Factor XI anion‐binding sites are required for productive interactions with polyphosphate

Geng, Yipeng; Verhamme, Ingrid M.; Smith, Stephanie A.; Cheng, Qiufang; Sun, Mao-fu; Sheehan, John P.; Morrissey, James H.; Gailani, David

doi:10.1111/jth.12414

Cited by 42 publications

(66 citation statements)

References 37 publications

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“…We recently observed that these regions are also required for polyP to enhance the pro-thrombotic capacity of FXIa to inhibit TFPI (unpublished observation). These mechanisms may partially explain why the loss of the FXI catalytic domain ABS has an antithrombotic effect in a mouse model of thrombosis [31]. Also, mice lacking both FIX and FXI are more resistant to chemical injury-induced arterial thrombosis than are mice deficient in FIX alone [6], further supporting the notion that FXI promotes thrombosis through mechanisms beyond the activation of FIX.…”

Section: Fxi and Thrombosismentioning

confidence: 99%

“…Each FXI subunit contains anion-binding sites (ABSs) on its A3 and catalytic domains that are required for heparin-mediated inhibition of FXIa by antithrombin (AT) and for polyP-mediated FXI activation by thrombin and FXIIa [31]. We recently observed that these regions are also required for polyP to enhance the pro-thrombotic capacity of FXIa to inhibit TFPI (unpublished observation).…”

Section: Fxi and Thrombosismentioning

confidence: 99%

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The hemostatic role of factor XI

Puy

Rigg

McCarty

2016

Thrombosis Research

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Coagulation factor (F)XI has been described as a component of the early phase of the contact pathway of blood coagulation, acting downstream of factor XII. However, patients deficient in upstream members of the contact pathway, including FXII and prekallikrein, do not exhibit bleeding complications, while FXI-deficient patients sometimes experience mild bleeding, suggesting FXI plays a role in hemostasis independent of the contact pathway. Further complicating the picture, bleeding risk in FXI-deficient patients is difficult to predict because bleeding symptoms have not been found to correlate with FXI antigen levels or activity. However, recent studies have emerged to expand our understanding of FXI, demonstrating that activated FXI is able to activate coagulation factors FX, FV, and FVIII, and inhibit the anti-coagulant tissue factor pathway inhibitor (TFPI). Understanding these activities of FXI may help to better diagnose which FXI-deficient patients are at risk for bleeding. In contrast to its mild hemostatic activities, FXI is known to play a significant role in thrombosis, as it is a demonstrated independent risk factor for deep vein thrombosis, ischemic stroke, and myocardial infarction. Recent translational approaches have begun testing FXI as an antithrombotic, with one promising clinical study showing that an anti-sense oligonucleotide against FXI prevented venous thrombosis in elective knee surgery. A better understanding of the varied and complex role of FXI in both thrombosis and hemostasis will help to allow better prediction of bleeding risk in FXI-deficient patients and also informing the development of targeted agents to inhibit the thrombotic activities of FXI while preserving hemostasis.

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Section: Fxi and Thrombosismentioning

confidence: 99%

Section: Fxi and Thrombosismentioning

confidence: 99%

The hemostatic role of factor XI

Puy

Rigg

McCarty

2016

Thrombosis Research

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“…PolyP is known to bind to thrombin via exosite II [10,11] and FXI via the anionbinding sites [7,10,37]; therefore, it is likely that polyP elicits it functions via a template mechanism. In this model, proteases bind to the surface via distinct exosites thereby lowering the dissociation constant and enhancing interaction with their target zymogens.…”

Section: Polyp-mediated Effects On the Contact Pathwaymentioning

confidence: 98%

Polyphosphate as a haemostatic modulator

Mutch

2016

Biochemical Society Transactions

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Platelets are small anuclear cells that play a central role in haemostasis. Platelets become activated in response to various stimuli triggering release of their granular contents into the surrounding milieu. One of these types of granules, termed dense granules, have been found to contain polyphosphate (polyP) in addition to other inorganic biomolecules, such as serotonin, ADP, ATP, PPi. Individuals deficient in dense granules exhibit bleeding tendencies, emphasizing their importance in haemostasis. Platelet polyP is of a relatively defined size, approximately 60-100 phosphate monomers in length. These linear polymers act at various points in the coagulation and fibrinolytic systems thereby modulating the haemostatic response. Due to its highly anionic nature, polyP lends itself to being a natural activator of the contact system. The contact system functions in multiple pathways including coagulation, fibrinolysis, inflammation and complement. Activation of the contact system accelerates thrombin generation, the terminal enzyme in the coagulation cascade. PolyP also modulates factors further downstream in the coagulation cascade to augment thrombin generation. The net effect is increased fibrin formation and platelet activation resulting in faster clot formation. PolyP is incorporated into the forming clot thereby modifying the structure of the resulting fibrin network and its susceptibility to degradation by certain plasminogen activators. In conclusion, release of platelet polyP at the site of injury may facilitate clot formation and augment clot stability thereby promoting wound healing.

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“…Like fXII, fXI undergoes autoactivation if polyphosphate is present [72], so we tested the ability of fXII-T to cleave fXI lacking an active site serine (fXI-S557A) to take autoactivation out of the equation [73]. FXII-T cleaves fXI-S557A to a form that migrates with fXIa on western blot (figure 4E).…”

Section: The Activity Of Fxii-tmentioning

confidence: 99%

Single-chain factor XII: a new form of activated factor XII

Ivanov

Matafonov

Gailani

2017

Current Opinion in Hematology

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Purpose Exposure of blood to foreign surfaces induces reciprocal conversion of the plasma proteins factor XII (fXII) and plasma prekallikrein (PPK) to the proteases α-fXIIa and α-kallikrein. This process, called contact activation, has a range of effects on host defense mechanisms, including promoting coagulation. The nature of the triggering mechanism for contact activation is debated. One hypothesis predicts that fXII has protease activity, either intrinsically or upon surface-binding, that initiates contact activation. We tested this by assessing the proteolytic activity of a recombinant fXII variant that cannot be converted to α-fXIIa. Recent findings The proteolytic activity of fXII-T (for “triple” mutant), a variant with alanine substitutions for arginine at activation cleavage sites (Arg334, Arg344, and Arg353) was tested with known α-fXIIa substrates. FXII-T activates PPK in solution, and the reaction is enhanced by polyphosphate, an inducer of contact activation released from platelets. In the presence of polyphosphate, fXII-T converts fXII to α-fXIIa, and also converts the coagulation protein factor XI to its active form. Summary The findings support the hypothesis that contact activation is initiated through activity intrinsic to single-chain fXII, and indicate that pre-existing α-fXIIa is not required for induction of contact activation.

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Factor XI anion‐binding sites are required for productive interactions with polyphosphate

Cited by 42 publications

References 37 publications

The hemostatic role of factor XI

The hemostatic role of factor XI

Polyphosphate as a haemostatic modulator

Single-chain factor XII: a new form of activated factor XII

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