Polyphosphate suppresses complement via the terminal pathway

Wat, Jovian Ming Wai; Foley, Jonathan H.; Krisinger, Michael J.; Ocariza, Linnette Mae; Lei, Victor; Wasney, Gregory A.; Lameignère, Emilie; Strynadka, N.C.J.; Smith, Stephanie A.; Morrissey, James H.; Conway, Edward M.

doi:10.1182/blood-2013-07-515726

Cited by 54 publications

(63 citation statements)

References 62 publications

(79 reference statements)

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“…50 Recent data highlighted the important role of HRG in modulating FXIIa activity and function. [51][52][53] HRG binds to FXIIa with incredibly high affinity in the presence of Zn 21 ions, 51 and both are released from platelet a-granules upon activation.…”

Section: Discussionmentioning

confidence: 99%

Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Mitchell

Lionikiene

Georgiev

et al. 2016

Blood

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Key Points• PolyP significantly augments the plasminogen activator capacity of FXIIa.• Platelet-bound fibrin acts as a reservoir for plasminogen, FXII(a), and polyP.Activated factor XII (FXIIa) has plasminogen activator capacity but its relative contribution to fibrinolysis is considered marginal compared with urokinase and tissue plasminogen activator. Polyphosphate (polyP) is released from activated platelets and mediates FXII activation. Here, we investigate the contribution of polyP to the plasminogen activator function of aFXIIa. We show that both polyP 70 , of the chain length found in platelets (60-100 mer), and platelet-derived polyP significantly augment the plasminogen activation capacity of aFXIIa. PolyP 70 stimulated the autoactivation of FXII and subsequent plasminogen activation, indicating that once activated, aFXIIa remains bound to polyP 70 . Indeed, complex formation between polyP 70 and aFXIIa provides protection against autodegradation. Plasminogen activation by bFXIIa was minimal and not enhanced by polyP 70 , highlighting the importance of the anion binding site. PolyP 70 did not modulate plasmin activity but stimulated activation of Glu and Lys forms of plasminogen by aFXIIa. Accordingly, polyP 70 was found to bind to FXII, aFXIIa, and plasminogen, but not bFXIIa. Fibrin and polyP 70 acted synergistically to enhance aFXIIa-mediated plasminogen activation. The plasminogen activator activity of the aFXIIa-polyP 70 complex was modulated by C1 inhibitor and histidine-rich glycoprotein, but not plasminogen activator inhibitors 1 and 2. Platelet polyP and FXII were found to colocalize on the activated platelet membrane in a fibrin-dependent manner and decorated fibrin strands extending from platelet aggregates. We show that in the presence of platelet polyP and the downstream substrate fibrin, aFXIIa is a highly efficient and favorable plasminogen activator. Our data are the first to document a profibrinolytic function of platelet polyP. (Blood. 2016;128(24):2834-2845

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Section: Discussionmentioning

confidence: 99%

Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Mitchell

Lionikiene

Georgiev

et al. 2016

Blood

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“…Polyphosphate, i.e. linear polymers of orthophosphate (NaPO 3 ) linked by phosphoanhydride bonds, was reported to bind to C1-INH [54], and just published data demonstrate the C1-INH potentiating activity of polyphosphate consisting of 130 units [55]. Based on the tested gravimetric and molar concentrations its effect was, however, considerably weaker than that of heparin.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans – Structure-Activity Relationships

2016

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The serpin C1 inhibitor (C1-INH) is the only regulator of classical complement activation as well as the major regulator of the contact system. Its importance is demonstrated by hereditary angioedema (HAE), a severe disease with potentially life-threatening attacks due to deficiency or dysfunction of C1-INH. C1-INH replacement is the therapy of choice in HAE. In addition, C1-INH showed to have beneficial effects in other diseases characterized by inappropriate complement and contact system activation. Due to some limitations of its clinical application, there is a need for improving the efficacy of therapeutically applied C1-INH or to enhance the activity of endogenous C1-INH. Given the known potentiating effect of heparin on C1-INH, sulfated glycans (SG) may be such candidates. The aim of this study was to characterize suitable SG by evaluating structure-activity relationships. For this, more than 40 structurally distinct SG were examined for their effects on C1-INH, C1s and FXIIa. The SG turned out to potentiate the C1s inhibition by C1-INH without any direct influence on C1s. Their potentiating activity proved to depend on their degree of sulfation, molecular mass as well as glycan structure. In contrast, the SG had no effect on the FXIIa inhibition by C1-INH, but structure-dependently modulated the activity of FXIIa. Among the tested SG, β-1,3-glucan sulfates with a Mr ≤ 10 000 were identified as most promising lead candidates for the development of a glycan-based C1-INH amplifier. In conclusion, the obtained information on structural characteristics of SG favoring C1-INH potentiation represent an useful elementary basis for the development of compounds improving the potency of C1-INH in diseases and clinical situations characterized by inappropriate activation of complement and contact system.

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“…85, 86 Interestingly, polyP destabilizes C5b,6 in the terminal pathway of complement, reducing the lytic capacity of the membrane attack complex. 87 This latter finding indicates that polyP can also be anti-inflammatory.…”

Section: Polyp In Thrombosismentioning

confidence: 93%

2013 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

Smith

Morrissey

2015

ATVB

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Polyphosphate is a highly anionic, linear polymer of inorganic phosphates that is found throughout biology, including in many infectious microorganisms. Recently, polyphosphate was discovered to be stored in a subset of the secretory granules of human platelets and mast cells, and to be secreted upon activation of these cells. Work from our laboratory and others has now shown that polyphosphate is a novel, potent modulator of the blood clotting and complement systems that likely plays roles in hemostasis, thrombosis, inflammation, and host responses to pathogens. Therapeutics targeting polyphosphate may have the potential to limit thrombosis with fewer hemorrhagic complications than conventional anticoagulant drugs that target essential proteases of the blood clotting cascade.

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Polyphosphate suppresses complement via the terminal pathway

Cited by 54 publications

References 62 publications

Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Polyphosphate colocalizes with factor XII on platelet-bound fibrin and augments its plasminogen activator activity

Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans – Structure-Activity Relationships

2013 Scientific Sessions Sol Sherry Distinguished Lecture in Thrombosis

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