Thrombin-activatable fibrinolysis inhibitor (TAFI) deficiency is compatible with murine life

Nagashima, Mariko; Yin, Zheng-Feng; Zhao, Lei; White, Kathy; Zhu, Yanhong; Lasky, Nina; Halks-Miller, Meredith; Broze, George J.; Fay, William P.; Morser, John

doi:10.1172/jci0212119

Cited by 134 publications

(167 citation statements)

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“…Our data suggest that plasma CPN, which is constitutively active, is important for acting as a "housekeeping" carboxypeptidase whereas TAFIa, generated at the site of tissue injury, is important for inactivation of excessive BK produced under inflammatory conditions. Previously, using a kaolin-induced writhing model, in which kaolin was administered intraperitoneally to activate factor XII and prekallikrein, TAFI-deficient mice failed to show any increased writhing response as compared with the wild-type mice, suggesting that either TAFIa does not play a significant role in modulating the activity of BK or that TAFI is not activated in this model (34). The kaolin writhing model is very different from the BK-induced hypotension model used in this study.…”

Section: Table II Fibrinogen and Platelet Counts Of Mice Infused Withmentioning

confidence: 56%

“…While this notion is amply supported by in vitro studies, the in vivo role of TAFI remains uncertain. TAFI-deficient mice had no gross phenotypic abnormalities and no differences in the rate of endogenous clot lysis could be demonstrated using a variety of acute or subacute clot lysis models (34). On the other hand, enhanced pulmonary clot lysis was found in TAFI deficiency superimposed on a partial plasminogen deficiency setting (37).…”

Section: Table II Fibrinogen and Platelet Counts Of Mice Infused Withmentioning

confidence: 99%

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Thrombin Activatable Fibrinolysis Inhibitor, a Potential Regulator of Vascular Inflammation

Myles

Nishimura

Yun

et al. 2003

Journal of Biological Chemistry

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The latent plasma carboxypeptidase thrombin-activable fibrinolysis inhibitor (TAFI) is activated by thrombin/thrombomodulin on the endothelial cell surface, and functions in dampening fibrinolysis. In this study, we examined the effect of activated TAFI (TAFIa) in modulating the proinflammatory functions of bradykinin, complement C5a, and thrombin-cleaved osteopontin. Hydrolysis of bradykinin and C5a and thrombin-cleaved osteopontin peptides by TAFIa was as efficient as that of plasmin-cleaved fibrin peptides, indicating that these are also good substrates for TAFIa. Plasma carboxypeptidase N, generally regarded as the physiological regulator of kinins, was much less efficient than TAFIa. TAFIa abrogated C5a-induced neutrophil activation in vitro. Jurkat cell adhesion to osteopontin was markedly enhanced by thrombin cleavage of osteopontin. This was abolished by TAFIa treatment due to the removal of the C-terminal Arg 168 by TAFIa from the exposed SV-VYGLR ␣ 4 ␤ 1 integrin-binding site in thrombin-cleaved osteopontin. Thus, thrombin cleavage of osteopontin followed by TAFIa treatment may sequentially up-and down-modulate the pro-inflammatory properties of osteopontin. An engineered anticoagulant thrombin, E229K, was able to activate endogenous plasma TAFI in mice, and E229K thrombin infusion effectively blocked bradykinin-induced hypotension in wild-type, but not in TAFI-deficient, mice in vivo. Our data suggest that TAFIa may have a broad anti-inflammatory role, and its function is not restricted to fibrinolysis.

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Section: Table II Fibrinogen and Platelet Counts Of Mice Infused Withmentioning

confidence: 56%

Section: Table II Fibrinogen and Platelet Counts Of Mice Infused Withmentioning

confidence: 99%

Thrombin Activatable Fibrinolysis Inhibitor, a Potential Regulator of Vascular Inflammation

Myles

Nishimura

Yun

et al. 2003

Journal of Biological Chemistry

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207

202

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“…Future studies involving crosses between fV Leiden mice and TAFI-deficient mice should prove useful in testing this hypothesis. 16,17 Additional studies are also necessary to examine other potential mechanisms by which fV Leiden produces an antifibrinolytic effect in vivo. For example, by promoting thrombin formation, fV Leiden could enhance the release of plasminogen activator inhibitor-1 from vascular wall cells.…”

Section: Discussionmentioning

confidence: 99%

Factor V ^Leiden Inhibits Fibrinolysis In Vivo

2004

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Background— Factor V Leiden (fV Leiden ) predisposes to thrombosis by enhancing thrombin formation. This study tested the hypothesis that fV Leiden inhibits fibrinolysis in vivo. Methods and Results— Radiolabeled clots were injected into the jugular veins of wild-type mice and mice heterozygous ( fV +/Q ) or homozygous ( fV Q/Q ) for fV Leiden . Mean percent clot lysis 5 hours later was significantly reduced in fV Q/Q mice (14.3±3.6%, n=13) compared with wild-type mice (40.2±7.0%, n=17; P <0.01) and intermediate in fV +/Q mice (29.4±8.7%, n=9; P <0.03 versus fV Q/Q , P =0.36 versus wild type). The rate of in vitro lysis of plasma clots prepared from fV +/Q or fV Q/Q mice was significantly slower than that of wild-type plasma clots, whereas in vitro clot lysis did not differ significantly between groups after inhibiting thrombin-activatable fibrinolysis inhibitor. Conclusions— fV Leiden inhibits fibrinolysis in vivo, suggesting an additional pathway by which this mutation promotes thrombosis.

