC concentrations in the presence of recombinant thrombomodulin. A direct ex vivo comparison between the effects of different classes of anticoagulants is possible with turbidimetric measurement of plasma clot formation and lysis. Anticoagulation inhibited clot formation in a plasma concentration manner for DOACs, INR dependent for phenprocoumon, and anti-Xa dependent for LMWH. Susceptibility to fibrinolysis increased with increasing DOAC concentrations.

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Section: Discussionsupporting

confidence: 90%

Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation

et al. 2018

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“…At high thrombin concentrations, thrombin is able to activate TAFI. This carboxypeptidase helps to protect fibrin polymers from enzymatic degradation through removal of C-terminal lysine residues that are important in tPA-mediated plasminogen activation (21). Our studies suggest that the cofactor function of FVa in feedback activation of the intrinsic pathway plays a role in this mechanism by stimulating thrombin formation to levels that promote TAFI activation.…”

Section: Discussionmentioning

confidence: 73%

Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma

Maas

Meijers

Marquart

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The mechanism by which the intrinsic pathway of coagulation contributes to physiological hemostasis is enigmatic. Thrombin activates factor XI, a key zymogen in this pathway, which leads to increased thrombin generation. As thrombin-dependent activation of factor XI in vitro is relatively inefficient, we hypothesized that a physiological cofactor supports this reaction in a plasma environment. We therefore investigated whether the cofactors of coagulation, activated factor V, activated factor VIII, high-molecular weight kininogen, or protein S, influenced activation of factor XI by thrombin. Only activated factor V stimulated activation of factor XI by thrombin in a purified system. Binding studies demonstrated that factor XI specifically interacts with both factor V and factor Va through multiple binding sites. We further investigated this cofactor function of activated factor V in plasma. Depletion of factor V, or the addition of activated protein C, decreased the activation of the intrinsic pathway by thrombin in plasma. However, activated protein C did not exert this effect in the plasma of a homozygous carrier of the prothrombotic factor V Leiden mutation. In conclusion, we propose a role for (activated) factor V as a cofactor in the activation of factor XI by thrombin. These findings offer insights into the coagulation system in both health and disease.coagulation | coagulation factor V | coagulation factor XI | feedback activation T he mechanism behind the activation of the intrinsic pathway of coagulation in vivo has been subject to discussion since the introduction of the model of coagulation (1, 2). The importance of the intrinsic pathway for physiological hemostasis is apparent from the bleeding phenotypes that are seen in factor VIII (FVIII) deficiency, factor IX (FIX) deficiency and, to a lesser extent, in factor XI (FXI) deficiency. In vitro, activation of the intrinsic pathway can be initiated by factor XII (FXII) on negatively charged surfaces, which results in clotting. However, the role of FXII-dependent coagulation in physiological hemostasis is controversial. FXII deficiency, for instance, protects against thrombosis in murine models (3), which conflicts with the protective role of high FXII antigen levels in epidemiological studies on thrombosis in humans (4), as well as with the absence of bleeding symptoms in FXII-deficient individuals. Additionally, FXII hyperactivity leads to angioedema, rather than to thrombosis (5), which corresponds with evidence that activation of the kallikrein-kinin system by FXII can take place independent of coagulation (6).As FXI deficiency, unlike FXII deficiency, is associated with mild bleeding phenomena, a FXI activator other than FXII is likely. Thrombin, the final and central enzyme of the coagulation cascade, can directly activate FXI, which leads to downstream formation of more thrombin (7,8). This feedback activation mechanism offered an alternative explanation for the existence of the intrinsic pathway: The amplification of minute amounts of thrombin, ...

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“…Hence, while the Gly(404)→Pro substitution affects protein C activation, other aspects of TM function are retained. These include activation of TAFI, that plays important roles in coagulation, inflammation, and extracellular matrix remodeling (47,48), and binding of the highly pro-inflammatory HMGB1 DNA binding protein (sometimes referred to as the "nuclear weapon in the immune system's arsenal"). HMGB1 binds to the cell surface receptor for advanced glycation endproducts (RAGE), which is involved in induction of fibrosis and intestinal inflammation and mucosal barrier loss (49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Ameliorates Radiation Enteropathy Development After Localized, Fractionated Irradiation by a Protein C-Independent Mechanism

Wang

Boerma

et al. 2007

International Journal of Radiation Oncology*Biology*Physics

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Regulation of Fibrinolysis by Thrombin Activatable Fibrinolysis Inhibitor, an Unstable Carboxypeptidase B That Unites the Pathways of Coagulation and Fibrinolysis

Cited by 137 publications

References 94 publications

Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation

Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation

Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma

Simvastatin Ameliorates Radiation Enteropathy Development After Localized, Fractionated Irradiation by a Protein C-Independent Mechanism

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