Influence of Factor Xllla Activity on Human Whole Blood Clot Lysis In Vitro

Jansen, J.W.C.M.; Haverkate, F.; Koopman, J; Nieuwenhuis, H. K.; Kluft, C.; Boschman, Th A C

doi:10.1055/s-0038-1651088

Cited by 60 publications

(39 citation statements)

References 25 publications

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“…In vitro studies suggest that fibrin-cross-linked ␣2-antiplasmin is an important determinant of the susceptibility of plasma clots to fibrinolysis. 21,25,27 In fact, Jansen et al 27 concluded that while factor XIIIa-mediated cross-linking inhibited fibrinolysis, its major inhibitory effect was mediated through the cross-linking of ␣2-antiplasmin to fibrin. In contrast, Francis and Marder, 26 in studies of supraphysiological doses of factor XIII, concluded that fibrin-fibrin cross-linking in and of itself contributes to fibrinolytic resistance.…”

Section: Discussionmentioning

confidence: 99%

The Contribution of Activated Factor XIII to Fibrinolytic Resistance in Experimental Pulmonary Embolism

Reed

Houng

1999

Circulation

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Background —The resistance of thrombi to fibrinolysis induced by plasminogen activators remains a major impediment to the successful treatment of thrombotic diseases. This study examines the contribution of activated factor XIII (factor XIIIa) to fibrinolytic resistance in experimental pulmonary embolism. Methods and Results —The fibrinolytic effects of specific inhibitors of factor XIIIa–mediated fibrin-fibrin cross-linking and α2-antiplasmin–fibrin cross-linking were measured in anesthetized ferrets with pulmonary emboli. Five experimental groups were treated with heparin (100 U/kg) and/or tissue plasminogen activator (TPA, 1 mg/kg) and the percent (mean±SD) lysis of emboli was determined: (1) control, normal factor XIIIa activity (14.1±4.8% lysis); (2) inhibited factor XIIIa activity (42.7±7.4%); (3) normal factor XIIIa activity+TPA (32.3±7.7%); (4) inhibited factor XIIIa activity+TPA (76.0±11.9%); and (5) inhibited α2-antiplasmin–fibrin cross-linking+TPA (54.7±3.9%). Inhibition of factor XIIIa activity increased endogenous lysis markedly (group 1 versus 2; P <0.0001), to a level comparable to that achieved with TPA (group 2 versus 3; P <0.05). Among groups receiving TPA, selective inhibition of factor XIII-mediated α2-antiplasmin–fibrin cross-linking enhanced lysis (group 3 versus 5; P <0.0005). Complete inhibition of factor XIIIa also amplified lysis (group 3 versus 4; P <0.0001) and had greater effects than inhibition of α2-antiplasmin cross-linking alone (group 4 versus 5; P <0.0005). No significant fibrinogen degradation occurred in any group. Conclusions —Factor XIIIa–mediated fibrin-fibrin and α2-antiplasmin–fibrin cross-linking both caused experimental pulmonary emboli to resist endogenous and TPA-induced fibrinolysis. This suggests that factor XIIIa may play a critical role in regulating fibrinolysis in human thrombosis.

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Section: Discussionmentioning

confidence: 99%

The Contribution of Activated Factor XIII to Fibrinolytic Resistance in Experimental Pulmonary Embolism

Reed

Houng

1999

Circulation

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“…Cross-linking by FXIIIa improves the mechanical strength, rigidity and elasticity of the clot and increases its resistance to fibrinolysis [11][12][13][14][15][16]. Inhibition of FXIIIa activity enhances fibrin degradation mediated by plasmin in vitro [17] and accelerates thrombolysis in animal models of venous and arterial thrombosis and in experimental pulmonary embolism [18][19][20].…”

Section: Fxiiia-i Induced Cross-l Linking Reactions In the Fibrin Clomentioning

confidence: 99%

“…Inhibition of the binding of α2-PI to fibrin considerably accelerates the lysis of the clot [17,40,41]. α2-PI mutated at its active site also enhanced fibrin degradation [42].…”