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“…Platelet poor plasma or platelet-rich plasma was prepared as described (24). Plasma clot lysis was performed as described previously (25). ELISAs, including D-dimer (Diagnostica Stago) and mouse plasmin⅐antiplasmin complexes (Molecular Innovations), were carried out according to the manufacturers' instructions.…”

Section: Methodsmentioning

confidence: 99%

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

He¹,

Sui

Xiong

et al. 2011

Journal of Biological Chemistry

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In response to blood vessel injury, hemostasis is initiated by platelet activation, advanced by thrombin generation, and tempered by fibrinolysis. The primary fibrinolytic protease, plasmin, can be activated either on a fibrin-containing thrombus or on cells. Annexin A2 (A2) heterotetramer (A2⅐p11) 2 is a key profibrinolytic complex that assembles plasminogen and tissue plasminogen activator and promotes plasmin generation. We now report that, in endothelial cells, plasmin specifically induces activation of conventional PKC, which phosphorylates serine 11 and serine 25 of A2, triggering dissociation of the (A2⅐p11) 2 tetramer. The resulting free p11 undergoes ubiquitinmediated proteasomal degradation, thus preventing further translocation of A2 to the cell surface. In vivo, pretreatment of A2 ؉/؉ but not A2 ؊/؊ mice with a conventional PKC inhibitor significantly reduced thrombosis in a carotid artery injury model. These results indicate that augmentation of fibrinolytic vascular surveillance by blockade of serine phosphorylation is A2-dependent. We also demonstrate that plasmin-induced phosphorylation of A2 requires both cleavage of A2 and activation of Toll-like receptor 4 on the cell surface. We propose that plasmin can limit its own generation by triggering a finely tuned "feedback" mechanism whereby A2 becomes serine-phosphorylated, dissociates from p11, and fails to translocate to the cell surface.The human hemostatic system represents a coordinated balance between procoagulant and anticoagulant/profibrinolytic activities. Together, these systems prevent blood loss while maintaining blood flow. Plasmin, the major protease of the fibrinolytic system, acts to digest insoluble fibrin into soluble fibrin degradation products. Plasmin generation is modulated by plasminogen activators and plasminogen activator inhibitors and is further regulated by binding of plasminogen and its activators to cell surface receptors (1). Membrane-associated annexin A2 (A2) 3 is part of a heterotetrameric complex in which the N termini of two copies of A2 bind to two copies of the S100 family protein, S100A10 (p11) (2). A2, a member of the annexin superfamily, consists of a highly conserved C-terminal phospholipid-binding core domain and an N-terminal ligandinteracting domain (3). Complex formation with p11 increases the affinity of A2 for calcium and phospholipids, thereby directing it to cellular membranes (4). Components of the (A2⅐p11) 2 tetramer, moreover, specifically bind tissue plasminogen activator (t-PA) and plasminogen and strongly enhance plasmin generation (5-8, 52).Several lines of evidence identify the (A2⅐p11) 2 complex as a significant regulator of fibrin balance in vivo. First, A2 Ϫ/Ϫ microvascular endothelial cells lack t-PA cofactor activity, and the fibrin content of highly perfused A2 Ϫ/Ϫ tissues is ϳ2-fold greater than that observed in wild type controls (9). In addition, arterial injury in A2 Ϫ/Ϫ mice is followed by a 2-fold increase in thrombotic vascular occlusion with an equivalent reduction in blood flo...

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Thrombin-activatable fibrinolysis inhibitor (TAFI) deficiency is compatible with murine life

Cited by 134 publications

References 56 publications

Thrombin Activatable Fibrinolysis Inhibitor, a Potential Regulator of Vascular Inflammation

Thrombin Activatable Fibrinolysis Inhibitor, a Potential Regulator of Vascular Inflammation

Factor V ^Leiden Inhibits Fibrinolysis In Vivo

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

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Thrombin-activatable fibrinolysis inhibitor (TAFI) deficiency is compatible with murine life

Cited by 134 publications

References 56 publications

Thrombin Activatable Fibrinolysis Inhibitor, a Potential Regulator of Vascular Inflammation

Thrombin Activatable Fibrinolysis Inhibitor, a Potential Regulator of Vascular Inflammation

Factor V Leiden Inhibits Fibrinolysis In Vivo

Feedback Regulation of Endothelial Cell Surface Plasmin Generation by PKC-dependent Phosphorylation of Annexin A2

Contact Info

Product

Resources

About

Factor V ^Leiden Inhibits Fibrinolysis In Vivo