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

Kravtsov, Dmitri V.; Matafonov, Anton; Tucker, Erik I.; Sun, Mao-fu; Walsh, Peter N.; Gruber, András; Gailani, David

doi:10.1182/blood-2009-02-203604

Cited by 132 publications

(160 citation statements)

References 46 publications

(62 reference statements)

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“…It was demonstrated that the activation of FXI by thrombin mediates the propagation of the coagulation reaction in plasma (7,8,13). We investigated whether FV(a) contributes to this mechanism.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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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“…32 Recalcifying plasma in the absence of thrombin did not induce clotting during the observation period ( Figure 3A second column from left) and had little effect on the relatively short clotting times with 1.25nM ␣-IIa ( Figure 3C). With ␣-IIa, results were not affected by antibodies that block FIX activation by FXIa (O1A6) 19 or FXI activation by FXIIa (14E11), 19,33 or by a FXIIa inhibitor (CTI), indicating any FXIa or FXIIa formed does not influence fibrin formation. rMz-IIa at 2.5nM induced clotting with recalcification, but not without it, indicating that ␣-IIa must be forming from endogenous prothrombin ( Figure 3D).…”

mentioning

confidence: 97%

“…18 FXI activation by ␣-IIa would explain the phenotypic differences between FXI and FXII deficiency. 19,20 FXI is a homolog of prekallikrein (PK), the zymogen of a protease (␣-kallikrein) involved in kinin formation. 17 Although FXI and PK are both FXIIa substrates, PK is not activated by ␣-IIa.…”

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confidence: 99%

Activation of factor XI by products of prothrombin activation

Matafonov

Sarilla

Sun

et al. 2011

Blood

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The prothrombinase complex converts prothrombin to ␣-thrombin through the intermediate meizothrombin (Mz-IIa). Both ␣-thrombin and Mz-IIa catalyze factor (F) XI activation to FXIa, which sustains ␣-thrombin production through activation of FIX. The interaction with FXI is thought to involve thrombin anion binding exosite (ABE) I. ␣-Thrombin can undergo additional proteolysis to ␤-thrombin and ␥-thrombin, neither of which have an intact ABE I. In a purified protein system, FXI is activated by ␤-thrombin or ␥-thrombin, and by ␣-thrombin in the presence of the ABE I-blocking peptide hirugen, indicating that a fully formed ABE I is not absolutely required for FXI activation. In a FXI-dependent plasma thrombin generation assay, ␤-thrombin, ␥-thrombin, and ␣-thrombins with mutations in ABE I are approximately 2-fold more potent initiators of thrombin generation than ␣-thrombin or Mz-IIa, possibly because fibrinogen, which binds to ABE I, competes poorly with FXI for forms of thrombin lacking ABE I. In addition, FXIa can activate factor FXII, which could contribute to thrombin generation through FXIIa-mediated FXI activation. The data indicate that forms of thrombin other than ␣-thrombin contribute directly to feedback activation of FXI in plasma and suggest that FXIa may provide a link between tissue factorinitiated coagulation and the proteases of the contact system. (Blood. 2011;118(2): 437-445) IntroductionThe trypsin-like protease ␣-thrombin (␣-IIa) is a key contributor to vital host responses to injury, including fibrin formation, 1-3 platelet and endothelial cell activation, 4 and inflammation. 5 During coagulation, prothrombin is converted to ␣-IIa through a series of proteolytic steps catalyzed by factor (F) Xa. 6,7 The process results in formation of a functional active site and expression of 2 anion binding exosites (ABE I and ABE II) that are required for ␣-IIa interactions with many substrates, receptors, and inhibitors (Table 1). [1][2][3]6 In the presence of FVa and phospholipid, FXa initially converts prothrombin to the protease meizothrombin (Mz-IIa; Figure 1A), 7-11 which expresses ABE I. 6 Mz-IIa is rapidly converted to ␣-IIa, which may undergo further proteolysis to form ␤-thrombin (␤-IIa) and ␥-thrombin (␥-IIa) ( Figure 1B), 2 proteases with reduced capacity to catalyze ABE I-dependent reactions. [9][10][11][12] Physiologic roles for ␤-IIa or ␥-IIa have not been established; however, both have been identified in clotting blood. 11 ␣-IIa up-regulates its own generation by activating the cofactors FV and FVIII, [1][2][3]9 and by converting FXI to the protease FXIa. 13,14 FXIa, in turn, sustains ␣-IIa generation by converting FIX to FIXa␤, 15 and possibly by activating FV and FVIII. 16 In the original cascade/ waterfall hypotheses of coagulation, FXI is activated by FXIIa 17,18 ; however, current models deemphasize this reaction based on the observation that FXI deficiency is associated with abnormal bleeding, whereas FXII deficiency is not. 18 FXI activation by ␣-IIa would explain the phenotypic di...

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“…3,4 Subsequent work provided a physiological basis by showing that activated platelets could sustain this reaction. 5,6 The laboratory of Dr Morrissey established the mechanism of this activation by showing that polyphosphate released from platelet-dense granules was the agent that promoted thrombin activation of factor XI.…”

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confidence: 99%

“…[4][5][6] Although impaired antimicrobial T-cell immunity posttransplant is frequently attributed to reduced T-cell recovery, competent adaptive immune responses require several steps, including T-cell activation by APCs such as dendritic cells (DCs). Moreover, there is a growing awareness that other immune cells besides ab T cells contribute to anti-CMV immunity posttransplant, and the pathophysiology of CMV reactivation involves more than just T-cell deficiency.…”

mentioning

confidence: 99%

Polyphosphates rock! A role in thrombosis?

Monroe

2015

Blood

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

Cited by 132 publications

References 46 publications

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

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

Activation of factor XI by products of prothrombin activation

Polyphosphates rock! A role in thrombosis?

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