Section: Fxiiia-i Induced Cross-l Linking Reactions In the Fibrin Clomentioning

confidence: 99%

Fibrin Stabilization (Factor XIII), Fibrin Structure and Thrombosis

Bereczky

Katona

Muszbek

2003

Pathophysiol Haemos Thromb

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“…Subsequent studies in whole blood and plasma showed that the formation of fibrin-fibrin crosslinks do not contribute significantly to the resistance of the clot to fibrinolysis, and thus that the stability of thrombi to lysis depends predominantly on crosslinking of a2AP into the thrombus. 32,33 Other studies showed that a2AP may also noncovalently bind to fibrin and fibrinogen, which could potentially serve to provide the proper orientation of the crosslinking sites of a2AP and fibrin to facilitate crosslinking of a2AP to fibrin. …”

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confidence: 99%

Natural heterogeneity of α2-antiplasmin: functional and clinical consequences

Abdul

Leebeek

Rijken

et al. 2016

Blood

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Human a2-antiplasmin (a2AP, also called a2-plasmin inhibitor) is the main physiological inhibitor of the fibrinolytic enzyme plasmin. a2AP inhibits plasmin on the fibrin clot or in the circulation by forming plasmin-antiplasmin complexes. Severely reduced a2AP levels in hereditary a2AP deficiency may lead to bleeding symptoms, whereas increased a2AP levels have been associated with increased thrombotic risk. a2AP is a very heterogeneous protein. In the circulation, a2AP undergoes both amino terminal (N-terminal) and carboxyl terminal (C-terminal) proteolytic modifications that significantly modify its activities. About 70% of a2AP is cleaved at the N terminus by antiplasmin-cleaving enzyme (or soluble fibroblast activation protein), resulting in a 12-amino-acid residue shorter form. The glutamine residue that serves as a substrate for activated factor XIII becomes more efficient after removal of the N terminus, leading to faster crosslinking of a2AP to fibrin and consequently prolonged clot lysis. In approximately 35% of circulating a2AP, the C terminus is absent. This C terminus contains the binding site for plasmin(ogen), the key component necessary for the rapid and efficient inhibitory mechanism of a2AP. Without its C terminus, a2AP can no longer bind to the lysine binding sites of plasmin(ogen) and is only a kinetically slow plasmin inhibitor. Thus, proteolytic modifications of the N and C termini of a2AP constitute major regulatory mechanisms for the inhibitory function of the protein and may therefore have clinical consequences. This review presents recent findings regarding the main aspects of the natural heterogeneity of a2AP with particular focus on the functional and possible clinical implications. (Blood. 2016; 127(5):538-545) Introduction a2-antiplasmin (a2AP, also called a2-plasmin inhibitor) is a key player in the fibrinolytic system (Figure 1). The fibrinolytic system is crucial for dissolving fibrin clots, facilitating tissue repair, and preventing clots from occluding vessels.1 Recent clinical studies have shown that reduced fibrinolysis (eg, due to an increase in a2AP level) is associated with an increase in both venous and arterial thrombotic risk. 2In contrast, an increase in fibrinolysis due to a2AP deficiency is associated with hemophilia-like bleeding symptoms, which typically occur after initial hemostasis as a result of the premature dissolution of fibrin. The phenotype of a2AP deficiency is heterogeneous. Complete congenital a2AP deficiency leads to severe bleeding with hemophilialike bleeding symptoms such as joint bleeding, whereas heterozygous a2AP-deficient patients typically have mild or no bleeding symptoms. 3,4 In addition, acquired a2AP deficiency may also occur in liver disease 5 and amyloidosis 6 or during fibrinolytic therapy. 7The main enzyme of the fibrinolytic system is the serine protease plasmin, which is predominantly responsible for the degradation of fibrin into rapidly cleared soluble fibrin degradation products (Figure 1). The inactive proenzyme plasminogen ca...

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Influence of Factor Xllla Activity on Human Whole Blood Clot Lysis In Vitro

Cited by 60 publications

References 25 publications

The Contribution of Activated Factor XIII to Fibrinolytic Resistance in Experimental Pulmonary Embolism

The Contribution of Activated Factor XIII to Fibrinolytic Resistance in Experimental Pulmonary Embolism

Fibrin Stabilization (Factor XIII), Fibrin Structure and Thrombosis

Natural heterogeneity of α2-antiplasmin: functional and clinical consequences

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